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David S. Kozin

Comprehensive Bibliography I am using

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REFERENCES

Abraham, H. D. (1980). Psychiatric illness in drug abusers. The New England Journal of Medicine, 302(15), 868-869.

Abraham, H. D. (1982). A chronic impairment of colour vision in users of LSD. The British Journal of Psychiatry : The Journal of Mental Science, 140, 518-520.

Forty-six users of the hallucinogen lysergic acid diethylamide were compared with 31 controls on a test of colour discrimination an average of two years after their last exposure to the drug. Controls performed better than users, and LSD users without flashbacks performed better than users with flashbacks. An analysis of variance between the three groups was significant at P less than 0.001. This study suggests that some users of LSD may have a sustained or irreversible impairment in colour discrimination.

Abraham, H. D. (1983). Inching toward Armageddon: a psychiatric view. The Yale Journal of Biology and Medicine, 56(2), 67-78.

The existence of thermonuclear arsenals capable of destroying much of humanity takes its origins from, and has an influence on, processes that are largely psychological. The threat to use a single nuclear bomb to resolve contemporary conflict is an anathema in part because complex nation-states did not evolve with surviving a nuclear war in mind. The atomic arms race has proceeded apace because of maladaptive psychological mechanism including denial, distortion, projection, and, most relevantly, the need to enhance bonding within groups by creating stereotypes. One consequence of the arms race is a climate of fear and hopelessness, and especially destructive effect of which is seen in children. The physician's role in the prevention of nuclear war is critical, but divided between contradictory roles. On one hand, the physician is traditionally identified as a non-political advocate of the sick; on the other, as an advocate for the public health. It is this second model that enables physicians most legitimately to work for the prevention of nuclear war and to deal with the psychiatric concomitants of a planet drifting toward disaster.

Abraham, H. D. (1983). L-5-hydroxytryptophan for LSD-induced psychosis. The American Journal of Psychiatry, 140(4), 456-458.

The serotonin precursor L-5-hydroxytryptophan reversed the symptoms of a 23-year-old man suffering from LSD-induced psychosis who participated in a randomized, double-blind crossover study of the drug and a placebo. This finding is compatible with the speculation that some LSD-induced psychotic disorders may be caused by a relative deficiency of CNS serotonin.

Abraham, H. D. (1983). Visual phenomenology of the LSD flashback. Archives of General Psychiatry, 40(8), 884-889.

One hundred twenty-three persons with a history of LSD use were studied for the presence of the LSD flashback phenomenon and compared with 40 control subjects. A syndrome emerged that included ten distance visual disturbances. It had lasted for five years in half of the population, was treatable with benzodiazepines, exacerbated by phenothiazines, and precipitated by 19 different stimuli, most commonly emergence into a dark environment. Sensitivity to LSD as determined by flashbacks appears to divide the study sample into three discrete subgroups. There may be a genetic basis to LSD sensitivity.

Abraham, H. D. (1986). Do psychostimulants kindle panic disorder? The American Journal of Psychiatry, 143(12), 1627-1628.

Abraham, H. D. (1989). Stimulants, panic, and BEAM EEG abnormalities. The American Journal of Psychiatry, 146(7), 947-948.

Abraham, H. D. (1993). Visual hallucinations in macular degeneration. The American Journal of Psychiatry, 150(11), 1758.

Abraham, H. D. (2000). Book reviews. General Hospital Psychiatry, 22(1), 57-58.

Abraham, H. D., & Aldridge, A. M. (1993). Adverse consequences of lysergic acid diethylamide. Addiction (Abingdon, England), 88(10), 1327-1334.

The continued endemic use of hallucinogenic drugs, and of LSD in particular, raises concern regarding their short and long term adverse consequences. The epidemiology of LSD abuse is reviewed suggesting an increase in LSD use among the young as the prevalence rates for other substances continues to fall. Evidence supports the association of LSD use with panic reactions, prolonged schizoaffective psychoses and post-hallucinogen perceptual disorder, the latter being present continually for as long as 5 years. Evidence does not support claims of genetic disorders arising from hallucinogens. In light of the foregoing, current data confirm earlier findings of long lasting psychopathology arising in vulnerable individuals from the use of LSD. A hypothetical long term molecular mechanism of adverse effects is proposed.

Abraham, H. D., Aldridge, A. M., & Gogia, P. (1996). The psychopharmacology of hallucinogens. Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology, 14(4), 285-298. doi:10.1016/0893-133X(95)00136-2

Hallucinogenic drugs have been inhaled, ingested, worshipped, and reviled since prehistory. With the purification and synthesis of bontanical preparations and the ensuing discovery of chemically unique agents, hope was raised regarding their therapeutic potential, but this hope has been clouded by an epidemic of abuse and an inventory of adverse effects. This review examines aspects of that controversy, including the history of hallucinogens, epidemiology of current hallucinogen abuse, the association of LSD use with prolonged psychoses and hallucinogen persisting perception disorder, and the efforts to demonstrate the drug's therapeutic efficacy. Human subject ramifications in hallucinogen experimentation are discussed. Future lines of research are suggested in human, animal, and tissue culture paradigms.

Abraham, H. D., Anderson, C., & Lee, D. (1997). Somatization disorder in sphincter of Oddi dysfunction. Psychosomatic Medicine, 59(5), 553-557.

OBJECTIVE: Sphincter of Oddi dysfunction (SOD) is a biliary disorder with a recognized pathophysiology and demonstrated surgical treatment. We sought to examine whether women with SOD were overrepresented on measures of somatization, sexual and physical abuse, socially compliant attitudes, and familial psychiatric illness. METHOD: We matched 33 women with SOD to 33 normal controls by age, sex, and race, and, with a case-controlled cross-sectional questionnaire, compared the groups on the study variables. Statistics included a chi 2 for categorical variables, t tests for scores of somatization and attitudes of social desirability, and Pearson correlation coefficients for post hoc associations of variables. Bonferroni corrections were used with chi 2 values to reduce capitalization by chance. RESULTS: SOD patients exhibited excessive nongastroenterological somatic complaints compared with controls (p < .0001). There was a statistical increase in reports of childhood sexual, but not physical, abuse in the SOD women (p < .02) compared with controls. The severity of the abuse correlated strongly with the severity of somatic complaints. There were no differences in social desirability attitudes or family psychiatric histories of the two groups. CONCLUSIONS: We conclude that SOD is associated with a high degree of somatization in adulthood, and a mean rate more than four times that of controls in self-reports of sexual abuse in childhood. The severity of childhood sexual abuse is correlated with the severity of somatization in later life. A psychological model for this disorder is suggested by the data. Increased psychiatric attention is indicated in the treatment of women with this disorder.

Abraham, H. D., Degli-Esposti, S., & Marino, L. (1999). Seroprevalence of hepatitis C in a sample of middle class substance abusers. Journal of Addictive Diseases, 18(4), 77-87.

Hepatitis C (HCV) is an indolent and often fatal disease affecting four million Americans commonly associated with low socioeconomic status. We assessed its prevalence in a sample of 334 consecutively admitted middle class substance abusers in a private urban hospital, and ascertained risk factors for its transmission. We found that the point prevalence rate for HCV was 27.7% among all substance abusers, and 76.7% among intravenous drug users. Using logistic regression, we found risk factors associated with HCV were intravenous drug use, needle sharing, prior liver disease, opioid dependence, HIV infection, and benzodiazepine dependence. Not found to increase infective risk were lower social class, male gender, African-American race, male homosexuality, unemployment, and the absence of private health insurance. Multiple viral genotype types were identified in this sample, suggesting diverse sources of transmission in the sample. This study documents an epidemic of HCV in an American middle class sample.

Abraham, H. D., & Duffy, F. H. (1991). Computed EEG abnormalities in panic disorder with and without premorbid drug abuse. Biological Psychiatry, 29(7), 687-690.

Abraham, H. D., & Duffy, F. H. (1996). Stable quantitative EEG difference in post-LSD visual disorder by split-half analysis: evidence for disinhibition. Psychiatry Research, 67(3), 173-187.

Hallucinogen persisting perceptual disorder (HPPD) may follow the ingestion of LSD or other hallucinogens in a subset of users. It is characterized by chronic, intermittent or constant visual hallucinations of many sorts persisting beyond the period of acute drug effects. We studied 44 LSD-induced HPPD subjects and 88 matched controls to search for spectral and evoked potential differences using quantitative EEG (qEEG). HPPD subjects demonstrated faster alpha frequency and shorter VER (visual evoked response) latency, consistent with prior animal and human data on response to acute LSD administration which suggest LSD-induced cortical disinhibition. AER (auditory evoked response) latency was prolonged consistent with a differential LSD effect upon visual and auditory systems. The exploratory T-statistic significance probability mapping (T-SPM) technique demonstrated HPPD-control differences mostly involving temporal and left parietal scalp regions, confirmed by a split-half analysis. Significant variables were all derived from the long latency flash VER and click AER. None were derived from spectral analyzed EEG data. Canonical correlation between SPM-derived measures and variables reflecting disease severity was highly significant. A between-group stepwise discriminant analysis based upon a full set of qEEG measures demonstrated 87% prospective classification success by jackknifing and 88% success in a separate split-half analysis.

Abraham, H. D., & Duffy, F. H. (2001). EEG coherence in post-LSD visual hallucinations. Psychiatry Research, 107(3), 151-163.

LSD use in certain individuals may result in chronic visual hallucinations, a DSM-IV syndrome known as hallucinogen persisting perception disorder (HPPD). We studied 38 HPPD subjects with a mean of 9.7 years of persistent visual hallucinations and 33 control subjects. Measures of local and medium distance EEG spectral coherence were calculated from all subjects. Coherence, a measure of spectral similarity over time, may estimate cortical coupling. In the eyes-open state in HPPD subjects, widespread reduction of coherence was noted. However, upon eye closure, the occipital region demonstrated augmented regional coherence over many frequencies but with reduced coherence of the occipital region to more distant regions. This occipital coherence increase correlated with previously reported shortened occipital visual evoked potential latency for HPPD subjects. We speculate from coherence and known clinical and psychophysical data that, in HPPD, there is widespread cortical inhibition in the eyes-opened state, but localized and isolated occipital disinhibition upon eye closure, a state known to facilitate hallucinatory experiences. An analogy is drawn to findings in the interictal and ictal epileptic focus. In HPPD, we speculate that occipital EEG hypersynchrony resulting from increased regional coherence, when coupled with relative isolation of visual cortex, especially upon eye closure, facilitates hallucinations and illusions.

Abraham, H. D., & Fava, M. (1999). Order of onset of substance abuse and depression in a sample of depressed outpatients. Comprehensive Psychiatry, 40(1), 44-50.

Drug abuse has been thought to cause depression, or to serve as a form of self-medication for depression. Our objective was to examine whether specific types of drug abuse preceded or followed the onset of depression. A retrospective, blinded case-controlled assessment of the drug and depressive history of depressed outpatients was conducted. Three hundred seventy-five patients with major depressive disorder were evaluated for comorbid drug dependence using the Structured Clinical Interview for DSM-III-R (SCID). They were selected from the psychiatric outpatient department of a metropolitan teaching hospital and grouped into homogeneous classes of drug dependence including alcohol, cannabis, cocaine, amphetamine, LSD, hypnosedative, opiate, and polysubstance use. We determined the percent of depressed patients with each specific type of drug abuse, their age of onset of depression and onset of specific drug abuse, and the mean number of lifetime depressive episodes for each patient. We found that alcohol dependence followed the onset of first life depression by 4.7 years (P = .02, two-tailed). Among polydrug-dependent patients, each drug abused followed the onset of depression, except for LSD, which coincided with the onset of depression. Among polydrug users, cocaine dependence occurred 6.8 years after the first major depressive episode (P = .007) and alcohol dependence 4.5 years after the onset of depression (P = .007). Opiate and sedative users had the least number of lifetime depressive episodes (3.7), and LSD and cocaine users had the greatest number (12.2). We conclude that alcohol and cocaine use in this sample of depressed outpatients conformed to a pattern of self-medication.

Abraham, H. D., & Howell, R. R. (1969). Human hepatic uridine diphosphate galactose pyrophosphorylase. Its characterization and activity during development. The Journal of Biological Chemistry, 244(4), 545-550.

Abraham, H. D., & Joseph, A. B. (1986). Bulimic vomiting alters pain tolerance and mood. International Journal of Psychiatry in Medicine, 16(4), 311-316.

Bulimia, a disorder of episodic binging and purging, remains without a known etiology. A case report is presented of a patient who attributed bulimic episodes to efforts at inducing euphoria. Experimental pain tolerance was increased by bulimic vomiting, blocked by naloxone, but not by saline. Vomiting was also associated with falls in depression and anxiety. Plasma ACTH and cortisol, putative markers for beta-endorphin, also rose following vomiting. It is hypothesized that in some bulimics, the disorder arises by virtue of an addiction to one's own internally released endogenous opioid peptides.

Abraham, H. D., & Mamen, A. (1996). LSD-like panic from risperidone in post-LSD visual disorder. Journal of Clinical Psychopharmacology, 16(3), 238-241.

Risperidone, a novel antipsychotic agent, is an antagonist of postsynaptic serotonin-2 and dopamine D2 receptors. In certain individuals, the hallucinogenic drug lysergic acid diethylamide (LSD) is associated with apparently lifelong continuous visual disturbances, characterized in DSM-IV as hallucinogen-persisting perception disorder (HPPD). Because the hallucinogenic mechanism of LSD is known to act in part at postsynaptic serotonin-2 receptors, it is noteworthy that three HPPD patients treated with risperidone reported an exacerbation of LSD-like panic and visual symptoms. We conclude that HPPD may be a relative contraindication for the use of risperidone.

Abraham, H. D., & Wolf, E. (1988). Visual function in past users of LSD: psychophysical findings. Journal of Abnormal Psychology, 97(4), 443-447.

Adamczyk, D. T. (1996). Visual phenomena, disturbances, and hallucinations Optometry Clinics : The Official Publication of the Prentice Society, 5(3-4), 33-52.

The visual system and its processing of sensory information can be affected in a variety of ways that may be either normal or associated with numerous disorders and diseases. Visual images produced by the intrinsic components of the eyes are often normal and are known as entoptic phenomena. In contrast, the visual system may be disrupted by various disorders and pathologic processes, which can result in metamorphopsia, transient loss of vision, and positive scotomas. Such disruptions can be secondary to retinal and optic nerve disease, migraines associated with visual auras, and cerebrovascular and neurologic diseases; they can also be side effects of certain drugs. In addition, the visual system may process incoming sensory information in such a way that what is seen is perceived incorrectly, i.e. illusion; or the visual system may produce images of things not really there, i.e. hallucination. Various types of visual phenomena, disturbances, and hallucinations are discussed. The numerous visual presentations need to be differentiated so that appropriate treatment, management, and patient education can be rendered.

Akerman, S., Holland, P. R., Lasalandra, M. P., & Goadsby, P. J. (2009). Oxygen inhibits neuronal activation in the trigeminocervical complex after stimulation of trigeminal autonomic reflex, but not during direct dural activation of trigeminal afferents. Headache, 49(8), 1131-1143. doi:10.1111/j.1526-4610.2009.01501.x

OBJECTIVE: To understand the mechanism of action of oxygen treatment in cluster headache. BACKGROUND: Trigeminal autonomic cephalalgias, including cluster headache, are characterized by unilateral head pain in association with ipsilateral cranial autonomic features. They are believed to involve activation of the trigeminovascular system and the parasympathetic outflow to the cranial vasculature from the superior salivatory nucleus (SuS) projections through the sphenopalatine ganglion, via the greater petrosal nerve of the VIIth (facial) cranial nerve. Cluster headache is remarkably responsive to treatment with oxygen, and yet our understanding of its mode of action is unknown. METHODS: Combining models of trigeminovascular nociception and a novel approach that activates the trigeminal-autonomic reflex, using SuS/facial nerve stimulation, we explored the effect of oxygen on trigeminal nerve activation as well as on autonomic responses through blood flow observations of the lacrimal duct/sac. RESULTS: Meningeal vasodilation and neuronal firing in the trigeminocervical complex (TCC), in response to dural electrical stimulation, was unaffected by treatment with 100% oxygen. Stimulation of the SuS via the facial nerve caused only marginal changes in dural blood vessel diameter, but did result in evoked firing in the TCC. Two populations of neurons were characterized, those responsive to 100% oxygen treatment, with a maximal inhibition of 33%, 20 minutes after the start of oxygen treatment (t(15) = 4.4, P < .0001). A second population of neurons were not inhibited by oxygen and tended to have shorter latency. Oxygen also inhibited evoked blood flow changes in the lacrimal sac/duct caused by SuS stimulation. CONCLUSIONS: The data provide the first systematic, experimental evidence for a mechanism of action of oxygen in cluster headache. The data show oxygen has no direct effect on trigeminal afferents, acting specifically on the parasympathetic/facial nerve projections to the cranial vasculature to inhibit both evoked trigeminovascular activation and activation of the autonomic pathway during cluster headache attacks. Moreover, the studies begin to characterize a novel laboratory model for the most painful primary headache syndrome known--cluster headache.

Alarcon, R. D., Dickinson, W. A., & Dohn, H. H. (1982). Flashback phenomena. Clinical and diagnostic dilemmas. The Journal of Nervous and Mental Disease, 170(4), 217-223.

The study of flashback phenomena has been neglected in recent years. A case study and a subsequent literature review examine areas about which conflicting opinions exist. Epidemiological studies have not arrived at universally acceptable classificatory schemes. Clinical approaches vary in accounts of phenomenology of the syndrome and the typology of personalities involved. Etiology remains unknown in spite of numerous theories, most of them not experimentally tested. Diagnostic studies may benefit from recent technological advances such as continuous electroencephalogram, computerized axial tomography scan, cerebral blood flow, and neuropsychological tests. The Diagnostic and Statistical Manual of Mental Disorders, 3rd Edition, does not seem to provide an adequate taxonomic niche for this disorder. Therapeutic interventions are examined and their results critically analyzed.

Al-Assmar, S. E. (1999). The seeds of the Hawaiian baby woodrose are a powerful hallucinogen. Archives of Internal Medicine, 159(17), 2090.

Alcantara, A. G. (1998). Is there a role for the alpha2 antagonism in the exacerbation of hallucinogen-persisting perception disorder with risperidone? Journal of Clinical Psychopharmacology, 18(6), 487-488.

Aldurra, G., & Crayton, J. W. (2001). Improvement of hallucinogen persisting perception disorder by treatment with a combination of fluoxetine and olanzapine: case report. Journal of Clinical Psychopharmacology, 21(3), 343-344.

Aouizerate, B., Martin-Guehl, C., & Tignol, J. (2004). Neurobiology and pharmacotherapy of social phobia. [Neurobiologie et pharmacotherapie de la phobie sociale] L'Encephale, 30(4), 301-313.

Social phobia (also known as social anxiety disorder) is still not clearly understood. It was not established as an authentic psychiatric entity until the diagnostic nomenclature of the American Psychiatric Association DSM III in 1980. In recent years, increasing attention among researchers has contributed to provide important information about the genetic, familial and temperamental bases of social phobia and its neurochemical, neuroendocrinological and neuroanatomical substrates, which remain to be further investigated. Up to date, there have been several findings about the possible influence of variables, including particularly genetic, socio-familial and early temperamental (eg behavioral inhibition) factors that represent risk for the later development of social phobia. Clinical neurobiological studies, based on the use of exogenous compounds such as lactate, CO2, caffeine, epinephrine, flumazenil or cholecystokinin/pentagastrin to reproduce naturally occurring phobic anxiety, have shown that patients with social phobia appear to exhibit an intermediate sensitivity between patients with panic disorder and control subjects. No difference in the rate of panic attacks in response to lactate, low concentrations of CO2 (5%), epinephrine or flumazenil was observed between patients with social phobia and normal healthy subjects, both being less reactive compared to patients with panic disorder. However, patients with social phobia had similar anxiety reactions to high concentrations of CO2 (35%), caffeine or cholecystokinin/pentagastrin than those seen in patients with panic disorder, both being more intensive than in controls. Several lines of evidence suggest specific neurotransmitter system alterations in social phobia, especially with regard to the serotoninergic, noradrenergic and dopaminergic systems. Although no abnormality in platelet serotonin transporter density has been found, patients with social phobia appear to show an enhanced sensitivity of both post-synaptic 5HT1A and 5HT2 serotonin receptor subtypes, as reflected by increased anxiety and hormonal responses to serotoninergic probes. Platelet 5HT2 receptor density has also been reported to be positively correlated to symptom severity in patients with social phobia. During anticipation of public speaking, heart rate was elevated in patients with social phobia compared to controls. Norepinephrine response to the orthostatic challenge test or to the Valsalva maneuver was also greater in patients with social phobia. While normal beta-adrenergic receptor number was observed in lymphocytes, a blunted response of growth hormone to clonidine, an a2-adrenergic agonist, was reported. This suggests reduced post-synaptic a2-adrenergic receptor functioning related to norepinephrine overactivity in social phobia. Decreased cerebrospinal fluid levels of the dopamine metabolite homovanillic acid have also been observed. There are relatively few reports of involvement of the adrenal and thyroid functions in social phobia, and all that has been noted is that patients with social phobia show an exaggerated adrenocortical response to a psychological stressor. Recent advances in neuro-imaging have contributed to find low striatal dopamine D2 receptor binding or low dopamine transporter site density in patients with social phobia. They have also demonstrated the involvement of the cortico-limbic pathways, including the prefrontal cortex, hippocampus and amygdala, which show an increased activity in different experimental conditions. These brain regions have extensively been reported to play an important role in the cognitive appraisal in determining the significance of environmental stimuli, in the emotional and mnemonic integration of information, and in the expression of contextual fear-conditioned behaviors, which might be disrupted in the light of the phenomelogical aspects of social phobia. A substantial body of literature based on case reports, open and placebo-controlled trials, has now clearly examined the efficacy of major classes of psychotropic agents including monoamine oxidase inhibitors, beta-blockers, selective serotonin reuptake inhibitors and benzodiazepines in social phobia. Until recently, irreversible non-selective monoamine oxidase inhibitors, of which phenelzine was the most extensively evaluated, were considered as the most efficacious treatment in reducing the symptomatology associated with social phobia in 50-70% of cases after 4 to 6 weeks. However, side effects and dietary restrictions limit their use. This led to the development of reversible inhibitors of monoamine oxidase A, for which careful dietary monitoring is not required. Moclobemide has been the most widely studied but produced unconvincingly therapeutic effects on social phobic symptoms. To date, selective serotonin reuptake inhibitors may be considered as a reasonable first-line pharmacotherapy for social phobia. There is growing evidence for the efficacy of the selective serotonin reuptake inhibitors fluvoxamine, fluoxetine, citalopram, paroxetine and sertraline. They have beneficial effects with response rates ranging from 50 to 80% in social phobia. It has been recommended that the treatment period should be extended at least 6 months beyond the early improvement achieved within the first 4 to 6 weeks. The overall advantages include tolerability with a low risk of adverse events. The benzodiazepines clonazepam and alprazolam have also been proposed for the treatment of social phobia. Symptomatic relief occurred in 40 to 80% of the cases with a relatively rapid onset of action within the first two weeks. Untoward effects, discontinuation-related withdrawal symptoms and abuse or dependence liability constitute major concerns about the use of benzodiazepines, so they should be reserved for cases unresponsive to the safer medications cited above. Beta-blockers such as atenolol and propanolol have commonly been employed in performance anxiety, decreasing autonomic symptoms (eg, tachycardia, sweating and dry mouth). However, they are not effective in the generalized form of social phobia. Other pharmacologic alternatives seem helpful for the management of social phobia, including venlafaxine, gabapentin, bupropion, nefazodone or augmentation with buspirone. Preliminary studies point to promising effects of these agents. Larger controlled clinical trials are now needed to confirm their potential role in the treatment of social phobia.

Appel, N. M., Mitchell, W. M., Garlick, R. K., Glennon, R. A., Teitler, M., & De Souza, E. B. (1990). Autoradiographic characterization of (+-)-1-(2,5-dimethoxy-4-[125I] iodophenyl)-2-aminopropane ([125I]DOI) binding to 5-HT2 and 5-HT1c receptors in rat brain. The Journal of Pharmacology and Experimental Therapeutics, 255(2), 843-857.

The 5-HT2 (serotonin) receptor has traditionally been labeled with antagonist radioligands such as [3H]ketanserin and [3H]spiperone, which label both agonist high-affinity (guanyl nucleotide-sensitive) and agonist low-affinity (guanyl nucleotide-insensitive) states of this receptor. The hallucinogen 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) is an agonist which labels the high-affinity guanyl nucleotide-sensitive state of brain 5-HT2 receptors selectively. In the present study, conditions for autoradiographic visualization of (+/-)-[125I]DOI-labeled 5-HT2 receptors were optimized and binding to slide-mounted sections was characterized with respect to pharmacology, guanyl nucleotide sensitivity and anatomical distribution. In slide-mounted rat brain sections (+/-)-[125I]DOI binding was saturable, of high affinity (KD approximately 4 nM) and displayed a pharmacologic profile typical of 5-HT2 receptors. Consistent with coupling of 5-HT2 receptors in the high-affinity state to a guanyl nucleotide regulatory protein, [125I]DOI binding was inhibited by guanyl nucleotides but not by adenosine triphosphate. Patterns of autoradiographic distribution of [125I]DOI binding to 5-HT2 receptors were similar to those seen with [3H]ketanserin- and [125I]-lysergic acid diethylamide-labeled 5-HT2 receptors. However, the density of 5-HT2 receptors labeled by the agonist [125I]DOI was markedly lower (30-50%) than that labeled by the antagonist [3H]ketanserin. High densities of [125I]DOI labeling were present in olfactory bulb, anterior regions of cerebral cortex (layer IV), claustrum, caudate putamen, globus pallidus, ventral pallidum, islands of Calleja, mammillary nuclei and inferior olive. Binding in hippocampus, thalamus and hypothalamus was generally sparse. Of note, choroid plexus, a site rich in 5-HT1c receptors had a high density of [125I]DOI binding sites but [3H]ketanserin binding in this region was low. Studies in which [125I]DOI binding to 5-HT2 receptors was blocked with spiperone revealed persisting robust [125I]DOI binding in choroid plexus, which was guanyl nucleotide-sensitive and displayed a pharmacologic profile consistent with its binding to 5-HT1c receptors. These studies suggest that [125I]DOI may be useful as a radiolabel for visualizing the agonist high-affinity state of 5-HT2 receptors and for visualizing 5-HT1c receptors.

Assmus, H., & Reimer, F. (1972). Accidental LSD intoxication in three siblings with flashback. [Akzidentelle LSD-Intoxikation bei drei Geschwistern im Kindesalter mit Nachhallpsychose (Flashback] Praxis Der Kinderpsychologie Und Kinderpsychiatrie, 21(6), 207-209.

Atarhouch, N., Hoffmann, E., Adam, S., Titeca, J., Stillemans, E., Fossion, P., Le Bon, O., & Servais, L. (2004). Evaluation of typical psychopathic traits with juvenile offenders. [Evaluation des traits caracteristiques de la psychopathie chez les adolescents delinquants] L'Encephale, 30(4), 369-375.

The concept of psychopathy has received many definitions for the first days of psychiatry. Recently, the Hare's Psychopathy Check List Revised has been created. This scale has the advantage to investigate the classically characteristic traits of the syndrome (need of stimulation, lack of culpability, superficial activity, lack of empathy, impassivity) and to point out the early development of behavior disturbances. In the American classification (DSM IV), oppositional and aggressive behavior in child and adolescent is grouped under the Conduct Disorder diagnostic criteria. This trouble appears to be a strong predictive factor of psychopathy in adult. Identifying the high risk factors of evolution to psychopathic personality would allow an earlier intervention and prevention by multisystemic interventions for example. The present study aims to evaluate in what measure characteristic traits of psychopathy in adults are present in severe juvenile offenders and to point out, in a second time, the differences between adolescents meeting the DSM IV criteria for Conduct Disorder and a control population by a dimensional personality inventory. METHOD: The sample consists in 47 severe juvenile offenders referred for at least 3 months by a Youth Court to a Public Institution for Youth Protection (Belgium, Wauthier-Braine, 1999-2001), who have given an oral contentment and completely fulfilled the Temperament and Character Inventory-TCI. We have collected data about: schooling year by year, number of fails, changes of school; antecedents of oppositional defiant disorder with provocation (ODD, DSM IV criteria); antecedent of Conduct Disorder (CD, DSM IV criteria); penal antecedents (Youth Judge, works of general interest, placements); medico-psychological antecedents (consultation to a psychologist or a psychiatrist, hospitalization, illness, surgical intervention); psychoactive drug use or abuse. We used the TCI--Temperament and Character Inventory. This is a dimensional personality inventory. Based on biological, genetic and clinical hypothesis, it describes 2 types of variables defining personality: Variables of temperament (genetically transmitted and biologically controlled), and Variables of character (learned part of the personality reflecting the degree of adaptation and maturity, varying with environment through development). We have chosen this tool because of its dimensional aspect. Adolescence being a time of psychological and personality changes, such a tool is more useful than a categorical one. We also used this tool to verify the existence of the specific triad described by Cloninger and Svrakic. According to these authors, psychopathic personality in adult is characterized by a specific triad in which novelty seeking is high while harm avoidance and reward dependence are low. These observations are highly correlated to Hare's definition of psychopathy. We give the principal scores for the 7 personality dimensions expressed in global scores (total of the items for each dimension) and pondered ones (global scores divided by the number of items of the dimension x 100). RESULTS: Statistical analysis was performed with the Stateview 5.0 t-test program for data analysis. Statistical results show the absence of a statistically significant difference between the 2 groups for TCI 1, 4.5 and 7 but a statistically significant difference for TCI 2, 3 and 6 (p <.0001). DISCUSSION: The first limitation of our study is linked to the sample composed of young adolescents placed in an Institution for Youth Protection who doesn't reflect the whole population of offenders. A second limitation is correlated to the randomization system: randomization for age but not for sex, ethnical and cultural origin and socioeconomic status. Our results with adolescent offenders don't completely meet the Cloninger's psychopathy triad in adults. Moreover, in literature data, aggressive behavior is correlated to high novelty seeking and associated with low harm avoidance, reward dependence and persistence in children, these items are predictive of antisocial behavior in teenage and young adulthood. In our sample where antisocial behaviors are severe, we should be expecting a high novelty seeking but that is not the case. Our results should be explained by the fact that adolescence in itself is a more powerful factor of high novelty seeking than psychopathic trait. Harm avoidance and reward dependence seem to be a real problem in offending population and reflect aggressive behaviors in adolescents (lack of harm perception, sensitivity and empathy). Another interesting element is the cooperation factor that is significantly lower in the study group. This seems to comfort the hypothesis of a lower social maturity in institutionalized adolescents. CONCLUSION: Regarding to a control group subjects from 15 to 25 years old, adolescent offenders observed in an Institution for Youth Protection show a significantly different profile in the TCI for Harm Avoidance, Reward Dependence and Cooperation. Regarding to adult psychopaths, adolescent offenders partially meet the classical diagnostic triad of psychopathy, what should be indicating that such adolescents already show emotional perturbations: lower harm avoidance, reward dependence and cooperation than control population. This third factor is not characteristic of psychopathy but reflects relational difficulties, which are important in adolescent offenders. So, our study point out the complex psychopathology of adolescent offenders and the coexistence in such adolescents of attachment disorder and the difficulty to treat them because of their multiple lacks (cognitive, psychopathological, familial and scholar). We think important to discuss the necessity of approaches based on the development of personal creative abilities and involving all the professionals concerned in the young's universe. Future researches should compare adolescent offenders and controls randomized for age, sex, socioeconomic, ethnical and cultural status. They also should test specifically the diagnostic triad of psychopathology developed by Cloninger, especially the novelty seeking dimension. Moreover, it would be interesting to integrate these results in a wider protocol and to compare them with clinical, forensic and neurocognitive data, individually and within the familial context.

Aziz, R., Lorberg, B., & Tampi, R. R. (2006). Treatments for late-life bipolar disorder. The American Journal of Geriatric Pharmacotherapy, 4(4), 347-364. doi:10.1016/j.amjopharm.2006.12.007

BACKGROUND: Bipolar affective disorder is not uncommon in the elderly; prevalence rates in the United States range from 0.1% to 0.4%. However, it accounts for 10% to 25% of all geriatric patients with mood disorders and 5% of patients admitted to geropsychiatric inpatient units. These patients often present a tremendous treatment challenge to clinicians. They frequently have differing treatment needs compared with their younger counterparts because of substantial medical comorbidity and age-related variations in response to therapy. Unfortunately, the management of geriatric bipolar disorder has been relatively neglected compared with the younger population. There continues to be a scarcity of published, controlled trials in the elderly, and no treatment algorithms specific to bipolar disorder in the elderly have been devised. OBJECTIVE: The goal of this article was to review the current literature on both the pharmacologic and nonpharmacologic management of late-life bipolar disorder. METHODS: English-language articles written on the treatment of bipolar disorder in the elderly were identified. The first step in data collection involved a search for evidence-based clinical practice guidelines in the Cochrane Database of Systematic Reviews (up until the third quarter of 2006). Systematic reviews were then located in the following databases: MEDLINE (1966-September 2006), EMBASE (1980-2006 [week 36]), and PsycINFO (1967-September 2006 [week 1]). Additional use was made of these 3 databases in searching for single randomized controlled trials, meta-analyses, cohort studies, case-control studies, case series, and case reports. "Elderly," used synonymously with "geriatric," was defined as individuals aged > or =60 years. However, to take into account ambiguity in the nomenclature, the key words aged, geriatric, elderly, and older were combined with words indicating pharmacologic treatments such as pharmacotherapy; classes of medications (eg, lithium, antidepressants, antipsychotics, anticonvulsants, benzodiazepines); and names of selected individual medications (eg, lithium, valproic acid, lamotrigine, carbamazepine, oxcarbazepine, topiramate, gabapentin, zonisamide, clozapine, risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole). These terms were then combined with the diagnostic terms bipolar disorder, mania, hypomania, depression, or bipolar depression. Finally, the terms ECT and psychotherapy were also queried in combination with indicators for age and diagnosis. A few articles on "older adults," usually defined as individuals aged 50 to 55 years, were also included. They may allow for possible extrapolation of data to the geriatric population. Additionally, several mixed-age studies were included for similar considerations. Case reports and case series were described for their potential heuristic value. RESULTS: Unfortunately, there is a considerable dearth of literature involving evidence-based clinical practice guidelines and even randomized controlled trials in elderly individuals with bipolar disorder. Available options for the treatment of bipolar disorder (including those for mania, hypomania, depression, or maintenance) in the elderly include lithium, antiepileptics, antipsychotics, benzodiazepines, antidepressants, electroconvulsive therapy (ECT), and psychotherapy. CONCLUSIONS: The data for the treatment of late-life bipolar disorder are limited, but the available evidence shows efficacy for some commonly used treatments. Lithium, divalproex sodium, carbamazepine, lamotrigine, atypical antipsychotics, and antidepressants have all been found to be beneficial in the treatment of elderly patients with bipolar disorder. Although there are no specific guidelines for the treatment of these patients, monotherapy followed by combination therapy of the various classes of drugs may help with the resolution of symptoms. ECT and psychotherapy may be useful in the treatment of refractory disease. There is a need for more controlled studies in this age group before definitive treatment strategies can be enumerated.

Baethge, C. (2003). Long-term treatment of schizoaffective disorder: review and recommendations. Pharmacopsychiatry, 36(2), 45-56. doi:10.1055/s-2003-39045

OBJECTIVE: To provide an overview of long-term treatment studies in schizoaffective disorder (SAD) and to draw conclusions for clinical decision-making. METHOD: Literature was identified by searches in Medline, Embase, and the Cochrane Controlled Trials Register as well as a hand-search of handbook and journal articles. Studies were considered relevant if they reported on trials of at least 6 months duration and if they presented data for the SAD patients in particular. RESULTS: Thirty-nine studies met the criteria and 18 used modern diagnostic criteria, i. e., RDC, DSM-III-R, -IV, or ICD-10. The studies focused on lithium, anticonvulsants, and antipsychotics. The scientific evidence for prophylactic efficacy of the different substances is poor. Nevertheless, the data encourage the use of lithium and carbamazepine in primarily affective patients and clozapine in primarily schizophrenic patients and possibly in mainly affective patients as well. CONCLUSIONS: There is a considerable need for prospective and controlled studies on the long-term treatment of SAD. However, it seems to be useful to subtype the disorder of the patients into primarily affective vs. schizophrenic schizoaffective disorder and schizodepressive vs. schizobipolar and to treat accordingly.

Ballenger, J. C. (2004). Remission rates in patients with anxiety disorders treated with paroxetine. The Journal of Clinical Psychiatry, 65(12), 1696-1707.

BACKGROUND: Approximately 50% to 60% of patients with depression and/or anxiety respond to treatment, but only a minority achieve remission. The continued presence of subsyndromal symptoms in treated depressed (and probably anxious) patients leads to higher relapse rates and increased utilization of health care resources. It is proposed that remission is the appropriate target in the treatment of both depression and the anxiety disorders. AIMS: Rigorous criteria for remission have been proposed for the anxiety disorders and are currently being applied in clinical studies. Using these criteria, data from the paroxetine clinical study database were retrospectively analyzed to determine remission rates following paroxetine treatment across a range of anxiety disorders in the largest analysis of remission data in the anxiety disorders to date. METHOD: These analyses included data from 16 short-term and 6 long-term, randomized, placebo-controlled studies in panic disorder, social anxiety disorder, obsessive-compulsive disorder, posttraumatic stress disorder (short term only), and generalized anxiety disorder (DSM-III-R or DSM-IV). Separate analyses were performed for each disorder, with short- and long-term data analyzed separately. RESULTS: In general, across the range of anxiety disorders studied, in both short- and long-term studies, remission rates were higher for paroxetine compared with placebo, using disorder-specific, global, and functional remission criteria both individually and combined. Remission occurred in a moderate proportion of paroxetine-treated patients after only 8 to 12 weeks of treatment, and longer-term therapy led to even higher remission rates. CONCLUSION: Paroxetine has demonstrated efficacy in treating patients to remission across the range of anxiety disorders studied. Our findings strongly suggest that continuing treatment with paroxetine (and probably other SSRI antidepressants) for 2 to 12 months increases the proportion of patients achieving clinical remission.

Barlow, H. B., & Sparrock, J. M. B. (1964). The Role of Afterimages in Dark Adaptation. Science, 144(3624), 1309-1314. doi:10.1126/science.144.3624.1309

Barron, S. P., Lowinger, P., & Ebner, E. (1970). A clinical examination of chronic LSD use in the community. Comprehensive Psychiatry, 11(1), 69-79. doi:DOI: 10.1016/0010-440X(70)90206-3

Baucum, A. J.,2nd, Rau, K. S., Riddle, E. L., Hanson, G. R., & Fleckenstein, A. E. (2004). Methamphetamine increases dopamine transporter higher molecular weight complex formation via a dopamine- and hyperthermia-associated mechanism. The Journal of Neuroscience : The Official Journal of the Society for Neuroscience, 24(13), 3436-3443. doi:10.1523/JNEUROSCI.0387-04.2004

Multiple high-dose administrations of methamphetamine (METH) both rapidly (within hours) decrease plasmalemmal dopamine (DA) uptake and cause long-term deficits in DA transporter (DAT) levels and other dopaminergic parameters persisting weeks to months in rat striatum. In contrast, either a single administration of METH or multiple administrations of methylenedioxymethamphetamine (MDMA) cause less of an acute reduction in DA uptake and little or no persistent dopaminergic deficits. The long-term dopaminergic deficits caused by METH have been suggested, in part, to involve the DAT. Hence, this study assessed the impact of METH and MDMA administration on the DAT protein per se. Results revealed that multiple administrations of METH promoted formation of higher molecular weight (>170 kDa) DAT-associated protein complexes 24-48 hr after treatment. This increase was attenuated by either preventing hyperthermia or pretreatment with the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine; notably, each of these manipulations has also been demonstrated previously to prevent the persistent deficits in dopaminergic function caused by METH treatment. In contrast, either a single injection of METH or multiple injections of MDMA caused little or no formation of these DAT complexes. The addition of the reducing agent beta-mercaptoethanol to samples prepared from METH-treated rats diminished the intensity of these complexes. Taken together, these data are the first to demonstrate higher molecular weight DAT complex formation in vivo and that such formation can be altered by both pharmacological and physiological manipulations. The implications of this phenomenon with regard to the neurotoxic potential of these stimulants are discussed.

Bayer, A. U., Thiel, H. -., Zrenner, E., Dichgans, J., Kuehn, M., Paulus, W., Ried, S., & Schmidt, D. (1997). Color vision tests for early detection of antiepileptic drug toxicity. Neurology, 48(5), 1394-1397.

A previous suggestion that antiepileptic drugs may induce color vision deficiencies prompted us to examine whether color vision deficiencies may occur at lower drug serum concentrations than those associated with symptoms of neurotoxicity. Eighty patients presenting with epilepsy received monotherapies of valproic acid, phenytoin, or carbamazepine; 18 patients did not receive antiepileptic drug therapy. Color vision was tested by the Farnsworth-Munsell 100-hue test, spectral sensitivity, and the newly developed tritan screening plates. Patients treated with phenytoin or carbamazepine developed blue-yellow color vision deficiencies. In contrast, patients exposed to valproic acid or receiving no drug treatment showed normal color vision. There was a significant correlation (p < 0.0001) between signs of neurotoxicity induced by phenytoin or carbamazepine and blue-yellow color vision deficiencies. In contrast, we found no correlation between these signs of neurotoxicity and the drug serum concentrations (p = 0.0637). Color vision testing in epileptic patients treated with phenytoin or carbamazepine appears to be a sensitive method for early detection and monitoring of clinical neurotoxicity.

Bellone, M., Cottencin, O., Rigot, J. M., & Goudemand, M. (2005). Study on psychiatric disorders and defensive process assessed by the "defense style questionnaire" in sterile males SAMPLE consulting in andrology. [Etude des troubles psychiatriques et des modalites defensives evaluees par le "Defense Style Questionnaire" (DSQ) dans un echantillon d'hommes steriles consultant en andrologie] L'Encephale, 31(4 Pt 1), 414-425.

BACKGROUNDS: The literature about artificial insemination and the associated psychological, psychiatric and sexual disorders is relatively rich. But the majority of these studies is made in gynaecology, with a feminine approach of the disorder. There are very few works led in andrology. This justified the investigation of new trails in order to understand better the clinical context of the sterile man. We undertake a study about the psychiatric disorders among sterile men and about the defense styles. These are a clinical entity recently introduced in the quantitative psychopathology research. The defense style questionnaire (DSQ) is a psychometric scale used in common practice in order to measure the defense styles. OBJECTIVES: We made this study in order to examine the psychiatric state of a sterile males sample consulting in andrology; to assess the defense style by means of the Bond and al DSQ-88 ; to look into a difference between the defensive process according to their clinical situation of azoospermic males or as the oligoazoospermic males and finally, to reveal a correlation between the psychiatric disorders developed in this sample of sterile males and the defensive process they used. METHOD: There were 42 people (22 azoospermic males and 20 oligoazoospermic males) aged between 23 and 49 years old in the analysed sample. These have been selected at the surgery of andrology at the RUHC of Lille, depending on their arrival order for 6 months. There was no significant difference between the two groups as far as the age and the education standard are concerned. The selection criteria were medical and somatic. Our sample population were divided into two groups: azoospermia (no spermatozoon found in the semen analysis) and oligoasthenospermia (decrease of the number and the mobility of the spermatozoa and an increase of the percentage of atypical forms). The method first consisted in the DSQ, followed by the analysis of the psychiatric state according to the DSM IV, a hetero questionnaire to collect some general information about infertility and a self questionnaire about the sexual, conjugal and social effects of infertility. The DSQ and the interviews took place in the andrology department with the same investigator trained for this job. RESULTS: We found in our sample 26.2% of psychiatric disorders according to the DSM IV with a significant over-representation of generalized anxious disorder and somatization disorder. The comparison between azoospermic males and oligoazoospermic males patients showed the absence of significative difference as far as psychiatric morbidity rate and the use of defense styles are concerned. DISCUSSION: Our sample defended himself in accordance with modalities similar to the general population and used defense mechanisms preferentially belonging to the mature defense style, such as humor, repression and anticipation. The psychiatric pathology was significantly correlated to the preferential use of withdrawal, consumption, reaction formation and lack of humor use. We also confirm in our study the fact that the subjects using especially neurotic defense styles are more likely to develop a psychiatric disorder than the others. Our male sample is a waiting population and threatened by failure. The situation of wait creates anxiety. We also know that infertility is one of the most stressful situations a couple might face. However, our study did not enable us to know the precise relations between generalized anxious disorder and infertility, especially whether the generalized anxious disorder preceded this pathology or not. The over-representation of a somatization disorder only allows us to acknowledge its existence. We can also deduce from that a possible link between infertility and psychic disorder, even if no research permitted to affirm to date the existence of interrelations linking infertility and psychic life. On the whole, this population was suffering despite 73.8% of the patients had no confirmed psychiatric disorder. It is the reason why a liaison psychiatry more inserted into highly specialized teams is interesting, especially because it includes a medical and psychological approach of such disorders. The defense mechanisms preferentially used by this population were humor, repression and anticipation. Humor can only be considered as a defense mechanism when it is applied to oneself. The population who has no psychiatric disorder more uses humor. Does humor protect against the development of a psychiatric pathology, as certain authors proved it ? On the other hand, is repression really protective? It didn't interfere in our study about the development of a psychiatric pathology. So we can suppose that repression was protective for our whole sample, but we can not prove it. However, we wonder if this mechanism works after the failure of an artificial insemination is announced. In which measure such a stress can be repressed out of the conscience field? As for anticipation, it is used by our population who is for the most part in good health. But the question is to know if our sample really envisaged all the different possible solutions or only the success of artificial insemination. As some other works, we confirm that the, psychiatric, people significantly use the neurotic style. Our psychiatric patients used less humor and more consumption, withdrawal and reaction formation than the sane people. Consumption is rarely considered as a defense mechanism by some other authors. And yet, consumption and the existence of psychiatric disorders were very closely linked. This association is found again with anxiety in other studies. The correlation between psychiatric disorder and withdrawal was veryimportant too. The DSM lV defines withdrawal as an apathetic withdrawal. It is not an apathetic withdrawal in our population because the average scores for the ,, activity >, defense mechanism remained high. In our sample, the use of this defense mechanism would encourage the expression of psychiatric troubles. The reaction formation quoted by Freud and Bergeret are both valorised in our society. What kinds of reaction formations use these men ? Are they pathological ? Our study can not answer to these questions. However, the DSQ items examining the reaction formation present its "socially promoted" aspect and forget the pathological one. It has been showed that the evaluation of the defense modalities in a certain type of population can allow the emergence of specific defense mechanisms. This can be considered as predictive factors of development of a mental pathology. The evaluation of specific mental defenses could permit to define vulnerability and affinity for given affections instead of simple personality traits or profiles. Most part of the works shows results in favour of the capacity of DSQ to assess the different defense mechanisms according to the diagnosis groups. But the insufficient numbers of studies moderate on the whole the hypothesis of the existence of specific defense mechanisms--protective factors and factors of vulnerability--linked to a given psychiatric disorder. CONCLUSION: There is not a difference of psychological effect in terms of degree of sterility. On the other hand, the existence of over-represented psychiatric disorders with sterile males compared with a control group force Consultation-Liaison psychiatrists and andrologists would be able to understand the pain beyond the need of acting by the artificial insemination. In our opinion, this justifies the fact that the patients should have the opportunity of expressing, in the department where they are treated, all the feelings inherent to their personal and conjugal drama as part of a specialized treatment. Our study confirms the difficulty to know whether some defense mechanisms are vulnerability factors for a certain psychiatric disorder or whether the defense mechanisms are an epiphenomenon of a particular psychiatric disorder. This is the reason why a lot of authors having worked with DSQ agree to conclude that additional prospective studies, which would permit to make a link between the defense mechanisms anda certain psychiatric pathology, are necessary. In the case we study, it is important to explore the defensive modalities before the infertility diagnosis and after the birth of a child, with a more important sample population. A better knowledge of the defensive modalities of such a population, used in a psychotherapeutic context could help to prevent the appearance of psychiatric disorders or, if not, to anticipate them.

Benazzi, F. (2007). Bipolar II disorder : epidemiology, diagnosis and management. CNS Drugs, 21(9), 727-740.

Bipolar II disorder (BP-II) is defined, by DSM-IV, as recurrent episodes of depression and hypomania. Hypomania, according to DSM-IV, requires elevated (euphoric) and/or irritable mood, plus at least three of the following symptoms (four if mood is only irritable): grandiosity, decreased need for sleep, increased talking, racing thoughts, distractibility, overactivity (an increase in goal-directed activity), psychomotor agitation and excessive involvement in risky activities. This observable change in functioning should not be severe enough to cause marked impairment of social or occupational functioning, or to require hospitalisation. The distinction between BP-II and bipolar I disorder (BP-I) is not clearcut. The symptoms of mania (defining BP-I) and hypomania (defining BP-II) are the same, apart from the presence of psychosis in mania, and the distinction is based on the presence of marked impairment associated with mania, i.e. mania is more severe and may require hospitalisation. This is an unclear boundary that can lead to misclassification; however, the fact that hypomania often increases functioning makes the distinction between mania and hypomania clearer. BP-II depression can be syndromal and subsyndromal, and it is the prominent feature of BP-II. It is often a mixed depression, i.e. it has concurrent, usually subsyndromal, hypomanic symptoms. It is the depression that usually leads the patient to seek treatment.DSM-IV bipolar disorders (BP-I, BP-II, cyclothymic disorder and bipolar disorder not otherwise classified, which includes very rapid cycling and recurrent hypomania) are now considered to be part of the 'bipolar spectrum'. This is not included in DSM-IV, but is thought to also include antidepressant/substance-associated hypomania, cyclothymic temperament (a trait of highly unstable mood, thinking and behaviour), unipolar mixed depression and highly recurrent unipolar depression.BP-II is underdiagnosed in clinical practice, and its pharmacological treatment is understudied. Underdiagnosis is demonstrated by recent epidemiological studies. While, in DSM-IV, BP-II is reported to have a lifetime community prevalence of 0.5%, epidemiological studies have instead found that it has a lifetime community prevalence (including the bipolar spectrum) of around 5%. In depressed outpatients, one in two may have BP-II. The recent increased diagnosing of BP-II in research settings is related to several factors, including the introduction of the use of semi-structured interviews by trained research clinicians, a relaxation of diagnostic criteria such that the minimum duration of hypomania is now less than the 4 days stipulated by DSM-IV, and a probing for a history of hypomania focused more on overactivity (increased goal-directed activity) than on mood change (although this is still required for a diagnosis of hypomania).Guidelines on the treatment of BP-II are mainly consensus based and tend to follow those for the treatment of BP-I, because there have been few controlled studies of the treatment of BP-II. The current, limited evidence supports the following lines of treatment for BP-II. Hypomania is likely to respond to the same agents useful for mania, i.e. mood-stabilising agents such as lithium and valproate, and the second-generation antipsychotics (i.e. olanzapine, quetiapine, risperidone, ziprasidone, aripiprazole). Hypomania should be treated even if associated with overfunctioning, because a depression often soon follows hypomania (the hypomania-depression cycle). For the treatment of acute BP-II depression, two controlled studies of quetiapine have not found clearcut positive effects. Naturalistic studies, although open to several biases, have found antidepressants in acute BP-II depression to be as effective as in unipolar depression; however, one recent large controlled study (mainly in patients with BP-I) has found antidepressants to be no more effective than placebo. Results from naturalistic studies and clinical observations on mixed depression, while in need of replication in controlled studies, indicate that antidepressants may worsen the concurrent intradepression hypomanic symptoms. The only preventive treatment for both depression and hypomania that is supported by several, albeit older, controlled studies is lithium. Lamotrigine has shown some efficacy in delaying depression recurrences, but there have also been several negative unpublished studies of the drug in this indication.

Bendtsen, L., Bigal, M. E., Cerbo, R., Diener, H. C., Holroyd, K., Lampl, C., Mitsikostas, D. D., Steiner, T. J., & Tfelt-Hansen, P. (2009). Guidelines for controlled trials of drugs in tension-type headache: second edition. Cephalalgia : An International Journal of Headache, doi:10.1111/j.1468-2982.2009.01948.x

Guidelines for controlled trials of drugs in tension-type headache: second edition. Cephalalgia 2009. London. ISSN 0333-1024 The Clinical Trials Subcommittee of the International Headache Society published its first edition of the guidelines on controlled trials of drugs in tension-type headache in 1995. These aimed 'to improve the quality of controlled clinical trials in tension-type headache', because 'good quality controlled trials are the only way to convincingly demonstrate the efficacy of a drug, and form the basis for international agreement on drug therapy'. The Committee published similar guidelines for clinical trials in migraine and cluster headache. Since 1995 several studies on the treatment of episodic and chronic tension-type headache have been published, providing new information on trial methodology for this disorder. Furthermore, the classification of the headaches, including tension-type headache, has been revised. These developments support the need for also revising the guidelines for drug treatments in tension-type headache. These Guidelines are intended to assist in the design of well-controlled clinical trials in tension-type headache.

Benemei, S., Appendino, G., & Geppetti, P. (2009). Pleasant natural scent with unpleasant effects: cluster headache-like attacks triggered by Umbellularia californica. Cephalalgia : An International Journal of Headache, doi:10.1111/j.1468-2982.2009.01988.x

Umbellularia californica, a shrub or tree indigenous to southwestern Oregon and northern California, is commonly known as headache tree, probably because it is reported that its scent can cause headache. Here, we report the case of a 69-year-old Italian gardener, affected during his young adult age by cluster headache, who, 10 years from his last cluster episode, developed shorter-lasting cluster-like headache attacks after and at any time he was exposed to U. californica scent. The present case indicates that, even though endogenous mechanisms causing the cluster headache were no longer present, susceptibility to exogenous triggers remains active in this patient, and suggests that identification of the constituent(s) of U. californica responsible for triggering cluster headache-like attacks may help in the understanding of the hitherto elusive mechanism of cluster headache.

Benneyworth, M. A., Smith, R. L., Barrett, R. J., & Sanders-Bush, E. (2005). Complex discriminative stimulus properties of (+)lysergic acid diethylamide (LSD) in C57Bl/6J mice. Psychopharmacology, 179(4), 854-862. doi:10.1007/s00213-004-2108-z

RATIONALE: The drug discrimination procedure is the most frequently used in vivo model of hallucinogen activity. Historically, most drug discrimination studies have been conducted in the rat. With the development of genetically modified mice, a powerful new tool has become available for investigating the mechanisms of drug-induced behavior. The current paper is part of an ongoing effort to determine the utility of the drug discrimination technique for evaluating hallucinogenic drugs in mice. OBJECTIVE: To establish the training procedures and characterize the stimulus properties of (+)lysergic acid diethylamide (LSD) in mice. METHODS: Using a two-lever drug discrimination procedure, C57Bl/6J mice were trained to discriminate 0.45 mg/kg LSD vs saline on a VI30 sec schedule of reinforcement, with vanilla-flavored Ensure serving as the reinforcer. RESULTS: As in rats, acquisition was orderly, but the training dose was nearly five-fold higher for mice than rats. LSD lever selection was dose-dependent. Time-course studies revealed a rapid loss of the LSD stimulus effects. The 5-HT(2A/2C) receptor agonist, 2,5-dimethoxy-4-bromoamphetamine [(-)DOB] (1.0 mg/kg), substituted fully for LSD and the 5-HT(1A) receptor agonist, 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) (1.6 mg/kg), substituted partially for LSD. Pretreatment with the 5-HT(2A) receptor-selective antagonist, MDL 100907, or the 5-HT(1A)-selective antagonist WAY 100635, showed that each antagonist only partially blocked LSD discrimination. Substitution of 1.0 mg/kg (-)DOB for LSD was fully blocked by pretreatment with MDL 100907 but unaltered by WAY 100635 pretreatment. CONCLUSIONS: These data suggest that in mice the stimulus effects of LSD have both a 5-HT(2A) receptor and a 5-HT(1A) receptor component.

Benneyworth, M. A., Smith, R. L., & Sanders-Bush, E. (2008). Chronic phenethylamine hallucinogen treatment alters behavioral sensitivity to a metabotropic glutamate 2/3 receptor agonist. Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology, 33(9), 2206-2216. doi:10.1038/sj.npp.1301600

Recent clinical studies in schizophrenic patients show that a selective agonist of group II metabotropic glutamate (mGlu) receptors has robust efficacy in treating positive and negative symptoms. Group II mGlu receptor agonists also modulate the in vivo activity of psychotomimetic drugs, reducing the ability of psychotomimetic hallucinogens to increase glutamatergic transmission. The use of mouse models provides an opportunity to investigate the dynamic action that mGlu2/3 receptors play in regulating the behavioral effects of hallucinogen-induced glutamatergic neurotransmission using genetic as well as pharmacological strategies. The current study sought to characterize the use of the two-lever drug discrimination paradigm in ICR (CD-1) mice, using the hallucinogenic 5-HT2A/2C receptor agonist (-)-2,5-dimethoxy-4-bromoamphetamine [(-)-DOB)] as a stimulus-producing drug. The (-)-DOB discriminative stimulus was dose-dependent, generalized to the hallucinogen lysergic acid diethylamide, and was potently blocked by the 5-HT2A receptor antagonist M100907. However, contrary to our prediction, the hallucinogen-induced discriminative stimulus was not regulated by mGlu2/3 receptors. In a series of follow-up studies using hallucinogen-induced head twitch response and phencyclidine-induced hyperlocomotion, it was additionally discovered that the repeated dosing regimen required for discrimination training attenuated the behavioral effects of the mGlu2/3 receptor agonist LY379268. Furthermore chronic studies, using a 14 day (-)-DOB treatment, confirmed that repeated hallucinogen treatment causes a loss of behavioral activity of mGlu2/3 receptors, likely resulting from persistent activation of mGlu2/3 receptors by a hallucinogen-induced hyperglutamatergic state.

Bergamin Oliver, Schoetzau Andreas, Sugimoto Keiko, & Zulauf Mario. (1998). The influence of iris color on the pupillary light reflex. Graefe's Archive for Clinical and Experimental Ophthalmology, 236(8), 567-570.

· Results: Iris color (blue vs brown) influenced statistically significantly (P · Methods: Pupil perimetry was performed on 50 healthy volunteers with the Octopus 1-2-3 automated perimeter. Within the 30-deg visual field 33 test locations were investigated four times. Stimulus parameters were Goldmann size V (1.72°) intensity 1632 cd/m2 stimulus time 200 ms background illumination 0 cd/m2 and interstimulus interval 3 s. Pupillometric parameters studied were initial pupil size amplitude (magnitude of pupillary contraction) latency time contraction time pre-PLR movement contraction velocity parameters were investigated by analysis of variance by the independent variables blue and brown irides.  · Background: This study was carried out to investigate the effect of iris color on the pupillary light reflex (PLR) in normal healthy volunteers. Abstract<· Conclusions: Pupillary contraction amplitude and velocity depended on iris color whereas pupil size and latency time were independent of iris color. Therefore iris color might be considered when evaluating pupillary movements in pupil perimetry. 0.05) amplitude (0.504 mm vs 0.594 mm) contraction time (401 ms vs 407 ms) contraction velocity (13.75 mm2/s vs 16.01 mm2/s) and redilation velocity (4.80 mm2/s vs 5.66 mm2/s). Iris color did not influence initial pupil size (4.78 mm vs 4.83 mm) latency time (520 ms vs 521 ms) (0.328 mm2/s vs 0.325 mm2/s).

Bøhn, S. K., Smeland, S., Sakhi, A. K., Thoresen, M., Russnes, K. M., Tausjø, J., Svilaas, A., Svilaas, T., & Blomhoff, R. (2006). Post-radiotherapy plasma total glutathione is associated to outcome in patients with head and neck squamous cell carcinoma. Cancer Letters, 238(2), 240-247. doi:DOI: 10.1016/j.canlet.2005.07.027

Bonavita, V., & De Simone, R. (2009). Redefining primary headaches. Neurological Sciences : Official Journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology, 30 Suppl 1, S1-5. doi:10.1007/s10072-009-0050-x

In the light of the pathophysiologic knowledge acquired in the recent years, a tentative redefinition is now possible of some types of headache until now defined as idiopathic, and indistinctly described as primary headaches. Cluster headache and trigeminal neuralgia are known examples of diseases classified as primary, which are, in contrast, well-defined diseases to be distinguished from headaches without any recognized anatomic site of lesion or pathogenesis. Another still debated condition, chronic migraine, is proposed here as the consequence of "processes" to be ascribed to mechanisms activated by other comorbid conditions. The observations supporting the possibility that allodynia represents the implicit process leading to pain progression, which occurs in some migraineurs, are discussed.

Bone Pina, I., Ramos Gorostiza, P., Villalba Yllan, P., & Valle Fernandez, J. (2000). Persisting and late onset psychotic disorder due to consumption of ecstasy (MDMA). [Trastorno psicotico persistente inducido por consumo de extasis (MDMA)] Actas Espanolas De Psiquiatria, 28(1), 61-65.

Let us present a case of recurrent paranoid psychotic episodes in a patient with a history of abuse of > (MDMA: 3, 4-methylenedioxymethamphetamine), that persisted after a long withdrawal time, that, in our opinion, after an exhaustive differential diagnosis, may be attributed to that consumption. The carachteristics of this case are formally and naturally equivalent to those referred to in other papers about paranoid psychosis after abuse of MDMA, in which the sudden appearance, and the symptomatolgy of an intense feeling of threat and physical violence outstands, accompanied by abnormal corporal perceptions. In the case hereby presented, the withdrawal time is longer than that described in other publications. Even though in some authors' opinion this should be considered as comorbility or dual diagnosis, in our opinion enough facts exist suggesting that this is not a case of functional mental disorder but an organic disorder secondary to the neurotoxic effect of MDMA.

Bonis, P. A., Trikalinos, T. A., Chung, M., Chew, P., Ip, S., DeVine, D. A., & Lau, J. (2007). Hereditary nonpolyposis colorectal cancer: diagnostic strategies and their implications. Evidence report/technology Assessment, (150)(150), 1-180.

OBJECTIVES: Hereditary Nonpolyposis Colorectal Cancer (HNPCC) has been defined clinically and genetically. The disorder has traditionally been recognized in kindreds with a clustering of related cancers in association with mutations in DNA mismatch repair genes. HNPCC is associated with a substantially increased risk for several forms of malignancy but particularly colorectal and endometrial cancer. There were three main objectives of this report: (1) to assess the sensitivity, specificity, and reliability of laboratory and genetic tests commonly used in evaluating patients for HNPCC (analytic validity); (2) to summarize the accuracy of commonly used clinical and laboratory characteristics for predicting the presence of HNPCC in patients with colorectal cancer (clinical validity) and use these estimates to describe the efficiency of various strategies for identifying patients with a mismatch repair mutation; (3) to describe the benefits and harms related to screening and testing patients with colorectal cancer and their family members for HNPCC. DATA SOURCES: Published literature identified through an electronic search (through April 2006), review of relevant bibliographies, and suggestions from technical experts. REVIEW METHODS: We evaluated studies critically and summarized the data qualitatively or by meta-analysis when studies used similar methodology and endpoints. We used decision trees to describe the efficiency of various strategies for identifying patients with HNPCC from a hypothetical population of patients with colorectal cancer. RESULTS: We included a total of 104 studies of which 40 addressed issues related to clinical validity, 3 to analytic validity, and 61 to benefits and harms. We identified only three studies on analytic validity and thus there exists a major gap in the published literature with regard to the accuracy and reliability of specific tests used in the evaluation of HNPCC. Among unselected patients with colorectal cancer who fulfilled the Amsterdam I criteria, 44% (95% CI: 35, 52%) carried pathogenic mismatch repair mutations (mainly in the MLH1 and MSH2 genes). The proportion was somewhat higher (51% [95% CI: 35, 66%]) among studies that performed sequencing on all available samples. The prevalence of MMR mutation carriers may be higher when genetic testing includes evaluation for large genomic deletions/rearrangements and when testing is also performed on MSH6 and PMS2. Approximately 71% (95% CI 63, 78%) of colorectal cancers from patients who fulfilled the Amsterdam I criteria demonstrated microsatellite instability while 40% (95% CI: 28, 53%) demonstrated loss of protein expression by immunohistochemistry. Of nine clinical strategies considered for detecting the presence of mismatch repair mutations in patients with colorectal cancer, the combination of three clinical predictors (age less than 50 years old at diagnosis; or a history of colorectal or endometrial cancer in a first degree family member; or the presence of multiple, synchronous or metachronous colorectal or endometrial cancers in the proband) combined with either immunohistochemistry (IHC) or MSI testing of tumor tissue identified a similar number of patients with mismatch repair mutations as other more complex strategies. There was little published information regarding potential harms associated with screening individuals with HNPCC-related cancers using clinical criteria (e.g. the Amsterdam criteria), MSI or IHC testing. Limited data suggested that testing probands for MMR mutations was not associated with severe psychological impact following formal counseling. Pre-test genetic counseling had good efficacy in improving knowledge about HNPCC and resulted in a high likelihood of proceeding with genetic testing, satisfaction in the decision to undergo genetic testing, and decreasing depression and distress levels among family members of HNPCC probands with cancer and among asymptomatic individuals from HNPCC families. Identification of HNPCC mutations was associated with an increase in the likelihood that family members of probands with CRC would undergo cancer-screening procedures. HNPCC family members who underwent cancer-screening procedures had a lower risk of developing HNPCC-related cancers and lower mortality rates than those who did not take actions. However, all of the relevant studies suggesting these benefits had important limitations. Survival was increased among asymptomatic HNPCC family members who received colonoscopy screening, regardless of their mutation status. There was limited direct evidence related to harms of the cancer-screening procedures in family members of probands with HNPCC. However, complication rates associated with these procedures in other settings are probably similar. CONCLUSIONS: This report characterizes the accuracy of clinical and laboratory predictors of MMR mutations that can be used to identify patients with an increased risk of having MMR mutations. However, the sensitivity, specificity, and reliability of the tests used to evaluate individuals for suspected HNPCC is not known confidently. Data regarding the net benefits and harms associated with predictive genetic testing in patients with HNPCC-related cancers and their families members is incomplete but suggest that such testing improves compliance with screening procedures. At-risk family members who undergo screening colonoscopy have a reduced risk of developing HNPCC-related cancers and lower mortality. However, all studies supporting these benefits had important limitations.

Boyden, J., & Berry, J. d. (2004). Children and youth on the front line : ethnography, armed conflict and displacement. New York: Berghahn Books.

Braga, R. J., Petrides, G., & Figueira, I. (2004). Anxiety disorders in schizophrenia. Comprehensive Psychiatry, 45(6), 460-468. doi:10.1016/j.comppsych.2004.07.009

Data regarding the co-occurrence of anxiety symptoms or syndromes in schizophrenia is scant. Hierarchical assumptions embedded in diagnostic systems and methodologic difficulties hamper the development of studies on accessory symptomatology outside of the core positive-negative-disorganized symptoms. Recent studies have repeatedly challenged these assumptions by presenting data on comorbid disorders in schizophrenia. We review the current knowledge about anxiety comorbidity in schizophrenia, and its relative prevalence, relevance, and treatment. A computerized search of the literature published from 1966 to July 2003 was conducted on Medline using the word "schizophrenia" and the words from the names of each anxiety disorder listed in DSM-IV, one at a time. Only studies including exclusively the diagnosis of schizophrenia were included. Only 15 studies were dedicated to the subject of anxiety comorbidity prevalence in schizophrenia. The most studied comorbidities were obsessive-compulsive disorder (OCD) and panic disorder, and most reports suggested them to be highly prevalent in schizophrenia. Posttraumatic stress disorder (PTSD) was the least studied (N = 2). Except for two pharmacologic studies in OCD, there were no double-blind randomized controlled trials regarding the treatment of anxiety in schizophrenia. Most case reports and open label trials tried conventional treatment for anxiety disorders with some degree of success. The literature indicates that anxiety comorbidities are prevalent in schizophrenia and conventional treatment for anxiety can help alleviate the symptoms in those patients. However, the body of data provided by research so far is still far from allowing evidence-based conclusions. Large studies with operationalized criteria, as well as comprehensive assessments of treatment response and outcome are needed to clarify the relationship between anxiety disorders and schizophrenia.

Bridle, C., Palmer, S., Bagnall, A. M., Darba, J., Duffy, S., Sculpher, M., & Riemsma, R. (2004). A rapid and systematic review and economic evaluation of the clinical and cost-effectiveness of newer drugs for treatment of mania associated with bipolar affective disorder. Health Technology Assessment (Winchester, England), 8(19), iii-iv, 1-187.

OBJECTIVES: To evaluate the clinical and cost-effectiveness of quetiapine, olanzapine and valproate semisodium in the treatment of mania associated with bipolar disorder. DATA SOURCES: Electronic databases; industry submissions made to the National Institute for Clinical Excellence. REVIEW METHODS: Randomised trials and economic evaluations that evaluated the effectiveness of quetiapine, olanzapine or valproate semisodium in the treatment of mania associated with bipolar disorder were selected for inclusion. Data were extracted by one reviewer into a Microsoft Access database and checked for quality and accuracy by a second. The quality of the cost-effectiveness studies was assessed using a checklist updated from that developed by Drummond and colleagues. Relative risk and mean difference data were presented as Forest plots but only pooled where this made sense clinically and statistically. Studies were grouped by drug and, within each drug, by comparator used. Chi-squared tests of heterogeneity were performed for the outcomes if pooling was indicated. A probabilistic model was developed to estimate costs from the perspective of the NHS, and health outcomes in terms of response rate, based on an improvement of at least 50% in a patient's baseline manic symptoms derived from an interview-based mania assessment scale. The model evaluated the cost-effectiveness of the alternative drugs when used as part of treatment for the acute manic episode only. RESULTS: Eighteen randomised trials met the inclusion criteria. Aspects of three of the quetiapine studies were commercial-in-confidence. The quality of the included trials was limited and overall, key methodological criteria were not met in most trials. Quetiapine, olanzapine and valproate semisodium appear superior to placebo in reducing manic symptoms, but may cause side-effects. There appears to be little difference between these treatments and lithium in terms of effectiveness, but quetiapine is associated with somnolence and weight gain, whereas lithium is associated with tremor. Olanzapine as adjunct therapy to mood stabilisers may be more effective than placebo in reducing mania and improving global health, but it is associated with more dry mouth, somnolence, weight gain, increased appetite, tremor and speech disorder. There was little difference between these treatments and haloperidol in reducing mania, but haloperidol was associated with more extrapyramidal side-effects and negative implications for health-related quality of life. Intramuscular olanzapine and lorazepam were equally effective and safe in one very short (24 hour) trial. Valproate semisodium and carbamazepine were equally effective and safe in one small trial in children. Olanzapine may be more effective than valproate semisodium in reducing mania, but was associated with more dry mouth, increased appetite, oedema, somnolence, speech disorder, Parkinson-like symptoms and weight gain. Valproate semisodium was associated with more nausea than olanzapine. The results from the base-case analysis demonstrate that choice of optimal strategy is dependent on the maximum that the health service is prepared to pay per additional responder. For a figure of less than 7179 British pounds per additional responder, haloperidol is the optimal decision; for a spend in excess of this, it would be olanzapine. Under the most favourable scenario in relation to the costs of responders and non-responders beyond the 3-week period considered in the base-case analysis, the incremental cost-effectiveness ratio of olanzapine is reduced to 1236 British pounds. CONCLUSIONS: In comparison with placebo, quetiapine, olanzapine and valproate semisodium appear superior in reducing manic symptoms, but all drugs are associated with adverse events. In comparison with lithium, no significant differences were found between the three drugs in terms of effectiveness, and all were associated with adverse events. Several limitations of the cost-effectiveness analysis exist, which inevitably means that the results should be treated with some caution. There remains a need for well-conducted, randomised, double-blind head-to-head comparisons of drugs used in the treatment of mania associated with bipolar disorder and their cost-effectiveness. Participant demographic, diagnostic characteristics, the treatment of mania in children, the use of adjunctive therapy and long-term safety issues in the elderly population, and acute and long-term treatment are also subjects for further study.

Broggi, G., Messina, G., & Franzini, A. (2009). Cluster headache and TACs: rationale for central and peripheral neuromodulation. Neurological Sciences : Official Journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology, 30 Suppl 1, S75-9. doi:10.1007/s10072-009-0082-2

Cluster headache, the most severe of primary headache conditions for functional and social impairment it provokes, has been recently the object of a great amount of clinical, physiopathological, surgical and functional neuroradiological studies aimed to uncover the real mechanisms which underlie its disabling manifestations. Refinement of methodological and systematic features of multidisciplinary researches in this field has been allowing for more and more precise delineations of the role of both peripheral and central nervous system's contribution in pathophysiology of the disease. Aim of this manuscript is the report of the present knowledge in the role of the different surgical options in the treatment of drug-resistant cluster headache and Short-lasting Unilateral neuralgiform headache attacks with Conjunctival injection and Tearing (SUNCT), which take into account their different hypothesized pathological mechanisms and which comprise central nervous system's approach (Deep Brain Stimulation [DBS] and peripheral approach, namely Occipital Nerve Stimulation (ONS) and Vagal Nerve Stimulation (VNS).

Buhrich, N., Morris, G., & Cook, G. (1983). Bromo-DMA: the Australasian hallucinogen? The Australian and New Zealand Journal of Psychiatry, 17(3), 275-279.

If the frequency of seizures by police of hallucinogens reflects the frequency with which various hallucinogens are ingested in Australasia, most toxic states resulting from hallucinogen abuse are due to Bromo-DMA and not to LSD as is commonly reported by the subjects. Two cases of intoxication with the new hallucinogen, Bromo-DMA, are reported. Both recovered within 24 hours following treatment with haloperidol.

Burstein, S. H., Friderichs, E., Kogel, B., Schneider, J., & Selve, N. (1998). Analgesic effects of 1',1' dimethylheptyl-delta8-THC-11-oic acid (CT3) in mice. Life Sciences, 63(3), 161-168.

The metabolic pathway leading to carboxylic acid derivatives of cannabinoids was discovered more than twenty years ago. While these compounds showed no cannabimimetic activity, subsequent work documented several biological responses both in vitro and in vivo for the THC acids. These include inhibition of eicosanoid synthesis, antiedema effects, antagonism to PAF actions, inhibition of leucocyte adhesion and anti nociception. In this report we present data further characterizing the analgesic properties of the title substance which is a potent synthetic member of this group. CT3 was effective in the mouse hot plate assay at 48 degrees C showing an ED-50 of 4.31 (3.37-5.83) mg/kg when administered i.v (10% Cremophor EL in saline). When given by gavage in peanut oil, it resulted in 30-40% MPE (maximum possible effect) at 10 mg/kg with the effect persisting for up to 5 hours. A more potent response was observed in the mouse p-phenylquinone writhing test. When given i.v., it showed an ED-50 of 1.24 (0.84-1.75) mg/kg. However, no activity was found with oral administration either in peanut oil or Cremophor EL. At 10 mg/kg i.v., a 100% inhibition of the writhing response was seen. The mouse formalin antinociception test was also studied in animals that received CT3 (4.64 mg/kg) i.v. using three behavioral parameters for activity. The drug showed decreases in each category when compared with vehicle/formalin treated mice. The formalin effect showed a typical two phase, time related, response in which CT3 caused a 64% reduction in the early phase and a 48% reduction in the late phase in a composite score of nociception. Interestingly, it did not alter motor function in the rota rod procedure at 4.64 mg/kg i.v.

Busanich, B. M., & Verscheure, S. D. (2006). Does McKenzie therapy improve outcomes for back pain? Journal of Athletic Training, 41(1), 117-119.

CLINICAL QUESTION: What is the clinical evidence base for McKenzie therapy in management of back pain? DATA SOURCES: Studies were identified using a computer-based literature search of 7 databases: MEDLINE, EMBASE, DARE, CINAHL, PEDro, the Cochrane Register of Clinical Trials (CENTRAL), and the Cochrane Database of Systematic Reviews. Search terms included McKenzie therapy, McKenzie treatment, and McKenzie method. Studies published before September 2003 were eligible. STUDY SELECTION: To be included in the review, each study had to fulfill the following criteria: (1) the study was a randomized or quasi-randomized controlled trial, (2) the subjects' primary complaint was nonspecific low back pain or neck pain with or without radiation to the extremities, (3) the authors investigated the efficacy of the McKenzie method/McKenzie treatment in comparison with no treatment, sham treatment, or another treatment, (4) individualized patient treatment and treatment were specified according to McKenzie principles, and (5) the authors reported at least one of the outcome measures of pain, disability, quality of life, work status, global perceived effect, medication use, medical visits, or recurrence. Studies were included with no language restriction and with subjects of all age groups, of either sex, and with any duration of symptoms. Studies were excluded if subjects had any of the following spinal conditions: cauda equina syndrome, cord compression, infection, fracture, neoplasm, inflammatory disease, pregnancy, any form of headache, whiplash-associated disorders, vertigo/dizziness, or vertebrobasilar insufficiency. DATA EXTRACTION: Data were independently extracted from each study by 2 investigators using a standardized data extraction form. The standardized data extraction form and experience level of the investigators were not included in the review. In studies with more than 2 treatment groups, the treatment contrast of more relevance to current Australian physiotherapy was selected. Data were also extracted for short-, intermediate-, and long-term follow-up based on the criteria suggested by the Cochrane Back Review Group. Short-term follow-up was defined as less than 3 months from onset of treatment. Intermediate-term follow-up was defined as at least 3 months and less than 12 months from onset of treatment. Long-term follow-up was defined as equal to or greater than 12 months. All eligible studies were rated for methodologic quality using the PEDro scale. The PEDro scale is a checklist that examines the "believability and the interpretability of trial quality."(1) The 11-item checklist yields a maximum score of 10 if all criteria are satisfied. The first item on the scale (Eligibility Criteria) is not scored. The PEDro scores were extracted from the PEDro database. If a study had not been entered into the database and scored, it was reviewed and scored by an experienced PEDro rater. MAIN RESULTS: Normalized data for pain and disability were given possible total scores of 100. The article's scores on the PEDro scale were average, ranging from 4 to 8 of 10. The most common flaw in the methods, which occurred in all 6 studies, was the failure to blind both the patient and therapist. Four of the 6 did not blind the researcher interpreting the data. For both pain and disability at short-term (12 months) outcomes or outcomes other than pain and disability (eg, quality of life). To date, no authors have compared McKenzie therapy with placebo or no treatment. Also, few data are available on the McKenzie method and its effect on neck pain. Future researchers should focus on these issues.

Callahan, S., Rousseau, A., Knotter, A., Bru, V., Danel, M., Cueto, C., Levasseur, M., Cuvelliez, F., Pignol, L., O'Halloran, M. S., & Chabrol, H. (2003). Diagnosing eating disorders: presentation of a new diagnostic test and an initial epidemiological study of eating disorders in adolescents. [Les troubles alimentaires: presentation d'un outil de diagnostic et resultats d'une etude epidemiologique chez les adolescents] L'Encephale, 29(3 Pt 1), 239-247.

Precise diagnosis of eating disorders has long been problematic. First off, although the DSM IV provides clear criteria, these are applicable to a very narrow range of disorders. Subclinical disorders, although well defined in the literature, are difficult to diagnose as no tool has been previously available. These subclinical disorders are particularly important if one considers that they are often precursors to more serious and life-threatening eating disorders. In addition, choice of diagnostic tool for eating disorders has also long been the cause of difficulty for both researchers and clinicians. Although interviews are favored for their in-depth approach, they are sometimes difficult to implement and often too long and costly to use on a regular basis. Most available questionnaires are limited by their approach to one or two diagnostic categories, and again, until now, no tool has fully addressed the issue of subclinical disorders. The goal of this work was to translate and use a new questionnaire, The Questionnaire for Eating Disorders (Q-EDD), which was developed in the United States and based on both DSM IV criteria as well as carefully developed subclinical disorder criteria. The Q-EDD can identify the major eating disorder categories while at the same time distinguishing between different qualities in each (for example restricting versus compensatory anorexia). Moreover, the Q-EDD can identify several subclinical disorder categories, providing useful insight into potentially dangerous evolution of these disorders. In collaboration with one of the original authors, the questionnaire was translated into French with careful attention to DSM IV criteria in order to preserve its original validity. The questionnaire was read by several professionals in psychology as well as lay people to assure its face validity and ease of use. Once the questionnaire was adequately translated and corrected, it was used for an epidemiological study with a large sample of adolescents and young adults (n=1 001) from several Junior High and High Schools in the greater metropolitan area of Toulouse, France. The schools were located in a variety of neighborhoods and represented a wide range of population, some of them being more academic oriented, others being more oriented towards practical training. The population was composed of 703 females and 298 males, with an average age of 17.06 years. In addition, the population included several different ethnic categories, all of which are similarly represented in the general French population. The results from the Q-EDD showed levels of various clinical disorders to replicate data from previous epidemiological studies with 1.5% of the population suffering from a serious clinical DSM IV disorder; 7.9% suffering from DSM IV disorders NOS; and 20.9% suffering subclinical disorders. In addition to this finding of 30% of the population with an eating disorder, it was noted that a large number of these young people fell into the severe underweight and low weight categories. Indeed, nearly 10% of this group were within the weight criteria for anorexia, despite the fact that they did not meet the other criteria. This finding seemed to warrant additional investigation, and as a result, a different cut-off for severe underweight was established using literature references; this cut-off was set at the 10(th) percentile for BMI based on age. Yet, even with this new cut-off, 6% of this population still met a severe underweight criteria suggestive of anorexic pathology. These results led to the formulation of 2 hypotheses to explain this finding, the first of which examines morphological differences, the second of which suggests cultural differences in terms of eating habits and diet. The French version of the Q-EDD appears to follow the psychometric properties of the original version, moreover it provides useful and rich data regarding eating disorders in a format that is simple and efficient.

Chessick, C. A., Allen, M. H., Thase, M., Batista Miralha da Cunha, A. B., Kapczinski, F. F., de Lima, M. S., & dos Santos Souza, J. J. (2006). Azapirones for generalized anxiety disorder. Cochrane Database of Systematic Reviews (Online), 3, CD006115. doi:10.1002/14651858.CD006115

BACKGROUND: Azapirones are a group of drugs that work at the 5-HT1A receptor and are used to treat patients suffering from generalized anxiety disorder (GAD). However, several studies have shown conflicting results. Whether azapirones are useful as first line treatment in general anxiety disorders still needs to be answered. OBJECTIVES: To assess the efficacy and the acceptability of azapirones for the treatment of GAD. SEARCH STRATEGY: Initially the Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register (CCDANCTR) and The Cochrane Central Register of Controlled Trials (CENTRAL) were searched, incorporating results of group searches of MEDLINE (1966 to June 2005), EMBASE (1980 to June 2005), CINAHL (1982 to June 2005), PsycLIT (1974 to June 2005), PSYNDEX (1977 to June 2005), and LILACS (1982 to June 2005). Subsequently the revised Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Registers (CCDANCTR-Studies and CCDANCTR-References) were searched on 21-10-2005. Reference lists of relevant papers and major text books of anxiety disorder were examined. Authors, other experts in the field and pharmaceutical companies were contacted for knowledge of suitable trials, published or unpublished. Specialist journals concerning azapirones were handsearched. SELECTION CRITERIA: Randomized controlled trials of azapirones, including buspirone versus placebo and/or other medication and/or psychological treatment, were included. Participants were males and females of all ages with a diagnosis of generalized anxiety disorder. DATA COLLECTION AND ANALYSIS: Data were extracted from the original reports independently by CC, MA and MT. The main outcomes studied were related to the objectives stated above. Data were analysed for generalized anxiety disorder versus placebo, versus other medication and versus psychological treatment separately. Data were analysed using Review Manager Version 4.2.7. MAIN RESULTS: Thirty six trials were included in the review, reporting on 5908 participants randomly allocated to azapirones and/or placebo, benzodiazepines, antidepressants, psychotherapy or kava kava. Azapirones, including buspirone, were superior to placebo in treating GAD. The calculated number needed to treat for azapirones using the Clinical Global Impression scale was 4.4 (95% confidence interval (CI) 2.16 to 15.4). Azapirones may be less effective than benzodiazepines and we were unable to conclude if azapirones were superior to antidepressants, kava kava or psychotherapy. Azapirones appeared to be well tolerated. Fewer participants stopped taking benzodiazepines compared to azapirones. The length of studies ranged from four to nine weeks, with one study lasting 14 weeks. AUTHORS' CONCLUSIONS: Azapirones appeared to be useful in the treatment of GAD, particularly for those participants who had not been on a benzodiazepine. Azapirones may not be superior to benzodiazepines and do not appear as acceptable as benzodiazepines. Side effects appeared mild and non serious in the azapirone treated group. Longer term studies are needed to show that azapirones are effective in treating GAD, which is a chronic long-term illness.

Chronicle, E., & Mulleners, W. (2004). Anticonvulsant drugs for migraine prophylaxis. Cochrane Database of Systematic Reviews (Online), (3)(3), CD003226. doi:10.1002/14651858.CD003226.pub2

BACKGROUND: Anticonvulsant drugs seem to be useful in clinical practice for the prophylaxis of migraine. This might be explained by a variety of actions of these drugs in the central nervous system that are probably relevant to the pathophysiology of migraine. OBJECTIVES: To describe and assess the evidence from controlled trials on the efficacy and tolerability of anticonvulsants for preventing migraine attacks in adult patients with migraine. SEARCH STRATEGY: We searched MEDLINE (from 1966 on) and the Cochrane Central Register of Controlled Trials (CENTRAL). Date of most recent search: April 2003. Additional information was gained from hand-searching specialist headache journals; correspondence with pharmaceutical companies, authors of reports, and experts in the field; and a wide variety of review articles and book chapters. SELECTION CRITERIA: Studies were required to be prospective, controlled trials of self-administered drug treatments taken regularly to prevent the occurrence of migraine attacks and/or to reduce the intensity of those attacks. DATA COLLECTION AND ANALYSIS: Studies were selected and data extracted by two independent reviewers. For migraine frequency data, standardized mean differences (SMDs) were calculated for individual studies and pooled across studies. For dichotomous data on significant reduction in migraine frequency, odds ratios (ORs) and numbers-needed-to-treat (NNTs) were similarly calculated. Adverse events were analyzed by calculating numbers-needed-to-harm (NNHs) for studies using similar agents. MAIN RESULTS: Fifteen papers were included in the review. Of these, 14 reported trials comparing anticonvulsants with placebo, as follows: four trials of divalproex sodium, three trials of topiramate, two trials of sodium valproate, two trials of gabapentin, and one trial each of carbamazepine, clonazepam, and lamotrigine. One paper reported a trial of sodium valproate versus an active comparator, flunarizine, and one trial of divalproex sodium versus placebo included a comparison against propranolol, also an active comparator. Data from 2024 patients were considered. Analysis of data from eight trials (n = 841) demonstrates that anticonvulsants, considered as a class, reduce migraine frequency by about 1.4 attacks per 28 days as compared to placebo (SMD -0.60; 95% confidence interval [CI] -0.93 to -0.26). Data from 10 trials (n = 1341) show that anticonvulsants, considered as a class, also more than double the number of patients for whom migraine frequency is reduced by 50% or more, relative to placebo (OR 3.90; 95% CI 2.61 to 5.82; NNT 3.8; 95% CI 3.2 to 4.6). For seven trials of sodium valproate and divalproex sodium, NNHs for five clinically important adverse events ranged from 6.6 to 16.3. For the three trials of topiramate, NNHs for eight adverse events (100-mg dose) ranged from 2.4 to 32.9. REVIEWERS' CONCLUSIONS: Anticonvulsants appear to be both effective in reducing migraine frequency and reasonably well tolerated. There is noticeable variation among individual agents, but there are insufficient data to know whether this is due to chance or variation in true efficacy. Neither clonazepam nor lamotrigine was superior to placebo (one trial each). Relatively few robust trials are available for agents other than sodium valproate/divalproex sodium. Two recently published and large trials of topiramate demonstrated reasonable efficacy, and one further trial of this agent is anticipated in the near future.

Cittadini, E., & Matharu, M. S. (2009). Symptomatic trigeminal autonomic cephalalgias. The Neurologist, 15(6), 305-312. doi:10.1097/NRL.0b013e3181ad8d67

BACKGROUND: The trigeminal autonomic cephalalgias (TACs) are a group of primary headache syndromes characterized by strictly unilateral head pain that occurs in association with ipsilateral cranial autonomic features. The group includes cluster headache, paroxysmal hemicrania, and short lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing. These syndromes differ in attack duration and frequency as well as the response to therapy. Most of the cases of these syndromes are primary headaches, though numerous symptomatic cases have been described albeit that it is difficult to establish a causal relationship with the underlying pathology in most cases. REVIEW SUMMARY: We reviewed the literature to identify the cases of symptomatic TACs that were likely to be secondary to the reported underlying lesion. We also attempted to identify any clinical features that may be pointers for distinguishing these cases from primary cases and thereby inform the diagnostic workup of these disorders. CONCLUSION: Forty cases of symptomatic TACs were identified. These symptomatic headaches were associated with atypical phenotypes, abnormal examination, and poor treatment response though a significant minority had a typical presentation. A relatively high proportion of all TACs were secondary to pituitary tumors. It is difficult to draw up guidelines for the diagnostic workup required on the basis of this small retrospective case series. It remains unclear whether every TAC patient requires neuroimaging, though if it is considered then magnetic resonance imaging is the preferred modality. In addition, we suggest that all TAC patients should be carefully assessed for pituitary disease related symptoms but further investigations with magnetic resonance imaging of the pituitary gland and pituitary hormonal profile should only be undertaken in patients with atypical features, abnormal examination, or those resistant to the appropriate medical treatment.

Claudino, A. M., Hay, P., Lima, M. S., Bacaltchuk, J., Schmidt, U., & Treasure, J. (2006). Antidepressants for anorexia nervosa. Cochrane Database of Systematic Reviews (Online), (1)(1), CD004365. doi:10.1002/14651858.CD004365.pub2

BACKGROUND: Anorexia Nervosa (AN) is an illness characterised by extreme concern about body weight and shape, severe self-imposed weight loss, and endocrine dysfunction. In spite of its high mortality, morbidity and chronicity, there are few intervention studies on the subject. OBJECTIVES: The aim of this review was to evaluate the efficacy and acceptability of antidepressant drugs in the treatment of acute AN. SEARCH STRATEGY: The strategy comprised of database searches of the Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register, MEDLINE (1966 to April 28th, 2005), EMBASE (1980 to week 36, 2004), PsycINFO (1969 to August week 5, 2004), handsearching the International Journal of Eating Disorders and searching the reference lists of all papers selected. Personal letters were sent to researchers in the field requesting information on unpublished or in-progress trials. SELECTION CRITERIA: All randomised controlled trials of antidepressant treatment for AN patients, as defined by the Diagnostic and Statistical Manual, fourth edition (DSM-IV) or similar international criteria, were selected. DATA COLLECTION AND ANALYSIS: Quality ratings were made giving consideration to the strong relationship between allocation concealment and potential for bias in the results; studies meeting criteria A and B were included. Trials were excluded if non-completion rates were above 50%. The standardised mean difference and relative risk were used for continuous data and dichotomous data comparisons, respectively. Whenever possible, analyses were performed according to intention-to-treat principles. Heterogeneity was tested with the I-squared statistic. Weight change was the primary outcome. Secondary outcomes were severity of eating disorder, depression and anxiety symptoms, and global clinical state. Acceptability of treatment was evaluated by considering non-completion rates. MAIN RESULTS: Only seven studies were included. Major methodological limitations such as small trial size and large confidence intervals decreased the power of the studies to detect differences between treatments, and meta-analysis of data was not possible for the majority of outcomes. Four placebo-controlled trials did not find evidence that antidepressants improved weight gain, eating disorder or associated psychopathology. Isolated findings, favouring amineptine and nortriptyline, emerged from the antidepressant versus antidepressant comparisons, but cannot be conceived as evidence of efficacy of a specific drug or class of antidepressant in light of the findings from the placebo comparisons. Non-completion rates were similar between the compared groups. AUTHORS' CONCLUSIONS: A lack of quality information precludes us from drawing definite conclusions or recommendations on the use of antidepressants in acute AN. Future studies testing safer and more tolerable antidepressants in larger, well designed trials are needed to provide guidance for clinical practice.

Cooper, H. A. (1955). HALLUCINOGENIC DRUGS. The Lancet, 265(6873), 1078-1079. doi:DOI: 10.1016/S0140-6736(55)91156-9

Costello, C. G. (1960). The Effects of Meprobamate on Perception: I. Apparent Movement. The British Journal of Psychiatry, 106(442), 322-325. doi:10.1192/bjp.106.442.322

Six subjects were tested under two conditions each on two separate occasions. The two conditions were: (i) administration of placebo, (ii) administration of 600 mg. meprobamate. Testing on each day was done once before administration of the treatment and 1, 2[1/2], 3[1/2] and 4[1/2] hours after administration. The results showed that, as predicted, meprobamate lowers the upper threshold of apparent movement.

Cranney, A., Horsley, T., O'Donnell, S., Weiler, H., Puil, L., Ooi, D., Atkinson, S., Ward, L., Moher, D., Hanley, D., Fang, M., Yazdi, F., Garritty, C., Sampson, M., Barrowman, N., Tsertsvadze, A., & Mamaladze, V. (2007). Effectiveness and safety of vitamin D in relation to bone health. Evidence report/technology Assessment, (158)(158), 1-235.

OBJECTIVES: To review and synthesize the literature in the following areas: the association of specific circulating 25(OH)D concentrations with bone health outcomes in children, women of reproductive age, postmenopausal women and elderly men; the effect of dietary intakes (foods fortified with vitamin D and/or vitamin D supplementation) and sun exposure on serum 25(OH)D; the effect of vitamin D on bone mineral density (BMD) and fracture or fall risk; and the identification of potential harms of vitamin D above current reference intakes. DATA SOURCES: MEDLINE® (1966-June Week 3 2006); Embase (2002-2006 Week 25); CINAHL (1982-June Week 4, 2006); AMED (1985 to June 2006); Biological Abstracts (1990-February 2005); and the Cochrane Central Register of Controlled Trials (2nd Quarter 2006). REVIEW METHODS: Two independent reviewers completed a multi-level process of screening the literature to identify eligible studies (title and abstract, followed by full text review, and categorization of study design per key question). To minimize bias, study design was limited to randomized controlled trials (RCTs) wherever possible. Study criteria for question one were broadened to include observational studies due to a paucity of available RCTs, and question four was restricted to systematic reviews to limit scope. Data were abstracted in duplicate and study quality assessed. Differences in opinion were resolved through consensus or adjudication. If clinically relevant and statistically feasible, meta-analyses of RCTs on vitamin D supplementation and bone health outcomes were conducted, with exploration of heterogeneity. When meta-analysis was not feasible, a qualitative systematic review of eligible studies was conducted. RESULTS: 167 studies met our eligibility criteria (112 RCTs, 19 prospective cohorts, 30 case-controls and six before-after studies). The largest body of evidence on vitamin D status and bone health was in older adults with a lack of studies in premenopausal women and infants, children and adolescents. The quality of RCTs was highest in the vitamin D efficacy trials for prevention of falls and/or fractures in older adults. There was fair evidence of an association between low circulating 25(OH)D concentrations and established rickets. However, the specific 25(OH)D concentrations associated with rickets is uncertain, given the lack of studies in populations with dietary calcium intakes similar to North American diets and the different methods used to determine 25(OH)D concentrations. There was inconsistent evidence of an association of circulating 25(OH)D with bone mineral content in infants, and fair evidence that serum 25(OH)D is inversely associated with serum PTH. In adolescents, there was fair evidence for an association between 25(OH)D levels and changes in BMD. There were very few studies in pregnant and lactating women, and insufficient evidence for an association between serum 25(OH)D and changes in BMD during lactation, and fair evidence of an inverse correlation with PTH. In older adults, there was fair evidence that serum 25(OH)D is inversely associated with falls, fair evidence for a positive association with BMD, and inconsistent evidence for an association with fractures. The imprecision of 25(OH)D assays may have contributed to the variable thresholds of 25(OH)D below which the risk of fractures, falls or bone loss was increased. There was good evidence that intakes from vitamin D-fortified foods (11 RCTs) consistently increased serum 25(OH)D in both young and older adults. Eight randomized trials of ultraviolet (UV)-B radiation (artificial and solar exposure) were small and heterogeneous with respect to determination of the exact UV-B dose and 25(OH)D assay but there was a positive effect on serum 25(OH)D concentrations. It was not possible to determine how 25(OH)D levels varied by ethnicity, sunscreen use or latitude. Seventy-four trials examined the effect of vitamin D(3) or D(2) on 25(OH)D concentrations. Most trials used vitamin D(3), and the majority enrolled older adults. In three trials, there was a greater response of serum 25(OH)D concentrations to vitamin D(3) compared to vitamin D(2), which may have been due to more rapid clearance of vitamin D(2) in addition to other mechanisms. Meta-analysis of 16 trials of vitamin D(3) was consistent with a dose-response effect on serum 25(OH)D when comparing daily doses of /= 400 IU. An exploratory analysis of the heterogeneity demonstrated a significant positive association comparable to an increase of 1 - 2 nmol/L in serum 25(OH)D for every 100 additional units of vitamin D although heterogeneity remained after adjusting for dose. Vitamin D(3) in combination with calcium results in small increases in BMD compared to placebo in older adults although quantitative synthesis was limited due to variable treatment durations and BMD sites. The evidence for fracture reduction with vitamin D supplementation was inconsistent across 15 trials. The combined results of trials using vitamin D(3) (700 - 800 IU daily) with calcium (500 - 1,200 mg) was consistent with a benefit on fractures although in a subgroup analysis by setting, benefit was primarily in elderly institutionalized women (fair evidence from two trials). There was inconsistent evidence across 14 RCTs of a benefit on fall risk. However, a subgroup analysis showed a benefit of vitamin D in postmenopausal women, and in trials that used vitamin D(3) plus calcium. In addition, there was a reduction in fall risk with vitamin D when six trials that adequately ascertained falls were combined. Limitations of the fall and fracture trials included poor compliance with vitamin D supplementation, incomplete assessment of vitamin D status and large losses to follow-up. We did not find any systematic reviews that addressed the question on the level of sunlight exposure that is sufficient to maintain serum 25(OH)D concentrations but minimizes risk of melanoma and non-melanoma skin cancer. There is little evidence from existing trials that vitamin D above current reference intakes is harmful. In most trials, reports of hypercalcemia and hypercalciuria were not associated with clinically relevant events. The Women's Health Initiative study did report a small increase in kidney stones in postmenopausal women aged 50 to 79 years whose daily vitamin D(3) intake was 400 IU (the reference intake for 50 to 70 years, and below the reference intake for > 70 years) combined with 1000 mg calcium. The increase in renal stones corresponded to 5.7 events per 10,000 person-years of exposure. The women in this trial had higher calcium intakes than is seen in most post-menopausal women. CONCLUSIONS: The results highlight the need for additional high quality studies in infants, children, premenopausal women, and diverse racial or ethnic groups. There was fair evidence from studies of an association between circulating 25(OH)D concentrations with some bone health outcomes (established rickets, PTH, falls, BMD). However, the evidence for an association was inconsistent for other outcomes (e.g., BMC in infants and fractures in adults). It was difficult to define specific thresholds of circulating 25(OH)D for optimal bone health due to the imprecision of different 25(OH)D assays. Standard reference preparations are needed so that serum 25(OH)D can be accurately and reliably measured, and validated. In most trials, the effects of vitamin D and calcium could not be separated. Vitamin D(3) (>700 IU/day) with calcium supplementation compared to placebo has a small beneficial effect on BMD, and reduces the risk of fractures and falls although benefit may be confined to specific subgroups. Vitamin D intake above current dietary reference intakes was not reported to be associated with an increased risk of adverse events. However, most trials of higher doses of vitamin D were not adequately designed to assess long-term harms.

Crino, R., Slade, T., & Andrews, G. (2005). The changing prevalence and severity of obsessive-compulsive disorder criteria from DSM-III to DSM-IV. The American Journal of Psychiatry, 162(5), 876-882. doi:10.1176/appi.ajp.162.5.876

OBJECTIVE: Relative to other mental disorders, the prevalence of obsessive-compulsive disorder (OCD) in the general population is not well established. Some epidemiological surveys have determined the prevalence of DSM-III OCD, but this is one of the first reports, to the authors' knowledge, of DSM-IV OCD's prevalence. METHOD: Data from the Australian National Survey of Mental Health and Well-Being, a nationally representative epidemiological survey of mental disorders, were analyzed. The prevalence and associated characteristics of DSM-IV OCD were identified, and then the data were rescored for DSM-III OCD. Cases defined by each system were compared. RESULTS: The 12-month prevalence of DSM-IV OCD was 0.6%, considerably less than found in surveys employing DSM-III diagnostic criteria. DSM-IV OCD showed significantly higher levels of comorbidity, disability, health service use, and treatment received. CONCLUSIONS: Changes in the reported prevalence and severity of OCD between DSM-III and DSM-IV cases are most likely a function of the differences in diagnostic criteria between DSM-III and DSM-IV.

Cummings, J. L., & Miller, B. L. (1987). Visual hallucinations. Clinical occurrence and use in differential diagnosis The Western Journal of Medicine, 146(1), 46-51.

Visual hallucinations occur in diverse clinical circumstances including ophthalmologic diseases, neurologic disorders, toxic and metabolic disorders and idiopathic psychiatric illnesses. Their content, duration and timing relate to their cause and provide useful differential diagnostic information. Hallucinations must be distinguished from delusions and confabulation. A systematic approach to differentiating among hallucinatory syndromes may improve diagnostic accuracy.

Dawson, K. A. (2001). A case study of space-time distortion during a total lunar eclipse following street use of LSD. Journal of Psychoactive Drugs, 33(3), 301-305.

Although psychedelics can induce "cosmic" consciousness through severe distortions of time and space perceptions, little attention has been given to examination of this psychopharmacological property. With the hope of providing an impetus to further research in this area, a case of cosmic perception under the influence of LSD is reported which included the apparent movement of consciousness to the lunar surface combined with the experience of remote viewing of the Milky Way galaxy. While the possibility of veridical remote viewing is unlikely, it is speculated that the neurocognitive action of LSD can sensitize the user to focused bright light, associated memories, and creative elaborations during actual eclipse events. Experimenters are urged to adopt precautions to avoid potentially detrimental effects of pharmacologically manipulating the space-time continuum.

de Rios, M. D., Grob, C. S., & Baker, J. R. (2002). Hallucinogens and redemption. Journal of Psychoactive Drugs, 34(3), 239-248.

This article examines drug substitution with regard to hallucinogens (ayahuasca, ibogaine, peyote and LSD) set within the concept of redemption. The model examines both religious and secular approaches to the contemporary use of hallucinogens in drug substitution, both by scientists and in religious settings worldwide. The redemptive model posits that the proper use of one psychoactive substance within a spiritual or clinical context helps to free an individual from the adverse effects of their addiction to another substance and thus restores them as functioning members of their community or group. Data is drawn from the U.S., Brazil, Peru, and West Africa. Two principle mechanisms for this are proposed: the psychological mechanism of suggestibility is examined in terms of the individual reaching abstinence goals from addictive substances such as alcohol and opiates. Neurophysiological and neurochemical mechanisms to understand the efficacy of such substitution are highlighted from ongoing research on hallucinogens. Research by two of the authors with the Unaio do Vegetal (UDV) Church in Brazil is examined in terms of the model.

Dependence on LSD and other hallucinogenic drugs. (1967). JAMA : The Journal of the American Medical Association, 202(1), 141-144.

Does risperidone exacerbate hallucinogen-persisting perception disorder? (1998). Brown University Psychopharmacology Update, 9(2), 8.

Reports on the findings of a case study published in a 1997 issue of the `Journal of Clinical Psychopharmacology,' about the effectiveness of risperidone in exacerbating hallucinogen-persisting perception disorder. Patient's medical background; Drug abuse history; Contraindications of risperidone.

Dröge, W. (2002). Aging-related changes in the thiol/disulfide redox state: implications for the use of thiol antioxidants. Experimental Gerontology, 37(12), 1333-1345. doi:DOI: 10.1016/S0531-5565(02)00175-4

Dumortier, G., Welniarz, B., Sauvebois, C., Medjdoub, H., Friche, H., Siad, N., & Degrassat, K. (2005). Prescription of psychotropic drugs in paediatry: approved indications and therapeutic perspectives. [Prescription des psychotropes en pedopsychiatrie: limites des indications officielles et perspectives therapeutiques] L'Encephale, 31(4 Pt 1), 477-489.

In France, psychotropic drugs may be classified in four categories according to their official data. The first category corresponds to psychotropic drugs with an approved indication available in paediatry. Theyare old agents (e.g. haloperidol, amitriptyline, benzodiazepines...) with the exception of methylphenidate (hyperactivity). The second one corresponds to pharmacological agents approved for some indications obtained with adults but not for a1l (i.e. restricted indication: e.g. sertraline approved in paediatry only for OCD but not for depression, risperidone approved only for the treatment of disruptive behaviors in children with subaverage IQs). For the third category, the psychotropic agent is either contraindicated or unadvised under the age of 15 or 18 years, by lack of data (e.g. most of SSRI or atypical antipsychotic drugs). For the last category, official data available in brief summaries offer no information on paediatric use and consequently their administration does not appear possible. Up to now, no approved use has been delivered to injection route (IM or IV) in France, except for an IM formulation of zuclopenthixol. Prescribing psychotropic drug has to respect good practices including close psychological and somatic monitoring that associates the young patient and his relative (psycho-education program). Particular key-points should be taken into consideration (i.e. pharmacokinetic and physiological specificities, risk of false passage under the age of 6 years with capsules or tablets, presence of alcohol in some oral solution or bitter aroma...). Beside these official data, many studies have been published but must be carefully interpreted according to their level of pertinence. Meta-analysis gather all randomised controlled trials published or not, analyse their specific pertinence and thus provide clinically relevant elements. Randomised controlled trials present clinical interest but key-points in study design must be checked (e.g. number of patients, inclusion and exclusion criteria, length of the study and clinical relevance of clinical scales...). Other studies like open trials or clinical cases do not offersufficient guarantees. Some randomised controlled trials of clinical relevance have been carried out in this population with new pharmacological classes (eg SSRI, atypical antipsychotic drugs) and may lead to extended indications in children and adolescents. According to bibliographic and official data, the main criteria in the prescribing choice may take into consideration the following sis stressing a poor benefit/risk ratio. SSRI may offer better prospects but their use has not been approved in this indication, until now. In OCD, sertraline shows great interest to enhance clinical response and represents the molecule of reference. No drug has been approved for mood disorders in children or adolescent, in France, contrary to USA where lithium can be administered over the age of 12 years. In addition, antiepileptic drugs like carbamazepine or divalproate have conducted to clinical improvement in some studies. Benzodiazepines, hydroxyzine and meprobamate use should be strictly restricted in case of anxiety symptoms but are the only agents approved in this indication despise promising results obtained with SSRI. Transitory insomnia may take advantage of alimemazine prescription (approved use over the age of 36 months). Some typical neuroleptics are indicated in tics or in behaviour disorders associated to autism or related syndromes but present clinical limitations and poor tolerability. Promising clinical trials (randomised or not) have been conducted with new atypical antipsychotic drugs like risperidone. In conclusion, present data available for paediatric use of psychotropic agents emphasizes that safety and effectiveness are not always well established in particular for the treatment of chronic disorders (long term tolerability assessment). Moreover, studies should be carried out to specify factors promoting adherence and quality of life for this young population in order to optimise clinical benefit of drug prescription.

Duncan, J. W. (1974). Persisting psychotic states in adolescent drug users. Child Psychiatry and Human Development, 5(1), 51-62.

Dundar, Y., Boland, A., Strobl, J., Dodd, S., Haycox, A., Bagust, A., Bogg, J., Dickson, R., & Walley, T. (2004). Newer hypnotic drugs for the short-term management of insomnia: a systematic review and economic evaluation. Health Technology Assessment (Winchester, England), 8(24), iii-x, 1-125.

OBJECTIVES: To assess the clinical and cost-effectiveness of zaleplon, zolpidem and zopiclone (Z-drugs) compared with benzodiazepines. DATA SOURCES: Electronic databases, reference lists of retrieved articles and pharmaceutical company submissions. REVIEW METHODS: Randomised controlled trials (RCTs) that compared either benzodiazepines to the Z-drugs or any two of the non-benzodiazepine drugs in patients with insomnia were included in the review. Data on the following outcome measures were considered: sleep onset latency, total sleep duration, number of awakenings, quality of sleep, adverse effects and rebound insomnia. A search was also undertaken for any study designs that evaluated issues related to adverse events (e.g. dependency and withdrawal symptoms). Full economic evaluations that compared two or more options and considered both costs and consequences including cost-effectiveness, cost-utility analysis or cost-benefit analysis undertaken in the context of high-quality RCTs were considered for inclusion in the review. RESULTS: Twenty-four studies, involving a total study population of 3909 patients, met the inclusion criteria. These included 17 studies comparing a Z-drug with a benzodiazepine and seven comparing a Z-drug with another Z-drug. The diversity of possible comparisons and the range of outcome measures in the review may be confusing. Outcomes were rarely standardised and, even when reported, differed in interpretation. In addition, variations in assessment and variety in the level of information provided make study comparisons difficult. As a result, meta-analysis has been possible on only a small number of outcomes. However, some broad conclusions might be reached based on the limited data provided. The existing published economic literature in this area is very limited. No relevant economic evaluations were identified for inclusion in the review. The industry submissions did not include detailed evidence of cost-effectiveness. Given the lack of robust clinical evidence, no economic model describing the costs and benefits of the newer hypnotic drugs for insomnia was developed. The systematic review provided in this report suggests that an agnostic approach to cost-effectiveness is required at this stage. In the short-term, no systematic evidence is available concerning significant outcome variations between either the different classes of drugs or between individual drugs within each class. Within this short-term horizon, the one element that does vary significantly is the acquisition cost of the individual drugs. CONCLUSIONS: The short-acting drugs seem equally effective and safe with minor differences that may lead a prescriber to favour one over another in different patients. There is no evidence that one is more cost-effective than any other. Analysis of the additional costs to the NHS, depending on the rate of change from benzodiazepine prescriptions to Z-drug prescriptions, at current levels of hypnotic prescribing, range from GBP2 million to GBP17 million per year. There are clear research needs in this area; in particular, none of the existing trials adequately compare these medications. It is suggested that further consideration should be given to a formal trial to allow head-to-head comparison of some of the key drugs in a double-blind RCT lasting at least 2 weeks, and of sufficient size to draw reasonable conclusions. We would also recommend that any such trial should include a placebo arm. It should also collect good-quality data around sleep outcomes and in particular quality of life and daytime drowsiness. We do not believe that any formal study of risk of dependency is feasible at present. Finally, the management of long-term insomnia is suggested for further investigation: considering the frequency of this symptom and its recurring course, the short-term trial of medication and lack of long-term follow-up undermine attempts to develop evidence-based guidelines for the use of hypnotics in this condition, or indeed for its whole management.

Durham, R. C., Chambers, J. A., Power, K. G., Sharp, D. M., Macdonald, R. R., Major, K. A., Dow, M. G., & Gumley, A. I. (2005). Long-term outcome of cognitive behaviour therapy clinical trials in central Scotland. Health Technology Assessment (Winchester, England), 9(42), 1-174.

OBJECTIVES: To establish the long-term outcome of participants in clinical trials of cognitive behaviour therapy (CBT) for anxiety disorders and psychosis, examining the effectiveness and cost-effectiveness associated with receiving CBT in comparison with alternative treatments. DESIGN: An attempt was made to contact and interview all of the participants in eight randomised, controlled, clinical trials of CBT for anxiety disorders and two randomised, controlled, clinical trials of CBT for schizophrenia conducted between 1985 and 2001. Case note reviews of healthcare resources used in the 2 years prior to entering the trials and the 2 years prior to follow-up interview were undertaken. SETTING: Mixed rural and urban settings in five localities in central Scotland. Anxiety disorder trials were conducted mainly in primary care and included three with generalised anxiety disorder, four with panic disorder and one with post-traumatic stress disorder (PTSD). The psychosis studies (one on relapse prevention and one with chronic disorder) were conducted in secondary care. PARTICIPANTS: Of the 1071 entrants to the 10 studies, 489 agreed to participate (46% of original entrants, 52% of those available to contact). INTERVENTIONS: Follow-up interviews took place between 1999 and 2003, 2-14 years after the original treatment. Interviews for Trials 1-8 were conducted by a research psychologist blind to original treatment condition. Interviews for Trials 9 and 10 were conducted by community psychiatric nurses also blind to treatment condition. Case note reviews were completed following the interview. MAIN OUTCOME MEASURES: For Trials 1-8 the main interview-based outcome measures were: Anxiety Disorders Interview Schedule-DSM-IV for diagnosis and co-morbidity, Clinical Global Severity (0-8) and the Hamilton Anxiety Rating Scale. The main patient-rated measures were: Brief Symptom Inventory, SF-36 II, Clinical Global Improvement (1-7), and the Positive and Negative Affect Scale. For Trials 9 and 10 the primary outcome measure was the interview-based Positive and Negative Syndrome Scale (PANSS). RESULTS: For the anxiety disorder studies (Trials 1-8), over half of the participants (52%) had at least one diagnosis at long-term follow-up, with significant levels of co-morbidity and health status scores comparable to the lowest 10% of the general population. Only 36% reported receiving no interim treatment for anxiety over the follow-up period with 19% receiving almost constant treatment. Patients with PTSD did particularly poorly. There was a 40% real increase in healthcare costs over the two time periods, mainly due to an increase in prescribing. A close relationship was found between poor mental and physical health for those with a chronic anxiety disorder. Treatment with CBT was associated with a better long-term outcome than non-CBT in terms of overall symptom severity but not with regard to diagnostic status. The positive effects of CBT found in the original trials were eroded over longer time periods. No evidence was found for an association between more intensive therapy and more enduring effects of CBT. Long-term outcome was found to be most strongly predicted by the complexity and severity of presenting problems at the time of referral, by completion of treatment irrespective of modality and by the amount of interim treatment during the follow-up period. The quality of the therapeutic alliance, measured in two of the studies, was not related to long-term outcome but was related to short-term outcome. The cost-effectiveness analysis showed no advantages of CBT over non-CBT. The cost of providing CBT in the original trials was only a very small proportion (6.4%) of the overall costs of healthcare for this population, which are high for both physical and mental health problems. In the psychosis studies (Trials 9 and 10), outcome was generally poor with only 10% achieving a 25% reduction in total PANSS scores from pretreatment to long-term follow-up, also cost-effectiveness analysis showed no advantages of CBT over non-CBT, although healthcare costs fell over the two time periods mainly owing to a reduction in inpatient costs. CONCLUSIONS: Psychological therapy services need to recognise that anxiety disorders tend to follow a chronic course and that good outcomes with CBT over the short term are no guarantee of good outcomes over the longer term. Clinicians who go beyond standard treatment protocols of about 10 sessions over a 6-month period are unlikely to bring about greater improvement. Poor outcomes over the long term are related to greater complexity and severity of presenting problems at the time of referral, failure to complete treatment irrespective of modality and the amount of interim treatment during the follow-up period. The relative gains of CBT are greater in anxiety disorders than in psychosis. Longitudinal research designs over extended periods of time (2-5 years), with large numbers of participants (500+), are required to investigate the relative importance of patient characteristics, therapeutic alliance and therapist expertise in determining the cost-effectiveness of CBT in the longer term.

Dyck, E. (2005). Flashback: psychiatric experimentation with LSD in historical perspective. Canadian Journal of Psychiatry.Revue Canadienne De Psychiatrie, 50(7), 381-388.

In the popular mind, d-lysergic acid diethylamide (LSD) research in psychiatry has long been associated with the CIA-funded experiments conducted by Ewen Cameron at the Allen Memorial Institute in Montreal, Quebec. Despite this reputation, a host of medical researchers in the post World War II era explored LSD for its potential therapeutic value. Some of the most widespread trials in the Western world occurred in Saskatchewan, under the direction of psychiatrists Humphry Osmond (in Weyburn) and Abram Hoffer (in Saskatoon). These medical researchers were first drawn to LSD because of its ability to produce a "model psychosis." Their experiments with the drug that Osmond was to famously describe as a "psychedelic" led them to hypothesize and promote the biochemical nature of schizophrenia. This brief paper examines the early trials in Saskatchewan, drawing on hospital records, interviews with former research subjects, and the private papers of Hoffer and Osmond. It demonstrates that, far from being fringe medical research, these LSD trials represented a fruitful, and indeed encouraging, branch of psychiatric research occurring alongside more famous and successful trials of the first generation of psychopharmacological agents, such as chlropromazine and imipramine. Ultimately, these LSD experiments failed for 2 reasons, one scientific and the other cultural. First, in the 1950s and early 1960s, the scientific parameters of clinical trials shifted to necessitate randomized controlled trials, which the Saskatchewan researchers had failed to construct. Second, as LSD became increasingly associated with student riots, antiwar demonstrations, and the counterculture, governments intervened to criminalize the drug, restricting and then terminating formal medical research into its potential therapeutic effects.

Dyer, C. (2002). NHS settles claim of patients treated with LSD. BMJ (Clinical Research Ed.), 324(7336), 501.

EFSA GMO Panel Working Group on Animal Feeding Trials. (2008). Safety and nutritional assessment of GM plants and derived food and feed: the role of animal feeding trials. Food and Chemical Toxicology : An International Journal Published for the British Industrial Biological Research Association, 46 Suppl 1, S2-70. doi:10.1016/j.fct.2008.02.008

In this report the various elements of the safety and nutritional assessment procedure for genetically modified (GM) plant derived food and feed are discussed, in particular the potential and limitations of animal feeding trials for the safety and nutritional testing of whole GM food and feed. The general principles for the risk assessment of GM plants and derived food and feed are followed, as described in the EFSA guidance document of the EFSA Scientific Panel on Genetically Modified Organisms. In Section 1 the mandate, scope and general principles for risk assessment of GM plant derived food and feed are discussed. Products under consideration are food and feed derived from GM plants, such as maize, soybeans, oilseed rape and cotton, modified through the introduction of one or more genes coding for agronomic input traits like herbicide tolerance and/or insect resistance. Furthermore GM plant derived food and feed, which have been obtained through extensive genetic modifications targeted at specific alterations of metabolic pathways leading to improved nutritional and/or health characteristics, such as rice containing beta-carotene, soybeans with enhanced oleic acid content, or tomato with increased concentration of flavonoids, are considered. The safety assessment of GM plants and derived food and feed follows a comparative approach, i.e. the food and feed are compared with their non-GM counterparts in order to identify intended and unintended (unexpected) differences which subsequently are assessed with respect to their potential impact on the environment, safety for humans and animals, and nutritional quality. Key elements of the assessment procedure are the molecular, compositional, phenotypic and agronomic analysis in order to identify similarities and differences between the GM plant and its near isogenic counterpart. The safety assessment is focussed on (i) the presence and characteristics of newly expressed proteins and other new constituents and possible changes in the level of natural constituents beyond normal variation, and on the characteristics of the GM food and feed, and (ii) the possible occurrence of unintended (unexpected) effects in GM plants due to genetic modification. In order to identify these effects a comparative phenotypic and molecular analysis of the GM plant and its near isogenic counterpart is carried out, in parallel with a targeted analysis of single specific compounds, which represent important metabolic pathways in the plant like macro and micro nutrients, known anti-nutrients and toxins. Significant differences may be indicative of the occurrence of unintended effects, which require further investigation. Section 2 provides an overview of studies performed for the safety and nutritional assessment of whole food and feed. Extensive experience has been built up in recent decades from the safety and nutritional testing in animals of irradiated foods, novel foods and fruit and vegetables. These approaches are also relevant for the safety and nutritional testing of whole GM food and feed. Many feeding trials have been reported in which GM foods like maize, potatoes, rice, soybeans and tomatoes have been fed to rats or mice for prolonged periods, and parameters such as body weight, feed consumption, blood chemistry, organ weights, histopathology etc have been measured. The food and feed under investigation were derived from GM plants with improved agronomic characteristics like herbicide tolerance and/or insect resistance. The majority of these experiments did not indicate clinical effects or histopathological abnormalities in organs or tissues of exposed animals. In some cases adverse effects were noted, which were difficult to interpret due to shortcomings in the studies. Many studies have also been carried out with feed derived from GM plants with agronomic input traits in target animal species to assess the nutritive value of the feed and their performance potential. Studies in sheep, pigs, broilers, lactating dairy cows, and fish, comparing the in vivo bioavailability of nutrients from a range of GM plants with their near isogenic counterpart and commercial varieties, showed that they were comparable with those for near isogenic non-GM lines and commercial varieties. In Section 3 toxicological in vivo, in silico, and in vitro test methods are discussed which may be applied for the safety and nutritional assessment of specific compounds present in food and feed or of whole food and feed derived from GM plants. Moreover the purpose, potential and limitations of the 90-day rodent feeding trial for the safety and nutritional testing of whole food and feed have been examined. Methods for single and repeated dose toxicity testing, reproductive and developmental toxicity testing and immunotoxicity testing, as described in OECD guideline tests for single well-defined chemicals are discussed and considered to be adequate for the safety testing of single substances including new products in GM food and feed. Various in silico and in vitro methods may contribute to the safety assessment of GM plant derived food and feed and components thereof, like (i) in silico searches for sequence homology and/or structural similarity of novel proteins or their degradation products to known toxic or allergenic proteins, (ii) simulated gastric and intestinal fluids in order to study the digestive stability of newly expressed proteins and in vitro systems for analysis of the stability of the novel protein under heat or other processing conditions, and (iii) in vitro genotoxicity test methods that screen for point mutations, chromosomal aberrations and DNA damage/repair. The current performance of the safety assessment of whole foods is mainly based on the protocols for low-molecular-weight chemicals such as pharmaceuticals, industrial chemicals, pesticides, food additives and contaminants. However without adaptation, these protocols have limitations for testing of whole food and feed. This primarily results from the fact that defined single substances can be dosed to laboratory animals at very large multiples of the expected human exposure, thus giving a large margin of safety. In contrast foodstuffs are bulky, lead to satiation and can only be included in the diet at much lower multiples of expected human intakes. When testing whole foods, the possible highest concentration of the GM food and feed in the laboratory animal diet may be limited because of nutritional imbalance of the diet, or by the presence of compounds with a known toxicological profile. The aim of the 90-days rodent feeding study with the whole GM food and feed is to assess potential unintended effects of toxicological and/or nutritional relevance and to establish whether the GM food and feed is as safe and nutritious as its traditional comparator rather than determining qualitative and quantitative intrinsic toxicity of defined food constituents. The design of the study should be adapted from the OECD 90-day rodent toxicity study. The precise study design has to take into account the nature of the food and feed and the characteristics of the new trait(s) and their intended role in the GM food and feed. A 90-day animal feeding trial has a large capacity (sensitivity and specificity) to detect potential toxicological effects of single well defined compounds. This can be concluded from data reported on the toxicology of a wide range of industrial chemicals, pharmaceuticals, food substances, environmental, and agricultural chemicals. It is possible to model the sensitivity of the rat subchronic feeding study for the detection of hypothetically increased amount of compounds such as anti-nutrients, toxicants or secondary metabolites. With respect to the detection of potential unintended effects in whole GM food and feed, it is unlikely that substances present in small amounts and with a low toxic potential will result in any observable (unintended) effects in a 90-day rodent feeding study, as they would be below the no-observed-effect-level and thus of unlikely impact to human health at normal intake levels. Laboratory animal feeding studies of 90-days duration appear to be sufficient to pick up adverse effects of diverse compounds that would also give adverse effects after chronic exposure. This conclusion is based on literature data from studies investigating whether toxicological effects are adequately identified in 3-month subchronic studies in rodents, by comparing findings at 3 and 24 months for a range of different chemicals. The 90-day rodent feeding study is not designed to detect effects on reproduction or development other than effects on adult reproductive organ weights and histopathology. Analyses of available data indicate that, for a wide range of substances, reproductive and developmental effects are not potentially more sensitive endpoints than those examined in subchronic toxicity tests. Should there be structural alerts for reproductive/developmental effects or other indications from data available on a GM food and feed, then these tests should be considered. By relating the estimated daily intake, or theoretical maximum daily intake per capita for a given whole food (or the sum of its individual commercial constituents) to that consumed on average per rat per day in the subchronic 90-day feeding study, it is possible to establish the margin of exposure (safety margin) for consumers. Results obtained from testing GM food and feed in rodents indicate that large (at least 100-fold) 'safety' margins exist between animal exposure levels without observed adverse effects and estimated human daily intake. Results of feeding studies with feed derived from GM plants with improved agronomic properties, carried out in a wide range of livestock species, are discussed. The studies did not show any biologically relevant differences in the parameters tested between control and test animals. (ABSTRACT TRUNCATED)

Eisen, M., Kaur, S., Rehema, A., Kullisaar, T., Vihalemm, T., Zilmer, K., Kairane, C., & Zilmer, M. (2004). Allergic contact dermatitis is accompanied by severe abnormal changes in antioxidativity of blood. Biomedecine & Pharmacotherapy, 58(4), 260-263. doi:DOI: 10.1016/j.biopha.2004.02.005

Ekbom, K., Waldenlind, E., & Tfelt-Hansen, P. (2009). Cluster headache and aura. Headache, 49(5), 786-787. doi:10.1111/j.1526-4610.2009.01417.x

Ellison, G. (1995). The N-methyl-D-aspartate antagonists phencyclidine, ketamine and dizocilpine as both behavioral and anatomical models of the dementias. Brain Research.Brain Research Reviews, 20(2), 250-267.

Phencyclidine (PCP) and ketamine can induce a model psychosis in drug addicts and exacerbate the symptoms of chronic schizophrenics. The model psychoses these drugs induce mimic a variety of schizophrenic symptoms, including flattened affect, dissociative thought disorder, depersonalization and catatonic states. These symptoms can persist for prolonged periods and chronic PCP and ketamine addicts have persisting memory deficits. Dizocilpine (MK-801) is a simpler drug than PCP or ketamine in its actions, but it shares with both the property of blocking in a non-competitive manner the N-methyl-D-aspartate (NMDA) ion-channel. Behavioral observations and drug-discrimination studies in animals indicate that PCP and dizocilpine are similar in their effects and they both have a neurotoxic effect on neurons in posterior cingulate cortex. Recent studies have indicated that both of these drugs, when given continuously for several days, further induce neuronal degeneration in other limbic structures. These include brain regions of rats related to olfaction, associated limbic structures such as piriform cortex and posterior regions of entorhinal cortex and in it's projections, through the perforant pathway, to dentate gyrus and other cells in ventral hippocampus. These degenerative consequences may be excitatory neurotoxic effects, for these compounds also induce an elevation in glucose metabolism maximal in just those structures where degeneration is observed and the degeneration involves entire cells, with all of their processes. It has been suggested these non-competitive NMDA antagonists induce an increase in firing rate in a limbic circuit which includes the perforant pathway. At least some competitive NMDA antagonists induce the same pattern of degeneration and altered glucose utilization. There is anatomical and functional evidence that alterations in these same limbic structures are present in the dementia syndrome manifested by some schizophrenics and most Alzheimer's patients. This suggests that these non-competitive NMDA antagonists may provide a more complete model of psychoses and memory disturbances than previously recognized, in that they can mimic both persisting symptomatology and neuroanatomical abnormalities. While the neurochemical underpinnings of this effect remain elusive, it appears to be both age and sex dependent. Further studies of the mechanisms by which NMDA antagonists induce increased glucose utilization and neurotoxicity in these limbic structures may clarify these alterations in this simplified Papez-like circuit.

Ellison, G. D., & Keys, A. S. (1996). Persisting changes in brain glucose uptake following neurotoxic doses of phencyclidine which mirror the acute effects of the drug. Psychopharmacology, 126(3), 271-274.

Phencyclidine (PCP) can induce a model psychosis which has a number of similarities to dementias and schizophrenia. In some cases the psychosis persists for prolonged periods after drug discontinuation. N-Methyl-D-aspartate (NMDA) antagonists such as PCP induce increases in glucose metabolism in a variety of brain structures but most notably in limbic regions such as retrosplenial, piriform, and entorhinal cortex, hippocampus, and olfactory tubercle. When given continuously for several days, these NMDA antagonists induced neural degeneration in these same critical limbic areas. In the present study regional 2-fluorodeoxyglucose (FDG) uptake was measured in rats at both 24 h and 10 days after neurotoxic, 5-day "binge" PCP administration. At 24 h after minipump removal there were persisting and large increases in glucose uptake in many brain regions, with maximal changes in the same limbic structures in which neurotoxicity has been observed. Surprisingly, many of these regions still showed elevated glucose metabolism after 10 days of recovery. These findings suggest an anatomical and neurochemical substrate for the persisting psychosis which can occur following PCP.

El-Mallakh, R. S., & Abraham, H. D. (2007). MDMA (Ecstasy). Annals of Clinical Psychiatry : Official Journal of the American Academy of Clinical Psychiatrists, 19(1), 45-52. doi:10.1080/10401230601163592

BACKGROUND: 3,4-Methylenedioxymethamphetamine (MDMA or Ecstasy) is a synthetic amphetamine analogue that is recreationally used to obtain a psychological effect of enhanced affiliative emotional response. Its use in Western countries appears to be increasing, particularly among young individuals. METHODS: Pertinent basic and clinical literature is critically reviewed. RESULTS: A significant body of literature suggests that the patterns of MDMA use differ from traditional drugs of abuse, with relatively uncommon dependence and escalation of dosage. Nonetheless, MDMA is also neurotoxic with significant deleterious effects on serotonergic neurons, memory, and mood. Despite this, there is a dearth of treatment strategies for both acute intoxication and consequences of longer term use. CONCLUSIONS: MDMA is an important drug of abuse that has a wide range of adverse consequences.

Espiard, M., Lecardeur, L., Abadie, P., Halbecq, I., & Dollfus, S. (2005). Hallucinogen persisting perception disorder after psilocybin consumption: a case study. European Psychiatry, 20(5-6), 458-460. doi:DOI: 10.1016/j.eurpsy.2005.04.008

Favazza, A. R., & Domino, E. F. (1969). Recurrent LSD experience (flashbacks) triggered by marihuana. University of Michigan Medical Center Journal, 35(4), 214-216.

Ferrari, A., Spaccapelo, L., Gallesi, D., & Sternieri, E. (2009). Focus on headache as an adverse reaction to drugs. The Journal of Headache and Pain, 10(4), 235-239. doi:10.1007/s10194-009-0127-1

There are a large number of drugs inducing headache as an adverse reaction. Nevertheless, headaches as adverse reactions to drugs have received limited attention. Non-serious adverse reactions, such as headache, are not quantified and described as accurately as serious, life threatening ones. However, non-serious reactions can also be extremely troublesome, above all when they are chronic: they can affect patients' quality of life and contribute to non-compliance. It is absolutely possible that the number of patients with headache as an adverse reaction, which is going to increase, considering the growing use of medications. Physicians should, therefore, be aware of this issue. Indeed, it is difficult to attribute the diagnosis of adverse drug reaction to a condition, headache, which is also a very common symptom in general population.

Fontaine, D., Lazorthes, Y., Mertens, P., Blond, S., Geraud, G., Fabre, N., Navez, M., Lucas, C., Dubois, F., Gonfrier, S., Paquis, P., & Lanteri-Minet, M. (2009). Safety and efficacy of deep brain stimulation in refractory cluster headache: a randomized placebo-controlled double-blind trial followed by a 1-year open extension. The Journal of Headache and Pain, doi:10.1007/s10194-009-0169-4

Chronic cluster headache (CCH) is a disabling primary headache, considering the severity and frequency of pain attacks. Deep brain stimulation (DBS) has been used to treat severe refractory CCH, but assessment of its efficacy has been limited to open studies. We performed a prospective crossover, double-blind, multicenter study assessing the efficacy and safety of unilateral hypothalamic DBS in 11 patients with severe refractory CCH. The randomized phase compared active and sham stimulation during 1-month periods, and was followed by a 1-year open phase. The severity of CCH was assessed by the weekly attacks frequency (primary outcome), pain intensity, sumatriptan injections, emotional impact (HAD) and quality of life (SF12). Tolerance was assessed by active surveillance of behavior, homeostatic and hormonal functions. During the randomized phase, no significant change in primary and secondary outcome measures was observed between active and sham stimulation. At the end of the open phase, 6/11 responded to the chronic stimulation (weekly frequency of attacks decrease >50%), including three pain-free patients. There were three serious adverse events, including subcutaneous infection, transient loss of consciousness and micturition syncopes. No significant change in hormonal functions or electrolytic balance was observed. Randomized phase findings of this study did not support the efficacy of DBS in refractory CCH, but open phase findings suggested long-term efficacy in more than 50% patients, confirming previous data, without high morbidity. Discrepancy between these findings justifies additional controlled studies (clinicaltrials.gov number NCT00662935).

Fotiou, D. F., Stergiou, V., Tsiptsios, D., Lithari, C., Nakou, M., & Karlovasitou, A. (2009). Cholinergic deficiency in Alzheimer's and Parkinson's disease: Evaluation with pupillometry. International Journal of Psychophysiology, 73(2), 143-149. doi:DOI: 10.1016/j.ijpsycho.2009.01.011

The aim of the study was to evaluate the cholinergic deficiency in Alzheimer's (AD) and Parkinson's disease (PD). For this purpose, pupil size changes and mobility were assessed using a fast-video pupillometer (263 frames/s). Twenty-three (23) patients with probable AD and twenty-two (22) patients with PD (eleven with cognitive impairment and eleven without) entered the study. A full record of the pupil's reaction to light was registered. From this data ten (10) parameters were measured and reported. Comparison of those parameters in both group of subjects followed. Patients with probable AD had abnormal pupillary function compared to healthy ageing. All the Pupil Light Reflex (PLR) variables significantly differed between the two groups (p < 0.005) except the Baseline Pupil Diameter after 2-min dark adaptation (D1) and the Minimum Pupil Diameter (D2). Maximum Constriction Acceleration (ACmax) was the best predictor in classifying a subject as normal or as an AD with a perfect classification ability (AUC = 1, p < 0.001). ACmax and Maximum Constriction Velocity (VCmax) were significantly lower in PD patients without and with coexisting cognitive impairment compared to normal subjects (p < 0.001). Patients with cognitive impairment had significantly lower levels of ACmax, VCmax and amplitude (AMP = D1–D2) than patients with no cognitive deficits. ACmax and secondarily VCmax were the best predictors in classifying a subject as normal or as a PD patient with or without cognitive impairment. Cognitive and memory impairment, which reflects a cholinergic deficit, may be a crucial pathogenetic factor for the decrease in the aforementioned pupillometric parameters. VCmax and ACmax can be considered as the most sensitive indicators of this cholinergic deficiency.

Frankel, F. H. (1994). The concept of flashbacks in historical perspective. The International Journal of Clinical and Experimental Hypnosis, 42(4), 321-336.

A computer search of the literature for papers indexed under "flashbacks" produced a list of 70 references, many found in publications on the topics of substance abuse and trauma. Several of these were letters or papers written in languages other than English. In all, the author reviewed 55 papers. Although most of these papers contained comments that addressed the subject matter to some extent as recurrences or reminiscences of past happenings, the variability in the use of the term leaves many unresolved questions regarding the veridicality of the imagery. Nothing in the presentations reviewed by the author clearly demonstrates the unidimensional nature of flashbacks nor any recognizable neurophysiological correlate. The content of a flashback appears to be at least as likely to be the product of imagination as it is of memory.

Frecska, E., & Luna, L. E. (2006). The adverse effects of hallucinogens from intramural perspective. Neuropsychopharmacologia Hungarica : A Magyar Pszichofarmakologiai Egyesulet Lapja = Official Journal of the Hungarian Association of Psychopharmacology, 8(4), 189-200.

Very recently, after a long-lasting, worldwide moratorium on research of hallucinogenic agents, a good number of advanced countries have been revising their position, and start to approve testing the physiological and therapeutic effects of hallucinogens in human subjects. The purpose of this article is to review safety information available in the literature on hallucinogen use, and sort out those data from the reported complications of their abuse. Because of prohibitory regulations of the last 35 years, there are difficulties in achieving this kind of evaluation. Our approach has to be broad, and at times retrospective, in contrast to the well-controlled, focused, prospective design of the premarketing trials of legal drugs. The article summarizes the analyses in anticipation of supportive regulatory changes for the use of hallucinogens in well controlled studies and strictly supervised clinical trials. Keywords: adverse effects, ayahuasca, N,N-dimethyltryptamine, hallucinogenic agents, ibogaine, lysergic acid diethylamide, N-methyl-3,4-methylenedioxyamphetamine, psilocybin, therapeutic use.

Frenzilli, G., Ferrucci, M., Giorgi, F. S., Blandini, F., Nigro, M., Ruggieri, S., Murri, L., Paparelli, A., & Fornai, F. (2007). DNA fragmentation and oxidative stress in the hippocampal formation: a bridge between 3,4-methylenedioxymethamphetamine (ecstasy) intake and long-lasting behavioral alterations. Behavioural Pharmacology, 18(5-6), 471-481. doi:10.1097/FBP.0b013e3282d518aa

Intake of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) in humans leads to marked behavioral alterations. In a recent paper, we demonstrated that chronic MDMA intake produces a latent hippocampal hyperexcitability that parallels a reduced threshold for limbic seizures and a slowing of electroencephalographic activity. These phenomena suggest an alteration in hippocampal function. So far, only a few studies have focused on the hippocampal formation as a potential target for the effects induced by MDMA. In this study we sought to evaluate whether the intrinsic cells of the hippocampus might be modified chronically by ecstasy intake. In particular, we examined whether administration of MDMA, at doses producing hippocampal hyperexcitability also produces rearrangements of DNA strands measured by the comet assay. We found that MDMA, at very low doses, comparable with those self-administered by humans, produces acute oxidative stress and DNA single and double-strand breaks, which persist together with long-lasting metabolic changes in the hippocampal formation. These persisting effects are accompanied by behavioral sensitization, reduced seizure threshold and long-lasting slowing of electroencephalographic activity, and hyperexcitability of the hippocampus, without affecting the basal ganglia. The present data indicate that the intake of very low doses of MDMA, comparable to those consumed by humans, produces selective hippocampal alterations which may underlie cognitive impairment and seizure susceptibility.

Fujiwara, M. (2001). Characteristics of abnormal behavior induced by delta 9-tetrahydrocannabinol in rats. Nippon Yakurigaku Zasshi.Folia Pharmacologica Japonica, 117(1), 35-41.

delta 9-Tetrahydrocannabinol (THC), one of the active compounds of marihuana, is known to induce drug dependence and tolerance, and its action is weaker than those of other abused drugs in humans and animals. Acute effects of THC, "high", "irritable" and "cognitive deficits" are more important than the drug dependence and tolerance. For this reason, we examined characteristics of abnormal behavior such as catalepsy-like immobilization, aggressive behavior including irritable aggression and muricide, and spatial cognition impairment induced by acute and chronic treatments of THC in rats. The catalepsy-like immobilization is related to a decrease in catecholaminergic and serotonergic neurons in the nucleus accumbens and amygdaloid nucleus and thus serves as a useful model for amotivational syndrome, one of cannabis psychoses. In aggressive behavior, muricide was determined by the housing condition. Muricide was induced if the rat was placed under an isolated housing condition within the period of the effect of single injection of THC. The behavioral change resembles exacerbation and flashback in humans. Spatial cognition is impaired by the interaction between cannabinoid (CB1) and 5-HT2 receptor in the dorsal raphe-hippocampal serotonergic neurons. Thus the abnormal behavior induced by THC can be a useful model for investigating mental function in humans and new drugs for the treatment of mental disorders.

Gaillard, M. C., & Borruat, F. X. (2003). Persisting visual hallucinations and illusions in previously drug-addicted patients. Klinische Monatsblatter Fur Augenheilkunde, 220(3), 176-178. doi:10.1055/s-2003-38173

BACKGROUND: Tetrahydrocannabinol (cannabis) and lysergic acid diethylamide (LSD) are psychomimetic agents that induce impairment of sensory perception. Illusions and hallucinations are mostly visual. Most frequently the visual phenomena occur in conjunction with drug abuse. PATIENTS AND METHODS: Three previously drug-addicted patients were examined for either persisting or spontaneously recurrent visual phenomena. Two patients complained of persisting visual illusions (vibrations, dyskinetopsia and impaired depth perception) during more than 12 months after an excessive use of cannabis. The third patient was a multiple drug abuser (LSD for 6 years) and complained of visual hallucinations and palinopsia following heavy ethanol intake, 20 years after stopping the use of any drug. RESULTS: Results from neuro-ophthalmic and neurological examinations were normal for the first two patients. The third patient presented abnormal visual fields with preserved visual acuity; electroencephalography was abnormal, suggesting an underlying toxic encephalopathy. CONCLUSIONS: Persistent visual illusions or hallucinations can occur during several months after an intake of cannabis. Flash-back phenomena are frequent amongst LSD abusers. They rarely occur at long times after the last intake (20 years in the present case); when they do so, precipitating factors are often present (ethanol, medication, anesthesia). Such phenomena reflect the cortical dysfunctions that can be induced by illegal substances.

Gaillard, R., Ouanas, A., Spadone, C., Llorca, P. M., Loo, H., & Bayle, F. J. (2006). Benzodiazepines and schizophrenia, a review of the literature. [benzodiazepines et schizophrenie, revue de la litterature] L'Encephale, 32(6 Pt 1), 1003-1010.

AIn this work, the authors have analysed the principal studies on the interest in the use of benzodiazepines in schizophrenia. The first double-controlled study concerning this question was conducted in 1961. The results of the first studies are criticisable due to the variability of the diagnostic and clinical assessment criteria, as well as to the divergences between the different conclusions. Through this review of literature, the authors wish to clarify the questions and hypothesis raised specify certain therapeutic strategies. MECHANISM OF GABA-ERGIC TREATMENTS: The analysis of the principle works on this question provides evidence on the use of benzodiazepines in schizophrenia. By fixing on their receptors, benzodiazepines facilitate GABA-ergic transmission. GABA is an inhibitor neurotransmitter. The GABA stimulation induced by benzodiazepines may be at the origin of a reduction of the pre-synaptic release of dopamine in the mesolimbic region. The GABA stimulation may also delay the post-synaptic adaptation of the dopaminergic neurons to neuroleptics. This phenomenon may enhance the activity of neuroleptics in resistant schizophrenia. Benzodiazepines would also have an effect on the mesoprefrontocortical regions where neuroleptics may be less efficient. It is interesting to note that this cerebral region is particularly sensitive to stress. This effect of benzodiazepines on the mesoprefrontocortical region might explain a preferentially beneficial effect in patients who have radiographic signs consistent with prefroncortical atrophy, although this observation remains preliminary. BENZODIAZEPINES IN MONOTHERAPY: In monotherapy their action on productive and deficient psychotic symptoms is greatly discussed and not very convincing. The main studies in the use of benzodiazepines alone ) are heterogeneous for their diagnosis criteria, their methodology and their results. The conclusions of the publications are not totally clear, and different points are to be criticized: heterogeneity of assessment criteria, heterogeneity and variability of methodology, use of non standardized scales, most of the studies are open studies, variability of benzodiazepines dose. BENZODIAZEPINES IN ASSOCIATION WITH NEUROLEPTICS: In few controlled studies, most authors have underlined ) the advantage of the association of benzodiazepines with neuroleptics. This association may act either on positive symptoms (hallucinations, delusions) or on negative symptoms. The latent period and the length of the effect of benzodiazepines in the treatment of psychotic patients remain unclear. According to certain studies, the therapeutic effect may appear in a short time, and then disappear within the fourth week. The association of benzodiazepines with neuroleptics is particularly helpful for patients with great anxiety, whether they have neuroleptic intolerance or not. There is no robust convergence about the type of benzodiazepines and their optimal dose in the treatment of schizophrenia. Their use may permit a reduction in the neuroleptic dose. They could increase the plasma concentration of neuroleptics and they might act on the mesoprefrontocortical regions where there are fewer dopaminergic auto receptors. BENZODIAZEPINES AND ANXIETY IN SCHIZOPHRENIA: States of anxiety, and in particular panic disorders that would participate in the exacerbation of psychotic symptoms, would benefit from the use of benzodiazepines. Anxiety can be considered as a major symptom of schizophrenia: insecure feelings and impressions of threatening events are frequent during schizophrenia. Interpretations or brutal hallucinations can lead to the feeling of imminent catastrophe or anxiety. Nevertheless, anxious phenomenons are under-estimated for many reasons: on the one hand, positive symptoms may hide anxiety, and on the other, the symptoms that are observed in patients treated with neuroleptics are often attributed to the neuroleptic side effects rather than linked to anxiety. Benzodiazepines and catatonia - Lorazepam has demonstrated its efficacy on catatonia. This effect seems to be specific of small doses of lorazepam (<5 mg/day). It should be compared to the effect of zolpidem in the same conditions. This prescription should be limited to acute catatonia, with no effect on chronic catatonia. Benzodiazepines and neuroleptic side effects - The use of benzodiazepines to treat some side effects of neuroleptics such as akathesia is reported by certain authors but remains little explained. They may have no effect or only small effects on tardive dyskinesia, but could reduce their incidence with the use of the smallest doses of neuroleptics in association with benzodiazepines. Safety of use - The safety of use of benzodiazepines in schizophrenia, particularly in association with neuroleptics is admitted, however recommended precautions with clozapine are to be noted. Benzodiazepine combined with clozapine clearly increases the frequency of cardiovascular and respiratory accidents. Some studies point out the risk of behavioural desinhibition and dysphoria. Their use should also be limited to patients with good compliancy, in order to avoid exacerbation of symptoms in the case of brutal interruption of the treatment. Dependency, which is an important issue in the use of benzodiazepines, seems much lesser in schizophrenia than in personality disorders and anxiety. Conversely, some studies point out the benefits of benzodiazepine use in schizophrenia, with their efficacy in the treatment and prevention of drug abuse. Finally, benzodiazepines contribute to the establishment of a good patient-doctor relationship, and may guarantee enhanced treatment compliancy.

Gao, K., Muzina, D., Gajwani, P., & Calabrese, J. R. (2006). Efficacy of typical and atypical antipsychotics for primary and comorbid anxiety symptoms or disorders: a review. The Journal of Clinical Psychiatry, 67(9), 1327-1340.

OBJECTIVE: The efficacy of antipsychotics in the treatment of primary or comorbid anxiety disorders or anxiety symptoms in major depressive disorder or bipolar disorder was reviewed. DATA SOURCES: English-language literature cited in MEDLINE from January 1, 1968, to December 31, 2005, was searched with the keywords anxiety disorder, anxiety symptoms, generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, posttraumatic stress disorder, social phobia, bipolar disorder, major depressive disorder, Hamilton Rating Scale for Anxiety, antipsychotics, typical antipsychotics, atypical antipsychotics, fluphenazine, haloperidol, perphenazine, pimozide, thiothixene, trifluoperazine, loxapine, molindone, chlorpromazine, mesoridazine, thioridazine, fluspirilene, penfluridol, pipothiazine, flupenthixol, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, aripiprazole, amisulpride, and clinical trial. Randomized, double-blind, placebo-controlled trials and open-label studies with a minimum of 20 subjects with a DSM-III/IV or ICD-10 diagnosis of anxiety disorder and studies without a DSM-III/IV or ICD-10 diagnosis of anxiety disorder but with Hamilton Rating Scale for Anxiety (HAM-A) scores as an outcome were prioritized. Studies on bipolar disorder or major depressive disorder with the analysis of changes in anxiety symptoms were reviewed. Early studies on neurosis/ anxiety or anxious depression without a HAM-A component were also reviewed. DATA SYNTHESIS: Six trials in primary generalized anxiety disorder (GAD), 15 in refractory obsessive-compulsive disorder (OCD), 8 in posttraumatic stress disorder (PTSD), 6 in neurosis with the HAM-A, 1 in social phobia, and 2 in anxiety symptoms in bipolar depression were identified. Low doses of trifluoperazine were superior to placebo in the treatment of GAD. Most of the less well-designed studies showed that other typical antipsychotics might be superior to placebo or as effective as benzodiazepines in the treatment of GAD and other anxiety conditions. In most studies, risperidone, olanzapine, and quetiapine augmentation to antidepressants was superior to placebo in treating refractory OCD and PTSD. Both olanzapine and quetiapine significantly reduced anxiety compared to placebo in studies of bipolar depression. CONCLUSION: Except for trifluoperazine, there is no large, well-designed study of antipsychotics in the treatment of primary or comorbid anxiety symptoms or disorders. The efficacy of these agents in various anxiety conditions needs to be further investigated with large, well-designed comparison studies.

Gensichen, J., Torge, M., Peitz, M., Wendt-Hermainski, H., Beyer, M., Rosemann, T., Krauth, C., Raspe, H., Aldenhoff, J. B., & Gerlach, F. M. (2005). Case management for the treatment of patients with major depression in general practices--rationale, design and conduct of a cluster randomized controlled trial--PRoMPT (PRimary care Monitoring for depressive Patient's Trial) [iSRCTN66386086]--study protocol. BMC Public Health, 5, 101. doi:10.1186/1471-2458-5-101

BACKGROUND: Depression is a disorder with high prevalence in primary health care and a significant burden of illness. The delivery of health care for depression, as well as other chronic illnesses, has been criticized for several reasons and new strategies to address the needs of these illnesses have been advocated. Case management is a patient-centered approach which has shown efficacy in the treatment of depression in highly organized Health Maintenance Organization (HMO) settings and which might also be effective in other, less structured settings. METHODS/DESIGN: PRoMPT (PRimary care Monitoring for depressive Patients Trial) is a cluster randomised controlled trial with General Practice (GP) as the unit of randomisation. The aim of the study is to evaluate a GP applied case-management for patients with major depressive disorder. 70 GPs were randomised either to intervention group or to control group with the control group delivering usual care. Each GP will include 10 patients suffering from major depressive disorder according to the DSM-IV criteria. The intervention group will receive treatment based on standardized guidelines and monthly telephone monitoring from a trained practice nurse. The nurse investigates the patient's status concerning the MDD criteria, his adherence to GPs prescriptions, possible side effects of medication, and treatment goal attainment. The control group receives usual care--including recommended guidelines. Main outcome measure is the cumulative score of the section depressive disorders (PHQ-9) from the German version of the Prime MD Patient Health Questionnaire (PHQ-D). Secondary outcome measures are the Beck-Depression-Inventory, self-reported adherence (adapted from Moriskey) and the SF-36. In addition, data are collected about patients' satisfaction (EUROPEP-tool), medication, health care utilization, comorbidity, suicide attempts and days out of work. The study comprises three assessment times: baseline (T0) , follow-up after 6 months (T1) and follow-up after 12 months (T2). DISCUSSION: Depression is now recognized as a disorder with a high prevalence in primary care but with insufficient treatment response. Case management seems to be a promising intervention which has the potential to bridge the gap of the usually time-limited and fragmented provision of care. Case management has been proven to be effective in several studies but its application in the private general medical practice setting remains unclear.

Gilman, S. E., & Abraham, H. D. (2001). A longitudinal study of the order of onset of alcohol dependence and major depression. Drug and Alcohol Dependence, 63(3), 277-286.

Alcohol dependence and major depression commonly occur together; however, few studies have assessed prospectively the magnitude of the risk that one disorder imparts on the subsequent occurrence of the other. We used data from the first two waves of the Epidemiologic Catchment Area community survey (n=14480) to estimate the odds of either major depression or alcohol dependence being followed by the other disorder after 1 year of follow-up. The odds of developing major depression associated with low, medium, and high levels of alcoholic symptoms at baseline were 1.66, 3.98, and 4.32 for females (P<0.001), and 1.19, 2.49, and 2.12 for males (P=0.026). Conversely, odds ratios indicating the 1-year follow-up risk of incident alcohol dependence within low, medium, and high categories of baseline depressive symptomatology were 2.75, 3.52, and 7.88 for females (P<0.001) and 1.50, 1.41, and 1.05 for males (P=0.091). Individuals with alcohol dependence appeared more likely to meet lifetime diagnostic criteria for both disorders after 1 year than individuals with depression. These results suggest that both alcohol dependence and major depression pose a significant risk for the development of the other disorder at 1 year.

Giorgi, F. S., Lazzeri, G., Natale, G., Iudice, A., Ruggieri, S., Paparelli, A., Murri, L., & Fornai, F. (2006). MDMA and seizures: a dangerous liaison? Annals of the New York Academy of Sciences, 1074, 357-364. doi:10.1196/annals.1369.035

In the past decades, there was a massive increase in the abuse of methylenedioxymethamphetamine (MDMA) in the Western countries. Seizure onset after MDMA is considered to be related mainly to its acute systemic effects (e.g., hyponatremia and hyperthermia). However, additional mechanisms might concur to it as well. Experiments aimed at disclosing the basis for such an acute effect have the advantage of profiting of controlled conditions and the "pure" compounds, as opposed to the limits of clinical data which are biased by several confounding factors. Amphetamines exert profound effect on different monoaminergic systems, which might participate to lowering of seizure threshold. Chronic effects of MDMA abuse on seizure threshold have not been explored in detail so far. Recent data showed that in mice receiving small, repeated doses of MDMA, a persisting pro-convulsant effect toward limbic seizures and metabolic hyperexcitability can be observed. In the present article, we reviewed these studies and we report our preliminary experimental data documenting the lack of mossy fiber sprouting at short time intervals following MDMA, when seizure susceptibility is already present.

Giuliani, D., Ferrari, F., & Ottani, A. (2000). The cannabinoid agonist HU 210 modifies rat behavioural responses to novelty and stress. Pharmacological Research : The Official Journal of the Italian Pharmacological Society, 41(1), 47-53. doi:10.1006/phrs.1999.0560

Experiments were performed on groups of rats after acute and sub-chronic treatment (once daily for 9 days) with the cannabinoid agonist HU 210 (25-100 microg kg(-1), i.p.) as well as 24 h and 7 days after the last drug injection. The animals underwent three behavioural tests in novel environments. In the observation cages (Test 1), rat locomotor activity was found to be dose-dependently reduced after acute and sub-chronic treatment at all doses and virtually unchanged during abstinence; grooming was potently inhibited by acute treatment but potentiated by the sub-chronic one at doses of 50 and 100 microg kg(-1), the effect of the higher dose persisting after 24 h and 7 days abstinence. Vocalization in animals in response to a tactile stimulus was highest after HU 210 at 100 microg kg(-1) in all experimental modes except after 7 days abstinence. In the X-maze (Test 2), sub-chronic HU 210 dose- dependently enhanced rat natural aversion for open arms, and this behaviour persisted during abstinence after the highest dose. Grooming in the X-maze was completely absent in rats acutely injected with HU 210 but potentiated in those sub-chronically treated or abstinent. In the swimming test (Test 3) rats sub-chronically treated at 50 and 100 pg kg(-1) displayed relevant wall-hugging and the same occurred 24 h after last injection. On the whole, our results are indicative of an anxiogenic-like effect of sub-chronic HU 210 at high doses and reflect the persistence of enhanced emotional response to novel environments when the treatment is discontinued.

Glauser, T., Ben-Menachem, E., Bourgeois, B., Cnaan, A., Chadwick, D., Guerreiro, C., Kalviainen, R., Mattson, R., Perucca, E., & Tomson, T. (2006). ILAE treatment guidelines: evidence-based analysis of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia, 47(7), 1094-1120. doi:10.1111/j.1528-1167.2006.00585.x

PURPOSE: To assess which antiepileptic medications (AEDs) have the best evidence for long-term efficacy or effectiveness as initial monotherapy for patients with newly diagnosed or untreated epilepsy. METHODS: A 10-member subcommission of the Commission on Therapeutic Strategies of The International League Against Epilepsy (ILAE), including adult and pediatric epileptologists, clinical pharmacologists, clinical trialists, and a statistician evaluated available evidence found through a structured literature review including MEDLINE, Current Contents and the Cochrane Library for all applicable articles from 1940 until July 2005. Articles dealing with different seizure types (for different age groups) and two epilepsy syndromes were assessed for quality of evidence (four classes) based on predefined criteria. Criteria for class I classification were a double-blind randomized controlled trial (RCT) design, >or=48-week treatment duration without forced exit criteria, information on >or=24-week seizure freedom data (efficacy) or >or=48-week retention data (effectiveness), demonstration of superiority or 80% power to detect a <or=20% relative difference in efficacy/effectiveness versus an adequate comparator, and appropriate statistical analysis. Class II studies met all class I criteria except for having either treatment duration of 24 to 47 weeks or, for noninferiority analysis, a power to only exclude a 21-30% relative difference. Class III studies included other randomized double-blind and open-label trials, and class IV included other forms of evidence (e.g., expert opinion, case reports). Quality of clinical trial evidence was used to determine the strength of the level of recommendation. RESULTS: A total of 50 RCTs and seven meta-analyses contributed to the analysis. Only four RCTs had class I evidence, whereas two had class II evidence; the remainder were evaluated as class III evidence. Three seizure types had AEDs with level A or level B efficacy and effectiveness evidence as initial monotherapy: adults with partial-onset seizures (level A, carbamazepine and phenytoin; level B, valproic acid), children with partial-onset seizures (level A, oxcarbazepine; level B, None), and elderly adults with partial-onset seizures (level A, gabapentin and lamotrigine; level B, None). One adult seizure type [adults with generalized-onset tonic-clonic (GTC) seizures], two pediatric seizure types (GTC seizures and absence seizures), and two epilepsy syndromes (benign epilepsy with centrotemporal spikes and juvenile myoclonic epilepsy) had no AEDs with level A or level B efficacy and effectiveness evidence as initial monotherapy. CONCLUSIONS: This evidence-based guideline focused on AED efficacy or effectiveness as initial monotherapy for patients with newly diagnosed or untreated epilepsy. The absence of rigorous comprehensive adverse effects data makes it impossible to develop an evidence-based guideline aimed at identifying the overall optimal recommended initial-monotherapy AED. There is an especially alarming lack of well-designed, properly conducted RCTs for patients with generalized seizures/epilepsies and for children in general. The majority of relevant existing RCTs have significant methodologic problems that limit their applicability to this guideline's clinically relevant main question. Multicenter, multinational efforts are needed to design, conduct and analyze future clinically relevant RCTs that can answer the many outstanding questions identified in this guideline. The ultimate choice of an AED for any individual patient with newly diagnosed or untreated epilepsy should include consideration of the strength of the efficacy and effectiveness evidence for each AED along with other variables such as the AED safety and tolerability profile, pharmacokinetic properties, formulations, and expense. When selecting a patient's AED, physicians and patients should consider all relevant variables and not just efficacy and effectiveness.

Glick, S. D., Rossman, K., Wang, S., Dong, N., & Keller, R. W.,Jr. (1993). Local effects of ibogaine on extracellular levels of dopamine and its metabolites in nucleus accumbens and striatum: interactions with D-amphetamine. Brain Research, 628(1-2), 201-208.

Systemic administration of ibogaine (40 mg/kg, i.p.) has been reported to induce both acute (1-3 h) and persistent (19-20 h) changes in extracellular levels of dopamine and its metabolites in the nucleus accumbens and striatum. In the present study, local administration of ibogaine to the striatum and nucleus accumbens produced effects that mimicked both the acute and persistent effects of systemic administration: perfusion with high concentrations (200 and 400 microM) of ibogaine mimicked the acute effects (decreased extracellular dopamine levels and increased extracellular metabolite levels) whereas perfusion with a low concentration (10 microM) of ibogaine mimicked the persistent effects (decreased extracellular levels of DOPAC). These results indicate that ibogaine acts directly in brain regions containing dopaminergic nerve terminals and that long-lasting effects of systemically administered ibogaine might be mediated by persisting low levels of ibogaine. Locally administered ibogaine (10 microM) was also found to enhance the effects of systemically administered D-amphetamine (1.25 mg/kg, i.p.) on extracellular dopamine levels, and conversely, systemically administered ibogaine (40 mg/kg, i.p.; 19 h pretreatment) enhanced the effects of locally administered D-amphetamine (1-10 microM). These results indicate that, in addition to a metabolic mechanism implicated previously, a pharmacodynamic mechanism contributes to the interaction between ibogaine and D-amphetamine. The relevance of such mechanisms to claims regarding ibogaine's anti-addictive properties is unclear.

Goadsby, P. J. (2009). Lacrimation, conjunctival injection, nasal symptoms... cluster headache, migraine and cranial autonomic symptoms in primary headache disorders -- what's new? Journal of Neurology, Neurosurgery, and Psychiatry, 80(10), 1057-1058. doi:10.1136/jnnp.2008.162867

Goodwin, G. M., Anderson, I., Arango, C., Bowden, C. L., Henry, C., Mitchell, P. B., Nolen, W. A., Vieta, E., & Wittchen, H. U. (2008). ECNP consensus meeting. Bipolar depression. Nice, March 2007. European Neuropsychopharmacology : The Journal of the European College of Neuropsychopharmacology, 18(7), 535-549. doi:10.1016/j.euroneuro.2008.03.003

DIAGNOSIS AND EPIDEMIOLOGY: DSM-IV, specifically its text revision DSM-IV-TR, remains the preferred diagnostic system. When employed in general population samples, prevalence estimates of bipolar disorder are relatively consistent across studies in Europe and USA. In community studies, first onset of bipolar mood disorder is usually in the mid-teenage years and twenties, and the occurrence of a major depressive episode or hypomania is usually its first manifestation. Since reliable criteria for delineating unipolar (UP) and bipolar (BI) depression cross-sectionally are currently lacking, there is a longitudinal risk - probably over 10% - that initial UP patients ultimately turn out as BP in the longer run. Its early onset implies a severe potential burden of disease in terms of impaired social and neuropsychological development, most of which is attributable to depression. BIPOLAR DEPRESSION IN CHILDREN: Bipolar I disorder is rare in prepubertal children, when defined according to unmodified DSM-IV-TR criteria. A broad diagnosis of bipolar disorder risks confounding with other childhood psychopathology and has less predictive value for bipolar disorder in adulthood than the conservative definition. Nevertheless, empirical studies of drug and other treatments and longitudinal studies to assess validity of the broadly defined phenotype in children and adolescents are desirable, rather than extrapolation from adult bipolar practice. The need for an increased capacity to conduct reliable trials in children and adolescents is a challenge to Europe, whose healthcare system should allow greater participation and collaboration than other regions, via clinical networks. ECNP will aspire to facilitate such developments. BIPOLAR DEPRESSION IN ADULTS - UNIPOLAR/BIPOLAR CONTRAST: Despite some differences in symptom profiles and severity measures, a cross-sectional categorical distinction between bipolar (BP) and unipolar (UP) depression is currently impossible. For regulatory purposes, a major depressive episode, meeting DSM-IV-TR criteria, remains the same diagnosis, irrespective of the overall course of the disorder. However, in refining diagnosis in future studies and DSM-V, a probabilistical approach to the UP/BP distinction is more likely to be informative as recommended by the International Society for Bipolar Disorders (ISBD). Anxiety is a commonly present, often at syndromal levels, in bipolar populations. Thus, RCT inclusion criteria for trials not targeting anxiety, should accept co-morbid anxiety disorders as part of the history and even current anxiety symptoms, where these are not dominating the mental state at recruitment to a study. Rapid cycling patients defined as those suffering from 4 or more episodes per year, may also be recruited into trials of bipolar depression without impairing assay sensitivity. Illness severity critically affects assay sensitivity. The minimum scores for entry into a bipolar depression trials should be >20 on HAM-D (17 item scale). However, efficacy is best detected in patients with HAM-D >24 at baseline. THE USE OF RATING SCALES IN BIPOLAR DEPRESSION: There is some dissatisfaction with the HAM-D or MADRS as the preferred primary outcome for trials, although they probably capture global severity adequately. Secondary measures to capture so-called atypical symptoms (such as hypersomnia or hyperphagia), or specific psychopathology more common in bipolar participants (such as lability of mood), could be informative as secondary measures. TREATMENT STUDIES IN BIPOLAR DEPRESSION: Monotherapy trials against placebo remain the gold-standard design for determining efficacy in bipolar depression. The confounding effects of co-medication are emerging from the literature on antidepressant studies in bipolar depression, often conducted in combination with antimanic agents to avoid possible switch to mood elevation. Three arm trials, including the compound to be tested, placebo, and a standard comparator, are generally preferred in order to ensure assay sensitivity and a better picture of benefit-risk ratio. However, in the absence of any gold-standard, two-arm trials may be enough. If efficacy happens to be proven as monotherapy, new compounds may be tested in adjunctive-medication placebo-controlled designs. Younger adults, without an established need for long-term medication, may be particularly suitable for clinical trials requiring placebo controls. The conversion rate of initial UP depression, converting to become BP in the long run is estimated to be 10%. Switch to mania or hypomania may be the consequence of active treatment for bipolar depression. Some medicines such as the tricyclic antidepressants and venlafaxine may be more likely to provoke switch than others, but this increased rate of switch may not be seen until about 10 weeks of treatment. Twelve week trials against placebo are necessary to determine the risk of switch and to establish continuing effects. Careful assessment at 6-8 weeks is required to ensure that patients who are failing to respond do not continue in a study for unacceptable periods of time. To capture a switch event, studies should include scales to define the phenomenology of the event (e.g. hypomania or mania) and its severity. These may be best applied shortly after the clinical decision that switch is occurring. Long-term treatment is commonly required in bipolar disorder. Trials to detect maintenance of effect or continued response in bipolar depression should follow a 'relapse prevention' design: i.e. patients are treated in an index episode with the medicine of interest and then randomized to either continue the active treatment or placebo. However, acute withdrawal of active medication after treatment response might artificially enhance effect size due to active drug withdrawal effects. A short taper is usually desirable. Longer periods of stabilisation are also desirable for up to 3 months: protocol compliance may then be difficult to achieve in practice and so will certainly make studies more difficult and expensive to conduct. The addition of a medicine to other agents during or after the resolution of a depressive or manic episode, and its subsequent investigation as monotherapy against placebo to prevent further relapse (as in the lamotrigine maintenance trials) is clinically informative. Assay sensitivity and patient acceptability are enhanced if the outcome in long-term studies is 'time to intervention for a new episode' for discontinuation designs.

Gouzoulis-Mayfrank, E., Daumann, J., & Sass, H. (2002). Chronic neurotoxic damage in ecstasy (MDMA) users. Review of the current state of research. [Neurotoxische Langzeitschaden bei Ecstasy (MDMA)-Konsumenten. Uberblick uber den aktuellen Wissensstand] Der Nervenarzt, 73(5), 405-421.

The popular dance drug ecstasy (3,4-methylenedioxymethamphetamine, or MDMA, and some analogues) causes selective and persistent neurotoxic damage of the central serotonergic system in laboratory animals. Serotonin plays a role in numerous functional systems in the CNS. Consequently, various abnormalities including psychiatric, vegetative, neuroendocrine, and cognitive disorders might be expected in humans following damage of the central serotonergic system. In recent years, the questions of possible functional disorders following ecstasy-induced neurotoxicity were addressed in several cross-sectional studies with drug users. In this review we summarize and evaluate the quality of design of these studies. Despite large methodological problems, evidence accumulates in favor of persisting brain damage in ecstasy users resulting in subtle cognitive deterioration. Findings of relatively low memory performance associated with heavy ecstasy use are highly consistent across different studies and user populations. In addition, low performance in tests of higher executive function were reported in some but not all studies. The important questions about progression, persistence, or reversibility of damage after long periods of abstinence have to be addressed in future studies with longitudinal design.

Green, S., Buchbinder, R., & Hetrick, S. (2003). Physiotherapy interventions for shoulder pain. Cochrane Database of Systematic Reviews (Online), (2)(2), CD004258. doi:10.1002/14651858.CD004258

BACKGROUND: The prevalence of shoulder disorders has been reported to range from seven to 36% of the population (Lundberg 1969) accounting for 1.2% of all General Practitioner encounters in Australia (Bridges Webb 1992). Substantial disability and significant morbidity can result from shoulder disorders. While many treatments have been employed in the treatment of shoulder disorders, few have been proven in randomised controlled trials. Physiotherapy is often the first line of management for shoulder pain and to date its efficacy has not been established. This review is one in a series of reviews of varying interventions for shoulder disorders, updated from an earlier Cochrane review of all interventions for shoulder disorder. OBJECTIVES: To determine the efficacy of physiotherapy interventions for disorders resulting in pain, stiffness and/or disability of the shoulder. SEARCH STRATEGY: MEDLINE, EMBASE, the Cochrane Clinical Trials Regiter and CINAHL were searched 1966 to June 2002. The Cochrane Musculoskeletal Review Group's search strategy was used and key words gained from previous reviews and all relevant articles were used as text terms in the search. SELECTION CRITERIA: Each identified study was assessed for possible inclusion by two independent reviewers. The determinants for inclusion were that the trial be of an intervention generally delivered by a physiotherapist, that treatment allocation was randomised; and that the study population be suffering from a shoulder disorder, excluding trauma and systemic inflammatory diseases such as rheumatoid arthritis. DATA COLLECTION AND ANALYSIS: The methodological quality of the included trials was assessed by two independent reviewers according to a list of predetermined criteria, which were based on the PEDro scale specifically designed for the assessment of validity of trials of physiotherapy interventions. Outcome data was extracted and entered into Revman 4.1. Means and standard deviations for continuous outcomes and number of events for binary outcomes were extracted where available from the published reports. All standard errors of the mean were converted to standard deviation. For trials where the required data was not reported or not able to be calculated, further details were requested from first authors. If no further details were provided, the trial was included in the review and fully described, but not included in the meta-analysis. Results were presented for each diagnostic sub group (rotator cuff disease, adhesive capsulitis, anterior instability etc) and, where possible, combined in meta-analysis to give a treatment effect across all trials. MAIN RESULTS: Twenty six trials met inclusion criteria. Methodological quality was variable and trial populations were generally small (median sample size = 48, range 14 to 180). Exercise was demonstrated to be effective in terms of short term recovery in rotator cuff disease (RR 7.74 (1.97, 30.32), and longer term benefit with respect to function (RR 2.45 (1.24, 4.86). Combining mobilisation with exercise resulted in additional benefit when compared to exercise alone for rotator cuff disease. Laser therapy was demonstrated to be more effective than placebo (RR 3.71 (1.89, 7.28) for adhesive capsulitis but not for rotator cuff tendinitis. Both ultrasound and pulsed electromagnetic field therapy resulted in improvement compared to placebo in pain in calcific tendinitis (RR 1.81 (1.26, 2.60) and RR 19 (1.16, 12.43) respectively). There is no evidence of the effect of ultrasound in shoulder pain (mixed diagnosis), adhesive capsulitis or rotator cuff tendinitis. When compared to exercises, ultrasound is of no additional benefit over and above exercise alone. There is some evidence that for rotator cuff disease, corticosteroid injections are superior to physiotherapy and no evidence that physiotherapy alone is of benefit for Adhesive Capsulitis REVIEWER'S CONCLUSIONS: The small sample sizes, variable methodological quality and heterogeneity in terms of population studied, physiotherapy intervention employed and length of follow up of randomised controlled trials of physiotherapy interventions results in little overall evidence to guide treatment. There is evidence to support the use of some interventions in specific and circumscribed cases. There is a need for trials of physiotherapy interventions for specific clinical conditions associated with shoulder pain, for shoulder pain where combinations of physiotherapy interventions, as well as, physiotherapy interventions as an adjunct to other, non physiotherapy interventions are compared. This is more reflective of current clinical practice. Trials should be adequately powered and address key methodological criteria such as allocation concealment and blinding of outcome assessor.

Gresch, P. J., Smith, R. L., Barrett, R. J., & Sanders-Bush, E. (2005). Behavioral tolerance to lysergic acid diethylamide is associated with reduced serotonin-2A receptor signaling in rat cortex. Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology, 30(9), 1693-1702. doi:10.1038/sj.npp.1300711

Tolerance is defined as a decrease in responsiveness to a drug after repeated administration. Tolerance to the behavioral effects of hallucinogens occurs in humans and animals. In this study, we used drug discrimination to establish a behavioral model of lysergic acid diethylamide (LSD) tolerance and examined whether tolerance to the stimulus properties of LSD is related to altered serotonin receptor signaling. Rats were trained to discriminate 60 microg/kg LSD from saline in a two-lever drug discrimination paradigm. Two groups of animals were assigned to either chronic saline treatment or chronic LSD treatment. For chronic treatment, rats from each group were injected once per day with either 130 microg/kg LSD or saline for 5 days. Rats were tested for their ability to discriminate either saline or 60 microg/kg LSD, 24 h after the last chronic injection. Rats receiving chronic LSD showed a 44% reduction in LSD lever selection, while rats receiving chronic vehicle showed no change in percent choice on the LSD lever. In another group of rats receiving the identical chronic LSD treatment, LSD-stimulated [35S]GTPgammaS binding, an index of G-protein coupling, was measured in the rat brain by autoradiography. After chronic LSD, a significant reduction in LSD-stimulated [35S]GTPgammaS binding was observed in the medial prefrontal cortex and anterior cingulate cortex. Furthermore, chronic LSD produced a significant reduction in 2,5-dimethoxy-4-iodoamphetamine-stimulated [35S]GTPgammaS binding in medial prefrontal cortex and anterior cingulate cortex, which was blocked by MDL 100907, a selective 5-HT2A receptor antagonist, but not SB206553, a 5-HT2C receptor antagonist, indicating a reduction in 5-HT2A receptor signaling. 125I-LSD binding to 5-HT2A receptors was reduced in cortical regions, demonstrating a reduction in 5-HT2A receptor density. Taken together, these results indicate that adaptive changes in LSD-stimulated serotonin receptor signaling may mediate tolerance to the discriminative stimulus effects of LSD.

Griffiths, R. R., Richards, W. A., McCann, U., & Jesse, R. (2006). Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance. Psychopharmacology, 187(3), 268-83; discussion 284-92. doi:10.1007/s00213-006-0457-5

RATIONALE: Although psilocybin has been used for centuries for religious purposes, little is known scientifically about its acute and persisting effects. OBJECTIVES: This double-blind study evaluated the acute and longer-term psychological effects of a high dose of psilocybin relative to a comparison compound administered under comfortable, supportive conditions. MATERIALS AND METHODS: The participants were hallucinogen-naive adults reporting regular participation in religious or spiritual activities. Two or three sessions were conducted at 2-month intervals. Thirty volunteers received orally administered psilocybin (30 mg/70 kg) and methylphenidate hydrochloride (40 mg/70 kg) in counterbalanced order. To obscure the study design, six additional volunteers received methylphenidate in the first two sessions and unblinded psilocybin in a third session. The 8-h sessions were conducted individually. Volunteers were encouraged to close their eyes and direct their attention inward. Study monitors rated volunteers' behavior during sessions. Volunteers completed questionnaires assessing drug effects and mystical experience immediately after and 2 months after sessions. Community observers rated changes in the volunteer's attitudes and behavior. RESULTS: Psilocybin produced a range of acute perceptual changes, subjective experiences, and labile moods including anxiety. Psilocybin also increased measures of mystical experience. At 2 months, the volunteers rated the psilocybin experience as having substantial personal meaning and spiritual significance and attributed to the experience sustained positive changes in attitudes and behavior consistent with changes rated by community observers. CONCLUSIONS: When administered under supportive conditions, psilocybin occasioned experiences similar to spontaneously occurring mystical experiences. The ability to occasion such experiences prospectively will allow rigorous scientific investigations of their causes and consequences.

Gury, C. (2004). Schizophrenia, diabetes mellitus and antipsychotics. [schizophrenie, diabete et antipsychotiques] L'Encephale, 30(4), 382-391.

During the last years, a contribution of antipsychotic drugs in the increase of diabetes prevalence in schizophrenic population has been repetitively suggested. The debate focused mainly on the second-generation antipsychotics. The analysis of the scientific literature indicates however that this discussion is not recent and an increase of diabetes prevalence in schizophrenic populations was already described before the introduction of neuroleptics. Then, after the introduction of the first neuroleptics in the 1950s, an increase of diabetes prevalence was reported among treated patients and the same alarms occurred in the 1990s after the introduction of second-generation antipsychotics. These treatments were related to an increase of glucose tolerance impairment, type II diabetes and diabetic acidoketosis. Recent epidemiological studies have confirmed the increase prevalence of diabetes in schizophrenic patients, particularly in schizophrenic patients before any antipsychotic treatment. Among the suggested mechanisms, there are sedentary life (due to hospitalisation and sedative effects of neuroleptics), food imbalance, shared genetic factors for diabetes and schizophrenia. Moreover, the frequency of the metabolic syndrome is increased in schizophrenic populations. This syndrome associates blood glucose increase, lipid metabolism disorders and android obesity. This could explain--via an increase of the cortisol production--the increase of mortality due to cardiovascular diseases observed in schizoprhenic patients. Thus, it seems well established that schizophrenia is associated with an increased risk for diabetes. It is however more difficult to evaluate the role of antipsychotic treatment as a causative factor of diabetes. Indeed, there are many published case reports or diabetes or diabetic acidoketosis after an antipsychotic treatment, but the level of evidence in controlled trials is low. Many studies were performed on large databases, but were retrospective and subjected to many flaws: concomitant diseases not taken into account, diabetes status evaluated by drug consumption, unknown diabetes status before antipsychotic treatment, etc. In the few prospective studies performed, no significant differences between the atypical versus typical antipsychotics were evidenced for new cases of diabetes. Moreover, in general population, the glucose tolerance impairment is underdiagnosed and it is estimated that people with a glucose tolerance impairment have a 5-10% annual risk of type II diabetes. Thus, this concern has to be replaced among the world epidemic increase of diabetes and in a population of patients whose the disease itself and life style are risk factors for diabetes. Some studies have explored the pathophysiological mechanisms that could support a diabetogenic effect of antipsychotics. Although it does not seem to be a direct effect of antipsychotics on insulin secretion by pancreatic cells, body weight increase has been evidence for both typical and atypical antipsychotics. However, it remains unclear whether this weight increase is responsible for a visceral adiposity, which is a risk factor better fitted to the cardiovascular mortality tha the body weight itself. Other hypotheses involving an effect on the leptin, which regulates the appetite, have been proposed. In waiting of new prospective controlled studies, and without denying the impact of antipsychotics on the glucose and lipid metabolisms (on the weight increase, for example), it should be recognized that the benefit/risk ratio remains largely in favour of the treatment, particularly for the atypical antipsychotics, more effective and better tolerated at the neurological level than the conventional antipsychotics. One of the benefits of the mainly articles in professional media about this concern is to draw attention on the metabolism disorders in schizophrenic patients, which are important risk factor of their frequent cardiovascular surmortality whatever the causes. Consequently, it is advised to monitor glucose and lipid metabolisms of schizophrenic patients before and during their treatment (body weight, fast blood glucose, blood cholesterol and triglycerides). In conclusion, schizophrenic patients are a population with an increased metabolic risk, which is a cause of their increased mortality. Although these data are known since a long time ago, this population does not benefit from the same metabolic follow-up than the non-schizophrenic population. The debate on the possible relationship between diabetes and antipsychotics should be also taken as a helpful recall of the necessity to follow simple rules of prevention and monitoring in this at-risk population. This should make it possible to preserve the benefit of the antipsychotics, the contribution of which in the treatment of schizophrenia is not any more to demonstrate.

Halpern, A. L., Halpern, J. H., & Doherty, S. B. (2008). "Enhanced" interrogation of detainees: do psychologists and psychiatrists participate? Philosophy, Ethics, and Humanities in Medicine : PEHM, 3, 21. doi:10.1186/1747-5341-3-21

After revelations of participation by psychiatrists and psychologists in interrogation of prisoners at Guantanamo Bay and Central Intelligence Agency secret detention centers, the American Psychiatric Association and the American Psychological Association adopted Position Statements absolutely prohibiting their members from participating in torture under any and all circumstances, and, to a limited degree, forbidding involvement in interrogations. Some interrogations utilize very aggressive techniques determined to be torture by many nations and organizations throughout the world. This paper explains why psychiatrists and psychologists involved in coercive interrogations violate the Geneva Conventions and the laws of the United States. Whether done with ignorance of professional ethical obligations or not, these psychiatrists and psychologists have crossed an ethical barrier that may best be averted from re-occurring by teaching medical students and residents in all medical specialties about the ethics principles stemming from the 1946-1947 Nuremberg trials and the Geneva Conventions, together with the Ethics Codes of the World Medical Association and the American Medical Association; and, with regard to psychiatric residents and psychological trainees, by the teaching about The Principles of Medical Ethics With Annotations Especially Applicable to Psychiatry and the Ethical Principles of Psychologists and Code of Conduct, respectively. In this way, all physicians and psychologists will clearly understand that they have an absolute moral obligation to "First, do no harm" to the human beings they professionally encounter.

Halpern, J. H., & Pope, H. G.,Jr. (2003). Hallucinogen persisting perception disorder: what do we know after 50 years? Drug and Alcohol Dependence, 69(2), 109-119.

'Flashbacks' following use of hallucinogenic drugs have been reported for decades; they are recognized in DSM-IV as 'Hallucinogen Persisting Perception Disorder (Flashbacks)', or HPPD. We located and analyzed 20 quantitative studies between 1955 and 2001 examining this phenomenon. However, many of these studies were performed before operational criteria for HPPD were published in DSM-III-R, so they are difficult to interpret in the light of current diagnostic criteria. Overall, current knowledge of HPPD remains very limited. In particular (1) the term 'flashbacks' is defined in so many ways that it is essentially valueless; (2) most studies provide too little information to judge how many cases could meet DSM-IV criteria for HPPD; and consequently (3) information about risk factors for HPPD, possible etiologic mechanisms, and potential treatment modalities must be interpreted with great caution. At present, HPPD appears to be a genuine but uncommon disorder, sometimes persisting for months or years after hallucinogen use and causing substantial morbidity. It is reported most commonly after illicit LSD use, but less commonly with LSD administered in research or treatment settings, or with use of other types of hallucinogens. There are case reports, but no randomized controlled trials, of successful treatment with neuroleptics, anticonvulsants, benzodiazepines, and clonidine. Although it may be difficult to collect large samples of HPPD cases, further studies are critically needed to augment the meager data presently available regarding the prevalence, etiology, and treatment of HPPD.

Halpern, J. H., Sholar, M. B., Glowacki, J., Mello, N. K., Mendelson, J. H., & Siegel, A. J. (2003). Diminished interleukin-6 response to proinflammatory challenge in men and women after intravenous cocaine administration. The Journal of Clinical Endocrinology and Metabolism, 88(3), 1188-1193.

Cocaine abuse is associated with increased rates of infections, including human immunodeficiency virus, and cocaine has immunomodulatory effects in experimental animal and cellular models. When challenged by antigens, tissues release cytokine polypeptides that signal a complex balance of cellular and humoral immune responses. Placement of indwelling venous catheters also leads to surrounding tissue inflammation, mediated partially by local production and release of the proinflammatory cytokine, IL-6. Thus, catheter placement provides a model for examination of cocaine's immunological effects. Thirty healthy men and women with a history of cocaine use participated in this study of neuroendocrine and immunological responses to iv injection of 0.4 mg/kg cocaine or saline placebo. After injection, blood samples were collected from the antecubital vein of the opposite arm via an indwelling venous catheter at 2, 4, 8, 12, 16, 20, 30, 40, 60, 80, 120, 180, and 240 min. Cocaine, ACTH, cortisol, and dehydroepiandrosterone concentrations peaked at 8, 12, 40, and 20 min, respectively. Stimulation of IL-6 at 240 min was markedly reduced in subjects receiving cocaine compared with subjects receiving placebo (3.85 +/- 0.49 vs. 11.64 +/- 2.21 pg/ml; P = 0.0019, by two-tailed t test). Gender and menstrual cycle phase did not significantly influence most endocrine or IL-6 measures, although the small number of subjects limits the power of these comparisons. Because cocaine stimulates the hypothalamic-pituitary-adrenal axis, IL-6 suppression may be a consequence of corticosteroid release. Cocaine-induced suppression of proinflammatory IL-6 may mediate impaired host defenses to infections.

Hasse, H. E., & Waldmann, H. (1971). "Flashback": spontaneous psychotic episodes in adolescence resulting from psychedelic drug use. ["Flashback": Spontane psychotische Episoden als Folgeerscheinung des Phantasticagebrauchs Jugendlicher] Archiv Fur Psychiatrie Und Nervenkrankheiten, 214(4), 399-439.

Hay, P., Bacaltchuk, J., Claudino, A., Ben-Tovim, D., & Yong, P. Y. (2003). Individual psychotherapy in the outpatient treatment of adults with anorexia nervosa. Cochrane Database of Systematic Reviews (Online), (4)(4), CD003909. doi:10.1002/14651858.CD003909

BACKGROUND: Anorexia nervosa is a disorder of high morbidity and significant mortality. It is commonest in young adult women, in whom the incidence may be increasing. The focus of treatment has moved to an outpatient setting and a number of differing psychotherapies are presently used in treatment. OBJECTIVES: The aim of the present review was to evaluate the evidence from randomised controlled trials for the efficacy of outpatient psychotherapies used in the treatment of older adolescents and adults with anorexia nervosa SEARCH STRATEGY: The strategy comprised database searches of MEDLINE, EXTRAMED, EMBASE,PSYCLIT, CURRENT CONTENTS, Cochrane Collaboration Controlled Trials Register and the Depression and Anxiety Neuroses Cochrane Group (CCDAN), a hand-search of The International Journal of Eating Disorders, and he reference lists of all papers selected. Personal letters were sent to identified notable researchers published in the area, requesting information on trials that are unpublished or in progress. SELECTION CRITERIA: All randomised controlled trials of adult individual outpatient therapy for anorexia nervosa as defined by the DSM-IV or similar international criterion. Quality ratings were made according to the CCDAN criteria and in addition, whether the trial had examined treatment integrity. DATA COLLECTION AND ANALYSIS: A range of outcome variables were selected, including physical state, severity of eating disorder attitudes and beliefs, interpersonal function, and general psychiatric symptom severity. Continuous outcome data comparisons were made with the standardized mean difference statistic, and binary outcome comparisons made with the relative risk statistic. Reliability of data extraction and quality ratings were made with the kappa statistic. Sensitivity analyses to evaluate the effects of trial quality and subgroup analyses to explore specific questions of treatment effects from different settings, frequency and duration of therapies were planned. MAIN RESULTS: Six small trials only, two of which included children or adolescents, were identified from the search and aggregation of data was not possible. Bias was possible due particularly to lack of blinding of outcome assessments. The results in two trials suggested that 'treatment as usual' or similar may be less efficacious than a specific psychotherapy. No specific treatment was consistently superior to any other specific approach. Dietary advice as a control arm had a 100% non-completion rate in one trial. REVIEWER'S CONCLUSIONS: No specific approach can be recommended from this review. It is unclear why 'treatment as usual' performed so poorly or why dietary advice alone appeared so unacceptable as the reasons for non-completion were not reported. There is an urgent need for large well-designed trials in his area.

Haynes, J. (2009). Decoding visual consciousness from human brain signals. Trends in Cognitive Sciences, 13(5), 194-202. doi:DOI: 10.1016/j.tics.2009.02.004

Hay-Smith, E. J., Bo, K., Berghmans, L. C., Hendriks, H. J., de Bie, R. A., & van Waalwijk van Doorn, E. S. (2007). WITHDRAWN: Pelvic floor muscle training for urinary incontinence in women. Cochrane Database of Systematic Reviews (Online), (1)(1), CD001407. doi:10.1002/14651858.CD001407.pub2

BACKGROUND: Pelvic floor muscle training is the most commonly recommended physical therapy treatment for women with stress leakage of urine. It is also used in the treatment of women with mixed incontinence, and less commonly for urge incontinence. Adjuncts, such as biofeedback or electrical stimulation, are also commonly used with pelvic floor muscle training. The content of pelvic floor muscle training programmes is highly variable. OBJECTIVES: To determine the effects of pelvic floor muscle training for women with symptoms or urodynamic diagnoses of stress, urge and mixed incontinence, in comparison to no treatment or other treatment options. SEARCH STRATEGY: Search strategy: We searched the Cochrane Incontinence Group trials register (May 2000), Medline (1980 to 1998), Embase (1980 to 1998), the database of the Dutch National Institute of Allied Health Professions (to 1998), the database of the Cochrane Rehabilitation and Related Therapies Field (to 1998), Physiotherapy Index (to 1998) and the reference lists of relevant articles. We handsearched the proceedings of the International Continence Society (1980 to 2000). We contacted investigators in the field to locate studies. Date of the most recent searches: May 2000. SELECTION CRITERIA: Randomised trials in women with symptoms or urodynamic diagnoses of stress, urge or mixed incontinence that included pelvic floor muscle training in at least one arm of the trial. DATA COLLECTION AND ANALYSIS: Two reviewers assessed all trials for inclusion/exclusion and methodological quality. Data were extracted by the lead reviewer onto a standard form and cross checked by another. Disagreements were resolved by discussion. Data were processed as described in the Cochrane Handbook. Sensitivity analysis on the basis of diagnosis was planned and undertaken where appropriate. MAIN RESULTS: Forty-three trials met the inclusion criteria. The primary or only reference for 15 of these was a conference abstract. The pelvic floor muscle training programs, and comparison interventions, varied markedly. Outcome measures differed between trials, and methods of data reporting varied, making the data difficult to combine.Many of the trials were small. Allocation concealment was adequate in five trials, and nine trials used assessors masked to group allocation. Thirteen trials reported that there were no losses to follow up, seven trials had dropout rates of less than 10%, but in the remaining trials the proportion of dropouts ranged from 12% to 41%.Pelvic floor muscle training was better than no treatment or placebo treatments for women with stress or mixed incontinence. 'Intensive' appeared to be better than 'standard' pelvic floor muscle training. PFMT may be more effective than some types of electrical stimulation but there were problems in combining the data from these trials. There is insufficient evidence to determine if pelvic floor muscle training is better or worse than other treatments.The effect of adding pelvic floor muscle training to other treatments (e.g. electrical stimulation, behavioural training) is not clear due to the limited amount of evidence available. Evidence of the effect of adding other adjunctive treatments to PFMT (e.g. vaginal cones, intravaginal resistance) is equally limited. The effectiveness of biofeedback assisted PFMT is not clear, but on the basis of the evidence available there did not appear to be any benefit over PFMT alone at post treatment assessment.Long-term outcomes of pelvic floor muscle training are unclear. Side effects of pelvic floor muscle training were uncommon and reversible. A number of the formal comparisons should be viewed with caution due to statistical heterogeneity, lack of statistical independence, and the possibility of spurious confidence intervals in some instances. AUTHORS' CONCLUSIONS: Pelvic floor muscle training appeared to be an effective treatment for adult women with stress or mixed incontinence. Pelvic floor muscle training was better than no treatment or placebo treatments. The limitations of the evidence available mean that is difficult to judge if pelvic floor muscle training was better or worse than other treatments. Most trials to date have studied the effect of treatment in younger, premenopausal women. The role of pelvic floor muscle training for women with urge incontinence alone remains unclear. Many of the trials were small with poor reporting of allocation concealment and masking of outcome assessors. In addition there was a lack of consistency in the choice and reporting of outcome measures that made data difficult to combine. Methodological problems limit the confidence that can be placed in the findings of the review. Further, large, high quality trials are necessary.

Hedlund, C., Rapoport, A. M., Dodick, D. W., & Goadsby, P. J. (2009). Zolmitriptan nasal spray in the acute treatment of cluster headache: a meta-analysis of two studies. Headache, 49(9), 1315-1323. doi:10.1111/j.1526-4610.2009.01518.x

OBJECTIVE: To conduct an individual subject meta-analysis of available controlled studies of zolmitriptan nasal spray in the acute treatment of cluster headache. BACKGROUND: Two double-blind, placebo-controlled, randomized, crossover studies of zolmitriptan nasal spray in the acute treatment of cluster headache, with similar patient populations, protocol designs, doses, and clinical endpoints have been published. METHODS: In both double-blind studies, each patient was to treat 3 attacks, 1 with placebo, 1 with zolmitriptan 5 mg, and 1 with zolmitriptan 10 mg in a randomized, crossover manner. Headache intensity was rated on a 5-point scale (none to very severe). The primary endpoint was headache relief at 30 minutes post dose: reduction from moderate, severe, or very severe pain to mild or none. A multilevel, random-effects, logistic regression model was used to analyze the data. RESULTS: A total of 121 patients (100 male; 64.5% with episodic cluster headache) provided efficacy data for at least 1 attack. Zolmitriptan 5 mg and 10 mg were significantly more effective at providing headache relief at 30 minutes post treatment than placebo (odds ratio 3.48; 95% confidence interval 1.49-8.10 and odds ratio 8.68; 95% confidence interval: 3.35-22.5, respectively). For episodic cluster headache, response rates were 35.6%, 51.7%, and 73.7% for placebo, zolmitriptan 5 mg (odds ratio 2.5; P = .06 vs placebo), and 10 mg (odds ratio 9.9; P < .001 vs placebo), respectively. For chronic cluster headache, response rates were 17.2%, 41.9%, and 40.7% for placebo, zolmitriptan 5 mg (odds ratio 8.1; P = .035), and 10 mg (odds ratio 7.6; P = .046), respectively. Zolmitriptan was well tolerated in both studies with no serious adverse events reported. CONCLUSION: Zolmitriptan nasal spray at a dose of 5 mg and 10 mg is efficacious in the acute treatment of episodic and chronic cluster headache.

Heinrich, S. P., Mell, D., & Bach, M. (2009). Frequency-domain analysis of fast oddball responses to visual stimuli: A feasibility study. International Journal of Psychophysiology, 73(3), 287-293. doi:DOI: 10.1016/j.ijpsycho.2009.04.011

Event-related potential responses to oddball stimuli, including the P300 component, have been proposed as a diagnostic tool for discerning psychiatric or higher-level neural disorders from malingering, for instance in cases of unexplained visual loss. For clinical use, short recording durations and easy statistical assessment are highly desirable. With this aim, we investigated the feasibility of recording oddball responses in a fast steady-state regime. We used gratings with two possible orientations in a rapid oddball paradigm with an inter-stimulus interval of 214 ms. Six consecutive presentations of one stimulus type (frequent) were followed by a single presentation of the other (infrequent) stimulus type. Subjects were attending to the rare stimulus type. The electroencephalographic recordings were analyzed in the frequency domain. All subjects produced significant harmonic responses related to the processing of the rare stimulus, demonstrating the feasibility of the technique, with the potential of reducing recording times substantially compared to conventional slow stimulation. We furthermore found that the regularity of the occurrence of infrequent stimuli, which is necessary for frequency-domain analysis, does not per se reduce the P300 responses, as would have been expected in the framework of some hypotheses regarding the role of the P300.

Hermle, L., Kovar, K. A., Hewer, W., & Ruchsow, M. (2008). Hallucinogen-induced psychological disorders. [Halluzinogen-induzierte psychische Storungen] Fortschritte Der Neurologie-Psychiatrie, 76(6), 334-342. doi:10.1055/s-2008-1038191

OBJECTIVE: The purpose of this article is to provide an overview of the current research on hallucinogen induced psychiatric disorders. In addition to LSD and psilocybin hallucinogens of biologic origin are increasingly used by adolescents and young adults. METHODS: Relevant literature and related articles were identified by means of a computerized MEDLINE search including the years 1997 - 2007. As keywords "hallucinogen induced psychosis", "hallucinogen induced flashback", "hallucinogen persisting perception disorder (HPPD)" were used. Finally, 64 journal articles and books out of 103 were included in the review. RESULTS: Acute psychotic syndromes in adolescents are rarely due to intoxications with hallucinogenic drugs. However, clinical relevance of flashback phenomena as post-hallucinogenic psychiatric disorder has to be disputed. Because of the high popularity of biogenic hallucinogens and LSD knowledge of intoxications and resulting psychiatric disorders as well as medical complications and therapeutical approaches are clinically important. Especially intoxications with drugs of herbal origin like tropanalcaloids play an important role in emergency situations.

Herr, B. E., Abraham, H. D., & Anderson, W. (1991). Length of stay in a general hospital psychiatric unit. General Hospital Psychiatry, 13(1), 68-70.

Fifty psychiatric inpatients with a prolonged length of stay were compared to 50 control admissions for factors associated with prolonged hospitalizations in a general hospital. Seven variables were found to be significantly overrepresented among the long stayers, including treatment with electroconvulsive therapy, medical consultations, underemployment, dementia, disposition to a place other than home, absence of alcohol or drug abuse, and presence of psychosis without affective symptoms. The clinical and policy implications of these finding are discussed.

Higashida, R. T., Furlan, A. J., Roberts, H., Tomsick, T., Connors, B., Barr, J., Dillon, W., Warach, S., Broderick, J., Tilley, B., Sacks, D., Technology Assessment Committee of the American Society of Interventional and Therapeutic Neuroradiology, & Technology Assessment Committee of the Society of Interventional Radiology. (2003). Trial design and reporting standards for intra-arterial cerebral thrombolysis for acute ischemic stroke. Stroke; a Journal of Cerebral Circulation, 34(8), e109-37. doi:10.1161/01.STR.0000082721.62796.09

BACKGROUND AND PURPOSE: The National Institutes of Health (NIH) estimates that stroke costs now exceed 45 billion dollars per year. Stroke is the third leading cause of death and one of the leading causes of adult disability in North America, Europe, and Asia. A number of well-designed randomized stroke trials and case series have now been reported in the literature to evaluate the safety and efficacy of thrombolytic therapy for the treatment of acute ischemic stroke. These stroke trials have included intravenous studies, intra-arterial studies, and combinations of both, as well as use of mechanical devices for removal of thromboemboli and of neuroprotectant drugs, alone or in combination with thrombolytic therapy. At this time, the only therapy demonstrated to improve outcomes from an acute stroke is thrombolysis of the clot responsible for the ischemic event. There is room for improvement in stroke lysis studies. Divergent criteria, with disparate reporting standards and definitions, have made direct comparisons between stroke trials difficult to compare and contrast in terms of overall patient outcomes and efficacy of treatment. There is a need for more uniform definitions of multiple variables such as collateral flow, degree of recanalization, assessment of perfusion, and infarct size. In addition, there are multiple unanswered questions that require further investigation, in particular, questions as to which patients are best treated with thrombolysis. One of the most important predictors of clinical success is time to treatment, with early treatment of <3 hours for intravenous tissue plasminogen activator and <6 hours for intra-arterial thrombolysis demonstrating significant improvement in terms of 90-day clinical outcome and reduced cerebral hemorrhage. It is possible that improved imaging that identifies the ischemic penumbra and distinguishes it from irreversibly infarcted tissue will more accurately select patients for therapy than duration of symptoms. There are additional problems in the assessment of patients eligible for thrombolysis. These include being able to predict whether a particular site of occlusion can be successfully revascularized, predict an individual patient's prognosis and outcome after revascularization, and in particular, to predict the development of intracerebral hemorrhage, with and without clinical deterioration. It is not clear to assume that achieving immediate flow restoration due to thrombolytic therapy implies clinical success and improved outcome. There is no simple correlation between recanalization and observed clinical benefit in all ischemic stroke patients, because other interactive variables, such as collateral circulation, the ischemic penumbra, lesion location and extent, time to treatment, and hemorrhagic conversion, are all interrelated to outcome. METHODS: This article was written under the auspices of the Technology Assessment Committees for both the American Society of Interventional and Therapeutic Neuroradiology and the Society of Interventional Radiology. The purpose of this document is to provide guidance for the ongoing study design of trials of intra-arterial cerebral thrombolysis in acute ischemic stroke. It serves as a background for the intra-arterial thrombolytic trials in North America and Europe, discusses limitations of thrombolytic therapy, defines predictors for success, and offers the rationale for the different considerations that might be important during the design of a clinical trial for intra-arterial thrombolysis in acute stroke. Included in this guidance document are suggestions for uniform reporting standards for such trials. These definitions and standards are mainly intended for research trials; however, they should also be helpful in clinical practice and applicable to all publications. This article serves to standardize reporting terminology and includes pretreatment assessment, neurologic evaluation with the NIH Stroke Scale score, imaging evaluation, occlusion sites, perfusion grades, follow-up imaging studies, and neurologic assessments. Moreover, previously used and established definitions for patient selection, outcome assessment, and data analysis are provided, with some possible variations on specific end points. This document is therefore targeted to help an investigator to critically review the scales and scores used previously in stroke trials. This article also seeks to standardize patient selection for treatment based on neurologic condition at presentation, baseline imaging studies, and utilization of standardized inclusion/exclusion criteria. It defines outcomes from therapy in phase I, II, and III studies. Statistical approaches are presented for analyzing outcomes from prospective, randomized trials with both primary and secondary variable analysis. A discussion on techniques for angiography, intra-arterial thrombolysis, anticoagulation, adjuvant therapy, and patient management after therapy is given, as well as recommendations for posttreatment evaluation, duration of follow-up, and reporting of disability outcomes. Imaging assessment before and after treatment is given. In the past, noncontrast CT brain scans were used as the initial screening examination of choice to exclude cerebral hemorrhage. However, it is now possible to quantify the volume of early infarct by using contiguous, discrete (nonhelical) images of 5 mm. In addition, CT angiography by helical scanning and 100 mL of intravenous contrast agent can be used expeditiously to obtain excellent vascular anatomy, define the occlusion site, obtain 2D and 3D reformatted vascular images, grade collateral blood flow, and perform tissue-perfusion studies to define transit times of a contrast bolus through specific tissue beds and regions of interest in the brain. Dynamic CT perfusion scans to assess the whole dynamics of a contrast agent transit curve can now be routinely obtained at many hospitals involved in these studies. The rationale, current status of this technology, and potential use in future clinical trials are given. Many hospitals are also performing MR brain studies at baseline in addition to, or instead of, CT scans. MRI has a high sensitivity and specificity for the diagnosis of ischemic stroke in the first several hours from symptom onset, identifies arterial occlusions, and characterizes ischemic pathology noninvasively. Case series have demonstrated and characterized the early detection of intraparenchymal hemorrhage and subarachnoid hemorrhage by MRI. Echo planar images, used for diffusion MRI and, in particular, perfusion MRI are inherently sensitive for the susceptibility changes caused by intraparenchymal blood products. Consequently, MRI has replaced CT to rule out acute hemorrhage in some centers. The rationale and the potential uses of MR scanning are provided. In addition to established criteria, technology is continuously evolving, and imaging techniques have been introduced that offer new insights into the pathophysiology of acute ischemic stroke. For example, a better patient stratification might be possible if CT and/or MRI brain scans are used not only as exclusion criteria but also to provide individual inclusion and exclusion criteria based on tissue physiology. Imaging techniques might also be used as a surrogate outcome measure in future thrombolytic trials. The context of a controlled study is the best environment to validate emerging imaging and treatment techniques. The final section details reporting standards for complications and adverse outcomes; defines serious adverse events, adverse events, and unanticipated adverse events; and describes severity of complications and their relation to treatment groups. Recommendations are made regarding comparing treatment groups, randomization and blinding, intention-to-treat analysis, quality-of-life analysis, and efficacy analysis. This document concludes with an analysis of general costs associated with therapy, a discussion regarding entry criteria, outcome measures, and the variability of assessment of the different stroke scales currently used in the literature is also featured. CONCLUSIONS: In summary, this article serves to provide a more uniform set of criteria for clinical trials and reporting outcomes used in designing stroke trials involving intra-arterial thrombolytic agents, either alone or in combination with other therapies. It is anticipated that by having a more uniform set of reporting standards, more meaningful analysis of the data and the literature will be able to be achieved.

Hofmann, S. G., & Smits, J. A. (2008). Cognitive-behavioral therapy for adult anxiety disorders: a meta-analysis of randomized placebo-controlled trials. The Journal of Clinical Psychiatry, 69(4), 621-632.

OBJECTIVE: Cognitive-behavioral therapy (CBT) is frequently used for various adult anxiety disorders, but there has been no systematic review of the efficacy of CBT in randomized placebo-controlled trials. The present study meta-analytically reviewed the efficacy of CBT versus placebo for adult anxiety disorders. DATA SOURCES: We conducted a computerized search for treatment outcome studies of anxiety disorders from the first available date to March 1, 2007. We searched MEDLINE, PsycINFO, PubMed, Scopus, the Institute of Scientific Information, and Dissertation Abstracts International for the following terms: random*, cognitive behavior*therap*, cognitive therap*, behavior*therap*, GAD, generalized anxiety disorder, OCD, obsessive compulsive disorder, social phobia, social anxiety disorder, specific phobia, simple phobia, PTSD, post-traumatic stress disorder, and acute stress disorder. Furthermore, we examined reference lists from identified articles and asked international experts to identify eligible studies. STUDY SELECTION: We included studies that randomly assigned adult patients between ages 18 and 65 years meeting DSM-III-R or DSM-IV criteria for an anxiety disorder to either CBT or placebo. Of 1165 studies that were initially identified, 27 met all inclusion criteria. DATA EXTRACTION: The 2 authors independently identified the eligible studies and selected for each study the continuous measures of anxiety severity. Dichotomous measures reflecting treatment response and continuous measures of depression severity were also collected. Data were extracted separately for completer (25 studies for continuous measures and 21 studies for response rates) and intent-to-treat (ITT) analyses (6 studies for continuous measures and 8 studies for response rates). DATA SYNTHESIS: There were no significant differences in attrition rates between CBT and placebo. Random-effects models of completer samples yielded a pooled effect size (Hedges' g) of 0.73 (95% CI = 0.88 to 1.65) for continuous anxiety severity measures and 0.45 (95% CI = 0.25 to 0.65) for depressive symptom severity measures. The pooled odds ratio for completer treatment response rates was 4.06 (95% CI = 2.78 to 5.92). The strongest effect sizes were observed in obsessive-compulsive disorder and acute stress disorder, and the weakest effect size was found in panic disorder. The advantage of CBT over placebo did not depend on placebo modality, number of sessions, or study year. CONCLUSIONS: Our review of randomized placebo-controlled trials indicates that CBT is efficacious for adult anxiety disorders. There is, however, considerable room for improvement. Also, more studies need to include ITT analyses in the future.

Holsten, F. (1974). Flashbacks--late reactions after LSD and cannabis use among 78 drug addicts. ["Flashbacks"--senreaksjoner etter bruk av LSD og cannabis hos 78 stoffbrukere] Tidsskrift for Den Norske Laegeforening : Tidsskrift for Praktisk Medicin, Ny Raekke, 94(30), 2070-2077.

Holsten, F. (1976). Flashbacks: a personal follow-up. Archiv Fur Psychiatrie Und Nervenkrankheiten, 222(4), 293-304.

During the period 1971-1973, it was found that 53 out of 91 young drug abusers in a psychiatric hospital had experienced flashbacks. This applied to as many as 50 out of the 65 patients who had used LSD, but also to abusers of organic solvents and cannabis. As many as 38% of the patients were found to be severely incapacitated by their flashbacks. On a personal follow-up 1 1/2-4 years after the first therapeutic contact, 35 patients were still troubled by flashbacks. On the whole reactions were less intense than at the time of the first contact. No relation between the flashbacks and protracted psychotic development could be established. The overall clinical and social course was worse for patients with flashbacks than for the rest of the population. Patients still bothered by flashbacks used drugs and alcohol as sedatives to a greater extent than the rest.

Horowitz, M. J. (1969). Flashbacks: recurrent intrusive images after the use of LSD. The American Journal of Psychiatry, 126(4), 565-569.

Hoshi, R., Cohen, L., Lemanski, L., Piccini, P., Bond, A., & Curran, H. V. (2007). Ecstasy (MDMA) does not have long-term effects on aggressive interpretative bias: a study comparing current and ex-ecstasy users with polydrug and drug-naive controls. Experimental and Clinical Psychopharmacology, 15(4), 351-358. doi:10.1037/1064-1297.15.4.351

+/-3, 4-methylenedioxymethamphetamine (MDMA or ecstasy) remains a widely used recreational drug, which, in animals, can produce long-lasting changes to the brain's serotonergic system. As serotonin has been implicated in human aggression, it is possible that ecstasy users are at risk of increased aggression even after prolonged abstention from the drug. The objective of this study was to indirectly assess aggression in current and abstinent ecstasy users using an information-processing paradigm that measures cognitive bias toward material with aggressive content. The task employed has previously shown increased aggressive bias 3-4 days after ecstasy use. An interpretative bias task was administered to 105 male participants: 26 ex-ecstasy users, 25 current ecstasy users, 29 polydrug using controls, and 25 drug-naive controls. Accuracy and response times to process and recognize ambiguous sentences were tested. There were no group differences in aggressive interpretative bias. All 4 groups processed neutral sentences faster than aggressive sentences and were subsequently faster and more confident in recognizing neutral compared with aggressive sentences. Further, self-ratings of aggression also showed no group differences, even though self-rated impulsivity was significantly higher in current ecstasy users than in drug-naive controls. The findings that all groups were biased toward neutral and away from aggressive interpretations of ambiguous sentences add to the existing body of knowledge in suggesting that increased aggression found in ecstasy users a few days after taking the drug is a transient phenomenon and not a long-term, persisting effect.

Ikeda, A., Sekiguchi, K., Fujita, K., Yamadera, H., & Koga, Y. (2005). 5-methoxy-N,N-diisopropyltryptamine-induced flashbacks. The American Journal of Psychiatry, 162(4), 815. doi:10.1176/appi.ajp.162.4.815

Imai, N., Yagi, N., Konishi, T., Serizawa, M., & Kobari, M. (2009). Websites offer helpful information concerning consultation with headache specialists. Cephalalgia : An International Journal of Headache, doi:10.1111/j.1468-2982.2009.01915.x

Patients with severe primary headache may benefit from consultation with headache specialists, but doctor attendance rates in Japan are very low. More headache patients might consult headache specialists if these specialists were more widely recognized by the public. To determine what information prompted patients to seek consultation with a headache specialist, we questioned 256 primary headache patients about the source of the helpful information concerning consultation with headache specialists. From 191 patients, a total of 235 responses to the questionnaire were obtained. The most common response was 'websites' (33.2%), followed by 'professionals' (23.8%), 'acquaintances' (20.9%), 'print media' (6.8%) and 'TV/radio' (3.4%). Patients who indicated websites showed the most severe pain and highest impact of headache, and accounted for 52.4% of those with cluster headaches. Development of websites concerning headache specialists would seem likely to increase doctor attendance rates for patients with primary headache.

International journal of psychophysiology : official journal of the International Organization of Psychophysiology (1983). . Amsterdam ;New York: Elsevier Science Publishers.

Jebelli, A. K., Doan, N., & Ellison, G. (2002). Prenatal phencyclidine induces heightened neurodegeneration in rats in some brain regions, especially during 2nd trimester, but possible anti-apoptotic effects in others. Pharmacology & Toxicology, 90(1), 20-25.

Phencyclidine administered to the developing rat brain at high doses for a few hours during late foetal life induces apoptotic neurodegeneration in several brain regions. We sought to investigate whether prolonged, low level foetal exposure to phencyclidine during different gestational periods (2nd trimester versus 3rd trimester) would have different effects on several brain regions showing neurodegeneration as assessed using silver stains. Pregnant rats were treated with phencyclidine (5.45 mg/day) continuously for 5 days via minipumps, and the pups were either perfused immediately after birth and silver-stained for degeneration, or allowed to mature and then tested for behavioural deficits. In the newborn pups, there was a substantial increase in the number of agrophilic cells in entorhinal cortex and subiculum; this effect was greater when the drug was given during 2nd trimester. However, in the ventromedial nucleus of the hypothalamus, both the 2nd and 3rd trimester phencyclidine pups had significantly fewer degenerating cells than the controls. Behavioural tests of rotorod and open field performance in the pups allowed to mature indicated decreased motor coordination and hyperactivity in the 3rd trimester phencyclidine pups, but minimal alterations in the 2nd trimester pups. Thus, prenatal exposure to phencyclidine can have either neurodegenerative or antiapototic effects depending upon brain region, and there is a discrepancy between persisting behavioural deficits and amount of cell loss for time of maximal prenatal effect of the drug.

Johnson, M., Richards, W., & Griffiths, R. (2008). Human hallucinogen research: guidelines for safety. Journal of Psychopharmacology (Oxford, England), 22(6), 603-620. doi:10.1177/0269881108093587

There has recently been a renewal of human research with classical hallucinogens (psychedelics). This paper first briefly discusses the unique history of human hallucinogen research, and then reviews the risks of hallucinogen administration and safeguards for minimizing these risks. Although hallucinogens are relatively safe physiologically and are not considered drugs of dependence, their administration involves unique psychological risks. The most likely risk is overwhelming distress during drug action ('bad trip'), which could lead to potentially dangerous behaviour such as leaving the study site. Less common are prolonged psychoses triggered by hallucinogens. Safeguards against these risks include the exclusion of volunteers with personal or family history of psychotic disorders or other severe psychiatric disorders, establishing trust and rapport between session monitors and volunteer before the session, careful volunteer preparation, a safe physical session environment and interpersonal support from at least two study monitors during the session. Investigators should probe for the relatively rare hallucinogen persisting perception disorder in follow-up contact. Persisting adverse reactions are rare when research is conducted along these guidelines. Incautious research may jeopardize participant safety and future research. However, carefully conducted research may inform the treatment of psychiatric disorders, and may lead to advances in basic science.

Jurgens, T. P., Leone, M., Proietti-Cecchini, A., Busch, V., Mea, E., Bussone, G., & May, A. (2009). Hypothalamic deep-brain stimulation modulates thermal sensitivity and pain thresholds in cluster headache. Pain, 146(1-2), 84-90. doi:10.1016/j.pain.2009.07.006

Deep-brain stimulation (DBS) of the posterior hypothalamus has been shown to be clinically effective for drug-resistant chronic cluster headache, but the underlying mechanism is still not understood. The hypothalamus as an important centre of homeostasis is connected among others to the trigeminal system via the trigeminohypothalamic tract. We aimed to elucidate whether hypothalamic stimulation affects thermal sensation and pain perception only in the clinically affected region (the first trigeminal branch) or in other regions as well. Thus, we examined three groups: chronic cluster headache patients with unilateral DBS of the posterior hypothalamus (n = 11), chronic cluster headache patients without DBS (n = 15) and healthy controls (n = 29). Perception and pain thresholds for hot and cold stimuli were determined bilaterally in all subjects supraorbitally, at the forearm, and in the lower leg. In DBS patients, thresholds were determined with the stimulator activated and inactivated. Cold pain thresholds at the first trigeminal branch were increased on the stimulated side in the DBS group compared to healthy subjects (p = .015). The DBS group also had higher cold detection thresholds compared to non-implanted cluster headache patients (p < .05). Short-term interruption of stimulation did not induce any changes in DBS patients. Clinically relevant differences were found neither between non-stimulated cluster headache patients and healthy controls nor between the affected and the non-affected sides in the chronic cluster headache patients without DBS. These results support the notion that neurostimulation of the posterior hypothalamus is specific for cluster headache and only affects certain aspects of pain sensation.

Juve, J. L. (1972). Bad drug trips and flashbacks. Child Welfare, 51(1), 41-50.

Kang, J. K., Ryu, J. W., Choi, J. H., Merrill, R. L., & Kim, S. T. (2009). Application of ICHD-II criteria for headaches in a TMJ and orofacial pain clinic. Cephalalgia : An International Journal of Headache, doi:10.1111/j.1468-2982.2009.01866.x

Kang J-K, Ryu J-W, Choi J-H, Merrill RL & Kim ST. Application of ICHD-II criteria for headaches in a TMJ and orofacial pain clinic. Cephalalgia 2009. London. ISSN 0333-1024The aim of this study was to identify and diagnose headache in a temporomandibular joint and orofacial pain clinic population using the second edition of The International Classification of Headache Disorder criteria. In 502 temporomandibular disorder and orofacial pain patients, 246 patients (49%) were diagnosed with tension-type headache (TTH), followed by migraine without aura (14.5%), probable migraine (12.9%), migraine with aura (7%), probable TTH (4.8%) and cluster headache (0.2%). The prevalence of headaches was compared between male and female patients, and the prevalence of migraine was found to be higher in women than in men. In evaluating by age, the prevalence of migraine was highest in patients in their 20s and 30s and declined as age increased above 40. TTH showed the highest rate throughout all age groups, but it also decreased as age increased. In this study, the prevalence of migraine was lower than that reported in Dr Kim et al.'s study, and the prevalence of TTH much higher than that reported in the previous study. Of the headache patients, 81.1% presented with masseter muscle pain and 47.8% with temporal muscle pain. This finding suggests that pericranial muscle pain may be an inducing factor of primary headache.

Katzenschlager, R., Sampaio, C., Costa, J., & Lees, A. (2003). Anticholinergics for symptomatic management of Parkinson's disease. Cochrane Database of Systematic Reviews (Online), (2)(2), CD003735. doi:10.1002/14651858.CD003735

BACKGROUND: Anticholinergics were the first drugs available for the symptomatic treatment of Parkinson's disease and they are still widely used today, both as monotherapy and as part of combination regimes. They are commonly believed to be associated with a less favourable side effect profile than other antiparkinsonian drugs, in particular with respect to neuropsychiatric and cognitive adverse events. They have been claimed to exert a better effect on tremor than on other parkinsonian features. OBJECTIVES: To determine the efficacy and tolerability of anticholinergics in the symptomatic treatment of Parkinson's disease compared to placebo or no treatment. SEARCH STRATEGY: The literature search included electronic searches of the Cochrane Controlled Trials Register (The Cochrane Library, Issue 4, 2001), MEDLINE (1966 to 2001), Old Medline (1960-1965), Index Medicus (1927 - 1959), as well as handsearching the neurology literature including the reference lists of identified articles, other reviews and book chapters. SELECTION CRITERIA: Randomised controlled trials of anticholinergic drugs versus placebo or no treatment in de-novo or advanced Parkinson's disease, either as monotherapy or as an add-on to other antiparkinsonian drugs were included. Trials of anticholinergic drugs that were never in general clinical use were excluded. DATA COLLECTION AND ANALYSIS: Data was abstracted independently by two authors. Differences were settled by discussion among all authors. Data collected included patient characteristics, disease duration and severity, concomitant medication, interventions including duration and dose of anticholinergic treatment, outcome measures, rates of and reasons for withdrawals, and neuropsychiatric and cognitive adverse events. MAIN RESULTS: The initial search yielded 14 potentially eligible studies, five of which were subsequently excluded. In three cases this was because they dealt with substances that had never been marketed or had not been licensed for as far as could be traced back. One trial had been published twice in different languages. One study was excluded based on the assessment of its methodological quality. The remaining nine studies were all of double-blind cross-over design and included 221 patients. Trial duration was between five and 20 weeks and drugs investigated were benzhexol (mean doses: 8 to 20 mg/d), orphenadrine (mean dose not reported), benztropine (mean dose not reported), bornaprine (8 to 8.25 mg/d), benapryzine (200 mg/d), and methixine (45 mg/d). Only one study involved two anticholinergic drugs. Outcome measures varied widely across studies and in many cases, the scales applied were the authors' own and were not defined in detail. Incomplete reporting of methodology and results was frequent. The heterogeneous study designs as well as incomplete reporting precluded combined statistical analysis. Five studies used both tremor and other parkinsonian features as outcome measures. Outcome measures in these five studies were too different for a combined analysis and results varied widely, from a significant improvement in tremor only to significant improvement in other features but not in tremor. All studies except one (dealing with methixine) found a significant improvement from baseline on the anticholinergic drug in at least one outcome measure. The difference between placebo and active drug was reported in four studies and was found to be significant in all cases. No study failed to show superiority of the anticholinergic over placebo. The occurrence of neuropsychiatric and cognitive adverse events was reported in all but three studies (in 35 patients on active drug versus 13 on placebo). The most frequently reported reason for drop-outs from studies was in patients on placebo due to withdrawal from pre-trial anticholinergic treatment. REVIEWER'S CONCLUSIONS: As monotherapy or as an adjunct to other antiparkinsonian drugs, anticholinergics are more effective than placebo in improving motor function in Parkinson's disease. Neuropsychiatric and cognitive adverse events occur more frequently on anticholinergics than on placebo and are a more common reason for withdrawal than lack of efficacy. Results regarding a potentially better effect of the anticholinergic drug on tremor than on other outcome measures are conflicting and data do not strongly support a differential clinical effect on individual parkinsonian features. Data is insufficient to allow comparisons in efficacy or tolerability between individual anticholinergic drugs.

Kawasaki, A., & Purvin, V. (1996). Persistent palinopsia following ingestion of lysergic acid diethylamide (LSD). Archives of Ophthalmology, 114(1), 47-50.

OBJECTIVE: To identify a distinctive chronic visual complication of lysergic acid diethylamide (LSD) use. DESIGN: Description of the clinical findings in three patients with this disorder. SETTING: A neuro-ophthalmology referral center. RESULTS: All three patients experienced prolonged afterimages (palinopsia) during LSD intoxication and have continued to be symptomatic up to 3 years after they ceased to ingest the drug. Results of neuro-ophthalmologic and neurologic examinations and neuroimaging and electrophysiologic studies were normal. CONCLUSIONS: We have described three patients in whom persistent palinopsia developed following ingestion of LSD. Clinicians should inquire about past LSD use in all patients who initially have seemingly spontaneous, isolated palinopsia. Recognition of this distinctive clinical syndrome associated with LSD use might avoid unnecessary anxiety and excessive diagnostic tests for patients with this disorder.

King, W.,Jr, & Ellison, G. (1989). Long-lasting alterations in behavior and brain neurochemistry following continuous low-level LSD administration. Pharmacology, Biochemistry, and Behavior, 33(1), 69-73.

Groups of rats were administered either 80 micrograms LSD-25 continuously over seven days using subcutaneous minipumps, or were given the same total amount of drug in seven daily injections, or were administered vehicle. When tested long after cessation of drug administration, persisting alterations in behavior and brain were found in the continuous LSD groups. In social open-field tests, this consisted of decreased social distance between animals; this effect increased upon repeated testing. In uptake of labeled ligands, this was reflected predominantly by decreased 3H-LSD binding in several limbic regions. LSD appears to have especially persisting neurotoxic effects when administered in a continuous, low-level fashion.

Kolmel, H. W. (1985). Complex visual hallucinations in the hemianopic field Journal of Neurology, Neurosurgery, and Psychiatry, 48(1), 29-38.

From 120 patients with an homonymous hemianopia 16 experienced complex visual hallucinations in the hemianopic field. The brain lesion was located in the occipital lobe, though damage was not limited to this area. Complex hallucinations appeared after a latent period. They were weak in colour and stereotypical in appearance, which allowed differentiation from visual hallucinations of other causes. Different behaviour after saccadic eye movement differentiated between complex visual hallucinations in the hemianopic field and visual auras of an epileptic origin.

Lambru, G., Castellini, P., Manzoni, G. C., & Torelli, P. (2009). Post-traumatic cluster headache: from the periphery to the central nervous system? Headache, 49(7), 1059-1061. doi:10.1111/j.1526-4610.2009.01456.x

A correlation between head trauma and cluster headache is believed to exist. We report a case of post-traumatic episodic cluster headache that fulfills the criteria of the International Classification of Headache Disorders, 2nd edition. The distinctive features of this case are: a close temporal relation between head trauma and headache onset; pain ipsilateral to the side of trauma; mild severity of trauma; episodic course well-responsive to low doses of verapamil. Given the close temporal relation between the 2 events, multiple hypotheses can be advanced about a possible role of head trauma in the pathogenesis of cluster headache.

Landray, M., Nuttall, S., Lydakis, C., Martin, U., Maxwell, S., & Lip, G. (1998). Oxidative stress after thrombolysis. The Lancet, 352(9132), 960-960. doi:DOI: 10.1016/S0140-6736(05)61514-0

Larbi, A., Kempf, J., & Pawelec, G. (2007). Oxidative stress modulation and T cell activation. Experimental Gerontology, 42(9), 852-858. doi:DOI: 10.1016/j.exger.2007.05.004

Lauterbach, E. C., Abdelhamid, A., & Annandale, J. B. (2000). Posthallucinogen-like visual illusions (palinopsia) with risperidone in a patient without previous hallucinogen exposure: possible relation to serotonin 5HT2a receptor blockade. Pharmacopsychiatry, 33(1), 38-41.

BACKGROUND: Previous reports document visual illusions resembling hallucinogen persisting perception disorder (HPPD) after risperidone treatment in patients with histories of previous LSD exposure. METHODS: We report a case with visual disturbances resembling HPPD after each of three consecutive risperidone dose increases. RESULTS: Contrasting with previous reports, our patient lacked any history of substance abuse, particularly hallucinogen exposure. She lacked neurologic or other contributory illnesses. Illusions generally remitted within 48 hours each time. Coadministration of trazodone and clonazepam may have contributed to these phenomena, although clonazepam has been used to treat this condition. She had been unusually sensitive to the side-effects of many psychotropics. CONCLUSIONS: This case is unique due to the absence of substance abuse. This and another report note heightened sensitivity to medication side-effects. Visual phenomena resembling HPPD evidently can occur with risperidone and, possibly, other atypical antipsychotics and certain antidepressants regardless of previous hallucinogen use. Several lines of evidence implicate reduced 5HT2a serotonin receptor stimulation rather than increased 5HT2c stimulation.

Lefort, G., Moyen, B., Beaufils, P., de Billy, B., Breda, R., Cadilhac, C., Clavert, J. M., Djian, P., Fenoll, B., Giacomelli, M. C., Gicquel, P., Gicquel-Schlemmer, B., Journeau, P., Karger, C., Laptoiu, D., Lefort, G., Mainard-Simard, L., Moyen, B., Negreanu, I., Prove, S., Robert, H., Thaunat, M., & Versier, G. (2006). Osteochondritis dissecans of the femoral condyles: report of 892 cases. [L'osteochondrite dissequante des condyles femoraux] Revue De Chirurgie Orthopedique Et Reparatrice De l'Appareil Moteur, 92(5 Suppl), 2S97-2S141.

PURPOSE OF THE STUDY: Osteochondritis rarely involves the femoral condyles. Discovery in this localization raises several questions concerning the nature of the articular cartilage, the potential for spontaneous healing, and, in the event of a free fragment, the outcome after its loss or repair. MATERIAL AND METHODS: This multicentric study included 892 pediatric and adult cases, the cutoff between two series being defined by fusion of the inferior growth plate. We excluded medical or surgical osteochondritis, cases involving the patella, osteochondral fractures, juvenile polyosteochondrosis, adult osteonecrosis, and osteochondritis beginning after the age of 50 years. RESULTS: Mean age at diagnosis was 16.5 years. Mean age at treatment onset was 22 years. Pain was the predominant symptom. 80% of cases were unilateral and 70% involved the medial condyle. The anatomic lesions were different in adults, showing more advanced degradation. At diagnosis, Bedouelle stages Ia and IIb constituted 80% of the cases observed among children while in adults, 66% were Bedouelle stages IIb to IV. Outcome was very good for the majority of children with Hughston clinical stage 4 while half of the x-rays were Hughston stage 3 and 4. There were thus a large percentage of children with abnormal xrays whose disease history was not yet terminated. In the adult series, the percentages of Hughston 3 and 4 was about the same as clinically. The x-rays were rarely perfectly normal since half of the clinical stage 3 patients were noted in stage 4. An abnormal x-ray with a very good clinical presentation was observed in a very large proportion of patients. DISCUSSION: It is difficult to interpret the plain x-ray and identify patients with a potentially unfavorable prognosis. We defined three radiographic classes: defect, nodule and empty notch. The Bedouelle classification uses information from all available explorations, particularly MRI and arthroscopy. Numerous therapeutic methods are used. Interruption of sports activities is the first intention treatment for children. Data in the literature and the findings of this symposium do not demonstrate any beneficial effect of immobilization on healing compared with simple abstention from sports activities. Transchondral perforation is a simple operation with low morbidity. In 85% of cases, it was used for lesions with an intact joint cartilage considered stable in 96% of cases. Healing was achieved in six months for 48% if the growth plate had not fused. The fragment was fixed in 43% of the cases with a loose cartilage fragment. Outcome was fair but degraded with the state of the joint cartilage and thus the stability of the fragment. Fixation must stabilize the fragment but not prevent further consolidation via osteogenesis. This is why deep perforations are drilled beyond the ossified area and additional osteochondral grafts are used. The Wagner operation gives less satisfactory results than more complicated procedures. Removal of a sequestrum is a simple, minimally invasive procedure with an uneventful postoperative period, but in the long term it favors osteoarthritic degradation, especially when performed in adults. Mosaic grafts give good mid term results. Morbidity is low especially if the grafts are harvested above the notch. The question of chondrolysis around the grafts was beyond the scope of this study. Chondrocyte grafting is difficult to accomplish and is expensive. The mid term results are good for large lesions. Osteotomy is logical only in the event of early stage osteoarthritic degradation. DECISION ALGORITHM IN CHILDREN AND ADOLESCENTS: If the plain x-ray reveals a defect (class I), simple interruption of sports activities should be proposed. Two situations can then develop. First, in a certain number of patients, the pain disappears as the defective zone ossifies progressively. Complete cure is frequent before the age of 12 years. In the second situation, the knee remains painful and the x-ray does not change or worsens to a class II nodular formation. In this case an MRI must be obtained to determine whether the joint cartilage is normal. There are two possibilities. First, the osteochondral fragment is viable and most probably will become completely re-integrated, particularly if the lesion is far from the growth plate. Necrosis is the other possibility. Transchondral perforations are needed in this case. If on the contrary the cartilage is altered, there is little hope for spontaneous cure. Arthroscopy may be needed to complete the exploration. Fragments, especially if there is a large surface area, must be fixed. Perforations to favor revascularization are certainly useful here. In the last situation (class III), the fragment wobbles on a thin attachment or has already fallen into the joint space. This is the type of problem generally observed in adults. The decision algorithm in adults is the same as in children for the rare nodular aspects (class II). There could be a discussion between transcartilage perforation and fixation. If there are a large number of fragments, fixation may not be fully successful and the lesion might be considered class III. For class III lesions, three operations can be used: removal of the sequestrum, mosaic bone-cartilage grafts, or autologous chondrocyte grafts. At the same follow-up, mosaic grafts give better results than excision of sequestra. It may be useful to remove sequestra in a limited number of situations: if there is just a small area of osteochondritis, the lesion is old and partially healed, or the zone is non weight-bearing. For other lesions, we favor mosaic grafts. We still do not have enough follow-up to assess the long-term outcome with these mosaic grafts, but simple excision clearly favors osteoarthritic degradation. Can chondrocytes grafts be compared with mosaic grafts? Chondrocyte grafts have been used for very large lesions and have given results similar to mosaic grafts. It might also be possible to combine fixation of a loose fragment and a mosaic graft. LESSONS FROM THIS STUDY: 1) The prognosis of osteochondritis is better before than after fusion of the growth plate but the lesion does not always heal in children. 2) Presence of osteochondritis requires complementary anatomic and functional exploration to determine the stability and the vitality of the fragment. 3) Attention must be taken to perform transchondral perforations early enough, particularly in children. 4) Screw fixation is not always sufficient. The trophicity of the fragment and its blood supply must be improved. 5) Mosaic grafts are preferable to excision of the fragment. 6) Chondrocyte grafts will be more widely used in the future.

Leikin, J. B., Krantz, A. J., Zell-Kanter, M., Barkin, R. L., & Hryhorczuk, D. O. (1989). Clinical features and management of intoxication due to hallucinogenic drugs. Medical Toxicology and Adverse Drug Experience, 4(5), 324-350.

Hallucinogenic drugs are unique in that they produce the desired hallucinogenic effects at what are considered non-toxic doses. The hallucinogenic drugs can be categorised into 4 basic groups: indole alkaloid derivatives, piperidine derivatives, phenylethylamines and the cannabinols. The drugs reviewed include lysergic acid diethylamide (LSD), phencyclidine (PCP), cocaine, amphetamines, opiates, marijuana, psilocybin, mescaline, and 'designer drugs.' Particularly noteworthy is that each hallucinogen produces characteristic behavioural effects which are related to its serotonergic, dopaminergic or adrenergic activity. Cocaine produces simple hallucinations, PCP can produce complex hallucinations analogous to a paranoid psychosis, while LSD produces a combination of hallucinations, pseudohallucinations and illusions. Dose relationships with changes in the quality of the hallucinatory experience have been described with amphetamines and, to some extent, LSD. Flashbacks have been described with LSD and alcohol. Management of the intoxicated patient is dependent on the specific behavioural manifestation elicited by the drug. The principles involve differentiating the patient's symptoms from organic (medical or toxicological) and psychiatric aetiologies and identifying the symptom complex associated with the particular drug. Panic reactions may require treatment with a benzodiazepine or haloperidol. Patients with LSD psychosis may require an antipsychotic. Patients exhibiting prolonged drug-induced psychosis may require a variety of treatments including ECT, lithium and l-5-hydroxytryptophan.

Leipsic, J. S., Abraham, H. D., & Halperin, P. (1995). Neuroleptic malignant syndrome in the elderly. Journal of Geriatric Psychiatry and Neurology, 8(1), 28-31.

Four cases of neuroleptic malignant syndrome (NMS) were identified in a general hospital over a 5-year period. Two cases presented to the psychiatric consultation liaison service, and two were found by a computerized review of discharge diagnoses. Cases were examined for age, sex, administered neuroleptic potency and dose, premorbid history, prodromal symptoms, methods of treatment, and clinical outcome. The mean age of cases was found to be 14 years greater than the age of the non-NMS patient population. All NMS cases had premorbid neuropsychiatric disorders and recognizable prodromal symptoms. The mean neuroleptic dose was significantly lower than in previously reported cases. A systems model integrating premorbid factors, intercurrent illness, and drug effects in pathogenesis is presented.

Leone, M., & Bussone, G. (2009). Pathophysiology of trigeminal autonomic cephalalgias. Lancet Neurology, 8(8), 755-764. doi:10.1016/S1474-4422(09)70133-4

Cluster headache, paroxysmal hemicrania, and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) are primary headaches recently classified together as trigeminal autonomic cephalalgias (TACs). The causes of these headaches have long been debated, with "peripheral" hypotheses in opposition to "central" hypotheses. The available information indicates that the pain originates from within the brain in cluster headache. The hypothalamic activation observed during TAC attacks by use of functional neuroimaging, and the success of hypothalamic stimulation as a treatment, confirm that the posterior hypothalamus is crucial in the pathophysiology of these headaches. The posterior hypothalamus is now known to modulate craniofacial pain, and hypothalamic activation occurs in other pain disorders, suggesting that this brain area is likely to have a more complex role in the pathophysiology of TACs than that of a mere trigger. Hypothalamic activation might play a part in terminating rather than triggering attacks, and might also give rise to a central permissive state, allowing attacks to take place.

Leone, M., Franzini, A., Cecchini, A. P., Mea, E., Broggi, G., & Bussone, G. (2009). Costs of hypothalamic stimulation in chronic drug-resistant cluster headache: preliminary data. Neurological Sciences : Official Journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology, 30 Suppl 1, S43-7. doi:10.1007/s10072-009-0057-3

In about 20% of chronic cluster headache (CH) cases, drugs may become ineffective. Under these circumstances, steroids and triptans are frequently employed leading to fearful side effects in one and high costs in the other. The direct costs of drug-resistant chronic CH are mainly due to frequent medical consultations and frequent use of expensive drugs. In recent years, hypothalamic stimulation has been employed to treat drug-resistant chronic CH patients suffering multiple daily attacks and long-term results from different centres show a 60% overall benefit. Nine years since the introduction of this technique, we attempt a preliminary analysis of the direct costs of hypothalamic stimulation based on patients treated at our centre. We estimated the following direct costs as follows: cost of neurosurgery plus cost of equipment (electrode, connection and impulse generator = 25,000 euro), cost of hospital admissions in long-term follow-up (2,000 euro per admission), cost of single sumatriptan injection (25 euro). Number of daily sumatriptan injections in the year before and for each year after hypothalamic implantation was obtained from headache diaries. To estimate the saving due to the reduction in sumatriptan consumption following hypothalamic stimulation, we calculated the following for each year of follow-up after surgery: number of sumatriptan injections in the year before surgery minus number of sumatriptan injections in each year, updated to December 2008. In our 19 implanted patients, the costs of neurosurgery plus cost of equipment were 475,000 euro; the costs of hospital admissions during follow up were 250,000 euro. Reduction in sumatriptan consumption resulted in a total saving of 3,573,125 euro. Hence, in our 19 patients, the sumatriptan saving (3,573,125 euro) minus the direct costs due to operation and follow up hospitalisations (475,000 + 250,000) euro is equal to 2,848,125 euro. These preliminary results indicate that hypothalamic stimulation is associated with marked reduction of direct costs in the management of complete drug-resistant chronic CH.

Lerner, A. G., Finkel, B., Oyffe, I., Merenzon, I., & Sigal, M. (1998). Clonidine treatment for hallucinogen persisting perception disorder. The American Journal of Psychiatry, 155(10), 1460.

Lerner, A. G., Gelkopf, M., Oyffe, I., Finkel, B., Katz, S., Sigal, M., & Weizman, A. (2000). LSD-induced hallucinogen persisting perception disorder treatment with clonidine: an open pilot study. International Clinical Psychopharmacology, 15(1), 35-37.

A pilot open study was conducted in order to evaluate the efficacy of clonidine in the treatment of LSD-induced hallucinogen persisting perception disorder (HPPD). Eight patients fulfilled entrance criteria. All complained of HPPD for at least 3 months and were drug free at least 3 months. They received fixed low doses of clonidine, 0.025 mg, three times a day for 2 months. They were evaluated by the Clinical Global Impression Scale (CGI) and a self-report scale on the severity of symptoms (graded 0-5). Patients scored an average of 5.25 (SD = 0.46) on the CGI and 4 on the self-report scale at baseline, indicating marked psychopathology. One patient dropped out at week 3 and a second patient dropped out at week 5. Of the six patients remaining at the end of 2 months, the average CGI score was 2.5 (SD = 0.55) and the self-report scale score was 2, indicating mild symptomatology. LSD-related flashbacks associated with excessive sympathetic nervous activity may be alleviated with clonidine in some patients.

Lerner, A. G., Gelkopf, M., Skladman, I., Oyffe, I., Finkel, B., Sigal, M., & Weizman, A. (2002). Flashback and Hallucinogen Persisting Perception Disorder: clinical aspects and pharmacological treatment approach. The Israel Journal of Psychiatry and Related Sciences, 39(2), 92-99.

One unique characteristic of lysergic acid diethylamide (LSD) and LSD-like substances is the recurrence of some of the symptoms which appeared during the intoxication after the immediate effect of the hallucinogen has worn off. This recurring syndrome, mainly visual, has not been clearly understood, appreciated or distinguished from other clinical entities by clinicians. The terms Flashback and Hallucinogen Persisting Perception Disorder (HPPD) are used interchangeably in the professional literature. Flashback is a usually short-term, non-distressing, spontaneous, recurrent, reversible and benign condition accompanied by a pleasant affect. In contrast, HPPD is a generally long-term, distressing, spontaneous, recurrent, pervasive, either slowly reversible or irreversible, non-benign condition accompanied by an unpleasant dysphoric affect. Flashback and HPPD appear to be part of a vast and broad spectrum of non-psychopathological and psychopathological states reported by hallucinogen users. Pharmacological agents such as clonidine, perphenazine and clonazepan have been shown to ameliorate this syndrome in some of the individuals seeking treatment.

Lerner, A. G., Gelkopf, M., Skladman, I., Rudinski, D., Nachshon, H., & Bleich, A. (2003). Clonazepam treatment of lysergic acid diethylamide-induced hallucinogen persisting perception disorder with anxiety features. International Clinical Psychopharmacology, 18(2), 101-105. doi:10.1097/01.yic.0000053665.88477.46

An unique and intriguing characteristic of lysergic acid diethylamide (LSD) and LSD-like substances is the recurrence of some of the symptoms which appear during the intoxication, in the absence of recent intake of hallucinogens. Hallucinogen persisting perception disorder (HPPD) is a condition in which the re-experiencing of one or more perceptual symptoms causes significant distress or impairment in social, occupational or other important areas of functioning and may be extremely debilitating. Benzodiazepines are one of the recommended agents for the treatment of HPPD but it is unclear which of them may be more helpful. The goal of our investigation was to assess the efficacy of clonazepam in the treatment of LSD-induced HPPD. Sixteen patients fulfilled entrance criteria. All complained of HPPD with anxiety features for at least 3 months and were drug free at least 3 months. They received clonazepam 2 mg/day for 2 months. Follow-up was continued for 6 months. They were weekly evaluated during the 2 months of clonazepam administration and monthly during the follow-up period using the Clinical Global Impression Scale, a Self-report Scale and Hamilton Anxiety Rating Scale. Patients reported a significant relief and the presence of only mild symptomatology during the clonazepam administration. This improvement was clearly sustained and persisted during a 6-month follow-up period. This study suggests that high potency benzodiazepines like clonazepam, which has serotonergic properties, may be more effective than low-potency benzodiazepines in the treatment of some patients with LSD-induced HPPD.

Lerner, A. G., Oyefe, I., Isaacs, G., & Sigal, M. (1997). Naltrexone treatment of hallucinogen persisting perception disorder. The American Journal of Psychiatry, 154(3), 437.

Lerner, A. G., Shufman, E., Kodesh, A., Kretzmer, G., & Sigal, M. (2002). LSD-induced Hallucinogen Persisting Perception Disorder with depressive features treated with reboxetine: case report. The Israel Journal of Psychiatry and Related Sciences, 39(2), 100-103.

We would like to present the case of a patient who had a prior history of cannabis, ecstasy (MDMA) and LSD abuse and who developed both Hallucinogen Persisting Perception Disorder (HPPD) and a major depressive episode. Following two unsuccessful SSRIs trials, reboxetine was prescribed. During a six-month follow-up period on reboxetine 6 mg./day, no exacerbation of the visual disturbance or recurrence of the depressive features were reported. Reboxetine may have an alpha 2 adrenoreceptor modulating effect on both noradrenaline and serotonin release, thus reboxetine's alpha 2 adrenoreceptor modulating effect on noradrenaline release may affect sympathetic activity and be involved in the recovery process.

Lerner, A. G., Skladman, I., Kodesh, A., Sigal, M., & Shufman, E. (2001). LSD-induced Hallucinogen Persisting Perception Disorder treated with clonazepam: two case reports. The Israel Journal of Psychiatry and Related Sciences, 38(2), 133-136.

Benzodiazepines are recommended for the treatment of Hallucinogen Persisting Perception Disorder (HPPD), although it is unclear which may be more helpful. Two out-patients with LSD-induced HPPD were successfully treated with clonazepam. They had not responded to low potency benzodiazepines or low doses of classic antipsychotics. After clonazepam discontinuation they reported a marked improvement and only mild symptomatology which persisted during a six month follow-up period. High potency benzodiazepines like clonazepam, which has serotonergic properties, may be superior to low-potency benzodiazepines in the treatment of some patients with LSD-induced HPPD.

Lethaby, A. E., Cooke, I., & Rees, M. (2005). Progesterone or progestogen-releasing intrauterine systems for heavy menstrual bleeding. Cochrane Database of Systematic Reviews (Online), (4)(4), CD002126. doi:10.1002/14651858.CD002126.pub2

BACKGROUND: Heavy menstrual bleeding (HMB) is an important cause of ill health in women and it accounts for 12% of all gynaecology referrals in the UK. Heavy menstrual bleeding is clinically defined as greater than or equal to 80 ml of blood loss per menstrual cycle. However, women may complain of excessive bleeding when their blood loss is less than 80 ml. Hysterectomy is often used to treat women with this complaint but medical therapy may be a successful alternative.The intrauterine coil device was originally developed as a contraceptive but the addition of uterine relaxing hormones, progestogens, to these devices resulted in a large reduction in menstrual blood loss. Case studies of two types of progesterone or progestogen-releasing systems, Progestasert and Mirena, reported reductions of up to 90% and that dysmenorrhoea may be improved. Insertion, however, may be regarded as invasive by some women, which affects its acceptability as a treatment. Frequent intermenstrual bleeding and spotting is also likely during the first few months. OBJECTIVES: To determine the effectiveness and acceptability of progesterone or progestogen-releasing intrauterine devices in achieving a reduction in heavy menstrual bleeding. SEARCH STRATEGY: All studies which might describe randomised controlled trials of progesterone or progestagen-releasing intrauterine devices for the treatment of heavy menstrual bleeding were obtained by electronic searches of The Cochrane Library, MEDLINE (1966 to 2005) and EMBASE (1980 to 2005). Companies producing progestogen-releasing intrauterine devices and experts in the field were contacted for information on published and unpublished trials. SELECTION CRITERIA: Randomised controlled trials in women of reproductive age treated with progesterone or progestogen-releasing intrauterine devices versus no treatment, placebo, or other medical or surgical therapy for heavy menstrual bleeding within primary care, family planning or specialist clinic settings were eligible for inclusion. Women with postmenopausal bleeding, intermenstrual or irregular bleeding, or pathological causes of heavy menstrual bleeding were excluded. DATA COLLECTION AND ANALYSIS: Potential trials were independently assessed by three review authors and nine trials met the criteria for inclusion in the review. The reviewers extracted the data independently and data were pooled where appropriate. Odds ratios (OR) were estimated from the data for dichotomous outcomes and weighted mean differences (WMD) for continuous outcomes. The primary outcome was reduction in menstrual blood loss but incidence of side effects, changes in quality of life, satisfaction and acceptability measures were also assessed. MAIN RESULTS: Progesterone or progestogen-releasing intrauterine systems have not been compared to placebo or no treatment. Progestasert has been compared to a number of different medical therapies in one small study but no conclusions can be made about its effectiveness. The levonorgestrel-releasing intrauterine device (LNG IUS) has been compared to oral cyclical norethisterone (NET) administered on days 5 to 26 of the menstrual cycle in one trial and was significantly more effective although there was a large reduction in loss from baseline in both groups. Some short term side effects were more common in the LNG IUS group but a significantly greater proportion of women in this group were satisfied and willing to continue with their treatment. In one trial of women awaiting hysterectomy, where the LNG IUS was compared with a control group taking their existing medical therapy, a higher proportion of the women in the intrauterine device group cancelled their planned surgery after six months of treatment.The LNG IUS has been compared to an endometrial ablation: either transcervical resection of the endometrium (TCRE) (two trials) or balloon ablation (three trials). There was a significantly greater mean reduction in menstrual bleeding in one trial in those undergoing balloon ablation (WMD -45.2 units, 95% CI -56.9 to -33.5), a lower score on the pictorial blood loss chart (PBAC) (WMD 33.2 units, 95% CI 27.2 to 39.2) and higher rates of successful treatment in 3 trials including both balloon and TCRE (OR 0.28, 95% CI 0.14 to 0.58) but the rates of satisfaction with treatment was were similar. There was no conclusive evidence of changes in quality of life between groups but women with the LNG IUS had a greater incidence of progestogenic side effects within one year. The LNG IUS has been compared to hysterectomy in one trial. There was no evidence of a change in quality of life scores but the LNG IUS treatment had lower costs than with hysterectomy, both at one and five-years follow up. AUTHORS' CONCLUSIONS: The levonorgestrel-releasing intrauterine device (LNG IUS) is more effective than cyclical norethisterone (for 21 days) as a treatment for heavy menstrual bleeding. Women with an LNG IUS are more satisfied and willing to continue with treatment but experience more side effects, such as intermenstrual bleeding and breast tenderness.The LNG IUS results in a smaller mean reduction in menstrual blood loss (as assessed by the PBAC chart) than endometrial ablation but there is no evidence of a difference in the rate of satisfaction with treatment. Women with an LNG IUS experience more progestogenic side effects compared to women having TCRE for treatment of their heavy menstrual bleeding but there is no evidence of a difference in their perceived quality of life.The LNG IUS treatment costs less than hysterectomy but there is no evidence of a difference in quality of life measures between these groups.There are no data available from randomised controlled trials comparing progesterone-releasing intrauterine systems to either placebo or other commonly used medical therapies for heavy menstrual bleeding.

Linszen, D., & van Amelsvoort, T. (2007). Cannabis and psychosis: an update on course and biological plausible mechanisms. Current Opinion in Psychiatry, 20(2), 116-120. doi:10.1097/YCO.0b013e32803577fb

PURPOSE OF REVIEW: Cannabis use is the most commonly abused illicit substance. Its relation with psychosis remains a topic of debate. Epidemiological studies suggest that cannabis is a component cause accounting for approximately 10% of cases. An increasing number of studies have been published on neurobiological effects of cannabis and vulnerability of psychosis. RECENT FINDINGS: Acute cannabis administration can induce memory impairments, sometimes persisting months following abstinence. There is no evidence that residual effects on cognition remain after years of abstinence. The scarce literature on neuro-imaging mainly done in nonpsychotic populations, show little evidence that cannabis has effects on brain anatomy. Acute effects of cannabis include increases of cerebral blood flow, whereas long-term effects of cannabis include attenuation of cerebral blood flow. In animals Delta9-tetrahydrocannabinol enhances dopaminergic neurotransmission in brain regions known to be implicated in psychosis. Studies in humans show that genetic vulnerability may add to increased risk of developing psychosis and cognitive impairments following cannabis consumption. Delta9-tetrahydrocannabinol induces psychotic like states and memory impairments in healthy volunteers. SUMMARY: Simultaneously with increasing understanding of neurobiological cannabis effects, there is a lack of studies in people with psychosis. There are plausible mechanisms that might explain the psychotogenic effects of cannabis.

Llorca, P. M., Miadi-Fargier, H., Lancon, C., Jasso Mosqueda, G., Casadebaig, F., Philippe, A., Guillon, P., Mehnert, A., Omnes, L. F., Chicoye, A., & Durand-Zaleski, I. (2005). Cost-effectiveness analysis of schizophrenic patient care settings: impact of an atypical antipsychotic under long-acting injection formulation. [Analyse cout-efficacite des strategies de prise en charge des patients schizophrenes: place d'un antipsychotique atypique sous forme injectable a liberation prolongee] L'Encephale, 31(2), 235-246.

Schizophrenia is a disease affecting the young adults and amounts to approximately 300,000 people in France. The French public psychiatric sector takes care of approximately 150,000 adults schizophrenics: 50% benefit from ambulatory care, 50% are in partial or full-time hospitalization care. Schizophrenia represents the first diagnosis that psychiatric sectors take in charge. The costs associated with schizophrenia, mainly hospital costs, are important and were estimated at 2% of the total medical costs in France. In the French social welfare system, the social costs (pensions, allowances, managements of custody or guardianship by social workers) are also to be taken into account: it amounts to a third of the global direct cost. Schizophrenia also generates indirect costs (losses of productivity and premature deaths) which would be at least equal, or even more important, than direct medical costs. The non-compliance to the antipsychotic treatment is a major problem with people suffering from schizophrenia. Indeed the lack of compliance to the treatment, estimated at 20 to 40%, is a major handicap for schizophrenic patient stabilization. The poor level of compliance is due to many various causes: adverse effects that are considered unbearable, medicine viewed as persecutory, negation of the disease, nostalgia for the productive phases of the disease, lack of social support, complexity of the prescription, relapse itself. Compliance is thus influenced by the patient's clinical features, local provision of health care and the specific nature of the drug (adverse effects, pharmaceutical formulation). The atypical antipsychotics present fewer extrapyramidal side effects and reduce the cognitive deficits associated with the disease, which results in improved compliance. Long-acting injectable antipsychotics allow a better therapeutic compliance and thus better efficacy of the treatment. Several studies have shown a significant improvement in compliance related to the pharmaceutical formulation of antipsychotics. Hospitalization and relapse risks are lower in compliant than in non-compliant patients. OBJECTIVES: The main objective of this pharmacoeconomic analysis is to evaluate the impact in terms of medical benefits and costs of the following strategies: 1. Risperidone long-acting injection: first long-acting injectable atypical antipsychotic; 2. Haloperidol depot: long-acting injectable conventional neuroleptic; 3. Olanzapine: atypical antipsychotic available commercially in oral formulation. METHODS: The target population defined for the study are young schizophrenic patients treated for at least 1 year and whose disorder has not been diagnosed for longer than 5 years. The time horizon is 2 years. A cost-effectiveness analysis is performed. The perspective adopted is the French Health System. The main hypothesis of the model is that an increase in compliance linked to the use of long-acting injectable formulation could lead to an increased efficacy and a modification of the cost-effectiveness ratio. A decision tree was built. Six periods of follow-up are identified with a duration of 4-months per period. The tree contains 3 principal arms, each one corresponding to a specific treatment: risperidone LA injection, haloperidol decanoate and olanzapine. For each arm, at the chance node, two health states are identified: either the patient responds favourably to the treatment or does not respond favourably and requires a switch to another drug treatment. After a period of response, the patient can either remain in the same state or experiences a clinical deterioration. If the patient presents a clinical deterioration, he can either go back to a positive response state after a period of intensive follow-up or remain in an insufficient response state; in this case, a change of antipsychotic treatment is necessary. In the model, a patient should receive four different treatments before a long-term hospitalization takes put in place. According to the market authorization labelling, clozapine is proposed only as a 2nd or 3rd line therapeutic option, so when at least one or two successive neuroleptics have failed. The efficacy data used in the model are provided by clinical research recently published. These studies estimate the efficacy of oral risperidone, LA risperidone, olanzapine, and treatment by haloperidol. When available data in the literature were insufficient, the opinion of experts was sought. The effectiveness criteria is the rate of patients treated successfully: patients responding to the initial treatment with the possibility of experiencing one or two episodes of clinical deterioration but without requiring a switch to another drug during 2 years of follow-up. The base case is as follows: efficacy for oral risperidone is used for the LA risperidone strategy, increased by 10% within the first 4 months of follow-up; efficacy for oral haloperidol is used for haloperidol depot, increased by 5% within the first 4 months of follow-up; for olanzapine, observed data in clinical trials were applied. The hypotheses for long acting forms are rather conservative because the increase of efficacy which can be expected for the long-acting injectable formulations varies between 5% to more than 30% according to the literature data. The analysis of sensibility includes three scenarios: scenario 1: for LA risperidone, 5% of patients treated successfully improvement in regard to oral risperidone instead of 10% in the base case; scenario 2: for haloperidol depot, 10% of patients treated successfully improvement in regard of oral haloperidol instead of 5% in the base case; scenario 3: the results of an open trial conducted within the framework of the LA risperidone license are used, leading to an increase of up to 13,3% of the rate of successfully treated patients, compared to oral risperidone literature data. As for the side effects, only extrapyramidal symptoms were considered. Other side effects are described in the literature such as the obesity or the occurrence of a diabetes; these effects were not taken into account in the model, their impact on the cove-rage of schizophrenic patients and on resources utilisation being poorly known. Only direct medical costs were considered in the pharmaco-economic analysis. Two types of costs were identified: hospital costs and community care costs. The stays in overnight hospitalisation and day hospitalisation were derived from the Disease Related Groups (DRG) and valued from the data of the National Cost Study (Etude Nationale de Couts; 1999). The DRGs corresponding to the diagnosis of schizophrenia are the DRG 627 (complete hospitalization) and DRG 819 (day hospitalisation). Ambulatory care: procedures and visits, were valued in euros in reference with the tariffs for reimbursement issued in the Naming General of the Professional Acts (NGAP) and published by the French National Health Insurance (Year 2001). Medication consumption was quantified by using the daily dosage specified in the the MAA and the French prescription database IMS-Dorema. The cost of medicines was valued from tariffs 2001 (SEMPEX). LA risperidone price being not fixed to date, the reserved hypothesis is a 141,62 Euro retail price. As schizophrenia is listed among the diseases reimbursed at a 100% rate by the Health insurance, out of pocket expenses by patient are not considered in the analysis. The cost for the extrapyramidal effects was attributed to all the strategies. This cost was calculated according to the rates of extrapyramidal effects occurrence collected in the literature. Globally, in the published studies, the incidence of the side effects for the patients treated by olanzapine or risperidone is similar. It was thus decided by the experts to use the same rate of occurrence for extrapyramidal effects for olanzapine and risperidone (20%). This rate is 40% for haloperidol decanoate, 10% for oral clozapine. For the cost estimation, the expenses for treating a schizophrenic patient for two years were taken into account. RESULTS: The results show that in two years, LA risperidone is more effective than the two other antipsychotics. After 2 years, the rate of patients treated successfully is 82,7% for LA risperidone, 74,8% for olanzapine and 57,3% for haloperidol depot. The 2 year-cost per patient treated by LA risperidone is 14,055 Euro. This cost is 14,351 Euro and 17,203 Euro respectively for the strategies olanzapine and haloperidol depot. The cost-efficacy ratios per patient successfully treated are 16,995 Euro for the strategy LA risperidone, 19,186 Euro for olanzapine and 30,023 Euro for haloperidol depot. LA risperidone is a dominant strategy compared with both olanzapine and haloperidol depot. Scenario 1 shows that LA risperidone strategy remains the most effective. Indeed, this strategy allows a response increase of 3,5% regarding olanzapine strategy and of 21% regarding haloperidol depot strategy. Under the hypothesis tested in scenario 1, LA risperidone is a partial dominant strategy against olanzapine and a total dominant strategy against haloperidol depot. In scenario 2, as efficacy is improved for haloperidol decanoate (61,10%), a decrease of 1,763 Euro in the cost per patient treated is observed for this strategy. Cost per patient treated successfully and efficacy for LA risperidone and olanzapine are the same than in the base case. LA risperidone is a total dominant strategy against olanzapine and haloperidol decanoate. In scenario 3, the rate of patients treated successfully at 2 years is 88,6% for LA risperidone with a cost per patient of 12,347 Euro. LA risperidone is dominant against olanzapine and haloperidol depot. DISCUSSION AND CONCLUSION: The schizophrenia is a relatively frequent disease. (ABSTRACT TRUNCATED)

Lostumbo, L., Carbine, N., Wallace, J., & Ezzo, J. (2004). Prophylactic mastectomy for the prevention of breast cancer. Cochrane Database of Systematic Reviews (Online), (4)(4), CD002748. doi:10.1002/14651858.CD002748.pub2

BACKGROUND: Breast cancer is the most common cancer and the second most common cause of cancer-related death among North American and Western European women. Recent progress in understanding the genetic basis of breast cancer, along with rising incidence rates, have resulted in increased interest in prophylactic mastectomy as a method of preventing breast cancer, particularly in those with familial susceptibility. OBJECTIVES: The primary objective was to determine whether prophylactic mastectomy reduces death from any cause in women who have never had breast cancer and in women who have a history of breast cancer in one breast. The secondary objective was to examine the effect of prophylactic mastectomy on other endpoints including breast cancer incidence, breast cancer mortality, disease-free survival, physical morbidity, and psychosocial outcomes. SEARCH STRATEGY: Electronic searches were performed in the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Cancerlit, and the Science Citation Index. SELECTION CRITERIA: Inclusion criteria were studies in English of any design type including randomized or nonrandomized controlled trials, cohort studies, case-control studies, and case series with at least ten participants. Participants included women at risk for breast cancer in at least one breast. Interventions included all types of mastectomy performed for the purpose of preventing breast cancer, including subcutaneous mastectomy, total or simple mastectomy, modified radical mastectomy, and radical mastectomy. DATA COLLECTION AND ANALYSIS: Information on patients, interventions, methods, and results were extracted by at least two independent reviewers. Methodological quality was assessed based on how well each study minimized potential selection bias, performance bias, detection bias, and attrition bias. Data for each study were summarized descriptively; quantitative meta-analysis was not feasible due to heterogeneity of study designs and insufficient reporting. Data were analyzed separately for bilateral prophylactic mastectomy (BPM) and contralateral prophylactic mastectomy (CPM). MAIN RESULTS: Twenty-three studies, including more than 4,000 patients, met inclusion criteria. No randomized or nonrandomized controlled trials were found. Most studies were either case series or cohort studies. All studies had methodological limitations, with the most common source of potential bias being systematic differences between the intervention and comparison groups that could potentially be associated with a particular outcome. Thirteen studies assessed the effectiveness of BPM. No study assessed all-cause mortality after BPM. All studies reporting on incidence of breast cancer and disease-specific mortality reported reductions after BPM. Nine studies assessed psychosocial measures; most reported high levels of satisfaction with the decision to have prophylactic mastectomy (PM) but more variable satisfaction with cosmetic results. Only one study assessed satisfaction with the psychological support provided by healthcare personnel during risk counseling and showed that more women were dissatisfied than satisfied with the support they received in the healthcare setting. Worry over breast cancer was significantly reduced after BPM when compared both to baseline worry levels and to the groups who opted for surveillance rather than BPM. Three studies reported body image/feelings of femininity outcomes, and all reported that a substantial minority (about 20%) reported BPM had adverse effects on those domains. Six studies assessed contralateral prophylactic mastectomy. Studies consistently reported reductions in contralateral incidence of breast cancer but were inconsistent about improvements in disease-specific survival. Only one study attempted to control for multiple differences between intervention groups, and this study showed no overall survival advantage for CPM at 15 years. Two case series were exclusively focused on adverse events from prophylactic mastectomy with reconstruction, and both reported rates of unanticipated re-operations from 30% to 49%. REVIEWERS' CONCLUSIONS: While published observational studies demonstrated that BPM was effective in reducing both the incidence of, and death from, breast cancer, more rigorous prospective studies (ideally randomized trials) are needed. The studies need to be of sufficient duration and make better attempts to control for selection biases to arrive at better estimates of risk reduction. The state of the science is far from exact in predicting who will get or who will die from breast cancer. By one estimate, most of the women deemed high risk by family history (but not necessarily BRCA 1 or 2 mutation carriers) who underwent these procedures would not have died from breast cancer, even without prophylactic surgery. Therefore, women need to understand that this procedure should be considered only among those at very high risk of the disease.For women who had already been diagnosed with a primary tumor, the data were particularly lacking for indications for contralateral prophylactic mastectomy. While it appeared that contralateral mastectomy may reduce the incidence of cancer in the contralateral breast, there was insufficient evidence about whether, and for whom, CPM actually improved survival.Physical morbidity is not uncommon following PM, and many women underwent unanticipated re-operations (usually due to problems with reconstruction); however, these data need to be updated to reflect changes in surgical procedures and reconstruction.Regarding psychosocial outcomes, women generally reported satisfaction with their decisions to have PM but reported satisfaction less consistently for cosmetic outcomes, with diminished satisfaction often due to surgical complications. Therefore, physical morbidity and post-operative surgical complications were areas that should be considered when deciding about PM. With regard to emotional well-being, most women recovered well postoperatively, reporting reduced cancer worry and showing reduced psychological morbidity from their baseline measures; exceptions also have been noted. Of the psychosocial outcomes measured, body image and feelings of femininity were the most adversely affected.

Lous, J., Burton, M. J., Felding, J. U., Ovesen, T., Rovers, M. M., & Williamson, I. (2005). Grommets (ventilation tubes) for hearing loss associated with otitis media with effusion in children. Cochrane Database of Systematic Reviews (Online), (1)(1), CD001801. doi:10.1002/14651858.CD001801.pub2

BACKGROUND: Otitis media with effusion (OME), or 'glue ear', is very common in children, especially between the ages of one and three years with a prevalence of 10% to 30% and a cumulative incidence of 80% at the age of four years. OME is defined as middle ear effusion without signs or symptoms of an acute infection. OME may occur as a primary disorder or as a sequel to acute otitis media. The functional effect of OME is a conductive hearing level of about 25 to 30 dB associated with fluid in the middle ear. Both the high incidence and the high rate of spontaneous resolution suggest that the presence of OME is a natural phenomenon, its presence at some stage in childhood being a normal finding. Notwithstanding this, some children with OME may go on to develop chronic otitis media with structural changes (tympanic membrane retraction pockets, erosion of portions of the ossicular chain and cholesteatoma), language delays and behavioural problems. It remains uncertain whether or not any of these findings are direct consequences of OME. The most common medical treatment options include the use of decongestants, mucolytics, steroids, antihistamines and antibiotics. The effectiveness of these therapies has not been established. Surgical treatment options include grommet (ventilation or tympanostomy tube) insertion, adenoidectomy or both. Opinions regarding the risks and benefits of grommet insertion vary greatly. The management of OME therefore remains controversial. OBJECTIVES: To assess the effectiveness of grommet insertion compared with myringotomy or non-surgical treatment in children with OME. The outcomes studied were (i) hearing level, (ii) duration of middle ear effusion, (iii) well-being (quality of life) and (iv) prevention of developmental sequelae possibly attributable to the hearing loss (for example, impairment in impressive and expressive language development (measured using standardised tests), verbal intelligence, and behaviour). SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 1, 2003), MEDLINE (1966 to 2003), EMBASE (1973 to 2003) and reference lists of all identified studies. The date of the last systematic search was March 2003, and personal non-systematic searches have been performed up to August 2004. SELECTION CRITERIA: Randomised controlled trials (RCTs) evaluating the effect of grommets on hearing, duration of effusion, development of language, cognition, behaviour or quality of life. Only studies using common types of grommets (mean function time of 6 to 12 months) were included. DATA COLLECTION AND ANALYSIS: Data from studies were extracted by two reviewers and checked by the other reviewers. MAIN RESULTS: Children treated with grommets spent 32% less time (95% confidence interval (CI) 17% to 48%) with effusion during the first year of follow-up. Treatment with grommets improved hearing levels, especially during the first six months. In the randomised controlled trials that studied the effect of grommet insertion alone, the mean hearing levels improved by around 9 dB (95% CI 4 dB to 14 dB) after the first six months, and 6 dB (95% CI 3 dB to 9 dB) after 12 months. In the randomised controlled trials that studied the combined effect of grommets and adenoidectomy, the additional effect of the grommets on hearing levels was improvement by 3 to 4 dB (95% CI 2 dB to 5 dB) at six months and about 1 to 2 dB (95% CI 0 dB to 3 dB) at 12 months. Ears treated with grommets had an additional risk for tympanosclerosis of 0.33 (95% CI 0.21 to 0.45) one to five years later. In otherwise healthy children with long-standing OME and hearing loss, early insertion of grommets had no effect on language development or cognition. One randomised controlled trial in children with OME more than nine months, hearing loss and disruptions to speech, language, learning or behaviour showed a very marginal effect of grommets on comprehensive language. AUTHORS' CONCLUSIONS: The benefits of grommets in children appear small. The effect of grommets on hearing diminished during the first year. Potentially adverse effects on the tympanic membrane are common after grommet insertion. Therefore an initial period of watchful waiting seems to be an appropriate management strategy for most children with OME. As no evidence is yet available for the subgroups of children with speech or language delays, behavioural and learning problems or children with defined clinical syndromes (generally excluded from the primary studies included in this review), the clinician will need to make decisions regarding treatment for such children based on other evidence and indications of disability related to hearing impairment.This review does not resolve the discrepancy between parental and clinical observation of a beneficial treatment effect and the results in the reviewed RCT showing only a short-term effect on hearing and virtually no effect on development. Is the perceived, often dramatic, effect of grommets only a short-term one? Are some children more sensitive to OME-related hearing loss than others? If so, how do we identify them?Further research should focus upon indications. Studies should use sufficiently large sample sizes to show significant interactions. There is a need to determine the most suitable variables and appropriate "softer" outcomes to be the subject of these interaction tests. Interesting options include measures of speech-in-noise and binaural hearing.The generally modest results in the trials which are included in this review should make it easier to justify randomisation of more severely affected and higher-risk children in appropriately constructed trials. Randomised controlled trials are necessary in these children before more detailed conclusions about the effectiveness of grommets can be drawn.

Mackinnon, A., & Mulligan, R. (2005). The estimation of premorbid intelligence levels in French speakers. [Estimation de l'intelligence premorbide chez les francophones] L'Encephale, 31(1 Pt 1), 31-43.

Knowledge of cognitive performance earlier in life is essential in order to characterize precisely the extent to which these abilities have declined when an individual is diagnosed as having a dementing illness. The National Adult Reading Test (NART) was developed by Nelson and O'Connell to estimate premorbid intellectual ability in patients suffering from intellectual deterioration due to dementia. The test consists of 50 words, graded in difficulty, whose pronunciation cannot be determined from their spelling. The ability to successfully read irregularly spelt words is relatively robust in the face of current cognitive impairment and is a sensitive marker of intellectual attainment. Because the NART relies on orthographic irregularities in the English language, the construction of analogues of the test in other languages is not simply a matter of translation of the test content. Rather, words in the target language that have comparable properties to those in the NART must be sought. A French adaptation of the NART--the fNART--was developed by Bovet and calibrated on a small French-speaking Swiss sample. In a sample of 30 nondemented subjects, number of words pronounced correctly correlated highly with WAIS-R verbal and total IQ scores and less strongly with performance IQ (r = 0.43). Data available from an epidemiological survey undertaken in Geneva, Switzerland provided an opportunity to establish the measurement properties and construct validity of the fNART in a large sample unselected with respect to cognitive decline. In addition to the fNART, the survey incorporated a brief test battery assessing the domains of crystallized intelligence, memory and cognitive speed. An interview that enabled the diagnosis of dementia according to DSM IV criteria, the Mini Mental State Examination and the Psychogeriatric Assessment Scales (PAS) were also administered. If the fNART measures intellectual ability, substantial correlations between it and the test battery would be expected. Further validation of the test was sought by exploring its relation with years of education. The stability of the fNART was assessed by comparing the scores of subjects with and without dementia, and by examining the relationship of fNART scores to an informant-based report of change in cognitive performance from earlier in life assessed in the PAS. If the fNART is stable in the face of cognitive deterioration, no between-group differences or association with reported cognitive change would be expected. METHOD: Subjects were randomly selected from residents of the canton of Geneva aged over 65 years. The analyses reported here were undertaken on a sample of 368 persons who gave codable responses to at least 90% of the fNART items. They ranged in age from 65 to 94 years. Subjects were interviewed in their homes by trained lay interviewers. RESULTS: Cronbach's alpha for the forty-item scale was high (0.89). The percentage of subjects correctly pronouncing words ranged from 7.3% for "chamsin" to 96.7% for "agenda". Item response theory (IRT) models were fitted to the data. In a three-parameter model the value of the guessing (asymptote) parameter was vanishing small for all items. Accordingly, a two-parameter model was adopted. The discriminating power (slope) of items ranged considerably from 0.281 (rebus) to 1.192 (beotien). The average slope was 0.656. This corresponds to average factor loading of 0.528 (range 0.270 to 0.766.) The items measure a broad range of ability (mean threshold--0.719, sd = 1.540). Most items, however, discriminate at moderate levels. The parameter values obtained in the current study were compared to those estimated in a French sample of persons at risk of dementia . The correlation between item pairs for slope and parameter estimates was 0.53 and 0.70 respectively. This indicated substantial concordance between the samples regarding the difficulty of the items, but some differences in the power of groups to differentiate ability. In particular, a small number of words that performed very well in the "at risk" sample showed more moderate discrimination in the current study. Scores on the fNART were correlated with measures of crystallised intelligence, memory and cognitive speed. All correlations were statistically significant. With all tests entered a regression equation the multiple correlation coefficient was 0.63. Mean fNART scores of those suffering from DSM IV dementia and those meeting only Criterion A (multiple cognitive deficits) were lower than those of subjects meeting neither set of criteria. However subjects in the first two groups were older than subjects in the undemented group and had significantly lower educational attainment. When these two factors were controlled in an analysis of covariance, the magnitude of the differences between the groups, while still overall significantly different, was substantially reduced. A similar pattern of results applied when psychometric measures of cognitive state--the MMSE and the PAS Cognitive Impairment Scale--were used instead of diagnostic categories. The partial correlations of the fNART with the MMSE and PAS cognitive impairment scale controlling for age and education were 0.25 (P < 0.01) and -0.33 (P < 0.01) respectively. fNART scores did not differ between the sexes, nor were they significantly correlated with PAS Depression, Stroke or Behaviour Change scales. There was a small but significant correlation between the fNART and informant-assessed Cognitive Decline on the PAS. DISCUSSION: This study demonstrated the excellent measurement properties of a French adaptation of the National Adult Reading Test in a large probability sample of elderly native speakers and provided the first large-sample evidence to support the validity of the fNART as a test of intellectual functioning relatively robust to dementia status. The negligible values of the pseudo-guessing parameters suggest that the goal of choosing words whose pronunciation is not susceptible to guessing has been achieved. The average item discriminability was high and the words used covered the spectrum of ability. The finding of substantial relationships of cognitive performance and educational attainment with fNART scores is important in validating the test as a measure of premorbid cognitive ability. The low correlations of the fNART with informant-based assessment of cognitive decline and age support the fNART as being relative robust to decline in ability. The relationships observed in this French adaptation are comparable to those reported for the English instrument . However, subjects meeting DSM IV criteria for dementia or Criterion A only had lower scores than other subjects. Decline in NART scores with dementia has been observed, particularly in moderate and severe cases. Given that the mechanism of the fNART is the same as the NART it is to be expected that while generally robust to current dementia status, some decline in performance will occur with the progression of the disease. The relationships between the fNART and PAS scales was remarkably similar to those reported by Jorm et al. in an English-speaking sample between the PAS and NART. Although small, the correlation between the fNART and the PAS Cognitive Decline scale might have been expected to be non-significant if the measure were truly stable in the face of intellectual deterioration. However this correlation is mirrored in the original English instruments and may reflect the higher risk of dementia in persons of lower intellectual ability. CONCLUSION: Further research is desirable to improve the precision of the calibration of the scale against the WAIS-R. Nevertheless, this study has demonstrated that the fNART is a reliable and valid method of assessing premorbid intellectual ability in French speakers.

Madden, J. S. (1994). LSD and post-hallucinogen perceptual disorder. Addiction (Abingdon, England), 89(6), 762-763.

Maddison, P., & Newsom-Davis, J. (2003). Treatment for Lambert-Eaton myasthenic syndrome. Cochrane Database of Systematic Reviews (Online), (2)(2), CD003279. doi:10.1002/14651858.CD003279

BACKGROUND: Lambert-Eaton myasthenic syndrome is an autoimmune presynaptic disorder of neuromuscular transmission. Treatments have attempted to overcome the harmful autoimmune process, or to improve residual neuromuscular transmission, in order to reverse the principal neurological symptom of muscle weakness. OBJECTIVES: The objective was to examine the efficacy of all forms of treatment in Lambert-Eaton myasthenic syndrome. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group specialised trials register (September 2002), MEDLINE (January 1966 to November 2002) and EMBASE (January 1980 to November 2002). We checked the bibliographies in reports of the randomised trials and contacted authors to identify additional published or unpublished data. SELECTION CRITERIA: Types of studies: all randomised or quasi-randomised trials. Types of participants: all adults and children with a diagnosis of Lambert-Eaton myasthenic syndrome, with or without small-cell lung cancer. Types of interventions: any form of medical (pharmacological or physical) treatment. Types of outcome measures: Primary: change in the muscle strength scale score (Quantitative Myasthenia Gravis score), or limb muscle strength measured by myometry. Secondary: improvement in the mean amplitude of the resting compound muscle action potentials. The mean amplitude used was the mean of all muscles tested. DATA COLLECTION AND ANALYSIS: We identified three randomised controlled trials. Individual patient data were only available for one trial. MAIN RESULTS: The three eligible trials included two controlled trials of the effects of 3,4-diaminopyridine compared with placebo in a total of 38 patients with Lambert-Eaton myasthenic syndrome, one of which was of crossover design. A third crossover trial compared intravenous immunoglobulin treatment to placebo in nine patients with Lambert-Eaton myasthenic syndrome. A meta-analysis of the primary endpoint results of these trials was not possible because of differences in comparisons and endpoints and, in two trials, lack of individual patient data. EFFECTS OF 3,4-DIAMINOPYRIDINE: Two trials of 3,4-diaminopyridine reported a significant improvement in the primary endpoint of muscle strength score, or myometric limb measurement following treatment. Both trials also reported a significant improvement in the secondary endpoint of resting compound muscle action potential amplitude following 3,4-diaminopyridine, compared with placebo. A meta-analysis of the primary endpoint results was not possible because of marked differences in these two trials regarding primary outcome measures. However, a meta-analysis of the secondary endpoint (improvement in the amplitude of the mean resting compound muscle action potential) was possible. It was necessary to assume a known correlation (similarity) of the paired responses for each individual in the two treatment periods in order to properly allow for the crossover design of one of the two trials (the correlation coefficient was assumed to be 0.5 in calculations). Using this approach, meta-analysis revealed a significant overall benefit in compound muscle action potential amplitude after 3,4-diaminopyridine treatment. The overall weighted mean difference was 1.80 mV (95% confidence interval 0.82 to 2.78), favouring treatment. These results were not sensitive to the assumption made because the overall benefit estimated was still significant when the correlation was assumed to be less than 0.1. EFFECTS OF INTRAVENOUS IMMUNOGLOBULIN: A crossover trial reported a significant improvement in the primary outcome measure of myometric limb strength when patients received intravenous immunoglobulin compared to placebo infusions. This trial also demonstrated an improvement in the secondary outcome measure of change in the mean resting compound muscle action potential amplitude following intravenous immunoglobulin, but this improvement did not reach significance. Clinical improvement lasted for up to eight weeks. REVIEWER'S CONCLUSIONS: Limited evidence from randomised controlled trials showed that either 3,4-diaminopyridine or intravenous immunoglobulin improved muscle strength scores and compound muscle action potential amplitudes in patients with Lambert-Eaton myasthenic syndrome. There are insufficient data at present to quantify this treatment effect. Other possible treatments, such as plasma exchange, steroids and immunosuppressive agents have not been tested in randomised controlled trials.

Mainardi, F., Trucco, M., Maggioni, F., Palestini, C., Dainese, F., & Zanchin, G. (2009). Cluster-like headache. A comprehensive reappraisal. Cephalalgia : An International Journal of Headache, doi:10.1111/j.1468-2982.2009.01993.x

Among the primary headaches, cluster headache (CH) presents very particular features allowing a relatively easy diagnosis based on criteria listed in Chapter 3 of the International Classification of Headache Disorders (ICHD-II). However, as in all primary headaches, possible underlying causal conditions must be excluded to rule out a secondary cluster-like headache (CLH). The observation of some cases with clinical features mimicking primary CH, but of secondary origin, led us to perform an extended review of CLH reports in the literature. We identified 156 CLH cases published from 1975 to 2008. The more frequent pathologies in association with CLH were the vascular ones (38.5%, n = 57), followed by tumours (25.7%, n = 38) and inflammatory infectious diseases (13.5%, n = 20). Eighty were excluded from further analysis, because of inadequate information. The remaining 76 were divided into two groups: those that satisfied the ICHD-II diagnostic criteria for CH, 'fulfilling' group (F), n = 38; and those with a symptomatology in disagreement with one or more ICHD-II criteria, 'not fulfilling' group (NF), n = 38. Among the aims of this study was the possible identification of clinical features leading to the suspicion of a symptomatic origin. In the differential diagnosis with CH, red flags resulted both for F and NF, older age at onset; for NF, abnormal neurological/general examination (73.6%), duration (34.2%), frequency (15.8%) and localization (10.5%) of the attacks. We stress the fact that, on first observation, 50% of CLH presented as F cases, perfectly mimicking CH. Therefore, the importance of accurate, clinical evaluation and of neuroimaging cannot be overestimated.

Mampreso, E., Maggioni, F., Viaro, F., Disco, C., & Zanchin, G. (2009). Efficacy of oxygen inhalation in sumatriptan refractory "high altitude" cluster headache attacks. The Journal of Headache and Pain, doi:10.1007/s10194-009-0160-0

We describe the case of a 40-year-old woman, affected by episodic cluster headache, who presented with a cluster headache triggered by exposure to high altitude. Her attacks were refractory to sumatriptan, very effective at sea level, but responded to oxygen. A pathophysiological mechanism is proposed.

Mangini, M. (1998). Treatment of alcoholism using psychedelic drugs: a review of the program of research. Journal of Psychoactive Drugs, 30(4), 381-418.

Following Albert Hofmann's discovery of LSD's psychoactive properties in 1943, and previous to their scheduling as controlled substances, the psychedelic drugs were widely studied--six international conferences and hundreds of papers discussed their potential therapeutic usefulness. The observation that the frightening experience of delirium tremens sometimes led alcoholics to moderate their alcohol intake suggested to early psychedelic researchers that the "psychotomimetic" experience thought to be produced by LSD could be used to treat alcoholism. A number of hypothesis-generating studies employing a variety of research designs to examine this premise were completed, but relatively few controlled trials attempted hypothesis testing. After twenty-five years of study, a combination of flawed methodology, uneven results and social reprehension led to the abandonment of research on the therapeutic use of psychedelic drugs, leaving many avenues of inquiry unexplored and many questions unanswered. Today, after a thirty-year hiatus, this research is gradually being resumed, and there is renewed interest in the findings of previous studies. This article explores the history of one branch of psychedelic research, the therapeutic use of LSD in the treatment of alcoholism, and of the events that led to the relabeling of the "hallucinogens" as drugs of abuse.

Marais, B. J., Gie, R. P., Hesseling, A. C., Schaaf, H. S., Lombard, C., Enarson, D. A., & Beyers, N. (2006). A refined symptom-based approach to diagnose pulmonary tuberculosis in children. Pediatrics, 118(5), e1350-9. doi:10.1542/peds.2006-0519

BACKGROUND: Tuberculosis control programs place an almost exclusive emphasis on adults with sputum smear-positive tuberculosis, because they are most infectious. However, children contribute a significant proportion of the global tuberculosis caseload and experience considerable tuberculosis-related morbidity and mortality, but few children in endemic areas have access to antituberculosis treatment. The diagnostic difficulty experienced in endemic areas with limited resources has been identified as a major factor contributing to poor treatment access. In general, there is a sense of scepticism regarding the potential value of symptom-based diagnostic approaches, because current clinical diagnostic approaches are often poorly validated. The natural history of childhood tuberculosis demonstrates that symptoms may offer good diagnostic value if they are well defined and if appropriate risk stratification is applied. This study aimed to determine the value of well-defined symptoms to diagnose childhood pulmonary tuberculosis in a tuberculosis-endemic area. METHODS: A prospective, community-based study was conducted in Cape Town, South Africa. Specific well-defined symptoms were documented in all children 2 weeks' duration; study participants were thoroughly evaluated for tuberculosis. In addition, all of the children who received antituberculosis treatment during the study period were reviewed by the investigator, irrespective of study inclusion. This concurrent disease surveillance provided a comprehensive overview of all of the childhood tuberculosis cases, allowing accurate assessment of the possible disadvantages associated with this symptom-based diagnostic approach. In the absence of an acceptable gold standard test, optimal case definition is an important consideration. Children were categorized as "bacteriologically confirmed tuberculosis," "radiologically certain tuberculosis," "probable tuberculosis," or "not tuberculosis." Bacteriologically confirmed tuberculosis was defined as the presence of acid-fast bacilli on sputum microscopy and/or Mycobacterium tuberculosis cultured from a respiratory specimen. Radiologically certain tuberculosis was defined as agreement between both independent experts that the chest radiograph indicated certain tuberculosis in the absence of bacteriologic confirmation. Probable tuberculosis was defined as the presence of suggestive radiologic signs and good clinical response to antituberculosis treatment in the absence of bacteriologic confirmation or radiologic certainty. Good clinical response was defined as complete symptom resolution and weight gain of > or = 10% of body weight at diagnosis, within 3 months of starting antituberculosis treatment. Not tuberculosis was defined as spontaneous symptom resolution or no response to antituberculosis therapy in the absence of bacteriologic confirmation or radiologic signs suggestive of tuberculosis. Pulmonary tuberculosis was defined as a symptomatic child with: (1) bacteriologically confirmed tuberculosis, (2) radiologically confirmed tuberculosis, or (3) probable tuberculosis (as defined), excluding isolated pleural effusion. RESULTS: In total, 1024 children were referred for evaluation. Resolving symptoms were reported in 596 children (58.2%); 428 (41.8%) children with persistent, nonremitting symptoms at evaluation were investigated for tuberculosis. Pulmonary tuberculosis was diagnosed in 197 children; 96 were categorized as bacteriologically confirmed tuberculosis, 75 as radiologically certain tuberculosis, and 26 as probable tuberculosis. Combining a persistent nonremitting cough of > 2 weeks' duration, documented failure to thrive (in the preceding 3 months), and fatigue provided reasonable diagnostic accuracy in HIV-uninfected children (sensitivity: 62.6%; specificity: 89.8%; positive predictive value: 83.6%); the performance was better in the low-risk group (> or = 3 years; sensitivity: 82.3%; specificity: 90.2%; positive predictive value: 82.3%) than in the high-risk group ( 2 weeks' duration; study participants were thoroughly evaluated for tuberculosis. In addition, all of the children who received antituberculosis treatment during the study period were reviewed by the investigator, irrespective of study inclusion. This concurrent disease surveillance provided a comprehensive overview of all of the childhood tuberculosis cases, allowing accurate assessment of the possible disadvantages associated with this symptom-based diagnostic approach. In the absence of an acceptable gold standard test, optimal case definition is an important consideration. Children were categorized as "bacteriologically confirmed tuberculosis," "radiologically certain tuberculosis," "probable tuberculosis," or "not tuberculosis." Bacteriologically confirmed tuberculosis was defined as the presence of acid-fast bacilli on sputum microscopy and/or Mycobacterium tuberculosis cultured from a respiratory specimen. Radiologically certain tuberculosis was defined as agreement between both independent experts that the chest radiograph indicated certain tuberculosis in the absence of bacteriologic confirmation. Probable tuberculosis was defined as the presence of suggestive radiologic signs and good clinical response to antituberculosis treatment in the absence of bacteriologic confirmation or radiologic certainty. Good clinical response was defined as complete symptom resolution and weight gain of > or = 10% of body weight at diagnosis, within 3 months of starting antituberculosis treatment. Not tuberculosis was defined as spontaneous symptom resolution or no response to antituberculosis therapy in the absence of bacteriologic confirmation or radiologic signs suggestive of tuberculosis. Pulmonary tuberculosis was defined as a symptomatic child with: (1) bacteriologically confirmed tuberculosis, (2) radiologically confirmed tuberculosis, or (3) probable tuberculosis (as defined), excluding isolated pleural effusion. RESULTS: In total, 1024 children were referred for evaluation. Resolving symptoms were reported in 596 children (58.2%); 428 (41.8%) children with persistent, nonremitting symptoms at evaluation were investigated for tuberculosis. Pulmonary tuberculosis was diagnosed in 197 children; 96 were categorized as bacteriologically confirmed tuberculosis, 75 as radiologically certain tuberculosis, and 26 as probable tuberculosis. Combining a persistent nonremitting cough of > 2 weeks' duration, documented failure to thrive (in the preceding 3 months), and fatigue provided reasonable diagnostic accuracy in HIV-uninfected children (sensitivity: 62.6%; specificity: 89.8%; positive predictive value: 83.6%); the performance was better in the low-risk group (> or = 3 years; sensitivity: 82.3%; specificity: 90.2%; positive predictive value: 82.3%) than in the high-risk group ( 2 weeks' duration; objective weight loss [documented failure to thrive] during the preceding 3 months; and reported fatigue) provided good diagnostic accuracy in HIV-uninfected children > or = 3 years of age, with clinical follow-up providing additional value. The approach performed less well in children < 3 years. However, the presence of a persistent, nonremitting cough together with documented failure to thrive still provided a fairly accurate diagnosis (sensitivity: 68.3%; specificity: 80.1%; positive predictive value: 82.1%), illustrating the importance of regular weight monitoring in young children. Clinical follow-up also offered additional diagnostic value, but caution is required, because very young children have an increased risk of rapid disease progression. The approach performed poorly in HIV-infected children. Recent household contact with an adult index case seemed to provide more diagnostic value than a positive tuberculin skin test, but novel T-cell-based assays may offer the only real improvement in sensitivity to diagnose M. tuberculosis infection in HIV-infected children. The variable diagnostic value offered by this symptom-based diagnostic approach illustrates the importance of risk stratification, as demonstrated by the fact that 11 (91.7%) of 12 children with severe disease manifestations who failed to meet the entry criteria were < 3 years of age or HIV infected. Particular emphasis should be placed on the provision of preventive chemotherapy after documented exposure and/or infection in these high-risk children. Study limitations include the small number of HIV-infected children, but on the positive side, the large number of HIV-uninfected children permitted adequate evaluation in this important group. It is often forgotten that HIV-uninfected children constitute the majority of child tuberculosis cases, even in settings where HIV is endemic. This study demonstrates the importance of ascertaining a child's HIV status before symptom-based diagnosis is attempted. Because children were recruited at both the clinic and hospital level, some selection bias may have been introduced; however, the only significant difference between the 2 groups was the proportion of HIV-infected children. Pulmonary tuberculosis was diagnosed with different levels of certainty, but no significant differences were recorded between these groups. CONCLUSIONS: Pulmonary tuberculosis can be diagnosed with a reasonable degree of accuracy in HIV-uninfected children using a simple symptom-based approach. This offers the exciting prospect of improving treatment access for children, particularly in resource-limited settings where current access to antituberculosis treatment is poor.

Markel, H., Lee, A., Holmes, R. D., & Domino, E. F. (1994). LSD flashback syndrome exacerbated by selective serotonin reuptake inhibitor antidepressants in adolescents. The Journal of Pediatrics, 125(5 Pt 1), 817-819.

Two adolescents with a long history of abuse of lysergic acid diethylamide (LSD) and symptoms consistent with major depressive disorder, on initiation of antidepressant therapy with selective serotonin reuptake inhibitor agents, had the new onset or worsening of LSD flashback syndrome. The similarity in neuroreceptor physiology for both LSD and serotonin suggests that the LSD flashback syndrome may be induced by these drugs in patients with a history of LSD abuse.

Matefy, R. E., & Krall, R. G. (1974). An initial investigation of the psychedelic drug flashback phenomena. Journal of Consulting and Clinical Psychology, 42(6), 854-860.

Mathet, F., Martin-Guehl, C., Maurice-Tison, S., & Bouvard, M. P. (2003). Prevalence of depressive disorders in children and adolescents attending primary care. A survey with the Aquitaine Sentinelle Network. [Prevalence des troubles depressifs chez l'enfant et l'adolescent consultant en medecine generale] L'Encephale, 29(5), 391-400.

Since depressive disorders in children and adolescents have not been widely studied in the context of gene-ral medicine, we conducted an epidemiological survey among general practitioners (GP's) consulted by young subjects aged 7 to 17 years for various reasons. OBJECTIVE: The aims were the following: to estimate the prevalence of depressive disorders in general practice, to detect the eventual existence of particular clinical forms, to assess the frequency of comorbid disorders and to determine to what degree these disorders were diagnosed by GP's. METHOD: The study was conducted over 6 months in concert with 45 practitioners of the Aquitaine Sentinelle Network because of their strong experience in the field of epidemiological surveys, especially regarding psychiatric disorders. The population included all consecutive attenders aged 7 to 17 years. Consent to participate was obtained from children and adolescents and their parents. Finally 155 patients took part. A two-stage epidemiologic strategy was used, including screening tests in the first stage and semi structured interview by clinician in the second stage for diagnostic confirmation. During the first stage, information was obtained from children and adolescents and general practitioners using three questionnaires. The self-report questionnaire Center for Epidemiological Studies Depression (CES-D) was used for screening depression in 13 to 17 years old adolescents and the 20 items of the scale were modified to make it more comprehensible and relevant for children aged 7 to 12. The cut-off of 21 used in France appeared to be the more appropriate in both males and females and was taken to indicate high likelihood of depressive disorder. Therefore people with score 21 or more were approached for the second stage. The Child Behavior Checklist (CBCL), an instrument of well-established validity and reliability, provided information from parents about the child's behavior and competencies. Demographic and environmental data, as well as the reason for the visit and the presence of associated psychological factors were collected from a questionnaire devised for the study and completed by the practitioner. The 21 patients initially detected were invited to take part in the second stage. A total of 18 agreed to meet the psychiatrist. Sex-ratio female/male of this sample was 1,25 and mean age was 12,5 years. All of them underwent the Schedule for Affective Disorders and Schizophrenia for School Aged Children (Kiddie-SADS), a semi structured research interview of established validity. Diagnoses were made according to the DSM IV criteria (American Psychiatric Association). RESULTS: Results showed that more than one child out of 10 aged less than 13 years had a depressive disorder, and that the prevalence in the adolescent sub-group was 5%. Major depressive episode was present in 6% of the children sample, dysthymia in 4% and maladjustment disorder with depressive mood in about 1%. All depressive disorders were moderate. Atypical depression (in the Anglosaxon sense of the term) was present in half of the depressed adolescents. Other disorders included anxiety disorders with a rate of about 4% overanxious in the adolescent sample, obsessive compulsive disorder, panic disorder. Disruptive disorders were considerably less common. Psychiatric comorbidity, usually involving different types of emotional disorders, was present in about 50% of psychiatric cases, with a prevalence of anxiety disorders. The reasons why depressed subjects consulted were not specific. The most common reasons for visiting the GP were the somatic complaints with a rate of 50% in both populations, whatever the CES-D's score was. A few per cent of patients attending primary care presented with mental health complaints, and the rate was similar in the two populations. Frequency of consultation was not a discriminant factor of depression. Familial cohesion and school performance were not associated with the CES-D's score, nor familial psychiatric history. Personal psychiatric history was related to depression, whereas the occurrence of bereavement made the CES-D score positive but was not significantly associated with fully- blown depression. Finally, we estimated that 70% of diagnoses of depression were not made during the consultation with GP's. CONCLUSION: No particular characteristic of depressed children consulting GP's could be established. These findings underline the importance of training GP's in the screening of depressive disorders in children and adolescents. A better knowledge that young general practice attenders have high rates of depressive disorders may facilitate more rapid referral for psychiatric assessment and treatment.

Mathias, S., Lubman, D. I., & Hides, L. (2008). Substance-induced psychosis: a diagnostic conundrum. The Journal of Clinical Psychiatry, 69(3), 358-367.

OBJECTIVE: To critically examine the DSM-IV-TR criteria for substance-induced psychotic disorder (SIPD). DATA SOURCES: Leading electronic databases (such as MEDLINE, PubMed) were searched for the years 1992 through 2007, using combinations of the following key search terms: substance abuse/dependence, alcohol, marijuana, cannabis, methamphetamine, crack, cocaine, amphetamine, ecstasy, ketamine, phencyclidine, LSD, mental health, drug-induced psychosis, substance-induced psychosis, psychosis, and schizophrenia. References identified from bibliographies of pertinent articles and books in the field were also collected and reviewed. DATA EXTRACTION: Only research studies or case reports/series that presented data on populations diagnosed with SIPD by using clinical or structured diagnostic interviews and that were published in English were used to assess the validity of the current SIPD criteria. DATA SYNTHESIS: We identified 49 articles that presented clinical data on SIPD. Almost half of these publications were case reports, with 18 articles specifically focusing on delineating the clinical characteristics or outcomes of individuals diagnosed with SIPD. While several large studies have recently been conducted to assess the stability of SIPD, there is a dearth of research that rigorously examines the validity of DSM-IV diagnostic criteria across substances. CONCLUSIONS: There remains a striking paucity of information on the outcome, treatment, and best practice for substance-associated psychotic episodes. Further work is clearly required before the advent of DSM-V. We propose an alternative, broader classification that better reflects the current evidence base, inferring association rather than causation.

Mauricio Sierra, M. D., Ph.D. (2009). Depersonalization: A New Look at a Neglected Syndrome. New York: Cambridge University Press.

Depersonalization is a dissociative disorder, causing alteration in the perception or experience of the self and a detachment from reality. This is a fascinating and clinically relevant phenomenon neglected within psychiatry. Far from being a rare condition, it can be as prevalent as schizophrenia or bipolar disorder and frequently occurs in association with other neuropsychiatric conditions. This is an up-to-date review of depersonalization, dealing with the subject from a wide range of perspectives and covering historical, conceptual, clinical, trans-cultural, pharmacological and neurobiological factors. It discusses recent neuroimaging studies providing fresh insights into the condition and opening up new opportunities to manage the symptoms with pharmacologic and psychotherapeutic interventions. As a reference book on depersonalization it represents a timely and highly relevant contribution to fill an unjustified gap in the psychiatric literature. It will be relevant to psychiatrists and clinical psychologists, as well as primary care practitioners, neurologists and psychiatric nurses.

McCambridge, J., Winstock, A., Hunt, N., & Mitcheson, L. (2007). 5-Year trends in use of hallucinogens and other adjunct drugs among UK dance drug users. European Addiction Research, 13(1), 57-64. doi:10.1159/000095816

AIMS: To describe and assess trends in the use of hallucinogens and other adjunct drugs over a 5-year period. DESIGN: Repeated-measures cross-sectional survey. SETTING AND PARTICIPANTS: Annual magazine-based survey targeting people who use drugs in dance contexts. MEASUREMENTS: Lifetime use prevalence (ever used); age of first use; current use prevalence (any use within the last month), and extent of use within the last month (number of days used) for LSD, psilocybin, ketamine, GHB and nitrates. FINDINGS: Prevalence increases for psilocybin, ketamine, GHB and nitrates use have been detected, with a sharp recent rise in current psilocybin use in 2002-2003 contrasting with more gradual and comprehensive evidence of increased ketamine use throughout the period 1999-2003. The declining prevalence of LSD use in general population surveys is replicated in this sentinel population study. CONCLUSIONS: The rise in prevalence of hallucinogen and other adjunct drugs identified among dance drug users may be mirrored by wider prevalence increases among young people with a consequent need to study these trends carefully and to develop effective interventions, where required.

McGee, R. (1984). Flashbacks and memory phenomena. A comment on "Flashback phenomena--clinical and diagnostic dilemmas". The Journal of Nervous and Mental Disease, 172(5), 273-278.

Alarcon, Dickinson, and Dohn (J. Nerv. Ment. Dis., 170: 217-223, 1982) recently reviewed the phenomenon of memory flashback following use of hallucinogenic drugs. They point out that while there are a considerable number of explanations concerning the flashback mechanism, little is known about the real causes. This paper examines flashback following drug ingestion in the light of other memory phenomena concerned with "cued retrieval" effects. Such phenomena may include dream recall, delayed post-traumatic stress, mood influence on memory, and drug effects on memory. Rather than view flashbacks as "pathological" in some sense, it may be better to view them as instances of normal memory processes, which may, nevertheless, be accompanied by emotional distress. Such a view relates flashbacks to a wider memory literature, and also makes them amenable to investigation using research designs derived from that literature.

Merry, S., McDowell, H., Hetrick, S., Bir, J., & Muller, N. (2004). Psychological and/or educational interventions for the prevention of depression in children and adolescents. Cochrane Database of Systematic Reviews (Online), (1)(1), CD003380. doi:10.1002/14651858.CD003380.pub2

BACKGROUND: Depression is the fourth most important disease in the estimation of the burden of disease Murray 1996 and is a common problem with prevalence rates estimated to be as high as 8% in young people. Depression in young people is associated with poor academic performance, social dysfunction, substance abuse, suicide attempts, and completed suicide (NHMRC 1997). This has precipitated the development of programmes aimed at preventing the onset of depression. This review evaluates evidence for the effectiveness of these prevention programmes. OBJECTIVES: To determine whether psychological and/or educational interventions (both universal and targeted) are effective in reducing risk of depressive disorder by reducing depressive symptoms immediately after intervention or by preventing the onset of depressive disorder in children and adolescents over the next one to three years. SEARCH STRATEGY: The Cochrane Depression, Anxiety and Neurosis Group trials register (August 2002), MEDLINE (1966 to December Week 3 2002), EMBASE (1980 to January Week 2 2003), PsychInfo (1886 to January Week 2 2003) and ERIC (1985 to December 2002) were searched. In addition, conference abstracts, the reference lists of included studies, and other reviews were searched and experts in the field were contacted. SELECTION CRITERIA: Each identified study was assessed for possible inclusion by two independent reviewers based on the methods sections. The determinants for inclusion were that the trial include a psychological and/or educational prevention programme for young people aged 5 to 19 years-old, who did not meet DSM or ICD criteria for depression and/or did not fall into the clinical range on standardised, validated, and reliable rating scales of depression. DATA COLLECTION AND ANALYSIS: The methodological quality of the included trials was assessed by two independent reviewers according to a list of pre-determined criteria, which were based on quality ratings devised by Moncrieff and colleagues (Moncrieff 2001). Outcome data was extracted and entered into Revman 4.2. Means and standard deviations for continuous outcomes and number of events for dichotomous outcomes were extracted where available. For trials where the required data were not reported or could not be calculated, further details were requested from first authors. If no further details were provided, the trial was included in the review and described, but not included in the meta-analysis. Results were presented for each type of intervention: targeted or universal interventions; and educational or psychological interventions and if data were provided, by gender. Where possible data were combined in meta-analyses to give a treatment effect across all trials.Sensitivity analysis were conducted on studies rated as "adequate" or "high" quality, that is with a score over 22, based on the scale by Moncrieff et al (Moncrieff 2001). The presence of publication bias was assessed using funnel plots. MAIN RESULTS: Studies were divided into those that compared intervention with an active comparison or placebo (i.e. a control condition that resembles the intervention being investigated but which lacks the elements thought to be active in preventing depression) and those that used a "wait-list" or no intervention comparison group. Only two studies fell into the former category and neither showed effectiveness although one study was inadequately powered to show a difference and in the other the "placebo" contained active therapeutic elements, reducing the ability to demonstrate a difference from intervention. Psychological interventions were effective compared with non-intervention immediately after the programmes were delivered with a significant reduction in scores on depression rating scales for targeted (standardised mean difference (SMD) of -0.26 and a 95% confidence interval (CI) of -0.40 to -0.13 ) but not universal interventions (SMD -0.21, 95% CI -0.48, 0.06), with a significant effect maintained on pooling data (SMD -0.26, 95% CI -0.36, -0.15). While small effect sizes were reported, these were associated with a significant reduction in depressive episodes. The overall risk difference after intervention translates to "numbers needed to treat" (NNT) of 10.The most effective study is the targeted programme by Clarke (Clarke 2001) where the initial effect size of -0.46 is associated with an initial risk difference of -0.22 and NNT 5. There was no evidence of effectiveness for educational interventions. Reports of effectiveness for boys and girls were contradictory. The quality of many studies was poor, and only two studies made allocation concealment explicit. Sensitivity analysis of only high quality studies did not alter the results significantly. The only analysis in which there was significant statistical heterogeneity was the sub-group analysis by gender where there was variability in the response to different programmes for both girls and boys.For the most part funnel plots indicate findings are robust for short term effects with no publication bias evident. There are too few studies to comment on whether there is publication bias for studies reporting long-term (12-36 month) follow-up. REVIEWER'S CONCLUSIONS: Although there is insufficient evidence to warrant the introduction of depression prevention programmes currently, results to date indicate that further study would be worthwhile. There is a need to compare interventions with a placebo or some sort of active comparison so that study participants do not know whether they are in the intervention group or not, to investigate the impact of booster sessions to see if effectiveness immediately after intervention can be prolonged, ideally for a year or longer, and to consider practical implementation of prevention programmes when choosing target populations. Until now most studies have focussed on psychological interventions. The potential effectiveness of educational interventions has not been fully investigated. Given the gender differences in prevalence, and the change in these that occurs in adolescence with a disproportionate increase in prevalence rates for girls, it is likely that girls and boys will respond differently to interventions. Although differences have been reported in studies in this review the findings are contradictory and a more definitive delineation of gender specific responses to interventions would be helpful.

Meyer, E. L., Laurell, K., Artto, V., Bendtsen, L., Linde, M., Kallela, M., Tronvik, E., Zwart, J. A., Jensen, R. M., & Hagen, K. (2009). Lateralization in cluster headache: a Nordic multicenter study. The Journal of Headache and Pain, 10(4), 259-263. doi:10.1007/s10194-009-0129-z

A slight predominance of cluster pain on the right side has been reported in several studies. The aim of this large retrospective Nordic multicenter study was to estimate the prevalence of right- and left-sided pain in cluster headache (CH) patients with side-locked pain, the prevalence of side shifts in episodic and chronic CH patients, and the occurrence of cranial autonomic symptoms related to pain side. Among 383 cluster patients, 55 (14%) had experienced pain side shift. Of the remaining 328 individuals without side shift, there was no significant difference between the occurrence of right-sided and left-sided pain (54 vs. 46%). The prevalence of side shift was similar for episodic and chronic CH and the occurrence of cranial autonomic symptoms was not influenced by the pain side. In conclusion, previous reports of a side difference in location of cluster pain could not be confirmed in this large Nordic sample.

Military, S. C. (1984). Intervention. New York, N.Y.: Military Studies Center.

Miller, H. G., & Li, R. M. (2004). Measuring hot flashes: summary of a National Institutes of Health workshop. Mayo Clinic Proceedings.Mayo Clinic, 79(6), 777-781.

The etiology and mechanism of hot flashes remain incompletely understood. Future studies of hormonal and neurologic systems may provide promising leads to improve our understanding of the basic phenomenon and perhaps also shed light on the placebo effect. However, this is likely a complex undertaking. Critical to this effort is the ability to reliably identify when a hot flash has occurred. The leading objective measure in use today--sternal skin conductance monitoring--has some limitations in ambulatory settings. However, a more severe limitation is the inability of sternal skin conductance to provide any information on duration, intensity, and interference with activities. Ultimately, researchers desire a convenient and cost-effective sensor for monitoring hot flashes without cumbersome electrodes that might become compromised if a subject experiences extensive sweating or takes a shower and one that can capture data continuously for relatively long periods of observation. However, researchers also need well-characterized methods for collecting self-reported data. If the primary concern is helping women with hot flashes find relief, then subjective measures collected through diaries or interviews cannot be dismissed. Given the importance of this information, it would make sense to undertake methodologic research to ensure that the best possible systems are used to collect valid and reliable information. The factors that we want to measure with respect to hot flashes are likely to change over time as more is learned about the underlying phenomenon. This will probably be an evolutionary process, one involving decisions about what biological factors will be most useful for the task at hand, what technologies might be available or easily adaptable, which measures should be bundled together to maximize the precision of data collected with the available technology, and the analysis of the data to generate new hypotheses and perhaps the need for new measurement tools. Investigators face several challenges when considering the design of studies of hot flashes. Substantial placebo effects and small sample sizes have produced studies with equivocal findings. The placebo effect, while remarkable in its dimensions in some studies of hot flash interventions, is not understood. Distinguishing placebo effects from the natural dissipation of symptoms over time would be extremely helpful. Similarly, the ability to induce a placebo effect to reduce the discomfort and annoyance associated with hot flashes might be helpful. The use of neuroimaging technology offers potential for greater understanding of the placebo effect. The group concluded that better measures of hot flashes require improved knowledge in several areas: The physical processes underlying hot flashes, which will identify additional factors to measure and the factors that influence the perception and reporting of hot flashes. Improved sternal skin conductance systems, with additional tools to be developed when other factors of hot flashes are identified. The performance characteristics of questionnaires and diaries to collect self-reported data on hot flash frequency. Improved and validated instruments for collecting data on intensity and interference with daily activities. The mechanism(s) of action of placebo, which may also help distinguish natural attrition of symptoms from placebo effect. Animal models to elucidate triggers and mechanisms of hot flashes and to screen potential treatments. Investigators interested in studying hot flashes face complex issues. The incomplete understanding of the basic physiology underlying hot flashes clearly calls for further work in this area. Some mechanistic studies cannot be conducted with human subjects; thus, animal models are needed. Animal models could be particularly helpful for understanding the neurobiology of hot flashes and perhaps placebo effects. Bringing scientists together from different fields would appear to be a promising approach to moving this area forward. Scientific advances are being made increasingly at the interfaces of traditional disciplines, and approaches to science are becoming more integrative. Finding appropriate collaborators from other disciplines is not necessarily easy, and meeting a collaborator from another discipline is only the first step in building a multidisciplinary research team. Effective teams begin with compelling reasons for their existence, but further incentives must be developed to ensure full realization of their potential. The success of team science depends on individuals who are comfortable with boundary-crossing activities. Working as part of a team that is seeking solutions to complex problems requires a willingness to work in an interdisciplinary environment, to collaborate with different types of organizations, and to recognize the importance of a variety of roles in the project. It is likely that a multidisciplinary approach to hot flash research would be helpful given the number of physiologic, clinical, and behavioral factors involved. For example, psychologists and sociologists could contribute to identifying factors that may influence the placebo effect, such as pill color; developing and validating questionnaire items and diary formats; ascertaining the effect of mode of data collection on the quality of the resulting data; and determining the best ways to provide information to subjects. However, if they were part of a multidisciplinary team that included basic scientists, clinicians, and bioengineers, different questions might be asked, and better tools might be developed to collect both subjective and objective data on hot flashes. The increasing emphasis on collaborative science is also embraced at the NIH level. Since May 2002, the NIH has been engaged in a series of activities collectively known as the "NIH Roadmap," whose goal, in keeping with the NIH mission of uncovering new knowledge about the prevention, detection, diagnosis, and treatment of disease and disability, is to accelerate both the pace of discovery in these key areas and the translation of therapies from bench to bedside. The timing of this workshop to assess measures of hot flashes appears auspicious for several reasons. First, the issue of refining and validating self-reported measures of symptoms through the use of biomarkers and multidisciplinary research teams is consonant with an NIH Roadmap initiative. Second, the new National Institute for Biomedical Imaging and Bioengineering at the NIH offers impetus for linking biomedical, social, and behavioral scientists with bioengineers to assess and improve existing technology or develop new technologies to collect data on physiological markers specific to hot flashes. Third, people are already purchasing and using CAM modalities or are resuming hormone therapy for relief of hot flashes, and they and their clinicians are eager for and deserve more information on the safety and efficacy of these remedies.

Morehead, D. B. (1997). Exacerbation of hallucinogen-persisting perception disorder with risperidone. Journal of Clinical Psychopharmacology, 17(4), 327-328.

Moskowitz, A., Schafer, I., & Dorahy, M. (2009). Psychosis, Trauma and Dissociation: Emerging Perspectives on Severe Psychopathology Wiley.

In the 100 years since Eugen Bleuler unveiled his concept of schizophrenia, which had dissociation at its core, the essential connection between traumatic life events, dissociative processes and psychotic symptoms has been lost. Psychosis, Trauma and Dissociation is the first book to attempt to reforge this connection, by presenting challenging new findings linking these now disparate fields, and by comprehensively surveying, from a wide range of perspectives, the complex relationship between dissociation and psychosis. A cutting-edge sourcebook, Psychosis, Trauma and Dissociation brings together highly-respected professionals working in the psychosis field with renowned clinicians and researchers from the fields of traumatic stress, dissociation and the dissociative disorders, and will be of interest to those working with or studying psychotic or dissociative disorders, as well as trauma-related conditions such as borderline personality disorder or complex post-traumatic stress disorder. It makes an invaluable contribution to the burgeoning literature on severe mental disorders and serious life events. The book has three sections: Connecting trauma and dissociation to psychosis - an exploration of the links between trauma, dissociation and psychosis from a wide range of historical and theoretical perspectives. Comparing psychotic and dissociative disorders - a presentation of empirical and clinical perspectives on similarities and differences between the two sets of disorders. Assessing and treating hybrid and boundary conditions - consideration of existing and novel diagnostic categories, such as borderline personality disorder and dissociative psychosis, that blend or border dissociative and psychotic disorders, along with treatment perspectives emphasising humanistic and existential concerns.

Moskowitz, D. (1971). Use of haloperidol to reduce LSD flashbacks. Military Medicine, 136(9), 754-756.

Mula, M., Pini, S., Calugi, S., Preve, M., Masini, M., Giovannini, I., Conversano, C., Rucci, P., & Cassano, G. B. (2008). Validity and reliability of the Structured Clinical Interview for Depersonalization-Derealization Spectrum (SCI-DER) Neuropsychiatric Disease and Treatment, 4(5), 977-986.

THIS STUDY EVALUATES THE VALIDITY AND RELIABILITY OF A NEW INSTRUMENT DEVELOPED TO ASSESS SYMPTOMS OF DEPERSONALIZATION: the Structured Clinical Interview for the Depersonalization-Derealization Spectrum (SCI-DER). The instrument is based on a spectrum model that emphasizes soft-signs, sub-threshold syndromes as well as clinical and subsyndromal manifestations. Items of the interview include, in addition to DSM-IV criteria for depersonalization, a number of features derived from clinical experience and from a review of phenomenological descriptions. Study participants included 258 consecutive patients with mood and anxiety disorders, 16.7% bipolar I disorder, 18.6% bipolar II disorder, 32.9% major depression, 22.1% panic disorder, 4.7% obsessive compulsive disorder, and 1.5% generalized anxiety disorder; 2.7% patients were also diagnosed with depersonalization disorder. A comparison group of 42 unselected controls was enrolled at the same site. The SCI-DER showed excellent reliability and good concurrent validity with the Dissociative Experiences Scale. It significantly discriminated subjects with any diagnosis of mood and anxiety disorders from controls and subjects with depersonalization disorder from controls. The hypothesized structure of the instrument was confirmed empirically.

Mula, M., Pini, S., Calugi, S., Preve, M., Masini, M., Giovannini, I., Rucci, P., & Cassano, G. B. (2009). Distinguishing affective depersonalization from anhedonia in major depression and bipolar disorder Comprehensive Psychiatry, doi:10.1016/j.comppsych.2009.03.009

Murtaza, M., Kisat, M., Daniel, H., & Sonawalla, A. B. (2009). Classification and clinical features of headache disorders in Pakistan: a retrospective review of clinical data. PloS One, 4(6), e5827. doi:10.1371/journal.pone.0005827

BACKGROUND: Morbidity associated with primary headache disorders is a major public health problem with an overall prevalence of 46%. Tension-type headache and migraine are the two most prevalent causes. However, headache has not been sufficiently studied as a cause of morbidity in the developing world. Literature on prevalence and classification of these disorders in South Asia is scarce. The aim of this study is to describe the classification and clinical features of headache patients who seek medical advice in Pakistan. METHODS AND RESULTS: Medical records of 255 consecutive patients who presented to a headache clinic at a tertiary care hospital were reviewed. Demographic details, onset and lifetime duration of illness, pattern of headache, associated features and family history were recorded. International Classification of Headache Disorders version 2 was applied. 66% of all patients were women and 81% of them were between 16 and 49 years of age. Migraine was the most common disorder (206 patients) followed by tension-type headache (58 patients), medication-overuse headache (6 patients) and cluster headache (4 patients). Chronic daily headache was seen in 99 patients. Patients with tension-type headache suffered from more frequent episodes of headache than patients with migraine (p<0.001). Duration of each headache episode was higher in women with menstrually related migraine (p = 0.015). Median age at presentation and at onset was lower in patients with migraine who reported a first-degree family history of the disease (p = 0.003 and p<0.001 respectively). CONCLUSIONS/SIGNIFICANCE: Patients who seek medical advice for headache in Pakistan are usually in their most productive ages. Migraine and tension-type headache are the most common clinical presentations of headache. Onset of migraine is earlier in patients with first-degree family history. Menstrually related migraine affects women with headache episodes of longer duration than other patients and it warrants special therapeutic consideration. Follow-up studies to describe epidemiology and burden of headache in Pakistan are needed.

Naditch, M. P., & Fenwick, S. (1977). LSD flashbacks and ego functioning. Journal of Abnormal Psychology, 86(4), 352-359.

Naveh, N., Weissman, C., Muchtar, S., Benita, S., & Mechoulam, R. (2000). A submicron emulsion of HU-211, a synthetic cannabinoid, reduces intraocular pressure in rabbits. Graefe's Archive for Clinical and Experimental Ophthalmology = Albrecht Von Graefes Archiv Fur Klinische Und Experimentelle Ophthalmologie, 238(4), 334-338.

PURPOSE: To study the ocular hypotensive effect of a nonpsychotropic cannabinoid, HU-211 (11 -hydroxy-delta8-tetra-hydrocannabinol, dimethylheptyl), an N-methyl-D-aspartate (NMDA) agonist, in normotensive rabbits. METHODS: The cannabinoid HU-211, being lipophilic, was incorporated into a stable oil-in-water submicron sterile emulsion, consisting of 0.12% (w/w) HU-211. A single- dose, randomized and double-masked study was designed, using a Digilab 30R pneumotonometer to measure intraocular pressure (IOP) in normotensive rabbits. RESULTS: Application of a single dose of HU-211 ophthalmic preparation resulted in an IOP reduction of 5.3 mmHg (24% of baseline), first evident at 1.5 h post application and persisting for over 6 h. A small but significant lowering of pressure (12.5% of baseline) occurred in the contralateral eyes of HU-211 treated rabbits, lasting for 4 h post treatment. CONCLUSION: Our work demonstrated that HU-211, incorporated into submicron emulsion, caused a 6-h-long reduction in IOP in the treated eye, with a lesser reduction in the contralateral untreated eye.

Neisser, U. (1967). Cognitive psychology. New York,: Appleton-Century-Crofts.

Neisser, U. (1982). Memory observed : remembering in natural contexts. San Francisco: W.H. Freeman.

Nelson, H. D., Nygren, P., Walker, M., & Panoscha, R. (2006). Screening for speech and language delay in preschool children: systematic evidence review for the US Preventive Services Task Force. Pediatrics, 117(2), e298-319. doi:10.1542/peds.2005-1467

BACKGROUND: PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Published in the public domain by the American Academy of Pediatrics.Speech and language development is a useful indicator of a child's overall development and cognitive ability and is related to school success. Identification of children at risk for developmental delay or related problems may lead to intervention services and family assistance at a young age, when the chances for improvement are best. However, optimal methods for screening for speech and language delay have not been identified, and screening is practiced inconsistently in primary care. PURPOSE: We sought to evaluate the strengths and limits of evidence about the effectiveness of screening and interventions for speech and language delay in preschool-aged children to determine the balance of benefits and adverse effects of routine screening in primary care for the development of guidelines by the US Preventive Services Task Force. The target population includes all children up to 5 years old without previously known conditions associated with speech and language delay, such as hearing and neurologic impairments. METHODS: Studies were identified from Medline, PsycINFO, and CINAHL databases (1966 to November 19, 2004), systematic reviews, reference lists, and experts. The evidence review included only English-language, published articles that are available through libraries. Only randomized, controlled trials were considered for examining the effectiveness of interventions. Outcome measures were considered if they were obtained at any time or age after screening and/or intervention as long as the initial assessment occurred while the child was or =2 screening techniques in 1 population, and comparisons of a single screening technique across different populations are lacking. Fourteen good- and fair-quality randomized, controlled trials of interventions reported significantly improved speech and language outcomes compared with control groups. Improvement was demonstrated in several domains including articulation, phonology, expressive language, receptive language, lexical acquisition, and syntax among children in all age groups studied and across multiple therapeutic settings. Improvement in other functional outcomes such as socialization skills, self-esteem, and improved play themes were demonstrated in some, but not all, of the 4 studies that measured them. In general, studies of interventions were small and heterogeneous, may be subject to plateau effects, and reported short-term outcomes based on various instruments and measures. As a result, long-term outcomes are not known, interventions could not be compared directly, and generalizability is questionable. CONCLUSIONS: Use of risk factors to guide selective screening is not supported by studies. Several aspects of screening have been inadequately studied to determine optimal methods, including which instrument to use, the age at which to screen, and which interval is most useful. Trials of interventions demonstrate improvement in some outcome measures, but conclusions and generalizability are limited. Data are not available addressing other key issues including the effectiveness of screening in primary care settings, role of enhanced surveillance by primary care physicians before referral for diagnostic evaluation, non-speech and language and long-term benefits of interventions, and adverse effects of screening and interventions.

Newcomer, J. W. (2005). Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review. CNS Drugs, 19 Suppl 1, 1-93.

Increasing numbers of reports concerning diabetes, ketoacidosis, hyperglycaemia and lipid dysregulation in patients treated with second-generation (or atypical) antipsychotics have raised concerns about a possible association between these metabolic effects and treatment with these medications. This comprehensive literature review considers the evidence for and against an association between glucose or lipid dysregulation and eight separate second-generation antipsychotics currently available in the US and/or Europe, specifically clozapine, olanzapine, risperidone, quetiapine, zotepine, amisulpride, ziprasidone and aripiprazole. This review also includes an assessment of the potential contributory role of treatment-induced weight gain in conferring risk for hyperglycaemia and dyslipidaemia during treatment with different antipsychotic medications. Substantial evidence from a variety of human populations, including some recent confirmatory evidence in treated psychiatric patients, indicates that increased adiposity is associated with a variety of adverse physiological effects, including decreases in insulin sensitivity and changes in plasma glucose and lipid levels. Comparison of mean weight changes and relative percentages of patients experiencing specific levels of weight increase from controlled, randomised clinical trials indicates that weight gain liability varies significantly across the different second generation antipsychotic agents. Clozapine and olanzapine treatment are associated with the greatest risk of clinically significant weight gain, with other agents producing relatively lower levels of risk. Risperidone, quetiapine, amisulpride and zotepine generally show low to moderate levels of mean weight gain and a modest risk of clinically significant increases in weight. Ziprasidone and aripiprazole treatment are generally associated with minimal mean weight gain and the lowest risk of more significant increases. Published studies including uncontrolled observations, large retrospective database analyses and controlled experimental studies, including randomised clinical trials, indicate that the different second-generation antipsychotics are associated with differing effects on glucose and lipid metabolism. These studies offer generally consistent evidence that clozapine and olanzapine treatment are associated with an increased risk of diabetes mellitus and dyslipidaemia. Inconsistent results, and a generally smaller effect in studies where an effect is reported, suggest limited if any increased risk for treatment-induced diabetes mellitus and dyslipidaemia during risperidone treatment, despite a comparable volume of published data. A similarly smaller and inconsistent signal suggests limited if any increased risk of diabetes or dyslipidaemia during quetiapine treatment, but this is based on less published data than is available for risperidone. The absence of retrospective database studies, and little or no relevant published data from clinical trials, makes it difficult to draw conclusions concerning risk for zotepine or amisulpride, although amisulpride appears to have less risk of treatment-emergent dyslipidaemia in comparison to olanzapine. With increasing data from clinical trials but little or no currently published data from large retrospective database analyses, there is no evidence at this time to suggest that ziprasidone and aripiprazole treatment are associated with an increase in risk for diabetes, dyslipidaemia or other adverse effects on glucose or lipid metabolism. In general, the rank order of risk observed for the second-generation antipsychotic medications suggests that the differing weight gain liability of atypical agents contributes to the differing relative risk of insulin resistance, dyslipidaemia and hyperglycaemia. This would be consistent with effects observed in nonpsychiatric samples, where risk for adverse metabolic changes tends to increase with increasing adiposity. From this perspective, a possible increase in risk would be predicted to occur in association with any treatment that produces increases in weight and adiposity. However, case reports tentatively suggest that substantial weight gain or obesity may not be a factor in up to one-quarter of cases of new-onset diabetes that occur during treatment. Pending further testing from preclinical and clinical studies, limited controlled studies support the hypothesis that clozapine and olanzapine may have a direct effect on glucose regulation independent of adiposity. The results of studies in this area are relevant to primary and secondary prevention efforts that aim to address the multiple factors that contribute to increased prevalence of type 2 diabetes mellitus and cardiovascular disease in populations that are often treated with second-generation antipsychotic medications.

Nichenametla, S. N., Ellison, I., Calcagnotto, A., Lazarus, P., Muscat, J. E., & Richie Jr., J. P. (2008). Functional significance of the GAG trinucleotide-repeat polymorphism in the gene for the catalytic subunit of γ-glutamylcysteine ligase. Free Radical Biology and Medicine, 45(5), 645-650. doi:DOI: 10.1016/j.freeradbiomed.2008.05.012

γ-Glutamylcysteine ligase (GCL) is the rate-limiting enzyme in glutathione (GSH) synthesis. A GAG-repeat polymorphism in the 5′ UTR of the gene coding for the catalytic subunit of GCL (GCLC) has been associated with altered GSH levels in vitro. Thus, we hypothesized that this polymorphism is associated with altered GCL activity and blood GSH levels in vivo. A total of 256 healthy United States black and white adults were genotyped for the GAG polymorphism and blood GSH levels were measured. In a subset of 107 individuals, blood GCL activity was determined. Five alleles with 4, 7, 8, 9, and 10 GAG repeats were observed. The most prevalent genotype was 7/9 (40%) followed by 7/7 (32%) and 9/9 (11%). GSH levels were 15% lower in 9/9 individuals than 7/9 individuals (P = 0.05). GCL activity was 21% lower in 9/9 individuals than 7/7 individuals (P = 0.04). A decreasing trend of GCL activity was observed in the order of 7/7 > 7/9 > 9/9 (P = 0.04). These findings show that 9/9 individuals have lower blood GSH levels, which is likely due to a decrease in GCL activity. Such individuals might be more susceptible to oxidative stress-related diseases than individuals with other genotypes.

Niveau, G. (2002). Cannabis-related flash-back, a medico-legal case. [Flash-back cannabique, un cas medico-legal] L'Encephale, 28(1), 77-79.

Cannabis is a psychoactive drug more and more widely consumed in industrialized countries and in the world. Amongst the numerous effects it can induce, flashback phenomena have been scientifically recognized only since the 70's. This case regards a young man who offended a friend without any objective reason. The report of the forensic psychiatrist demonstrated that the offense was committed under the influence of a cannabis flashback. The last time the offender had consummed cannabis, probably from Netherland, was two weeks before the acts. A plasmatic detection was realized and showed a level at 6 ng/mL, thirty minutes after the beginning of the flashback. This case confirms the clinical entity of cannabis flashback and gives an exceptional indication on THC blood concentration at the time of the relapse. But the pharmacokinetics of the phenomenon are largely unknown and long term studies concerning the metabolism, not only of THC but also of its metabolites, are needful. On the forensic standpoint, the possible participation of flashback phenomena must not be neglected when grounds of unexplained accidents or crimes are searched.

Niwa, K., & Tokoro, T. (1997). Measurement of temporal summation of visual acuity with use of modified tachistoscope. Japanese Journal of Ophthalmology, 41(6), 403-408. doi:DOI: 10.1016/S0021-5155(97)00082-8

Norton, J. W., & Corbett, J. J. (2000). Visual perceptual abnormalities: hallucinations and illusions Seminars in Neurology, 20(1), 111-121.

Visual perceptual abnormalities may be caused by diverse etiologies which span the fields of psychiatry and neurology. This article reviews the differential diagnosis of visual perceptual abnormalities from both a neurological and a psychiatric perspective. Psychiatric etiologies include mania, depression, substance dependence, and schizophrenia. Common neurological causes include migraine, epilepsy, delirium, dementia, tumor, and stroke. The phenomena of palinopsia, oscillopsia, dysmetropsia, and polyopia among others are also reviewed. A systematic approach to the many causes of illusions and hallucinations may help to achieve an accurate diagnosis, and a more focused evaluation and treatment plan for patients who develop visual perceptual abnormalities. This article provides the practicing neurologist with a practical understanding and approach to patients with these clinical symptoms.

Nourooz-Zadeh, J., Smith, C. C. T., & Betteridge, D. J. (2001). Measures of oxidative stress in heterozygous familial hypercholesterolaemia. Atherosclerosis, 156(2), 435-441. doi:DOI: 10.1016/S0021-9150(00)00677-8

Nousiainen, I., Kälviäinen, R., & Mäntyjärvi, M. (2000). Color vision in epilepsy patients treated with vigabatrin or carbamazepine monotherapy. Ophthalmology, 107(5), 884-888. doi:DOI: 10.1016/S0161-6420(00)00077-4

Purpose

Ntais, C., Pakos, E., Kyzas, P., & Ioannidis, J. P. (2005). Benzodiazepines for alcohol withdrawal. Cochrane Database of Systematic Reviews (Online), (3)(3), CD005063. doi:10.1002/14651858.CD005063.pub2

BACKGROUND: Alcohol withdrawal syndrome is a cluster of symptoms that occurs in alcohol-dependent people after cessation or reduction in alcohol use. This systematic review focuses on the evidence of benzodiazepines' use in the treatment of alcohol withdrawal symptoms. OBJECTIVES: To evaluate the effectiveness and safety of benzodiazepines in the treatment of alcohol withdrawal. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 4, 2004), MEDLINE (1966 to October 2004) and EU-PSI PSI-Tri database with no language and publication restrictions. We also screened references of retrieved articles. SELECTION CRITERIA: All randomized controlled trials examining the effectiveness and safety of a benzodiazepine in comparison with a placebo or other pharmacological intervention or other benzodiazepine were considered. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality and extracted data. MAIN RESULTS: Fifty-seven trials, with a total of 4,051 people were included. Despite the considerable number of randomized controlled trials, there was a very large variety of outcomes and of different rating scales and relatively limited quantitative synthesis of data was feasible. Benzodiazepines offered a large benefit against alcohol withdrawal seizures compared to placebo (relative risk [RR] 0.16; 95% confidence interval [CI] 0.04 to 0.69; p = 0.01). Benzodiazepines had similar success rates as other drugs (RR 1.02; 95% CI 0.92 to 1.12) or anticonvulsants in particular (RR 1.00; 95% CI 0.87 to 1.16) and offered a significant benefit for seizure control against non-anticonvulsants (RR 0.23; 95% CI 0.07 to 0.75; p = 0.02), but not against anticonvulsants (RR 1.99; 95% CI 0.46 to 8.65). Changes in Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) scores at the end of treatment were similar with benzodiazepines versus other drugs, although some small studies showed isolated significant differences for other, less commonly, used scales. Data on other comparisons were very limited, thus making quantitative synthesis for various outcomes not very informative. AUTHORS' CONCLUSIONS: Benzodiazepines are effective against alcohol withdrawal symptoms, in particular seizures, when compared to placebo. It is not possible to draw definite conclusions about the relative effectiveness and safety of benzodiazepines against other drugs in alcohol withdrawal, because of the large heterogeneity of the trials both in interventions and assessment of outcomes but the available data do not show prominent differences between benzodiazepines and other drugs in success rates.

Ohlsson, A., & Aher, S. M. (2006). Early erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Cochrane Database of Systematic Reviews (Online), 3, CD004863. doi:10.1002/14651858.CD004863.pub2

BACKGROUND: Hematocrit falls after birth in preterm infants due to physiological factors and blood letting. Low plasma levels of erythropoietin (EPO) in preterm infants provide a rationale for the use of EPO to prevent or treat anemia. OBJECTIVES: Primary objective:To assess the effectiveness and safety of early initiation of EPO (initiated before eight days after birth) in reducing red blood cell transfusions in preterm and/or low birth weight infants.Secondary objectives:Subgroup analyses of low ( 500 IU/kg/week) doses of EPO and, within these subgroups, analyses of the use of low ( 5 mg/kg/day) doses of supplemental iron, in reducing red blood cell transfusions in these infants. SEARCH STRATEGY: The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE, EMBASE, CINAHL, abstracts from scientific meetings published in Pediatric Research and reference lists of identified trials and reviews were searched in November 2005. No language restrictions were applied. SELECTION CRITERIA: Randomised or quasi-randomized controlled trials of early initiation of EPO treatment (started before 8 days of age) vs. placebo or no intervention in preterm ( 5 mg/kg/day) doses of supplemental iron, in reducing red blood cell transfusions in these infants. SEARCH STRATEGY: The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE, EMBASE, CINAHL, abstracts from scientific meetings published in Pediatric Research and reference lists of identified trials and reviews were searched in November 2005. No language restrictions were applied. SELECTION CRITERIA: Randomised or quasi-randomized controlled trials of early initiation of EPO treatment (started before 8 days of age) vs. placebo or no intervention in preterm ( 5 mg/kg/day) doses of supplemental iron, in reducing red blood cell transfusions in these infants. SEARCH STRATEGY: The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE, EMBASE, CINAHL, abstracts from scientific meetings published in Pediatric Research and reference lists of identified trials and reviews were searched in November 2005. No language restrictions were applied. SELECTION CRITERIA: Randomised or quasi-randomized controlled trials of early initiation of EPO treatment (started before 8 days of age) vs. placebo or no intervention in preterm ( 3 retinopathy of prematurity (ROP) in the EPO group [typical RR; 1.71 (95% CI 1.15, 2.54); typical RD; 0.05 (95% CI 0.01, 0.09); NNTH; 20 (95% CI 11, 100)]. The non-significant results for ROP (any stage reported) showed a similar trend. The increased risk for ROP may be associated with use of higher doses of supplemental of iron in the EPO group than in the control group. The rates for mortality, sepsis, intraventricular haemorrhage, periventricular leukomalacia, necrotizing enterocolitis, bronchopulmonary dysplasia, neutropenia, hypertension, length of hospital stay or long-term neurodevelopmental outcomes were not significantly change by the administration of EPO. AUTHORS' CONCLUSIONS: Early administration of EPO reduces the use one or more red blood cell transfusions, the volume of red blood cells transfused, and the number of donors and transfusions the infant is exposed to following study entry. The small reductions are of limited clinical importance. Any donor exposure is likely not avoided as most studies included infants, who had received red cell transfusions prior to trial entry. There was a significant increase in the rate of ROP (stage >3). Animal data and observational studies in humans support a possible association between treatment with EPO and the development of ROP. EPO does not significantly decrease or increase any of the other important neonatal adverse outcomes including mortality. The incidence of ROP should be ascertained in the studies that have already been conducted but did not report on this outcome. Any ongoing research should deal with the issue of ROP and evaluate the current clinical practice that will limit donor exposure through satellite units. Research efforts should focus on limiting donor exposure (to as few donors as possible) during the first few days of life in sick neonates, when red blood cell transfusions are most likely to be required and cannot be prevented by early (or late) EPO treatment. Due to the limited benefits and the increased risk of ROP, early administration of EPO is not recommended.

Ohlsson, A., Walia, R., & Shah, S. (2008). Ibuprofen for the treatment of patent ductus arteriosus in preterm and/or low birth weight infants. Cochrane Database of Systematic Reviews (Online), (1)(1), CD003481. doi:10.1002/14651858.CD003481.pub3

BACKGROUND: A patent ductus arteriosus (PDA) complicates the clinical course of preterm infants, increasing their risks of developing chronic lung disease (CLD), necrotizing enterocolitis (NEC), and intraventricular hemorrhage (IVH). Indomethacin is used as standard therapy to close a PDA, but is associated with reduced blood flow to the brain, kidneys and gastrointestinal tract. Ibuprofen, another cyclo-oxygenase inhibitor, may be as effective as indomethacin, with fewer side effects. OBJECTIVES: To determine the effectiveness and safety of ibuprofen compared to placebo or no intervention for closing a PDA in preterm and/or low birth weight infants.To determine the effectiveness and safety of ibuprofen compared to other cyclo-oxygenase inhibitors (including indomethacin, mefenamic acid) for closing a PDA in preterm and/or low birth weight infants. SEARCH STRATEGY: Randomized or quasi-randomized controlled trials (RCTs) comparing ibuprofen to placebo or indomethacin or mefenamic acid for therapy of PDA were identified by searching the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3, 2007), MEDLINE (1996 - August 2007), CINAHL (1982 - August 2007), EMBASE (1980 - August 2007), reference lists of published RCTs and abstracts from the Pediatric Academic Societies and the European Society for Pediatric Research meetings published in Pediatric Research (1991 - April 2005) or on their website (to August 2007). No language restrictions were applied. SELECTION CRITERIA: 1) Design: Randomized or quasi-randomized controlled trials2) Population: Preterm (< 37 weeks gestational age) or low birth weight infants (< 2500 g) with a clinically or echocardiographically diagnosed PDA3) Intervention: Administration of ibuprofen (orally or intravenously) for the closure of PDA4) Outcomes: At least one of the following outcomes were reported: failure to close a PDA, mortality, surgical ductal ligation, intraventricular haemorrhage (IVH), periventricular leukomalacia (PVL), NEC, decreased urine output, retinopathy of prematurity (ROP), chronic lung disease (CLD), sepsis, pulmonary hemorrhage, pulmonary hypertension, duration of supplementary oxygen, duration of mechanical ventilation, duration of hospital stay, and serum creatinine levels following treatment. DATA COLLECTION AND ANALYSIS: At least two review authors worked independently at each step of the original review, then compared results and resolved differences. The current update was conducted by one review author (AO). Methodological quality of eligible studies was assessed according to blinding of randomization, of intervention and of outcome assessment, and completeness of follow up. Weighted treatment effects, calculated using RevMan 4.2.10, included typical relative risk (RR), typical risk difference (RD), number needed to treat to benefit (NNT) or harm (NNH), and weighted mean difference (WMD), all with 95% confidence intervals (CI). A fixed effect model was used for meta-analyses. Heterogeneity tests including the I-squared test (I(2)) were performed to assess the appropriateness of pooling the data. MAIN RESULTS: No studies using mefenamic acid were identified. Sixteen studies enrolling 876 infants were identified. Four additional trials were identified for this update and two studies published as abstracts were now available as full articles. One study compared ibuprofen to placebo, but the results were not reported unblinded to intervention group. Fifteen studies including 740 infants compared the effectiveness of ibuprofen to indomethacin for the closure of a PDA. For the primary outcome (failure of ductal closure), there was no statistically significant difference between ibuprofen and indomethacin groups [typical RR 0.99 (95% CI 0.78, 1.27); typical RD 0.00 (95% CI -0.06, 0.06)]. There were no statistically significant differences in mortality, reopening of the ductus, need for surgical duct ligation, duration of ventilator support, duration of supplementary oxygen, pulmonary hemorrhage, pulmonary hypertension, CLD, IVH, PVL, NEC, intestinal perforation, gastrointestinal bleed, time to full enteral feeds, time to regain birth weight, ROP, sepsis, duration of hospitalization. Ibuprofen treatment was associated with statistically significantly lower serum creatinine levels after treatment (6 trials, 336 infants; WMD - 8.2 (95% CI -13.3, -3.2) mmol/L and lower incidence of 'decreased urine output' [3 trials, 336 infants; typical RR; 0.22 (95% CI 0.09, 0.51); typical RD -0.12 (95% CI -0.18, -0.06); NNT 8 (95% CI 6,17)]. There was moderate heterogeneity of treatment effect for the outcomes 'time to regain birth weight' and 'decreased urine output". Heterogeneity was not noted for other outcomes. For several of these outcomes, the sample size was small and the estimates imprecise. There are not enough data available regarding the effectiveness of oral ibuprofen compared with indomethacin to close a PDA [3 trials, 69 infants; typical RR 1.41 (95% CI 0.68, 2.93); typical RD 0.10 (95% CI -0.10, 0.30)]. Pulmonary hypertension was noted in one infant receiving ibuprofen to close a PDA enrolled in a trial in this review and an additional report of such a case was identified from the literature. AUTHORS' CONCLUSIONS: No statistically significant difference in the effectiveness of ibuprofen compared to indomethacin in closing a PDA was found. Ibuprofen compared with indomethacin reduces the risk of oliguria and is associated with lower serum creatinine levels following treatment. Pulmonary hypertension has been observed in three infants after prophylactic use of ibuprofen and one infant receiving ibuprofen for treatment in this review developed pulmonary hypertension. One additional case of pulmonary hypertension following treatment with ibuprofen to close a PDA was identified from the literature. The available data support the use of either drug for the treatment of a PDA. As both drugs are equally effective in closing a PDA, the clinician needs to weigh the potential side effects of one drug vs. the other when making a decision which drug to use. The most urgent research question to be answered is whether ibuprofen compared to indomethacin confers an improved rate of intact survival (survival without impairment) at 18 months corrected age and at the age of school entry.

Ono, H., Sakamoto, A., & Sakura, N. (2001). Plasma total glutathione concentrations in healthy pediatric and adult subjects. Clinica Chimica Acta, 312(1-2), 227-229. doi:DOI: 10.1016/S0009-8981(01)00596-4

Oomen, K. P., van Wijck, A. J., Hordijk, G. J., & de Ru, J. A. (2009). Sluder's neuralgia: a trigeminal autonomic cephalalgia? Cephalalgia : An International Journal of Headache, doi:10.1111/j.1468-2982.2009.01919.x

Oomen KPQ, van Wijck AJM, Hordijk GJ & de Ru JA. Sluder's neuralgia: a trigeminal autonomic cephalalgia? Cephalalgia 2009. London. ISSN 0333-1024The objective was to formulate distinctive criteria to substantiate our opinion that Sluder's neuralgia and cluster headache are two different clinical entities. A systematic review was carried out of all available, original literature on Sluder's neuralgia. Pain characteristics, periodicity and associated signs and symptoms were studied and listed according to frequency of appearance. Eleven articles on Sluder's neuralgia were evaluated. Several differences between Sluder's neuralgia and cluster headache became evident. Based on described symptoms, new criteria for Sluder's neuralgia could be formulated. Sluder's neuralgia and cluster headache could possibly be regarded as two different headache syndromes, and Sluder's neuralgia could be a trigeminal autonomic cephalalgia.

O'Shea, B., & Fagan, J. (2001). Lysergic acid diethylamide. Irish Medical Journal, 94(7), 217.

Osmond, H. (1973). The medical and scientific importance of hallucinogens. The Practitioner, 210(255), 112-119.

Palenzona, C. (1968). Hallucinogens. Medical and social aspects. [Gli allucinogeni. Gli aspetti medici e sociali] Minerva Medica, 59(46 Suppl), 15-17.

Passie, T., Schneider, U., & Emrich, H. M. (2002). Persisting continuous visual perception disorder in a chronic MDMA ('ecstasy') user. The Australian and New Zealand Journal of Psychiatry, 36(2), 266-267.

Paulsen, H. G., & Laeng, B. (2006). Pupillometry of Grapheme-Color Synaesthesia. Cortex, 42(2), 290-294. doi:DOI: 10.1016/S0010-9452(08)70354-X

Pavlakis, N., Schmidt, R., & Stockler, M. (2005). Bisphosphonates for breast cancer. Cochrane Database of Systematic Reviews (Online), (3)(3), CD003474. doi:10.1002/14651858.CD003474.pub2

BACKGROUND: Bone is the most common site of metastatic disease associated with breast cancer affecting more than half of women during the course of their disease. Bone metastases are a significant cause of morbidity due to pain, pathological fractures, hypercalcaemia and spinal cord compression, and contribute to mortality. Bisphosphonates, which inhibit osteoclast-mediated bone resorption, are standard care for tumour-associated hypercalcaemia, and have been shown to reduce bone pain, improve quality of life, and to delay skeletal events and reduce their number in patients with multiple myeloma. Several randomized controlled trials have evaluated the role of bisphosphonates in breast cancer. OBJECTIVES: To assess the effect of bisphosphonates on skeletal events, bone pain, quality of life and survival in women with early and advanced breast cancer. SEARCH STRATEGY: Randomized controlled trials were identified using the specialized register maintained by the Cochrane Breast Cancer Group (the search was applied to the databases Medline, Central/CCTR, Embase, CancerLit, and included handsearches from a number of other relevant sources). See: Cochrane Collaboration Collaborative Review Group in Breast Cancer search strategy. SELECTION CRITERIA: Randomized controlled trials evaluating skeletal events in women with metastatic breast cancer and early breast cancer comparing: 1. treatment with a bisphosphonate with the same treatment without a bisphosphonate 2. treatment with one bisphosphonate with treatment with a different bisphosphonate. DATA COLLECTION AND ANALYSIS: Studies were selected by two independent reviewers. Studies fulfilling the eligibility criteria were evaluated for quality, particularly concealment of allocation to randomized groups. Data were extracted from the published papers or abstracts independently by the two primary reviewers for each of the specified endpoints (skeletal events, bone pain, quality of life and survival). Data on skeletal events and survival were presented as numbers of events, risk ratios and ratios of event rates. Meta-analyses were based on the fixed-effects model (Mantel-Haenszel). Subjective qualitative ratings were used to summarize the quality of life and pain data. MAIN RESULTS: Twenty one randomized studies were included. All studies in advanced breast cancer included women with clinically evident bone metastases (osteolytic and/or mixed osteolytic/osteoblastic) by plain xray and/or radionucleotide bone scans. In nine studies that included 2189 women with advanced breast cancer and existing bone metastases, bisphosphonates reduced the risk of developing a skeletal event by 17% (RR 0.83; 95% confidence interval (CI) 0.78-0.89; P < 0.00001). This effect was more modest, but still highly significant if episodes of hypercalcaemia were excluded (10 studies, 2656 women, RR 0.85; 95% CI 0.79-0.91 P = 0.0001). Overall, intravenous bisphosphonates reduce the risk of developing a skeletal event by 17 % (95% CI 0.78-0.89) compared with oral bisphosphonates, which reduce the risk of developing a skeletal event by 16 % (95% CI 0.76-0.93). Of the currently available bisphosphonates, 4 mg IV zolendronate reduces the risk of developing a skeletal event by 41% (RR 0.59, 95% CI 0.42-0.82), compared with 33 % by 90 mg IV pamdronate (RR 0.77, 95% CI 0.69-0.87), 18 % by 6 mg IV ibandronate (RR 0.82, 95% CI 0.67-1.00), 14 % by 50mg oral ibandronate (RR 0.86, 95% CI 0.73-1.02) and 16 % by 1600 mg oral clodronate (RR 0.84, 95% CI 0.72-0.98).Compared with placebo or no bisphosphonate, with bisphosphonates the skeletal event rate was lower in all of 12 studies in women with clinically evident bone metastases (median reduction of 29%, range 14-48%); statistically significant reductions were reported in 10 trials (four intravenous pamidronate, two oral clodronate, one intravenous ibandronate and two oral ibandronate, a single intravenous zolendronate study).Studies of intravenous zolendronate, pamidronate and oral clodronate in women with advanced breast cancer and clinically evident bone metastases showed significant delays in the median time to a skeletal event. Event-free survival was also reported to be longer in women receiving 6 mg of ibandronate compared with controls.Compared with placebo or no bisphosphonate, with bisphosphonates significant improvements in bone pain were reported in seven studies (90 mg iv pamidronate, 4 mg iv zolendronate, 6 mg iv ibandronate, 1600 mg oral clodronate and 50 mg oral ibandronate). Eight studies tested the effect of bisphosphonates compared with placebo on patient-rated quality of life using a referenced scale. Improvements in global quality of life were reported in only the three studies of iv and oral ibandronate.Treatment with bisphosphonates does not appear to affect survival in women with advanced breast cancer.Intravenous zolendronate (4 mg) appeared to be as effective as pamidronate (90mg) when directly compared in a single randomized double-blind study, based on the risk of developing a skeletal related event, the median time to first skeletal event and skeletal morbidity rate (events per year). Updated re-evaluation of the primary data in the overall population, by multiple event analysis using the method of Anderson-Gill, showed a reduction in the risk of developing any skeletal complication (including hypercalcamia) of 20 % (zolendronate 4 mg compared with pamidronate 90 mg, RR = 0.80, 95% CI 0.66 - 0.97, p = 0.025), suggesting a possible advantage of zolendronate 4 mg compared with pamidronate 90 mg.In the three studies of bisphosphonates in 320 women with advanced breast cancer without clinically evident bone metastases, there was no significant reduction in the incidence of skeletal events (RR 0.99; 95% CI 0.67-1.47; P = 0.97). In the three studies of oral clodronate that included 1653 women with early breast cancer, there was no statistically significant evidence of reduction in the risk of developing skeletal metastases (RR 0.82; 95% CI 0.66-1.01; P = 0.07), or of visceral metastases (RR 0.95; 95% CI 0.80-1.12, p = 0.53). However there was evidence of improved survival (RR 0.82; 95% CI 0.69-0.97, p = 0.02). However there was statistically significant heterogeneity among these studies and a random effects meta-analysis emphasizes the uncertainty of this finding (RR 0.75; 95% CI 0.45 - 1.25; p = 0.19). Toxicity or adverse events were described in 18 of the 21 studies. In general, few serious adverse events were reported. Toxicity associated with bisphosphonates is generally mild and infrequent. Renal toxicity is the main issue with intravenous zolendronate and is dose (8 mg) and infusion time related (< 15 minutes). With daily oral calcium (500 mg) and vitamin D (300-400IU) no significant renal impairment or hypocalcamia was observed with a 15 minute infusion of 4 mg IV zolendronate compared with 90 mg pamidronate. Monitoring of renal function with every cycle of zolendronate was undertaken in all studies and is recommended in practice. No significant renal toxicity was observed with intravenous pamidronate or ibandronate. Mild gastrointestinal toxicity is the main toxicity with oral clodronate and oral ibandronate. AUTHORS' CONCLUSIONS: In women with advanced breast cancer and clinically evident bone metastases, the use of bisphosphonates (oral or intravenous) in addition to hormone therapy or chemotherapy, when compared with placebo or no bisphosphonates, reduces the risk of developing a skeletal event and the skeletal event rate, as well as increasing the time to skeletal event. Some bisphosphonates may also reduce bone pain in women with advanced breast cancer and clinically evident bone metastases and may improve global quality of life. The optimal timing of initiation of bisphosphonate therapy and duration of treatment is uncertain. In women with early breast cancer the effectiveness of bisphosphonates remains an open question for research.

Pelissolo, A., Maniere, F., Boutges, B., Allouche, M., Richard-Berthe, C., & Corruble, E. (2007). Anxiety and depressive disorders in 4,425 long term benzodiazepine users in general practice. [Troubles anxieux et depressifs chez 4 425 patients consommateurs de benzodiazepines au long cours en medecine generale] L'Encephale, 33(1), 32-38.

Consumption rates of anxiolytic drugs, and especially of benzodiazepines, remain very high in France compared to other Western countries, whereas clinical guidelines limit their indications to short term treatments and only for some precise anxiety disorders. Recent epidemiologic surveys in the community indicated that more than 15% of people used once or more an anxiolytic drug in the past year. The issue of chronic treatments is particularly crucial because of their poor benefit/risk ratio in most anxiety disorders (limited efficacy, cognitive side effects, withdrawal and dependence problems). To address this important public health issue, and knowing that, in France, benzodiazepines are prescribed mainly by general physicians, our aims were to explore psychiatric diagnoses in GP's patients with chronic use of anxiolytic benzodiazepines. We included 4 425 patients consuming such drugs regularly for six months or more, and assessed their anxiety and depression symptoms through various clinical scales (Hospital Anxiety and Depressive scale - HAD, Clinical Global Impression scale - CGI, Sheehan Disability Scale - SDS, Cognitive Dependence to Benzodiazepines scale - CDB) and with the Mini International Neuropsychiatric Interview for DSM IV criteria. Only 2.2% of the subjects had neither anxious nor depressive symptoms as indicated by low scores on both subscores (less than 8) of the HAD scale, used as a screener. Nearly three quarters of the 4,257 subjects (73.2%), had CGI scores of at least 5 (markedly ill to extremely ill). Social and familial disability was also high in more than 40% of the sample (marked to extreme disruption according to SDS scores). About half of the sample had CDB scores suggesting a benzodiazepine dependence. According to the MINI, 85.1% of the patients had at least one current DSM IV diagnosis of affective disorder. The most frequent diagnoses were major depressive episode (60%), generalized anxiety disorder (61.2%), and panic disorder (22.5%). An anxiety and depressive comorbidity wad found in 41.9% of the subjects. Some methodological limitations must be taken into account in the discussion of our results, and especially the fact that the included patients were not supposed to be totally representative of all patients consuming anxiolytic benzodiazepines in general practice. However, the size of our sample is sufficiently large to limit possible biases in patient selection. The main result of this study is that a great majority of the patients had significant symptomatology, in particular major depressive episodes and generalized anxiety disorder, often with marked severity and disability. These data are in line with the knowledge of a lack of efficacy of benzodiazepines in depressive and most anxiety disorders, despite long term treatment. They also confirm the current guidelines which recommend prescribing serotoninergic antidepressants, and not benzodiazepines, when long term treatments are needed for severe and chronic affective disorders. This epidemiologic study leads to the conclusion that a specific and attentive diagnostic assessment should be done in all patients receiving benzodiazepines for more than three months, in order to purpose in many cases other long term therapeutic strategies.

Pennypacker, K. R., Yang, X., Gordon, M. N., Benkovic, S., Miller, D., & O'Callaghan, J. P. (2000). Long-term induction of Fos-related antigen-2 after methamphetamine-, methylenedioxymethamphetamine-, 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine- and trimethyltin-induced brain injury. Neuroscience, 101(4), 913-919.

A long-term induction of Fos-related antigens has been shown in neurons after brain injury, suggesting that Fos-related antigens are involved in enhancing the transcription of genes related to the process of regeneration and repair. In the present study, we report that levels of Fos-related antigen-2 are elevated in several models of chemically induced brain injury. Trimethyltin, which causes degeneration of neurons primarily in the hippocampus and other limbic regions, results in a five-fold induction of Fos-related antigen-2 immunoreactivity in neurons in the pyramidal and dentate layers of the hippocampus starting at seven days post-treatment and persisting for 60days. Methamphetamine and methylenedioxymethamphetamine, agents which cause degeneration of dopaminergic nerve terminals in the striatum of the mouse, cause an increase in Fos-related antigen-2 immunoreactivity which begins at three days post-treatment and returns to basal levels by days 5 and 15, respectively. Treatment with 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine elevated levels of Fos-related antigen-2 in the mouse striatum at three days post-treatment. This abbreviated time-course of Fos-related antigen-2 induction is consistent with less severe insult (terminal damage) relative to trimethyltin (cell death), but induction occurs during the period of regeneration and repair in both models. Dexfenfluramine, a non-neurotoxic amphetamine, does not induce Fos-related antigen-2 expression. Decreasing core temperature of the mouse, which blocks amphetamine-induced neurotoxicity, also blocks Fos-related antigen-2 induction.In summary, Fos-related antigen-2 is induced in models of both cell death and terminal degeneration, suggesting that this transcription factor may serve as a universal signal transduction molecule involved in the regulation of genes related to regeneration and repair in the CNS.

Perel, A., & Davidson, J. T. (1976). Recurrent hallucinations following ketamine. Anaesthesia, 31(8), 1081-1083.

Recurrent hallucinations appeared in an 11-year-old boy during 5 days following ketamine anaesthesia. Previous anaesthesia with ketamine and adequate diazepam supplementation did not produce any such effect. The phenomenon of delayed recurring hallucinations is a rare but dangerous side-effect of ketamine, not unlike LSD flashbacks. The described case lends support to previous reports on the value of diazepam in the prevention of post-ketamine perceptual abnormalities.

Pienaar, E. D., Young, T., & Holmes, H. (2006). Interventions for the prevention and management of oropharyngeal candidiasis associated with HIV infection in adults and children. Cochrane Database of Systematic Reviews (Online), 3, CD003940. doi:10.1002/14651858.CD003940.pub2

BACKGROUND: Oral candidiasis (OC) associated with human immunodeficiency virus (HIV) infection occurs commonly and recurs frequently, often presenting as an initial manifestation of the disease. Left untreated these lesions contribute considerably to the morbidity associated with HIV infection. Interventions aimed at preventing and treating HIV-associated oral candidal lesions form an integral component of maintaining the quality of life for affected individuals. OBJECTIVES: To determine the effects of any intervention in preventing or treating OC in children and adults with HIV infection. SEARCH STRATEGY: The search strategy was based on that of the HIV/AIDS Cochrane Review Group. The following electronic databases were searched for randomised controlled trials for the years 1982 to 2005: Medline; AIDSearch; EMBASE and CINAHL. The Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effectiveness and the Cochrane Central Register of Controlled Trials (CENTRAL) was also searched through May 2005. The abstracts of relevant conferences, including the International Conferences on AIDS and the Conference on Retroviruses and Opportunistic Infections, as indexed by AIDSLINE, were also reviewed. The strategy was iterative, in that references of included studies were searched for additional references. All languages were included. SELECTION CRITERIA: Randomised controlled trials (RCTs) of palliative, preventative or curative therapy were considered, irrespective of whether the control group received a placebo. Participants were HIV positive adults. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the methodological quality of the trials and extracted data. Study authors were contacted for additional data where necessary. MAIN RESULTS: Four trials were conducted in developing countries with eleven of the trials conducted in the United States of America. Twenty eight trials (n=3225) were included. Nineteen trials investigated treatment and nine trials the prevention of OC. One trial, comparing fluconazole and ketoconazole, investigated the treatment of OC in children. Eighteen of the included studies reported CD4 cell counts. None of the included studies investigated the effects of HAART or any other form of antiretroviral treatment on OC treatment or prevention.TreatmentTreatment was assessed in the majority of trials looking at both clinical and mycological cures. In the majority of comparisons there was only one trial. Compared to nystatin, fluconazole favoured clinical cure in adults(1 RCT; n=167; RR 1.69; 95% CI 1.27 to 2.23). There was no difference with regard to clinical cure between fluconazole compared to ketoconazole (2 RCTs; n=83; RR 1.27; 95% CI 0.97 to 1.66), itraconazole (2 RCTs; n=434; RR 1.05; 95% CI 0.94 to 1.16) or clotrimazole (2 RCTs; n=358; RR 1.14; 95% CI 0.92 to 1.42). When compared with clotrimazole, both fluconazole (2 RCTs; n=358; RR 1.47; 95% CI 1.16 to 1.87) and itraconazole (1 RCT; n=123; RR 2.20; 95% CI 1.43 to3.39) proved to be better for mycological cure. Both gentian violet (1 RCT; n=96; RR 5.28; 95% CI 1.23 to 22.55) and ketoconazole (1 RCT; n=92; RR 5.22; 95% CI 1.21 to 22.53) were superior to nystatin in bringing about clinical cure.PreventionSuccessful prevention was defined as the prevention of a relapse while receiving prophylaxis. Fluconazole was compared with placebo in one trial (5 RCTs; n=599; RR 0.61; 95% CI 0.5 to 0.74) and with no treatment in another (1 RCT; n=65; RR 0.16; 95% CI 0.08 to 0.34). In both instances the prevention of clinical episodes was favoured by fluconazole. Comparing continuous fluconazole treatment with intermittent treatment (1 RCT; n=62; RR 0.37; 95% CI 0.15 to 0.92), prevention is favoured by the continuous treatment. AUTHORS' CONCLUSIONS: Implications for practiceDue to only one study in children it is not possible to make recommendations for treatment or prevention of OC in children. Amongst adults, there were few studies per comparison. Due to insufficient evidence no conclusion could be made about the effectiveness of clotrimazole, nystatin, amphotericin B, itraconazole or ketoconazole with regard to OC prophylaxis. In comparison to placebo, fluconazole is an effective preventative intervention. However, the potential for resistant Candida organisms to develop, as well as the cost of prophylaxis, might impact the feasibility of implementation. No studies were found comparing fluconazole with other interventions. Direction of findings suggests that ketoconazole, fluconazole, itraconazole and clotrimazole improved the treatment outcomes.Implications for researchThere is an urgent need for gentian violet and other less expensive anti-fungal drugs for OC treatment to be evaluated in larger studies. More well designed treatment trials with larger sample size are needed to allow for sufficient power to detect differences in not only clinical, but also mycological response and relapse rates. There is also a strong need for more research to be done on the treatment and prevention of OC in children as it is reported that OC is the most frequent fungal infection in children and adolescents who are HIV positive. More research on the effectiveness of less expensive interventions also needs to be done in resource-poor settings. Currently few trials report outcomes related to quality of life, nutrition, or survival. Future researchers should consider measuring these when planning trials. Development of resistance remains under-studied and more work must be done in this area.It is recommended that trials be more standardised and conform more closely to CONSORT as this will improve research and also clinical practice.

Pihlajamaa, J., Suvisaari, J., Henriksson, M., Heila, H., Karjalainen, E., Koskela, J., Cannon, M., & Lonnqvist, J. (2008). The validity of schizophrenia diagnosis in the Finnish Hospital Discharge Register: findings from a 10-year birth cohort sample. Nordic Journal of Psychiatry, 62(3), 198-203. doi:10.1080/08039480801983596

The purpose of this study was to investigate the diagnostic validity of schizophrenia in the Finnish Hospital Discharge Register (FHDR) with a large, epidemiologically representative sample using a multidiagnostic approach (DSM-III-R, DSM-IV, ICD-10), and to find additional criteria that could be used to improve the validity of schizophrenia diagnosis in future register-based research that utilizes the FHDR. The study population consisted of all individuals (n=877) who were born in Helsinki, Finland, between 1 January 1951 and 31 December 1960, and who had had at least one diagnosis of schizophrenia, schizophreniform disorder or schizoaffective disorder in the FHDR. All their available hospital case notes were collected. The total number of subjects for whom case notes were obtained was 806. We used the OPCRIT system (version 3.4) to produce diagnoses according to ICD-10, DSM-III-R and DSM-IV criteria based on the information extracted from the hospital case notes. We examined the distribution of the DSM-III-R, DSM-IV and ICD-10 diagnoses generated by the OPCRIT and calculated the proportion of individuals who received the same diagnosis in the FHDR and in the OPCRIT assessment. The proportion of subjects who received a core schizophrenia spectrum diagnosis (schizophrenia, schizoaffective disorder or schizophreniform disorder) in both the FHDR and OPCRIT assessment varied between 75% (DSM-III-R criteria) and 78% (ICD-10 criteria). Of the subjects with a narrow schizophrenia diagnosis in the FHDR, between 74% (DSM-IV) and 78% (ICD-10) received a diagnosis of schizophrenia in the reassessment depending on the diagnostic criteria applied. Eighty per cent of those who had received a core schizophrenia spectrum FHDR diagnosis after 1982 (vs. 56% of those who had received their last schizophrenia diagnosis in 1982 or before) received a DSM-IV diagnosis of core schizophrenia spectrum disorder. Of the 58 subjects in the sample who had been given at various times diagnoses of both core schizophrenia diagnosis and bipolar I diagnosis in FHDR, 43% received a core schizophrenia spectrum diagnosis according to DSM-IV criteria. The validity of the FHDR schizophrenia diagnosis is acceptable for large-scale register studies and comparable with that of other Nordic registers. Diagnostic validity can be further improved by selecting subjects who have core schizophrenia spectrum disorder as the latest diagnosis, by omitting cases diagnosed before 1982, and by excluding cases with a register diagnoses of both a core schizophrenia spectrum and bipolar I disorder.

Plosker, G. L., & Figgitt, D. P. (2003). Rituximab: a review of its use in non-Hodgkin's lymphoma and chronic lymphocytic leukaemia. Drugs, 63(8), 803-843.

Rituximab is an anti-CD20 monoclonal antibody that has demonstrated efficacy in patients with various lymphoid malignancies, including indolent and aggressive forms of B-cell non-Hodgkin's lymphoma (NHL) and B-cell chronic lymphocytic leukaemia (CLL). While the optimal use of the drug in many clinical settings has yet to be clarified, two pivotal trials have established rituximab as a viable treatment option in patients with relapsed or refractory indolent NHL, and as a standard first-line treatment option when combined with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy in elderly patients with diffuse large B-cell lymphoma (the most common type of aggressive NHL). The former was a noncomparative trial in relapsed indolent NHL (follicular and small lymphocytic subtypes) with clinical responses achieved in about half of patients treated with rituximab 375 mg/m(2) intravenously once weekly for 4 weeks, which was similar to some of the most encouraging results reported with traditional chemotherapeutic agents. The latter was a randomised comparison of eight cycles of CHOP plus rituximab 375 mg/m(2) intravenously (one dose per cycle) versus CHOP alone in previously untreated elderly patients (60 to 80 years of age) with diffuse large B-cell lymphoma. In this pivotal trial, 2-year event-free and overall survival were significantly higher with rituximab plus CHOP, and there was no increase in clinically significant adverse effects compared with CHOP alone. Treatment with rituximab is generally well tolerated, particularly in terms of adverse haematological effects and serious or opportunistic infections relative to standard chemotherapy. Infusion-related reactions occur in the majority of patients treated with rituximab; these are usually mild to moderate flu-like symptoms that decrease in frequency with subsequent infusions. In approximately 10% of patients, however, severe infusion-related reactions develop (e.g. bronchospasm, hypotension). These reactions are usually reversible with appropriate interventions and supportive care but there have been rare reports of fatalities. CONCLUSIONS: Clinical trials with rituximab indicate that the drug has broad application to B-cell malignancies, although further clarification is needed to determine its optimal use in many of these clinical settings. Importantly, rituximab in combination with CHOP chemotherapy has emerged as a new treatment standard for previously untreated diffuse large B-cell lymphoma, at least in elderly patients. Compared with conventional chemotherapy, rituximab is associated with markedly reduced haematological events such as severe neutropenia, as well as associated infections. Rituximab may be particularly suitable for elderly patients or those with poor performance status, and its tolerability profile facilitates its use in combination with cytotoxic drugs. PHARMACODYNAMIC PROPERTIES: Rituximab is a mouse/human chimaeric IgG(1)-kappa monoclonal antibody that targets the CD20 antigen found on the surface of malignant and normal B lymphocytes. Although treatment with rituximab induces lymphopenia in most patients, typically lasting about 6 months, a full recovery of B lymphocytes in the peripheral blood is usually seen 9-12 months after therapy, as CD20 is not expressed on haematopoietic stem cells. CD20 is, however, expressed on >90% of B-cell non-Hodgkin's lymphomas (NHL) and to a lesser degree on B-cell chronic lymphocytic leukaemia (CLL) cells.Although not fully elucidated, the cytotoxic effects of rituximab on CD20-positive malignant B cells appears to involve complement-dependent cytotoxicity, complement-dependent cellular cytotoxicity, antibody-dependent cellular cytotoxicity and induction of apoptosis. In addition, in vitro data indicate that rituximab sensitises tumour cells to the effects of conventional chemotherapeutic drugs. PHARMACOKINETIC PROPERTIES: Serum rituximab concentrations increased in proportion to dose across a wide range of single- and multiple-dose intravenous regimens in patients with B-cell NHL. When administll NHL. When administered at a dose of 375 mg/m(2) once weekly for 4 weeks in a pivotal trial in patients with relapsed or refractory indolent B-cell NHL (follicular or small lymphocytic subtypes), peak serum concentrations essentially doubled from the first (239.1 mg/L) to the fourth (460.7 mg/L) infusion, while elimination half-life (t(1/2)) increased from 76.3 to 205.8 hours (3.2 to 8.6 days). The concomitant increase in serum rituximab concentrations and t(1/2) with each successive infusion may be due, at least in part, to the elimination of circulating CD20-positive B cells and reduction or saturation of CD20-binding sites after the initial infusions of rituximab. The pharmacokinetic properties of rituximab are also characterised by wide inter-individual variability, and serum drug concentrations that are correlated with clinical response. Although pharmacokinetic data are limited in patients with aggressive forms of NHL, such as diffuse large B-cell lymphoma, rituximab appears to have a similar pharmacokinetic profile in these patients to that in patients with indolent B-cell NHL. The pharmacokinetics of rituximab are also reported to be similar whether the drug is administered with or without cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy. THERAPEUTIC USE: A number of studies have demonstrated efficacy of intravenous rituximab in patients with various lymphoid malignancies of B-cell origin, including indolent (e.g. follicular lymphoma) and aggressive (e.g. diffuse large B-cell lymphoma) forms of NHL, and CLL, but the drug has not yet been approved for use in CLL, and approved indications in NHL vary between countries. In the US, for example, rituximab is available for the treatment of patients with low-grade or follicular, relapsed or refractory, CD20-positive B-cell NHL. In Europe, the drug has similar approval for relapsed or refractory follicular NHL as in the US, but has also been approved for use in combination with CHOP chemotherapy for the most common aggressive form of NHL (CD20-positive, diffuse large B-cell lymphoma). Rituximab was approved for these indications primarily on the basis of results from two pivotal trials. In Japan, rituximab has been approved for indolent B-cell NHL and mantle cell lymphoma (an aggressive form of B-cell NHL), primarily on the basis of results of a Japanese phase II trial. Indolent NHL: Results of several studies evaluating rituximab 375 mg/m(2) once weekly for 4 weeks in patients with indolent forms of B-cell NHL (primarily follicular and small lymphocytic lymphomas) showed objective response (OR) rates ranging from approximately 40-60% in those receiving the drug for relapsed or refractory indolent B-cell NHL, and slightly higher (50-70%) for those receiving rituximab as first-line therapy. In a pivotal trial in 166 patients with relapsed or refractory low-grade or follicular B-cell NHL, intent-to-treat (ITT) analysis showed an OR rate of 48%, and a projected median time to progression of 13 months.Encouraging data are also emerging on the use of rituximab in combination with chemotherapeutic agents (e.g. CHOP, fludarabine-containing regimens) or other drugs (e.g. interferon-alpha2a) in previously untreated patients with indolent forms of B-cell NHL (primarily follicular and small lymphocytic subtypes). Rates for OR were consistently around 95%, with the majority being complete responses (CRs). Follow-up data from a study in 40 patients with low-grade or follicular B-cell NHL treated with rituximab plus CHOP as first-line therapy showed that responses were durable with a progression-free survival and median duration of response >5 years.Bcl-2 gene rearrangement (t14;18) occurs in malignant cells in up to 85% of patients with follicular lymphoma, and minimal residual disease in peripheral blood and bone marrow can be monitored using polymerase chain reaction (PCR). In several studies assessing blood and/or bone marrow, rituximab has achieved molecular response (conversion from PCR-positive to PCR-negative bcl-2 status) in at least half of the patients. Aggressive NHL: Studies with rituximab as monotherapy in aggressive B-cell NHL, a potentially curable disorder, have generally been restricted to patients with relapsed or recurrent disease, since CHOP has traditionally been the standard first-line treatment regimen. However, promising results from phase II monotherapy studies prompted further clinical investigation of rituximab in conjunction with chemotherapy. Thus, most studies with rituximab in patients with aggressive forms of B-cell NHL have involved combination therapy, including a pivotal randomised trial comparing eight cycles of standard CHOP therapy plus rituximab 375 mg/m(2) (one dose per cycle) versus CHOP alone in 399 previously untreated elderly patients (60-80 years of age) with diffuse large B-cell lymphoma. Results of the pivotal trial showed a clear advantage for rituximab plus CHOP versus CHOP in terms of event-free survival (primary endpoint) at 2 years (57% vs 38%, p < 0.001). Overall survival at 2 years (70% vs 57%, p < 0.01) and CR rate (76% vs 63%, p < 0.01) were also higher with the rituximab-CHOP combination. Other, smaller trials with rituximab in combination with CHOP or other chemotherapeutic regimens, either as first-line therapy or for patients with relapsed or refractory aggressive B-cell NHL, have also shown promising results in terms of clinical response rates.CLL: In relatively small trials (n < 40) conducted primarily in patients with relapsed or refractory B-cell CLL, rituximab monotherapy (various regimens) achieved OR rates of 23-45%, with median duration of response ranging from approximately 3-10 months. (ABSTRACT TRUNCATED)

Plosker, G. L., & Figgitt, D. P. (2004). Repaglinide : a pharmacoeconomic review of its use in type 2 diabetes mellitus. PharmacoEconomics, 22(6), 389-411.

Repaglinide (Prandin), NovoNorm, GlucoNorm, an oral insulin secretagogue, was the first meglitinide analogue to become available for use in patients with type 2 diabetes mellitus. The drug lowers postprandial glucose excursions by targeting early-phase insulin release, an effect thought to be important in reducing long-term cardiovascular complications of diabetes. Repaglinide provided similar overall glycaemic control to that achieved with glibenclamide (glyburide), as assessed by glycosylated haemoglobin (HbA(1c)) and fasting blood glucose levels, and was generally well tolerated in well designed clinical trials. Its rapid onset and relatively short duration of action allow for flexible meal schedules. Two modelled US cost-effectiveness analyses projected lifetime costs and outcomes for a hypothetical cohort of patients with type 2 diabetes. Both analyses projected long-term complications using data on HbA(1c) level changes from short-term clinical trials. Repaglinide plus rosiglitazone was dominant over rosiglitazone in one analysis, and repaglinide plus metformin was dominant over nateglinide plus metformin in the other. A similar Canadian analysis showed a favourable incremental cost-effectiveness ratio (<dollars US 1000 per QALY gained; 2001 values) for patients who switched from a sulphonylurea to repaglinide versus those who remained on sulphonylurea therapy. Long-term outcomes were projected using short-term clinical trial data on postprandial blood glucose level changes in the Canadian study. All three cost-effectiveness analyses are available as abstracts/posters. Two US cost analyses (both published in full) have also been conducted comparing the short-term costs (<or=3 years) of repaglinide, with or without metformin, versus other oral antidiabetic regimens. Results of these analyses are somewhat equivocal because of study design issues and/or a lack of statistically significant differences between treatment groups. In conclusion, repaglinide as monotherapy or in combination with other antidiabetic agents, such as metformin or rosiglitazone, achieves good metabolic control, similar to that achieved with comparable glibenclamide regimens. Severe hypoglycaemic episodes are less common with repaglinide than some sulphonylureas, including glibenclamide. Modelled cost-effectiveness analyses conducted in North America showed favourable results for repaglinide-containing regimens versus comparators, largely attributed to projected reductions in long-term cardiovascular complications using short-term data on changes in glycaemic parameters from clinical trials. Results of these cost-effectiveness analyses (all of which have been published as abstracts/posters) should be interpreted with caution since various assumptions regarding long-term costs and outcomes were necessarily incorporated into the economic models. While repaglinide is a useful addition to the available treatment options in type 2 diabetes, potential long-term advantages versus other agents, such as reducing cardiovascular complications, require confirmation.The prevalence of diabetes mellitus is projected to increase to over 3% of the world's population ( approximate, equals 220 million people) by the year 2010. Globally, 97% of patients with diabetes have type 2 disease, although in industrialised countries the proportion of type 2 disease is about 90%. In 2010, an estimated 14.85 million individuals in the US and 2.88 million in the UK will be diagnosed with type 2 diabetes. In addition, approximately one-third to one-half of individuals with diabetes are unaware that they have the disease, and are therefore undiagnosed. Diabetes is associated with significant morbidity, mortality and economic consequences. For the year 2002 in the US, direct medical costs associated with diabetes (type 1 and 2) were estimated at dollars US 91.8 billion (70% of total costs) and indirect costs at dollars US 39.8 billion (30%), for a total of dollars US 132 billion. Data from more than 7000 patients in eight European countries indicate tha the mean cost per patient with diabetes was dollars US 2928 annually (1999 values), and the proportion of total healthcare expenditure directed toward diabetes ranged from 1.6% to 6.6% depending on the country. Several analyses focusing specifically on type 2 disease showed, not surprisingly, that costs were higher among patients with diabetic complications than in those without complications. Repaglinide, a meglitinide analogue, is an oral insulin secretagogue that reduces postprandial glucose excursions by targeting postprandial insulin release. In clinical trials in patients with type 2 diabetes, repaglinide was usually administered at a dosage of 0.5-4 mg three times daily before meals as monotherapy or in combination with other agents. In placebo-controlled trials of up to 24 weeks' duration in patients with type 2 diabetes, repaglinide achieved statistically significant improvements in glycaemic control, as assessed by glycosylated haemoglobin (HbA(1c)), fasting blood glucose (FBG) and/or postprandial blood glucose (PPBG) levels compared with placebo. Preprandial administration of repaglinide achieved similar glycaemic control to glibenclamide (glyburide) 1.75-15 mg/day and better glycaemic control than glipizide 5-15 mg/day in 1-year, double-blind, randomised trials in patients with type 2 disease, the vast majority of whom had previously received oral antidiabetic therapy.Several randomised, open-label studies have evaluated repaglinide as part of combination therapy over 3-6 months in patients with type 2 diabetes who had inadequate glycaemic control with previous drug therapy. In general, results showed statistically significant improvements in glycaemic control when repaglinide was used in combination with metformin, various thiazolidinediones, or metformin plus bedtime insulin compared with monotherapy with either comparator drug in each study (or metformin plus bedtime insulin in one trial). Other studies in this patient population indicate that metformin plus repaglinide is associated with significantly better glycaemic control than metformin plus nateglinide 60-120 mg three times daily over 16 weeks, and similar glycaemic control to that achieved with metformin in combination with either glibenclamide or glimepiride for up to 1 year.Good glycaemic control has also been achieved with preprandial administration of repaglinide in flexible meal schedules. This was demonstrated in a placebo-controlled trial and in a large, prospective survey of patients receiving repaglinide in a clinical setting.The tolerability profile of repaglinide is characterised by adverse events of mild-to-moderate intensity similar to those associated with sulphonylureas. The most frequently reported adverse events with repaglinide include hypoglycaemia, upper respiratory infection, headache, other respiratory events, musculoskeletal events and gastrointestinal events. Severe episodes of hypoglycaemia are rare with repaglinide and occur approximately 2-2.5 times less frequently than with sulphonylureas. In addition, available data indicate that repaglinide may be less likely to increase bodyweight than various commonly used sulphonylurea agents. In general, repaglinide is also well tolerated when used as part of combination therapy.Repaglinide is metabolised by the cytochrome P450 (CYP) 3A4 enzyme system and therefore has the potential to interact with other CYP3A4 substrates when administered concurrently. A number of studies in healthy volunteers have shown no clinically significant pharmacokinetic drug interactions when repaglinide was administered concomitantly with digoxin, theophylline, warfarin, cimetidine, ketoconazole, rifampicin (rifampin), ethinylestradiol, simvastatin or nifedipine. However, a clinically significant increase in systemic exposure to repaglinide occurs when clarithromycin and repaglinide are administered concurrently, which may necessitate a reduction in repaglinide dosage. Moreover, a potentially hazardous interaction occurs when gemfibrozil (alone or with itraconazole) is used concomitantly with repaglinide. In view of the marked increase in systemic exposure to repaglinide, the combination of repaglinide and gemfibrozil should be avoided if possible.Pharmacoeconomic Analyses of RepaglinideTwo US cost analyses have been conducted with repaglinide in patients with type 2 diabetes (both published in full). One was a retrospective analysis of pharmacy and medical claims data from a large managed care organisation in which costs were adjusted for age, gender and comorbidities. Total adjusted (year 2000) cost per patient over a 9-month period was numerically lower for those treated with a combination of repaglinide plus metformin (dollars US 8924) than for patients who received metformin only (dollars US 9448), metformin plus glibenclamide (dollars US 9576) or repaglinide only (dollars US 11910), although there were no statistically significant differences between treatment groups. The other study, a literature-based decision-tree analysis, projected the proportion of patients achieving a target HbA(1c) level (<7%) and the associated direct medical costs over a 3-year period from the time of diagnosis. Among six different treatment regimens evaluated, costs ranged from dollars US 6106 with glipizide gastrointestinal therapeutic system (GITS) to dollars US 9298 with repaglinide monotherapy (2001/2002 values). Probabilistic sensitivity analysis indicated that first-line therapy with glipizide GITS or metformin would be associated with lower total medical costs than rosiglitazone or repaglinide monotherapy.Three cost-effectiveness analyses, all of which are modelled studies published as abstracts and/or posters, have been conducted with repaglinide in patients with type 2 diabetes. (ABSTRACT TRUNCATED)

Polosan, M., Millet, B., Bougerol, T., Olie, J. P., & Devaux, B. (2003). Psychosurgical treatment of malignant OCD: three case-reports. [Traitement psychochirurgical des TOC malins: a propos de trois cas] L'Encephale, 29(6), 545-552.

Surgery can be proposed for some patients affected by psychiatric diseases such as severe, disabling and refractory affective disorders (depression), OCD and chronic anxiety states. It can be performed after a period of evolution of minimum 5 Years and after all other classical treatments have failed. For the last Years, different stereotactic techniques have been used: capsulotomy, cingulotomy, subcaudate tractotomy and limbic leukotomy, performed by radiofrequency thermolesions or radiosurgery (g rays). In the case of OCD, these procedures are supposed to affect some of the neural circuits between the frontal lobes and different structures of the limbic system, considered as central to OCD symptoms. As they cause smaller cerebral lesions than earlier surgical techniques (mostly open surgery techniques), modern stereotactic approaches have less clinical side effects, primarily less deficit in emotional reactivity and motivation. This type of treatment offers some hope to patients seriously disabled by OCD. These surgeries and especially their main side effects are mentioned briefly in this Article. The most current indications for psychosurgery are severe OCD and chronic major depressive disorder. The level of stress should be significant and assessed by clinical and social functioning scale scores (for the OCD: Y-BOCS>25, GAF>50). Patients affected by demential disorders, sociopathic or paranoiac personality disorder, substance abuse should be excluded as well as patients aged 65 Years over and less than 18 Years. Several studies evaluating the results of the surgical treatment showed significant improvement in 54% of cases. and a moderate improvement in 27% of them. These results seem unchanged a few Years later in 56% of cases. Despite the lack of controlled trials of neurosurgery and several bias in published reports, evidence suggests that the condition of intractable OCD patients may improve after this surgery. Although capsulotomy and cingulotomy are mainly used, the superiority of any of these four surgical techniques has not been established yet. In this Article, we reported 3 "malignant" OCD cases treated by different psychosurgery techniques: 2 of the cases showed a clinical improvement, whereas the third did not -benefit from surgery. All of them were suffering of OCD since childhood with a gradual clinical impairment, unless the -second patient who presented a severe impairment following an accident causing a ten-day coma. In all three cases social consequences of OCD were important: negative socio-professional and family-life consequences and depressive complication with suicide risk. All patients remained unresponsive or showed a very transient reaction to the other forms of therapy, including varied pharmacotherapy (potentiation pharmacotherapy strategies included), intensive psychotherapy, behavioural therapy and electro-convulsive therapy. Pre- and post-operative assessment included neurological, radiological, psychometric and neuropsychological examination. The free and informed consent of the patient was always required before surgery, notifying the nature of the procedure, the potential risks and outcome. The first patient benefited of a bilateral anterior cingulotomy by thermocoagulation in stereotactic conditions, followed, four years later, by a second complementary one because of a relapse which occurred a few months after the first intervention. A clinical improvement was noticed over a period of two years, though it was not sufficient according to the patient. The second patient benefited of a stereotactic cingulotomy associated with a limbic leucotomy: it was initially efficient on OCD as well as on thymic symptoms. Nevertheless the positive evolution on OCD is not perceived by the patient and has not been assessed until now by clinical rating scales. Anterior cingulotomy is undergone in the third case, who showed a significant improvement. Despite clomipramine administered secondary to the surgery, a slight relapse of obsessive ideas was noticed six months later. The postoperative side effects were transient and regressive after a few months; they were observed especially in the case of tractotomy (oedema and transient frontal syndrome). On the whole, morbidity seemed more important with extensive lesions, whereas recurrence rate may be higher with smaller lesions. We did not observe any consequences on personality or on cognitive functions of these patients. No additional -deficits were observed after surgery. Further research is needed in order to determine the optimal site and size of the lesions in terms of efficacy and safety. Although psychosurgery is still controversial from an ethical view point, this treatment appears to be an ultimate solution for these severe disabled patients. Psychosurgery is a safe and relatively effective treatment which should be carried out by an expert multidisciplinary team in these disorders; surgery should be considered as part of an entire treatment program including an appropriate psychiatric rehabilitation part. Research in this field is currently focused on MRI-guided basal ganglia stimulation techniques which would allow to target specific structures in a reversible way.

Rainero, I., Rubino, E., Gallone, S., Fenoglio, P., Negro, E., De Martino, P., Savi, L., & Pinessi, L. (2009). Cluster Headache is Associated With the Alcohol Dehydrogenase 4 (ADH4) Gene. Headache, doi:10.1111/j.1526-4610.2009.01569.x

(Headache 2009;**:**-**) Background/Objectives.- Alcohol is a well-known trigger factor for cluster headache attacks during the active phases of the disease. The alcohol dehydrogenase (ADH) pathway, which converts alcohol to the toxic substance acetaldehyde, is responsible for most of the alcohol breakdown in the liver. Humans have 7 ADH genes, tightly clustered on chromosome 4q21-q25, that encode different ADH isoforms. The ADH4 gene encodes the class II ADH4 pi subunit, which contributes, in addition to alcohol, to the metabolization of a wide variety of substrates, including retinol, other aliphatic alcohols, hydroxysteroids, and biogenic amines. The purpose of this study was to investigate the association of genetic variants within the ADH4 gene with cluster headache susceptibility and phenotype. Methods.- A total of 110 consecutive unrelated cluster headache patients and 203 age- and sex-matched healthy controls of Caucasian origin were involved in the study. Patients and controls were genotyped for 2 bi-allelic single nucleotide polymorphisms (SNPs) of the ADH4 gene: SNP1 - rs1800759 and SNP2 - rs1126671. Allele, genotype, and haplotype frequencies of the examined polymorphisms were compared between cases and controls. Results.- Genotype frequencies of the rs1126671 polymorphism resulted significantly different between cluster headache patients and controls (chi(2) = 10.269, P = .006). The carriage of the AA genotype, in comparison with remaining genotypes, was associated with a significantly increased disease risk (OR = 2.33, 95% CI: 1.25-4.37). Haplotype analysis confirmed the association between the ADH4 gene and the disease. No association between different clinical characteristics of cluster headache and the examined polymorphisms was found. Conclusion.- Our data suggest that cluster headache is associated with the ADH4 gene or a linked locus. Additional studies are warranted to elucidate the role of this gene in the etiopathogenesis of the disease.

Ranieri, A. L., Tufik, S., & de Siqueira, J. T. (2009). Refractory cluster headache in a patient with bruxism and obstructive sleep apnea: a case report. Sleep & Breathing = Schlaf & Atmung, 13(4), 429-433. doi:10.1007/s11325-009-0265-3

INTRODUCTION: This is a case report of a 39-year-old patient with a 14-year history of clinically refractory cluster headache (CH), also presenting obstructive sleep apnea (OSA) and complaining of tooth-grinding during sleep. DISCUSSION: Treatment of OSA with an intra-oral device allowed an immediate reduction in frequency and intensity of CH events. Furthermore, CH attacks did not occur during the 12-month follow-up period.

Reinisch, V. M., & Straube, A. (2009). Specific headache syndromes in the elderly. [Leitsymptom Kopfschmerzen: Was ist bei alten Patienten anders?] MMW Fortschritte Der Medizin, 151(13), 28-31.

Renou, S., Hergueta, T., Flament, M., Mouren-Simeoni, M. C., & Lecrubier, Y. (2004). Diagnostic structured interviews in child and adolescent's psychiatry. [Entretiens diagnostiques structures en psychiatrie de l'enfant et de l'adolescent] L'Encephale, 30(2), 122-134.

Structured diagnostic interviews, which evolved along the development of classification's systems, are now widely used in adult psychiatry, in the fields of clinical trials, epidemiological studies, academic research as well as, more recently, clinical practice. These instruments improved the reliability of the data collection and interrater reliability allowing greater homogenisation of the subjects taking part in clinical research, essential factor to ensure the reproducibility of the results. The diagnostic instruments, conversely to the clinical traditional diagnostic processes allow a systematic and exhaustive exploration of disorders, diagnostic criteria but also severity levels, and duration. The format of the data collection, including the order of exploration of the symptoms, is fixed. The formulation of the questions is tested to be univocal, in order to avoid confusions. In child and adolescent, researches in pharmacology and epidemiology increased a lot in the last decade and the standardisation of diagnostic procedures is becoming a key feature. This Article aims to make an assessment, a selection, and a description of the standardized instruments helping psychiatric diagnosis currently available in the field of child and adolescent's psychiatry. Medline and PsycINFO databases were exhaustively checked and the selection of the instruments was based on the review of four main criteria: i) compatibility with international diagnostic systems (DSM IV and/or ICD-10); ii) number of disorders explored; iii) peer reviewed Journals and iv) richness of psychometric data. After the analysis of the instruments described or mentioned in the literature, 2 structured interviews [the Diagnostic Interview Schedule for Children (DISC) and the Children's Interview for Psychiatric Syndromes (ChIPS)] and 4 diagnostic semi-structured interviews [the Schedule for Affective Disorders and Schizophrenia for School-Age Children (Kiddie-SADS), the Diagnostic Interview for Children and Adolescent (DICA), the Child and Adolescent Psychiatric Assessment (CAPA) and the Interview Schedule for Children and Adolescents ISCA)] were retained according to the 3 first criteria. All can be administered by clinicians, and x out of 6 can also be administered by lay-interviewers. All include a child/adolescent version and a parent version. Two instruments evaluate the presence of DSM IV axe II disorders: The ISCA explores the criteria of the Antisocial Personality Disorder. The CAPA evaluates Borderline, Obsessional-compulsive, Histrionic and Schizotypic Personality Disorders. Regarding the psychometric quality criterion, the selection was much more difficult because of the lack of data and the weakness of the samples studied in reliability studies. Interrater reliability appeared to be good for the 6 instruments, with kappas ranging from 0.5 to 1. This is usual in such instruments. The test-retest reliability was found to vary from bad to excellent depending on the instruments, the "informant" status (child/adolescent or parent), and the disorder explored, kappas ranging from 0.32 to 1. The worst results concerned face-to-face reliability studies which showed weak concordances for the diagnoses, whatever the procedure implemented: Diagnostic interview vs. i) Another diagnostic interview, vs. ii) An expert diagnosis or vs. iii) Scales and questionnaires. Overall, the K-SADS-PL appeared to be the instrument that has the best test-retest reliability for Anxious Disorders and Affective Disorders (the value kappa showing good to excellent reliabilities). Several important methodological observations emerged from this review. Firstly, the metrological data corresponding to the diagnoses according to DSM IV or ICD-10 criteria's were lacking. The face validity was globally satisfactory, but the data concerning their face-to-face validities and their test-retest reliability, although better than in the former versions, were limited because they were tested on small sample. In fact, it appeared that the agreements depend on the informant, the sample studied, the various diagnostic categories and the instrument used. Since the studies carried out by Cohen et al., with now obsolete versions of the DISC and K-SADS, no other study establishing a comparison between two EDS have been conducted. Consequently, the clinicians must be very careful before comparing DSM or ICD diagnoses generated by different instruments. The second point was the length of the interviews that appeared sometimes longer than instruments used in adults, considering the fact that diagnostic procedure implies two independent interviews, one with the child/adolescent and one with the adult referent. The minimum duration was found to be 1 h 30 for the Chips in clinical setting, while it could reach 4 h or more for the DISC IV or the ISCA. The interviews had to be often carried out in several sessions, so the assessment became very difficult in easily tired and/or distractible subjects. The third point referred to the necessity to consider multiple data sources in young patients during the diagnostic procedure, and the weakness of the levels of agreement generally reported between sources. Empirically, it was observed that the investigator granted more weight to the report of the children than to the parent's one, when the clinical judgement was necessary to synthesize the data. On another level, studies showed a high agreement on the factual contents or on the specific events (ex: hospitalization), like on the obvious symptoms (ex: enuresis). The parents report more problems of behaviour, school and relational difficulties, whereas the children report more fear, anxiety, obsessions and compulsions, or delusional ideas. In other words, it appeared that children were better informants in describing their mental states (internalised disorders), and that adults would bring more reliable information in describing externalised disorders. Like McClellan and Werry, we think that further researches are needed to clarify if and when this is the case. The last major point concerned the problem of language. These instruments must be used in the maternal language of the interviewees and they were developed for most of them into English only. For example, there is only one instrument available into French (the Kiddie SADS). Nowadays, it remains difficult to conduct international studies in child and adolescent psychiatry and/or to compare data is this domain. To conclude, the use of the EDS and EDSS brings many benefits, in academic researches as well as in clinical practice, but a more systematic use is limited by a certain number of parameters. The instruments currently available in child and adolescent are far from being optimal in terms of quality and quantity. It seems necessary and useful to contribute to their development and their improvement. In particular, the following points should be considered: drastic reduction of the length of the interviews; simplification in the use of these instruments, during the interviews, but also in the treatment of the data collected during the final phase of diagnosis generation, the clinician having to carry out ceaseless returns to check the presence or not of each diagnostic criterion; reduction of the duration of the highly necessary training, which can be easily solved by the global simplification of the instruments; quantitative and qualitative improvements of psychometric properties, in particular in terms of sensitivity, specificity and face-to-face validity. Finally, it is highly necessary to continue to develop structured diagnostic interviews adapted to the assessment of child and adolescent psychiatric diagnoses keeping in mind simplicity, feasibility and reliability. Developing this kind of instruments is hard, expensive, and sometimes tiresome but it remains the inescapable stage to produce high quality data in the future.

Reutens, S., Nielsen, O., & Sachdev, P. (2010). Depersonalization disorder. Current Opinion in Psychiatry, doi:10.1097/YCO.0b013e3283387ab4

PURPOSE OF REVIEW: There is increasing interest in depersonalization disorder, in part because of the increased community awareness of the condition via the Internet. The disorder may be more prevalent than schizophrenia but is often misdiagnosed; hence, an update is timely. RECENT FINDINGS: Recent research has included characterization of the nosology and phenomenology of the disorder, whereas emerging evidence demonstrates a neurophysiological dampening down in addition to psychological dampening in the face of emotional stimulation. SUMMARY: Greater understanding of the clinical characteristics of this disorder will improve the reliability of diagnosis and aid the development of neurobiological and psychological models for empirical testing. Although response to current treatments has been disappointing, recent research has identified the basis for the development of new pharmacological and psychological treatments.

Reutens, S., Nielsen, O., & Sachdev, P. (2010). Depersonalization disorder. Current Opinion in Psychiatry, doi:10.1097/YCO.0b013e3283387ab4

PURPOSE OF REVIEW: There is increasing interest in depersonalization disorder, in part because of the increased community awareness of the condition via the Internet. The disorder may be more prevalent than schizophrenia but is often misdiagnosed; hence, an update is timely. RECENT FINDINGS: Recent research has included characterization of the nosology and phenomenology of the disorder, whereas emerging evidence demonstrates a neurophysiological dampening down in addition to psychological dampening in the face of emotional stimulation. SUMMARY: Greater understanding of the clinical characteristics of this disorder will improve the reliability of diagnosis and aid the development of neurobiological and psychological models for empirical testing. Although response to current treatments has been disappointing, recent research has identified the basis for the development of new pharmacological and psychological treatments.

Rickert, V. I., Siqueira, L. M., Dale, T., & Wiemann, C. M. (2003). Prevalence and risk factors for LSD use among young women. Journal of Pediatric and Adolescent Gynecology, 16(2), 67-75.

STUDY OBJECTIVE: To report the lifetime prevalence of lysergic acid diethylamide (LSD) and to identify unique correlates of using this substance in the last year among a large multiethnic sample of sexually active adolescent and young adult women aged 14 to 26 yrs. DESIGN, SETTING, PARTICIPANTS: A cross-sectional survey, administered at university-based ambulatory reproductive health clinics, was completed by 904 women between April and November of 1997 to identify risk factors associated with their use of LSD within the past 12 months. Subjects who reported lifetime, but not past 12 months', use of marijuana, LSD, or other illicit drugs were excluded, leaving a sample of 368 nonusers and 56 users of LSD. In addition, 231 young women who reported only using marijuana in the last year were used as a comparison group to identify unique factors associated with LSD use. RESULTS: Of the total sample (n=904), 13% (n=119) reported lifetime use of LSD, and 58% (n=536) reported lifetime use of marijuana. Logistic regression analyses controlling for age and race/ethnicity found distinct profiles for those who reported using LSD or only marijuana in the last year when compared to those who reported no substance use. Common to both groups was reporting being drunk at least 10 times during the last year, regular smoking of at least half a pack of cigarettes, and identification as a high-sexual-risk taker. However, LSD users as compared to nonusers were more likely to report white ethnicity (as compared to nonwhite), be less than or equal to 17 years of age (as compared to at least 18 years), report a history of physical abuse, and be categorized as having severe depressive symptomatology. In contrast, those who reported only using marijuana were more likely to report single marital status, young age at first intercourse, having half or more of their friends use marijuana, and poor grades. CONCLUSIONS: The female LSD user presents a distinct profile that might aid clinicians in identifying potential LSD use in this population as well as alerting clinicians to the relationship between LSD use and high-risk sexual behaviors.

Rider, D. A., Sinclair, A. J., & Young, S. P. (2003). Oxidative inactivation of CD45 protein tyrosine phosphatase may contribute to T lymphocyte dysfunction in the elderly. Mechanisms of Ageing and Development, 124(2), 191-198. doi:DOI: 10.1016/S0047-6374(02)00120-3

Ristic, A. J., Petrovic, I., Vojvodic, N., Jankovic, S., & Sokic, D. (2004). Phenomenology and psychiatric origins of psychogenic non-epileptic seizures. [Fenomenologija i psihijatrijska osnova psihogenih neepilepticnih napada] Srpski Arhiv Za Celokupno Lekarstvo, 132(1-2), 22-27.

INTRODUCTION: Psychogenic nonepileptic seizure (PNES) is a sudden change in a person's behavior, perception, thinking, or feeling that is usually time limited and resembles, or is mistaken for, epilepsy but does not have the characteristic electroencephalographic (EEG) changes that accompanies a true epileptic seizure [1]. It is considered that PNES is a somatic manifestation of mental distress, in response to a psychological conflict or other stressors [2]. A wide spectrum of clinical presentation includes syncope, generalized tonic-clonic seizure, simple and complex partial seizure, myoclonic seizure, frontal lobe seizures and status epilepticus [3]. Coexistence of epilepsy and PNES is seen in approximately 9% of cases [5]. Between 25-30% of patients referred to tertiary centers and initially diagnosed as refractory epilepsy were on further examination diagnosed as PNES [6, 7]. In DSM-IV [12] PNES are usually categorized under conversion disorder with seizures or convulsions. However, psychiatric basis of PNES may be anxiousness (panic attack), somatization or factitious disorder, simulation, dissociative disorders and psychosis [1]. AIM: The aim of the study was to establish clinical phenomenology and EEG characteristics as well as basic psychiatric disorder in patients with PNES. METHOD: In a retrospective study covering the period from January 1st 1999 till April 31st 2003, 24 patients (22 female, 2 male) treated at the institute of Neurology in Belgrade were analyzed. PNES were defined as sudden change in behavior incoherent with epileptiform activity registered on EEG. Possible PNES were determined on the basis of history data and clinical examination during the attack but definitive confirmation was established only by the finding of no ictal EEG changes during typical seizure of each patient. Patients with coexisting epilepsy were included in the study, too. At least two standard EEG (range 2-6, median 4) were performed at the beginning of diagnostic evaluation. Demographic data, clinical presentation (apparent loss of consciousness, type of convulsion and associated clinical signs) and placebo-induced seizures (administration of saline near the cubital vein) with EEG or video-EEG monitoring were analyzed. Basic psychiatric disorder was classified according to DSM IV classification criteria. RESULTS: Duration of PNES was 4.7 years (range from 2 months to 30 years). The time from onset to the diagnosis of PNES was 4.5 years. Epilepsy comorbidity was diagnosed in 9 patients (37.5%). The average time of use of antiepileptic drugs (AED) in the group of isolated PNES was 2.4 years and 20% of patients were treated with two or more AED. The vast majority of patients presented with bilateral convulsions (54.16%) with apparent loss of consciousness found in 91.6% of cases. Ictal iwury (16.7%), tongue bite (4.2%) and premonition of the seizure (17.4%) were uncommon. Variability in clinical presentation of seizures was found in over half of patients (57%). Psychological trigger could be determined in over 60% of patients. EEG findings in a group with isolated PNES suggesting the existence of epileptiform activity was found in one case. EEG monitoring of placebo-induced seizure was performed in 20 patients, of whom 19 (95%) showed typical habitual attack with no electroclinical correlate. In 70% of cases conversion disorder DSM-IV criteria were fulfilled. Somatization disorder and undifferentiated somatoform disorder were found in 3 patients. The diagnosis of factitious disorder was made in one case and only two patients were undiagnosed according to DSM-IV. DISCUSSION: Average delay from onset to diagnosis of PNES in larger studies was estimated to be approximately 7 years [8]. Even though diagnostic delay in our study was shorter, organizational reasons for this could not be found. Longer duration of a typical attack (compared to the epileptic seizure), apparent loss of consciousness, bilateral convulsion behavior and significant clinical variability in absence of typical epileptic elements such as tongue bite and ictal iwury could be the main clinical manifestation of PNES. We found rare interictal abnormalities (6.7%) in the group with isolated PNES and significant percentage (77.7%) in patients with coexisting epilepsy which is coherent with other reports [8]. The latest could lead to prolonged delay in appropriate diagnosis and suitable treatment. Clear psychological trigger wasn't noted in whole group of patients (61%). This, however, is not unusual since PNES represents a chronic disorder with repeated triggering that could lead to less significant role of the same psychological trigger in developed PNES. Even insufficiently resolved in ethical terms, placebo-induced procedure was of huge sensitivity. In clinical practice conversion disorder is hard to differ from malingering or implementation of secondary gain. One could make the conclusion only on the basis of detailed and careful estimation of the symptoms developing context. Conversion disorder is more prevalent among women (from 2:1 to 10:1) [4, 13] but modest percentage of affected men could be explained only by limited sample in this study. CONCLUSION: PNES is often replaced with epilepsy and in number of cases clinical differentiation is not easy. One should be acquainted with clinical presentation of PNES as well as its psychiatric origin in order to adequately recognize and treat the disorder.

Robbins, M. S., Tarshish, S., Napchan, U., & Grosberg, B. M. (2009). Images from headache: atypical cluster headache secondary to giant meningioma. Headache, 49(7), 1052-1053. doi:10.1111/j.1526-4610.2009.01470.x

Robert, P. H., Schuck, S., Dubois, B., Lepine, J. P., Gallarda, T., Olie, J. P., Goni, S., & Troy, S. (2003). Validation of the Short Cognitive Battery (B2C). Value in screening for Alzheimer's disease and depressive disorders in psychiatric practice. [Validation de la batterie cognitive courte (B2C). Interet pour le depistage precoce de la maladie d'Alzheimer et des troubles depressifs en pratique psychiatrique] L'Encephale, 29(3 Pt 1), 266-272.

Alzheimer's disease (AD) is a major healthcare challenge due to the increasing longevity of the population. Clinically prominent neuropsychological and neurological impairments, together with behavioral disorders characterize Alzheimer's disease (AD). In the past, behavioural and emotional disturbances received less attention than cognitive symptoms in studies of dementia. The association between cognitive and behavioural symptoms is complicated by the fact that such association could also occur with different patterns during depressive episode without dementia. Because Alzheimer's disease (AD) tends to be under diagnosed, there is an increasing need for accurate neuropsychological screening tools that are easy to administer by psychiatrists. The aim of the present study was to validate, in French, a sensitive and specific screening battery (B2C) designed to improve the discrimination between patients with AD, patients with depression, and healthy elderly subjects. POPULATION AND METHOD: The B2C was administered to 123 ambulatory subjects (mean age 76.4 2.3 years): divided in three groups of subjects. AD subjects were included (n=49) with a Mini-Mental Status Examination (MMSE) score of between 18 and 26, and a confirmed diagnosis (DSM IV) of mild to moderate AD. Subjects were not included if they were receiving treatment with an acetylcholinesterase inhibitor. The depressive group comprised elderly subjects (n=27) with at least two DSM IV criteria for a major depressive episode including the depressive mood criterion and a score of more than 17 on the Montgomery-Asberg Depression Rating Scale (MADRS). The healthy control group (n=47) comprised age-matched subjects with no neurological or psychiatric pathology. The B2C consists of four individual tasks derived from classical neuropsychological tests. Tasks were presented in the following order: temporal orientation test (knowledge of month, date, year, day of the week and time of day), 5 word test (task is originally derived from the Enhanced Cued Recall test), clock drawing test (In this widely used test, the subject had to draw a clock with all the numbers and then draw the clock hands at twenty minutes to four), and the semantic verbal fluency test (the subject was asked to generate as many words as possible from a given category in a fixed time period of 60 seconds). During the pre-study investigator meeting, the test procedure was adapted to ensure uniformity of practice in all centres. The B2C was administered one week to one month after the study inclusion date by a psychologist blinded to the patient groups and who had not participated in the subject's inclusion. Multivariate analysis was performed using a forced model of all four tests. Due to the nature of the dependent variable (AD vs controls and depressive vs control), the chosen discrimination model was a binary logistical regression model. Explanatory variables were limited to the variables of the test battery, and the dependent variable was the subject's status (AD, depressive or control). RESULTS: The mean results for each test are presented in Table II. The time taken to perform the tests was significantly higher (p=0.0001) for the AD group (11.2 minutes) when compared with both the control (7.6 minutes) and depressive group (8.2 minutes). In each of the four subtests, the AD subjects were significantly more impaired than the two other groups. Multivariate analysis was performed using a forced model of all four tests which provided correct classification of a high percentage of subjects (88.5%). The analysis followed a normal distribution and demonstrated that the AD patients were significantly impaired in all four tests of the B2C compared with controls. Depressive, elderly subjects were only impaired in verbal fluency. Multivariate analysis showed that, compared with controls, patients with mild AD were significantly impaired for all four tests. Response operating characteristics (ROC) analysis of the B2C showed: 93.8% sensitivity and 85% specificity for discriminating AD from control patients (table III), and 63% sensitivity and 96% specificity for discriminating AD from depressive patients (table IV). DISCUSSION: The main objective of this study was to demonstrate that the Short Cognitive Evaluation Battery developed in the French language is able to discriminate between patients suffering from AD and healthy elderly subjects. The results clearly demonstrate that AD patients were significantly impaired in all four tests of the B2C compared with the control group. The present study also supports the use of the screening battery for discriminating between AD and depressive subjects. The SCEB was less discriminatory for AD versus depressive patients than for AD versus controls. This could be due to the limited size of the depressive group. The verbal fluency test was the most sensitive for discriminating between AD and depression but this was at the expense of specificity. Other brief screening tests have already been developed in English speaking countries, In French language, the B2C appears to be a highly sensitive and specific tool for discriminating between patients with mild AD and healthy elderly individuals. Furthermore, in combination with clinical evaluation, the B2C could improve the specificity of the difficult discrimination between mild AD and depression. The next step of the validation process will include concurrent validity study and inclusion of a higher number of subjects with depressive symptoms.

Rocamora, J. F., Benadhira, R., Saba, G., Stamatadis, L., Kalalaou, K., Dumortier, G., Plaze, M., Aubriot-Delmas, B., Glikman, J., & Januel, D. (2005). Schizophrenia diagnostic announcement in a French psychiatric unit. [Annonce du diagnostic de schizophrenie au sein d'un service de psychiatrie de secteur] L'Encephale, 31(4 Pt 1), 449-455.

Announcement of schizophrenia diagnostic to the patients is a topical issue in France. The evolution in clinical practices, a better efficiency in therapeutic procedures and the fundamental right of the patient to obtain information have initialised the discussion of its interest. Spontaneous claim for information from the patient is rarely observed although awareness troubles might be reported at the instauration of the mental disorder or during its evolution. Methodological studies concerning the diagnostic announcement are limited. Except the Bayle studies recently published, only a few publications are available in France about the knowledge of their pathology and their need to be clearly informed. French scientific literature deals generally about medico-legal aspects of this information and consisted of survey about diagnostic announcement. International literature is more abundant and presents positive and negative aspects of the announcement. An information procedure of schizophrenia announcement to the patient has been developed in our hospitalisation unit of psychiatry. This procedure has taken place on the basis of the literature data, our specificity and our clinical experiences. For some Anglo-American psychiatrists who have proceeded to semi-structured interview in order to announce the diagnostic, information to the patients might improve the clinical relationship. Thus, compliance to the treatment is significantly increased. The ability of the patient to recognise the symptoms of the disease and to accept their consequences and the treatments is associated to a better social prognosis, daily activities and response to the treatment. The announcement impact justifies the prescription of neuroleptics, treatment that is notoriously perceived as prejudicial by the patients themselves or more commonly in the basic population. To obtain compliance to the treatment, a satisfactory acceptance of the mental disorder is required. Compliance is based on satisfactory information in order to gain the cooperation of the patient and its relative (10). Atkinson has classified four main types of arguments, the ethical principle to be informed, talk to explain and give sense to the symptoms, reduce the feeling of guilt perceived by the patient and his relative and enhance the collaboration between the patient and the nursing staff. According to Ferreri and Bayle studies French psychiatrists reluctance to announce schizophrenia diagnostic are the following: lack of request or of interrogations asked by the patient about their disease, diagnostic and prognosis uncertainty and irreversibility of the disease, complexity of the pathology and its origin which hinder an accessible explanation, cognitive disorders frequently observed with schizophrenic patients which may be associated with difficulties of understanding information, destabilization of the patient-nursing staff relationship and social stigmatisation risks. Other arguments like reluctance to give a "label" to the disease, too abstract diagnostic, a negative social vision and the possibility of discouragement for the relative are classically retrieved in French literature. In fact, divulgation of the term schizophrenia involves a panel of negative representations and is hindered by the confusion in the social imagination of such a term related with lost of control, quintessence of madness, dangerous behaviour possibilities, evil and incurability. Some psychiatrists do not transmit information arguing that significant obstruction of the future may be consecutive to the information. They prefer to use vague terms more socially acceptable like "nervous breakdown or depression, atypical or emotional disorder, dissociative troubles...". Information to the patient about his mental disorder is more frequent in psychiatry for affective, anxious and additive troubles than for schizophrenia. Our procedure of diagnostic announcement has been elaborated after preliminary discussion with the medical and nursing staff. Diagnostic of schizophrenia announcement has been presented by weighing the pros and cons according to the intemational literature. It clearly appeared that benefits for the patients prevail on the drawbacks. Nevertheless, inclusion and clinical supervision have to be carefully precised in particular to verify the ability to receive information. Short term objectives: deliver progressively information to the patient about his disease by means of an active and educational process with hope and optimism using a accessible language (explanation of each terms used with the intention of being well understood); quantify the impact of diagnostic announcement on the schizophrenic patient using clinical rating scales during a period of one month (clinical interview at day 1, day 7 and day 28). Mid term objectives: improve the global supervision and autonomy of schizophrenic by means of a therapeutic project helping the patient to become an active partner in the monitoring of his mental disorder; enhance a psycho-educational program after the procedure of announcement in order to optimise the observance of his treatment, increase his quality of life and answer to the requests of his relative; 45 patients (age 29.3 +/- 8.8 years old) have been included to be informed on their diagnostic since the elaboration of this procedure during a time period of 24 months. Time interval between the beginning of their pathology and the delivering of this information was 4.7 years. Most of them (56%) presented a paranoid type of schizophrenia. In most of the cases, the patients did not know their diagnostic or declared suffering from a diagnostic, which was erroneous; 80% of the 45 patients have complied with the procedure until its end. On more than 24 of following after the instauration of the diagnostic announcement procedure, these patients ha ve presented satisfactory observance to the medical supervision (medical consultation and drug intake); 60% of the patients were regularly present to their medical appointment. The number of patients included (45 patients) appears small compared to the time interval of the study (24 months) but was significant according to the great changes in our clinical approach. Thus, this procedure was not systematically applied, in particular the patients who did not want to be informed on their disease. Is it clinically relevant or not to announce diagnostic of schizophrenia to the patient? This issue remains questioned according to the few studies published at the present time, any consensus has been clearly presented on formal indications or contra-indications. If on an ethical side, this information appears logical, the medical and nursing staff should require special care. Special care must be taken before delivering information to the patients; each situation must be evaluated in order not to comply with an ideology of total and inadequate information, which could have serious consequences. Nevertheless, it appeared clearly that information must be given to stabilized patients with satisfactory insight. Moreover, psychotherapeutic projects become easier because patients awareness and understanding towards pathological symptoms are greatly improved. Partnership between patient and medical staff is the key of this dynamic and psycho-educative procedure, which opens new horizons in our therapeutic prospect.

Rowbotham, M. C. (2006). Pharmacologic management of complex regional pain syndrome. The Clinical Journal of Pain, 22(5), 425-429. doi:10.1097/01.ajp.0000194281.74379.01

Few randomized controlled trials of oral pharmacotherapy have been performed in patients with complex regional pain syndrome (CRPS). The prevalence of CRPS is uncertain. Severe and advanced cases of CRPS are easily recognized but difficult to treat and constitute a minority compared with those who meet minimum criteria for the diagnosis. Unsettled disability or liability claims limit pharmaceutical industry interest in the disorder. Many studies are small or anecdotal, or are reported on only via posters at meetings. Targeting the process of bone resorption with bisphosphonate-type compounds such as calcitonin, clodronate, and alendronate has shown efficacy in three published randomized controlled trials. Intravenous phentolamine has been studied both alone and in comparison to intravenous regional blockade or stellate ganglion block. Steroids continue to be administered by multiple routes without large-scale placebo-controlled trials. Topical medications have received little attention. There has been considerable interest in the use of thalidomide and TNF-alpha blockers for CRPS, but no published controlled trials as of yet. Numerous other oral drugs, including muscle relaxants, benzodiazepines, antidepressants, anticonvulsants, and opioids, have been reported on anecdotally. Some therapies have been the subject of early controlled studies, without subsequent follow-up (eg, ketanserin) or without an analogous well-tolerated and equally effective oral treatment (eg, intravenous ketamine). Gabapentin, tricyclic antidepressants, and opioids have been proven effective for chronic pain in disorders other than CRPS. Each has shown a broad enough spectrum of analgesic activity to be cautiously recommended for treatment of CRPS until adequate randomized controlled trials settle the issue. The relative benefit of oral medications compared with the widely used treatments of intensive physical therapy, nerve blocks, sympathectomy, intraspinally administered drugs, and neuromodulatory therapies (eg, spinal cord stimulation) remains uncertain. In summary, treatment of CRPS has received insufficient study and remains largely empirical.

Rozen, T. D. (2009). Cluster Headache As the Result of Secondhand Cigarette Smoke Exposure During Childhood. Headache, doi:10.1111/j.1526-4610.2009.01542.x

Unique to cluster headache (CH) compared with all other primary headache conditions is its association with a personal history of cigarette smoking. Studies have indicated that greater than 80% of CH patients have a prolonged history of tobacco usage prior to CH onset. How tobacco exposure can lead to CH has not yet been elucidated. As secondhand smoke exposure during childhood has been linked to multiple medical illnesses could CH also be the result of childhood exposure to tobacco smoke? The United States Cluster Headache survey is the largest survey ever done of CH sufferers living in the United States. The survey addressed various clinical, epidemiologic, and economic issues related to CH. Several survey questions dealt with the issue of personal and parental smoking history. Results from the survey suggest that CH can result from secondhand cigarette smoke exposure during childhood as greater than 60% of non-smoking CH patients had parents who smoked. Strengthening the probable association between secondhand smoke exposure and the development of CH is the fact that double the number of survey responders developed CH at or before 20 years of age if during their childhood they lived with a parent who smoked cigarettes.

Ryan, R. E., Prictor, M. J., McLaughlin, K. J., & Hill, S. J. (2008). Audio-visual presentation of information for informed consent for participation in clinical trials. Cochrane Database of Systematic Reviews (Online), (1)(1), CD003717. doi:10.1002/14651858.CD003717.pub2

BACKGROUND: Informed consent is a critical component of clinical research. Different methods of presenting information to potential participants of clinical trials may improve the informed consent process. Audio-visual interventions (presented for example on the Internet, DVD, or video cassette) are one such method. OBJECTIVES: To assess the effects of providing audio-visual information alone, or in conjunction with standard forms of information provision, to potential clinical trial participants in the informed consent process, in terms of their satisfaction, understanding and recall of information about the study, level of anxiety and their decision whether or not to participate. SEARCH STRATEGY: We searched: the Cochrane Consumers and Communication Review Group Specialised Register (searched 20 June 2006); the Cochrane Central Register of Controlled Trials (CENTRAL), The Cochrane Library, issue 2, 2006; MEDLINE (Ovid) (1966 to June week 1 2006); EMBASE (Ovid) (1988 to 2006 week 24); and other databases. We also searched reference lists of included studies and relevant review articles, and contacted study authors and experts. There were no language restrictions. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials comparing audio-visual information alone, or in conjunction with standard forms of information provision (such as written or oral information as usually employed in the particular service setting), with standard forms of information provision alone, in the informed consent process for clinical trials. Trials involved individuals or their guardians asked to participate in a real (not hypothetical) clinical study. DATA COLLECTION AND ANALYSIS: Two authors independently assessed studies for inclusion and extracted data. Due to heterogeneity no meta-analysis was possible; we present the findings in a narrative review. MAIN RESULTS: We included 4 trials involving data from 511 people. Studies were set in the USA and Canada. Three were randomised controlled trials (RCTs) and the fourth a quasi-randomised trial. Their quality was mixed and results should be interpreted with caution.Considerable uncertainty remains about the effects of audio-visual interventions, compared with standard forms of information provision (such as written or oral information normally used in the particular setting), for use in the process of obtaining informed consent for clinical trials. Audio-visual interventions did not consistently increase participants' levels of knowledge/understanding (assessed in four studies), although one study showed better retention of knowledge amongst intervention recipients. An audio-visual intervention may transiently increase people's willingness to participate in trials (one study), but this was not sustained at two to four weeks post-intervention. Perceived worth of the trial did not appear to be influenced by an audio-visual intervention (one study), but another study suggested that the quality of information disclosed may be enhanced by an audio-visual intervention. Many relevant outcomes including harms were not measured. The heterogeneity in results may reflect the differences in intervention design, content and delivery, the populations studied and the diverse methods of outcome assessment in included studies. AUTHORS' CONCLUSIONS: The value of audio-visual interventions for people considering participating in clinical trials remains unclear. Evidence is mixed as to whether audio-visual interventions enhance people's knowledge of the trial they are considering entering, and/or the health condition the trial is designed to address; one study showed improved retention of knowledge amongst intervention recipients. The intervention may also have small positive effects on the quality of information disclosed, and may increase willingness to participate in the short-term; however the evidence is weak. There were no data for several primary outcomes, including harms. In the absence of clear results, triallists should continue to explore innovative methods of providing information to potential trial participants.Further research should take the form of high-quality randomised controlled trials, with clear reporting of methods. Studies should conduct content assessment of audio-visual and other innovative interventions for people of differing levels of understanding and education; also for different age and cultural groups. Researchers should assess systematically the effects of different intervention components and delivery characteristics, and should involve consumers in intervention development. Studies should assess additional outcomes relevant to individuals' decisional capacity, using validated tools, including satisfaction; anxiety; and adherence to the subsequent trial protocol.

Saidel, D. R., & Babineau, R. (1976). Prolonged LSD flashbacks as conversion reactions. The Journal of Nervous and Mental Disease, 163(5), 352-355.

This paper presents a case study of the background and treatment of a patient with prolonged LSD flashbacks. The hypothesis that flashbacks can be psychologically determined symptoms is supported by the dynamics of the case and the course of treatment. A second focus is a partial explanation for the often made observation that obessive-compulsive personalities are at increased risk for LSD flashbacks.

Salawu, F. K., Olokoba, A. B., & Danburam, A. (2009). A review of trigeminal autonomic cephalalgias: diagnosis and treatment. Nigerian Journal of Medicine : Journal of the National Association of Resident Doctors of Nigeria, 18(1), 17-24.

BACKGROUND: The trigeminal autonomic cephalalgias (TACs) include cluster headache, paroxysmal hemicrania and short-lasting, unilateral neuralgiform headache attacks with conjunctival injection and tearing and its close relative short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms. The primary objectives of this review are to highlight what is known about the trigeminal autonomic cephalalgias, looking at clinical headache characteristics, recognised treatments, and interesting new developments in pathogenesis. METHOD: Literature search was performed using the reference databases Medline, Science Citation Index and the Cochrane Library. The keywords used were 'cluster headache, paroxysmal hemicrania, SUNCT. Papers discovered by this search were reviewed, as were references cited therein. RESULTS: Cluster headache has the longest attack duration and relatively low attack frequency. Paroxysmal hemicrania has intermediate neuralgiform head attack frequency. Shortlasting unilateral neuralgiform headache attacks with conjunctival injection and tearing have the shortest attack duration and the highest attack frequency. CONCLUSION: The importance of diagnosing these syndromes resides in their excellent but highly selective response to treatment.

Sangani, P., Rutherford, G., & Wilkinson, D. (2004). Population-based interventions for reducing sexually transmitted infections, including HIV infection. Cochrane Database of Systematic Reviews (Online), (2)(2), CD001220. doi:10.1002/14651858.CD001220.pub2

BACKGROUND: Sexually transmitted infections (STI) are common in developing countries. The World Health Organisation (WHO) estimates that in 1999, 340 million new cases of syphilis, gonorrhoea, chlamydial infection and trichomoniasis occurred. Human immunodeficiency virus (HIV) infection is also common in developing countries. UNAIDS estimates that over 95% of the 40 million people infected with HIV by December 1999 live in developing countries (UNAIDS 2003). The STI and HIV epidemics are interdependent. Similar behaviours, such as frequent unprotected intercourse with different partners, place people at high risk of both infections, and there is clear evidence that conventional STIs increase the likelihood of HIV transmission. Several studies have demonstrated a strong association between both ulcerative and non-ulcerative STIs and HIV infection (Cameron 1989, Laga 1993). There is biological evidence, too, that the presence of an STI increases shedding of HIV, and that STI treatment reduces HIV shedding (Cohen 1997, Robinson 1997). Therefore, STI control may have the potential to contribute substantially to HIV prevention. OBJECTIVES: To determine the impact of population-based STI interventions on the frequency of HIV infection, frequency of STIs and quality of STI management. SEARCH STRATEGY: The following electronic databases were searched for relevant randomised trials or reviews:1) MEDLINE for the years 1966 to 2003 using the search terms "sexually transmitted diseases" and "human immunodeficiency virus infection"2) The Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effectiveness and the Cochrane Clinical Trials Register, in the most recent issue of the Cochrane Library3) The specialist registry of trials maintained by the Cochrane Infectious Diseases Group.4) EMBASE The abstracts of relevant conferences were searched, and reference lists of all review articles and primary studies were scanned. Finally, authors of included trials and other experts in the field were contacted as appropriate. SELECTION CRITERIA: Randomised controlled trials in which the unit of randomisation is either a community or a treatment facility. Studies where individuals are randomised were excluded. DATA COLLECTION AND ANALYSIS: Two reviewers independently applied the inclusion criteria to potential studies, with any disagreements resolved by discussion. Trials were examined for completeness of reporting. The methodological quality of each trial was assessed by the same two reviewers, with details recorded of randomisation method, blinding, use of intention-to-treat analysis and the number of patients lost to follow-up, using standard guidelines of the Cochrane Infectious Diseases Group. MAIN RESULTS: Five trials were included.Frequency of HIV infection: In Rakai, after 3 rounds of treatment of all community members for STIs, the rate ratio of incident HIV infection was 0.97 (95%CI 0.81 to 1.16), indicating no effect of the intervention. In Mwanza, the incidence of HIV infection in the intervention groups (strengthened syndromic management of STIs in primary care clinics) was 1.2% compared with 1.9% in the control groups (OR=0.58, 95% CI 0.42-0.70), corresponding to a 38% reduction (95%CI 15% to 55%) in HIV incidence in the intervention group. In the newest trial by Kamali et al, the rate ratio of behavioral intervention & STI management compared to control on HIV incidence was 1.00 (0.63-1.58, p=.98). These are consistent with Rakai data showing no effect of intervention.Frequency of STIs: In both Mwanza and Rakai, there was no significant reduction in gonorrhoea, chlamydia, urethritis, or reported STI symptoms among intervention communities. The prevalence ratio of syphilis between intervention and control groups in Rakai was 0.8 (95%CI 0.71-0.89), of trichmoniasis was 0.59 (0.38-0.91), and of bacterial vaginosis was 0.87 (0.74-1.02). In Mwanza, the prevalence of serologically diagnosed syphilis in the intervention community was 5% compared with 7% in the control community at the end of the trial (adjusted re7% in the control community at the end of the trial (adjusted relative risk 0.71 (95%CI 0.54-0.93). In Kamali et al, there was a significant decrease in gonorrhoea and active syphilis cases. Rate ratio for gonorrhoea was 0.29(0.12-0.71, p=0.016), active syphilis was 0.53(0.33-0.84,p=0.016). There was a trend towards significance with intervention on the use of condoms with the last casual partner; the rate ratio was 1.27(1.02-1.56,p=0.036).Quality of treatment: In Lima, following training of pharmacy assistants in STI syndromic management, symptoms were recognised as being due to an STI in 65% of standardised simulated patients (SSPs) visiting intervention and 60% of SSPs visiting control pharmacies (p=0.35). Medication was offered without referral to a doctor in most cases (83% intervention and 78% control, p=0.61). Of those SSPs offered medication, only 1.4% that visited intervention pharmacies and only 0.7% of those that visited control pharmacies (p=0.57) were offered a recommended regimen. Similarly in only 15% and 16% of SSP visits respectively was any recommended drug offered. However, education and counseling were more likely to be given to SSPs visiting intervention pharmacies (40% vs 27%, p=0.01). No SSPs were given partner cards or condoms. In Hlabisa, following the intervention targeting primary care clinic nurses (strengthened STI syndromic management and provision of STI syndrome packets containing recommended drugs, condom, partner cards and patient information leaflets), SSPs were more likely to be given recommended drugs in intervention clinics (83% vs 12%, p<0.005) and more likely to be correctly case managed [given correct drugs, partner cards and condoms] (88% vs 50%, p<0.005). There were no significant differences in the proportions adequately counseled (68% vs 46%, p=0.06), experiencing good staff attitude (84% vs 58%, p=0.07), and being consulted in privacy (92% vs 86%, p=0.4). There was no strong evidence of any impact on treatment-seeking behaviour, utilisation of services, or sexual behaviour in any of the four trials. REVIEWERS' CONCLUSIONS: There is limited evidence from randomised controlled trials for STI control as an effective HIV prevention strategy. Improved STI treatment services have been shown to reduce HIV incidence in an environment characterised by an emerging HIV epidemic (low and slowly rising prevalence), where STI treatment services are poor and where STIs are highly prevalent. There is no evidence for substantial benefit from treatment of all community members. The addition of the Kamali trial to the existing evidence supports the data from the Rakai trial of no effect. There are, however, other compelling reasons why STI treatment services should be strengthened, and the available evidence suggests that when an intervention is accepted it can substantially improve quality of services provided. The Kamali trial shows an increase in the use of condoms, a marker for improved risk behaviors. Further community-based randomised controlled trials that test a range of alternative STI control strategies are needed in a variety of different settings. Such trials should aim to measure a range of factors that include health seeking behaviour and quality of treatment, as well as HIV, STI and other biological endpoints.

Schein, L. A. (2006). Psychological effects of catastrophic disasters : group approaches to treatment. New York: Haworth Press.

Schroeder, K., & Fahey, T. (2004). Over-the-counter medications for acute cough in children and adults in ambulatory settings. Cochrane Database of Systematic Reviews (Online), (4)(4), CD001831. doi:10.1002/14651858.CD001831.pub2

BACKGROUND: Acute cough due to upper respiratory tract infection (URTI) is a common symptom. Many health practitioners recommend non-prescription over-the-counter (OTC) medicines as a first-line treatment for cough, but there is little evidence as to whether these drugs are effective. OBJECTIVES: To assess the effects of oral over-the-counter cough preparations for acute cough. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 2, 2004); MEDLINE (January 1966 to June Week 3, 2004); EMBASE (January 1990 to March 2004); and the UK Department of Health National Research Register (December 2003, http://www.update-software.com/National/nrr-frame.html). We also searched personal collections of references and reference lists of articles. We wrote to study investigators and pharmaceutical companies for information on further published or unpublished studies. There were no constraints based on language or publication status. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing oral OTC cough preparations with placebo in children and adults suffering from acute cough in ambulatory settings. We considered all cough outcomes (such as frequency and severity, continuous and categorical data, using different ways of measurement). The second outcomes of interest were adverse effects. DATA COLLECTION AND ANALYSIS: Two investigators screened potentially relevant citations independently. Any differences at any stage of the review were resolved by discussion. We also extracted data and assessed the quality of studies independently. We contacted investigators for additional information and performed quantitative analysis when appropriate data were available. MAIN RESULTS: Twenty four trials (17 in adults, seven in children) involving 3,392 people (2,876 adults and 516 children) were included.RESULTS OF STUDIES IN ADULTS: 1. Antitussives: Six trials compared antitussives with placebo. Codeine was no more effective than placebo in reducing cough symptoms. Two studies favoured dextromethorphan over placebo, whereas a third did not show an effect. Moguisteine was no more effective than placebo apart from a reduction of cough in a subgroup of participants with more severe night cough. 2. Expectorants: Two trials compared guaifenesin with placebo. In the larger study, 75 per cent of participants taking guaifenesin stated that the medicine was helpful compared to 31 per cent in the control group. In the second study, both groups showed improvement with respect to cough frequency and severity, with no statistically significant differences between groups. 3. Mucolytics: One trial compared a mucolytic with placebo. Active treatment reduced cough frequency and symptom scores on day four and eight. 4. Antihistamine-decongestant combinations: Two studies compared antihistamine-decongestant combinations with placebo. Antihistamine-decongestants were significantly more effective than placebo in one of the studies, whereas the other did not show any difference between the study groups. 5. Other drug combinations: Three studies compared combinations of drugs other than antihistamine-decongestant with placebo. Two studies were effective in reducing cough symptoms, and one study showed relief at night but not during the day. 6. Antihistamines: Three trials compared antihistamines with placebo. Antihistamines were no more effective than placebo in relieving cough symptoms.RESULTS OF STUDIES IN CHILDREN: 1. Antitussives: Antitussives were no more effective than placebo (one study) 2. Expectorants: No studies using expectorants met our inclusion criteria. 3. Mucolytics: The results of one trial favoured active treatment over placebo from day four until day 10. 4. Antihistamine-decongestant combinations: Two studies showed no difference between antihistamine-decongestant combinations and placebo. 5. Other drug combinations: One trial tested two paediatric cough syrups. Compared to placebo, both preparations showed a 'satisfactory response' in 46 per cent and 56 per cent of children compared to 21 per cent of children in the placebo group. One study compared an antitussive/bronchodilator combination in children, which showed no difference between the treatment groups. 6. Antihistamines: In one trial that tested antihistamines active treatment was no more effective than placebo. REVIEWERS' CONCLUSIONS: There is no good evidence for or against the effectiveness of OTC medicines in acute cough. The results of this review have to be interpreted with caution due to differences in study designs, populations, interventions and outcomes between studies. The numbers of studies in each group were small, and studies often showed conflicting results. Effect sizes in many studies were unclear and it is questionable as to whether all of the positive results are clinically relevant. More evidence about the effectiveness of OTC cough preparations would be helpful, as identification of effective self-care treatments may help reduce the burden of days lost at work due to acute cough as well as the number of consultations in primary care. Identification of ineffective preparations could avoid costs for consumers and health care providers.

Scott, M. E. (1971). The flashback phenomenon. Virginia Medical Monthly, 98(6), 317-320.

Seal, R. E. (1970). The current status of the hallucinogenic drugs. The Australian and New Zealand Journal of Psychiatry, 4(1), 64-67.

Shah, S. S., Ohlsson, A., Halliday, H., & Shah, V. S. (2007). Inhaled versus systemic corticosteroids for the treatment of chronic lung disease in ventilated very low birth weight preterm infants. Cochrane Database of Systematic Reviews (Online), (4)(4), CD002057. doi:10.1002/14651858.CD002057.pub2

BACKGROUND: Chronic lung disease (CLD) remains a serious and common problem among very low birth weight infants despite the use of antenatal steroids and postnatal surfactant therapy to decrease the incidence and severity of respiratory distress syndrome. Due to their anti-inflammatory properties, corticosteroids have been widely used to treat or prevent CLD. However, the use of systemic steroids has been associated with serious short and long-term adverse effects. Administration of corticosteroids topically through the respiratory tract might result in beneficial effects on the pulmonary system with fewer undesirable systemic side effects. OBJECTIVES: To determine the effect of inhaled versus systemic corticosteroids administered to ventilator dependent preterm neonates with birth weight < 1500 g or gestational age < 32 weeks after two weeks of life for the treatment of evolving CLD. SEARCH STRATEGY: Randomized and quasi-randomized trials were identified by searching the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3, 2007), MEDLINE (1966 - June 2007), EMBASE (1980 - June 2007), CINAHL (1982 - June 2007), reference lists of published trials and abstracts published in Pediatric Research or electronically on the Pediatric Academic Societies website (1990 - April 2007). SELECTION CRITERIA: Randomized or quasi-randomized trials comparing inhaled versus systemic corticosteroid therapy (irrespective of the dose and duration of therapy) starting after the first two weeks of life in ventilator dependent very low birth weight preterm infants. DATA COLLECTION AND ANALYSIS: Data were extracted regarding clinical outcomes including CLD at 28 days or 36 weeks postmenstrual age (PMA), mortality, combined outcome of death or CLD at 28 days of age or 36 weeks PMA, other pulmonary outcomes and adverse effects. All data were analyzed using RevMan 4.2.10. When appropriate, meta-analysis was performed using relative risk (RR), risk difference (RD), and weighted mean difference (WMD) along with their 95% confidence intervals (CI). If RD was statistically significant, the number needed to treat (NNT) was calculated. MAIN RESULTS: Data from one additional trial were available for inclusion in this update. Thus, five trials comparing inhaled versus systemic corticosteroids in the treatment of CLD were identified. Two trials were excluded as both included non-ventilator dependent patients and three trials qualified for inclusion in this review.Halliday et al (Halliday 2001) randomized infants at < 72 hours, while Rozycki et al (Rozycki 2003) and Suchomski et al (Suchomski 2002) randomized at 12 - 21 days. The data from the two trials of Rozycki et al and Suchmoski et al are combined using meta-analytic techniques. The data from the trial by Halliday et al are reported separately, as outcomes were measured over different time periods from the age at randomization.In none of the trials was there a statistically significant difference between the groups in the incidence of CLD at 36 weeks PMA among all randomized infants. The estimates for the trial by Halliday et al (Halliday 2001) were RR 1.10 (95% CI 0.82, 1.47), RD 0.03 (95% CI -0.08, 0.15); number of infants (n = 292).For the trials by Rozycki et al (Rozycki 2003) and Suchomski et al (Suchomski 2002) the typical RR was 1.02 (95% CI 0.83, 1.25) and the typical RD 0.01 (95% CI -0.11, 0.14); (number of infants = 139 ). There were no statistically significant differences between the groups in either trial for oxygen dependency at 28 days of age, death by 28 days or 36 weeks PMA, the combined outcome of death by or CLD at 28 days or 36 weeks PMA, duration of intubation, duration of oxygen dependence, or adverse effects. Information on the long-term neurodevelopmental outcomes was not available. AUTHORS' CONCLUSIONS: This review found no evidence that inhaled corticosteroids confer net advantages over systemic corticosteroids in the management of ventilator dependent preterm infants. Neither inhaled steroids nor systemic steroids can be recommended as standard treatment for ventilated preterm infants. There was no evidence of difference in effectiveness or side-effect profiles for inhaled versus systemic steroids. A better delivery system guaranteeing selective delivery of inhaled steroids to the alveoli might result in beneficial clinical effects without increasing side-effects. To resolve this issue, studies are needed to identify the risk/benefit ratio of different delivery techniques and dosing schedules for the administration of these medications. The long-term effects of inhaled steroids, with particular attention to neurodevelopmental outcome, should be addressed in future studies.

Shear, K., Jin, R., Ruscio, A. M., Walters, E. E., & Kessler, R. C. (2006). Prevalence and correlates of estimated DSM-IV child and adult separation anxiety disorder in the National Comorbidity Survey Replication. The American Journal of Psychiatry, 163(6), 1074-1083. doi:10.1176/appi.ajp.163.6.1074

OBJECTIVE: Despite its inclusion in DSM-IV, little is known about the prevalence or correlates of adult separation anxiety disorder or its relationship to the childhood disorder. Results of the first epidemiological study of adult separation anxiety disorder, to the authors' knowledge, and its relationship to childhood separation anxiety disorder are presented. METHOD: Data were from the National Comorbidity Survey Replication (NCS-R), a nationally representative survey of U.S. households. A fully structured, lay-administered diagnostic interview assessed a wide range of DSM-IV disorders, including separation anxiety disorder. No independent clinical validation was obtained of the assessment. RESULTS: Lifetime prevalence estimates of childhood and adult separation anxiety disorders were 4.1% and 6.6%, respectively. Approximately one-third of the respondents who were classified as childhood cases (36.1%) had an illness that persisted into adulthood, although the majority classified as adult cases (77.5%) had first onset in adulthood. The assessment of separation anxiety disorder in the NCS-R was comorbid with other NCS-R or DSM-IV disorders and associated with severe role impairment in roughly half of the comorbid cases and one-fourth of the pure cases. The majority of people with estimated adult separation anxiety disorder are untreated, even though many obtain treatment for comorbid conditions. CONCLUSIONS: Criteria for adult separation anxiety disorder should be refined in future editions of DSM because the disorder is likely to be much more common in adults than previously recognized. Research is needed to develop and evaluate treatments that take into consideration its high comorbidity with other DSM-IV disorders.

Sierras-Siegart, M. (2008). Despersonalization: Clinical and Neurobiological Aspects. Colombia Psiquiatry Review, 37(1), 40-55.

Sigafoos, J., Green, V. A., Edrisinha, C., & Lancioni, G. E. (2007). Flashback to the 1960s: LSD in the treatment of autism. Developmental Neurorehabilitation, 10(1), 75-81.

Between 1959 and 1974, several groups of researchers issued reports on the use of d-Lysergic Acid Diethylamide (LSD) in the treatment of children with autism. This paper reviews that literature to consider how the authors justified these studies, as well as their methods, results, and conclusions. The justification for using LSD was often based on the default logic that other treatment efforts had failed. Several positive outcomes were reported with the use of LSD, but most of these studies lacked proper experimental controls and presented largely narrative/descriptive data. Today there is renewed interest in the use of psychedelic drugs for therapeutic purposes. While this resurgence of research has not yet included children with autism, this review of the LSD studies from the 1960s and 1970s offers important lessons for future efforts to evaluate new or controversial treatments for children with autism.

Sillay, K. A., Sani, S., & Starr, P. A. (2009). Deep brain stimulation for medically intractable cluster headache. Neurobiology of Disease, doi:10.1016/j.nbd.2009.05.020

Cluster headache is the most severe primary headache disorder known. Ten to 20% of cases are medically intractable. DBS of the posterior hypothalamic area has shown effectiveness for alleviation of cluster headache in many but not all of the 46 reported cases from European centers and the eight cases studied at the University of California, San Francisco. This surgical strategy was based on the finding of increased blood flow in the posterior hypothalamic area on H(2)(15)O PET scanning during spontaneous and nitroglycerin-induced cluster headache attacks. The target point used, 4-5 mm posterior to the mamillothalamic tract, is in the border zone between posterior hypothalamus, anterior periventricular gray matter, and inferior thalamus. Recently, occipital nerve stimulation has shown efficacy, calling in question the use of DBS as a first line surgical therapy. In this report, we review the indications, techniques, and outcomes of DBS for cluster headache.

Simeon, D., & Hamilton, H. K. (2008). Depersonalization disorder and schizotypal personality disorder. Psychosis, Trauma and Dissociation: Emerging Perspectives on Severe Psychopathology,

Simeon, D., Kozin, D. S., Segal, K., & Lerch, B. (2009). Is depersonalization disorder initiated by illicit drug use any different? a survey of 394 adults. The Journal of Clinical Psychiatry, doi:10.4088/JCP.08m04370

OBJECTIVE: Previous studies have documented that in a substantial minority of individuals with depersonalization disorder, onset is first triggered by illicit drug ingestion. The goal of this study was to systematically compare a large sample of individuals with drug-initiated (D) versus non-drug-initiated (ND) chronic depersonalization. METHOD: We conducted an internet survey of 394 adults endorsing DSM-IV-TR depersonalization and/or derealization symptoms. Sixty-four questions were utilized to inquire about demographic and clinical characteristics, illness course, substance use history, and treatment response. The Cambridge Depersonalization Scale (CDS) was administered. The study was conducted from September 2005 to January 2006. RESULTS: Compared to the ND group (n = 198), the D group (n = 196) included more male and younger individuals. The 2 most common precipitating drugs were cannabis and hallucinogens, followed by ecstasy. The majority of participants had modest use histories prior to onset and never ingested subsequently. The 2 groups endorsed similar illness course, impairment, suicidality, and limited treatment response. The D group showed significantly greater improvement over time than the ND group (P = .002), although the groups did not differ in reported psychotherapy or pharmacotherapy effectiveness. The groups did not differ in CDS total score or on the 4 subscale scores of unreality of self, perceptual alterations, unreality of surroundings, and temporal disintegration. On the numbing subscale of the CDS, the ND group scored higher (P = .009) only prior to controlling for age and gender. CONCLUSION: The study strongly supports a uniform syndrome for chronic depersonalization/derealization regardless of precipitant.

Simeon, D., Kozin, D. S., Segal, K., Lerch, B., Dujour, R., & Giesbrecht, T. (2008). De-constructing depersonalization: further evidence for symptom clusters. Psychiatry Research, 157(1-3), 303-306. doi:10.1016/j.psychres.2007.07.007

Depersonalization disorder is defined in the DSM-IV-TR using a single symptom criterion, which does not do justice to the phenomenological complexity of the disorder. In 394 affected adults, the Cambridge Depersonalization Scale yielded five factors (numbing, unreality of self, perceptual alterations, unreality of surroundings, and temporal disintegration), put forth as symptom criteria for a better diagnosis of depersonalization disorder.

Simeon, D., & Hamilton, H. K. (2008). Psychosis, Trauma and Dissociation; Depersonalization Disorder and Schizotypal Personality Disorder , 209 <last_page> 220. doi:10.1002/9780470699652.ch15

Smith, J. A., Walters, G., & Johnston, D. (1980). LSD 'flashback' as a cause of diagnostic error. Postgraduate Medical Journal, 56(656), 421-422.

An emaciated, but otherwise physically normal young man presented with an acute psychosis resembling hallucinogenic drug abuse. His behaviour was so strange that the underlying pathology of severe pyloric stenosis was only detected when a chance measurement of urea and electrolytes was made, revealing gross biochemical abnormalities. His abnormal mental state persisted for more than one week and an LSD 'flashback' was postulated as the cause of the prolonged psychosis

Soto-Cabrera, E., Chavez-Valencia, V., Zermeno-Pohls, F., & Gonzalez-Aguilar, A. (2009). Symptomatic episodic cluster headache as the first symptom of a prolactinoma. [Cefalea en racimos episodica sintomatica, como primera manifestacion de prolactinoma] Revista De Neurologia, 49(3), 165-166.

Srividhya, R., Jyothilakshmi, V., Arulmathi, K., Senthilkumaran, V., & Kalaiselvi, P. (2008). Attenuation of senescence-induced oxidative exacerbations in aged rat brain by (−)-epigallocatechin-3-gallate. International Journal of Developmental Neuroscience, 26(2), 217-223. doi:DOI: 10.1016/j.ijdevneu.2007.12.003

Stein, D. J., & Simeon, D. (2009). Cognitive-Affective Neuroscience of Depersonalization. CNS SPECTRUMS, 14(9), 467-471.

Depersonalization disorder (DPD) is characterized by a subjective sense of detachment from one's own being and a sense of unreality. An examination of the psychobiology of depersonalization symptoms may be useful in understanding the cognitive-affective neuroscience of embodiment. DPD may be mediated by neurocircuitry and neurotransmitters involved in the integration of sensory processing and of the body schema, and in the mediation of emotional experience and the identification of feelings. For example, DPD has been found to involve autonomic blunting, deactivation of sub-cortical structures, and disturbances in molecular systems in such circuitry. An evolutionary perspective suggests that attenuation of emotional responses, mediated by deactivation of limbic structures, may sometimes be advantageous in response to inescapable stress.}

Stone, A. L., O'Brien, M. S., De La Torre, A., & Anthony, J. C. (2007). Who is becoming hallucinogen dependent soon after hallucinogen use starts? Drug and Alcohol Dependence, 87(2-3), 153-163. doi:10.1016/j.drugalcdep.2006.08.008

This study, based upon epidemiological survey data from the United States (U.S.) National Household Surveys on Drug Abuse (NHSDA) from 2000 to 2001, presents new estimates for the risk of developing a hallucinogen dependence syndrome within 24 months after first use of any hallucinogen (median elapsed time approximately 12 months). Subgroup variations in risk of becoming hallucinogen dependent also are explored. Estimates are derived from the NHSDA representative samples of non-institutionalized U.S. residents ages 12 and older (n=114,241). A total of 2035 respondents had used hallucinogens for the first time within 24 months prior to assessment. An estimated 2-3% of these recent-onset hallucinogen users had become dependent on hallucinogens, according to the NHSDA DSM-IV computerized diagnostic algorithm. Controlling for sociodemographic and other drug use covariates, very early first use of hallucinogens (age 10-11 years) is associated with increased risk of hallucinogen dependence (p<0.01). Excess risk of developing hallucinogen dependence was found in association with recent-onset use of mescaline; excess risk also was found for recent-onset users of ecstasy and of PCP. This study's evidence is consistent with prior evidence on a tangible but quite infrequent dependence syndrome soon after the start of hallucinogen use; it offers leads that can be confirmed or disconfirmed in future investigations.

Stone, A. L., Storr, C. L., & Anthony, J. C. (2006). Evidence for a hallucinogen dependence syndrome developing soon after onset of hallucinogen use during adolescence. International Journal of Methods in Psychiatric Research, 15(3), 116-130.

This study uses latent class methods and multiple regression to shed light on hypothesized hallucinogen dependence syndromes experienced by young people who have recently initiated hallucinogen use. It explores possible variation in risk. The study sample, identified within public-use data files of the 1999 National Household Survey on Drug Abuse (NHSDA), consists of 1186 recent-onset hallucinogen users, defined as having initiated hallucinogen use within 24 months of assessment (median elapsed time since onset of use -12 to 13 months). The recent-onset users in this sample were age 12 to 21 at the time of assessment and were between the ages of 10 and 21 at the time of their first hallucinogen use. The NHSDA included items to assess seven clinical features often associated with hallucinogen dependence, which were used in latent class modelling. Latent class analysis, in conjunction with prior theory, supports a three-class solution, with 2% of recent-onset users in a class that resembles a hallucinogen dependence syndrome, whereas 88% expressed few or no clinical features of dependence. The remaining 10% may reflect users who are at risk for dependence or in an early stage of dependence. Results from latent class regressions indicate that susceptibility to rapid transition from first hallucinogen use to onset of this hallucinogen dependence syndrome might be influenced by hallucinogenic compounds taken (for example, estimated relative risk, RR = 2.4, 95% CI = 1.6, 7.6 for users of MDMA versus users of LSD). Excess risk of rapid transition did not appear to depend upon age, sex, or race/ethnicity.

Strassman, R. J. (1984). Adverse reactions to psychedelic drugs. A review of the literature. The Journal of Nervous and Mental Disease, 172(10), 577-595.

The use of naturally occurring and synthetically derived compounds for their "psychedelic" effects has been a part of human culture for thousands of years. The basic pharmacology of the major synthetic psychedelic compounds (primarily lysergic acid diethylamide [LSD]-25) is described and reference is made to their potentially beneficial psychological effects. Adverse reactions, defined as dysphoric and/or maladaptive/dysfunctional responses to the use of these drugs, sometimes require careful clinical judgment in order to diagnose. These reactions can be effectively classified along a temporal continuum. Acute, short-lived reactions are often fairly benign, whereas chronic, unremitting courses carry a poor prognosis. Delayed, intermittent phenomena ("flashbacks") and LSD-precipitated functional disorders that usually respond to treatment appropriate for the non-psychedelic-precipitated illnesses they resemble, round out this temporal means of classification. The question of organic brain damage as well as permanent changes in personality, attitudes, and creativity in patients and normals who have repeatedly ingested psychedelic drugs is controversial, but tends to point to subtle or nonsignificant changes. Future areas for study of the psychedelics' pharmacological, psychological, and therapeutic effects are suggested.

Strassman, R. J. (1995). Hallucinogenic drugs in psychiatric research and treatment. Perspectives and prospects. The Journal of Nervous and Mental Disease, 183(3), 127-138.

Clinical research with hallucinogens has resumed after a generation's hiatus. To place these new studies in context, this article reviews the history of hallucinogens' use and abuse, discusses their pharmacological properties, and highlights previous human studies. Research with lysergic acid diethylamide and related hallucinogens with thousands of patients and control subjects was associated with acceptable safety when subjects were carefully screened, supervised, and followed up. Data were generated regarding hallucinogens' psychopharmacology, overlap with endogenous psychoses, and psychotherapeutic efficacy. Current American and European studies emphasize systematic psychopharmacology, in addition to psychotherapy protocols. Human hallucinogen research will help define unique mind-brain interfaces, and provide mechanistic hypotheses and treatment options for psychiatric disorders. It is critical that human hallucinogen research in the 1990s make use of state of the art methodologies, or consensually define when modifications are required. Training and supervisory issues also must be explicitly addressed.

Summ, O., Gregor, N., Marziniak, M., Gralow, I., Husstedt, I., & Evers, S. (2009). Cluster headache and alpha 1-antitrypsin deficiency. Cephalalgia : An International Journal of Headache, doi:10.1111/j.1468-2982.2009.01897.x

Little is known about the pathophysiology of cluster headache (CH), one of the most debilitating primary headaches. Interestingly, associations of lung affecting diseases or lifestyle habits such as smoking and sleep apnoea syndrome and CH have been described. Certain genotypes for alpha 1-antitrypsin (alpha(1)-AT) are considered risk factors for emphysema. Our aim was to investigate possible associations between common genotypes of the SERPINA1 gene and CH. Our study included 55 CH patients and 55 controls. alpha(1)-AT levels in serum and the genotype were analysed. Patients CH characteristics were documented. We could not detect any association between CH and a genotype that does not match the homozygous wild type for alpha(1)-AT. Interestingly, there is a significant difference of CH attack frequency in patients who are heterozygous or homozygous M allele carriers. We conclude that the presence of an S or Z allele is associated with higher attack frequency in CH.

Sunness, J. S. (2004). Persistent afterimages (palinopsia) and photophobia in a patient with a history of LSD use. Retina (Philadelphia, Pa.), 24(5), 805.

Taffe, M. A., Weed, M. R., Davis, S., Huitron-Resendiz, S., Schroeder, R., Parsons, L. H., Henriksen, S. J., & Gold, L. H. (2001). Functional consequences of repeated (+/-)3,4-methylenedioxymethamphetamine (MDMA) treatment in rhesus monkeys. Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology, 24(3), 230-239. doi:10.1016/S0893-133X(00)00185-8

Six rhesus monkeys were trained to stable performance on neuropsychological tests of memory, reinforcer efficacy, reaction time and bimanual motor coordination. Three monkeys were then exposed to a high-dose, short course regimen of (+/-)3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy") (4 days, 10 mg/kg i.m., b.i.d.). Following treatment, concentrations of 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF) were reduced by approximately 50% in the treated animals, and this effect persisted for approximately three months post-MDMA. Behavioral performance was disrupted during acute MDMA treatment but returned to baseline within one week following treatment. MDMA also produced persistent alterations in late peak latencies of brainstem auditory evoked potentials (BSAEP), lasting three months post-MDMA. Both CSF 5-HIAA concentrations and evoked potential latencies were normalized four months after treatment. These findings indicate that serotonergic alterations associated with MDMA use may result in persisting changes in brain function.

Teeple, R. C., Caplan, J. P., & Stern, T. A. (2009). Visual hallucinations: differential diagnosis and treatment Primary Care Companion to the Journal of Clinical Psychiatry, 11(1), 26-32.

Thomas, R., & Perera, R. (2006). School-based programmes for preventing smoking. Cochrane Database of Systematic Reviews (Online), 3, CD001293. doi:10.1002/14651858.CD001293.pub2

BACKGROUND: Smoking rates in adolescents are rising in some countries. Helping young people to avoid starting smoking is a widely endorsed goal of public health, but there is uncertainty about how to do this. Schools provide a route for communicating with a large proportion of young people, and school-based programmes for smoking prevention have been widely developed and evaluated. OBJECTIVES: To review all randomized controlled trials of behavioural interventions in schools to prevent children (aged 5 to12) and adolescents (aged 13 to18) starting smoking. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) and the Cochrane Tobacco Addiction Group's Specialized Register, MEDLINE, EMBASE, PsyclNFO, ERIC, CINAHL, Health Star, Dissertation Abstracts and studies identified in the bibliographies of articles. Individual MEDLINE searches were made for 133 authors who had undertaken randomized controlled trials in this area. SELECTION CRITERIA: Types of studies: those in which individual students, classes, schools, or school districts were randomized to the intervention or control groups and followed for at least six months.Types of participants: Children (aged 5 to12) or adolescents (aged 13 to18) in school settings.Types of interventions: Classroom programmes or curricula, including those with associated family and community interventions, intended to deter use of tobacco. We included programmes or curricula that provided information, those that used social influences approaches, those that taught generic social competence, and those that included interventions beyond the school into the community. We included programmes with a drug or alcohol focus if outcomes for tobacco use were reported.Types of outcome measures: Prevalence of non-smoking at follow up among those not smoking at baseline. We did not require biochemical validation of self-reported tobacco use for study inclusion. DATA COLLECTION AND ANALYSIS: We assessed whether identified citations were randomized controlled trials. We assessed the quality of design and execution, and abstracted outcome data. Because of the marked heterogeneity of design and outcomes, we computed pooled estimates only for those trials that could be analyzed together and for which statistical data were available. We predominantly synthesized the data using narrative systematic review. We grouped studies by intervention method (information; social competence; social influences; combined social influences/social competence; multi-modal programmes). Within each group, we placed them into three categories (low, medium and high risk of bias) according to validity using quality criteria for reported study design. MAIN RESULTS: Of the 94 randomized controlled trials identified, we classified 23 as category one (most valid). There was one category one study of information-giving and two of teaching social comeptence. There were thirteen category one studies of social influences interventions. Of these, nine found some positive effect of intervention on smoking prevalence, and four failed to detect an effect on smoking prevalence. The largest and most rigorous study, the Hutchinson Smoking Prevention Project, found no long-term effect of an intensive eight-year programme on smoking behaviour. There were three category one RCTs of combined social influences and social competence interventions: one provided significant results and one only for instruction by health educators compared to self-instruction.There was a lack of high quality evidence about the effectiveness of combinations of social influences and social competence approaches. There was one category one study providing data on social influences compared with information giving. There were four category one studies of multi-modal approaches but they provided limited evidence about the effectiveness of multi-modal approaches including community initiatives. AUTHORS' CONCLUSIONS: There is one rigorous test of the effects of information-giving about smoking. There are well-conducted randomized controlled trials to test the effects of social influences interventions: in half of the group of best quality studies those in the intervention group smoke less than those in the control, but many studies failed to detect an effect of the intervention. There are only three high quality RCTs which test the effectiveness of combinations of social influences and social competence interventions, and four which test multi-modal interventions; half showed significant positive results.

Tobin, J., & Flitman, S. (2009). Occipital nerve blocks: when and what to inject? Headache, 49(10), 1521-1533. doi:10.1111/j.1526-4610.2009.01493.x

INTRODUCTION: Occipital nerve block (ONB) is a promising treatment for headaches. Its indications, selection criteria, and best techniques are not clear, however. OBJECTIVE: To summarize in narrative format what is known about ONBs and what needs to be learned. METHODS: MD Consult and Google Scholar were searched using the terms occipital, suboccipital, block, and injection to identify relevant articles that were reviewed. This process was repeated for all additional pertinent articles identified from these articles, and so on, until no additional articles were identified. RESULTS: A total of 21 articles were identified. CONCLUSIONS: Occipital nerve block is an effective treatment for cervicogenic headache, cluster headache, and occipital neuralgia. While a double blinded randomized placebo controlled clinical trial is lacking, multiple open label studies reported favorable results for migraine. Two other possible uses of ONB worthy of further study are use as a rescue treatment and as an adjunctive treatment for medication overuse headache. ONB may be effective for tension headache, but only under very specific circumstances. ONB is either ineffective or only effective under as yet unstudied circumstances for hemicrania continua and chronic paroxysmal hemicrania. Some practitioners use occipital nerve (ON) tenderness to palpation (TTP) or reproduction of headache pain with ON pressure (RHPONP) as selection criteria for identifying appropriate patients. While only a clinical trial can produce a definitive answer, current evidence suggests that these selection criteria are not necessary for cervicogenic headache or cluster headache. Occipital neuralgia by definition involves TTP of the ONs. Whether RHPONP or ON TTP predicts success in migraine is unclear, and may relate to whether steroids are used. A single blinded randomized controlled trial evaluating local anesthetic with steroids vs local anesthetic alone for transformed migraine reported slightly worse results with steroids, but there are several alternate explanations for this finding other than steroids being counterproductive. The technique of repetitive ONBs deserves further study.

Tomioka, H., & Namba, K. (2006). Development of antituberculous drugs: current status and future prospects. Kekkaku : [Tuberculosis], 81(12), 753-774.

Worldwide, tuberculosis (TB) remains the most frequent and important infectious disease causing morbidity and death. One-third of the world's population is infected with Mycobacterium tuberculosis (MTB), the etiologic agent of TB. The World Health Organization estimates that about eight to ten million new TB cases occur annually worldwide and the incidence of TB is currently increasing. In this context, TB is in the top three, with malaria and HIV being the leading causes of death from a single infectious agent, and approximately two million deaths are attributable to TB annually. In particular, pulmonary TB, the most common form of TB, is a highly contagious and life-threatening infection. Moreover, enhanced susceptibility to TB in HIV-infected populations is another serious health problem throughout the world. In addition, multidrug-resistant TB (MDR-TB) has been increasing in incidence in many areas, not only in developing countries but industrialized countries as well, during the past decade. These situations, particularly the global resurgence of TB and the rapid emergence of MDR-TB, underscore the importance of the development of new antituberculous drugs and new protocols for efficacious clinical control of TB patients using ordinary antimycobacterial drugs. Concerning the development of new antituberculous drugs, the following points are of particular importance. (1) Development of drugs which display lasting antimycobacterial activity in vivo is desirable, since they can be administered with long intervals and consequently facilitate directly observed therapy and enhance patient compliance. (2) Development of novel antituberculosis compounds to combat MDR-TB is urgently needed. (3) The eradication of slowly metabolizing and, if possible, dormant populations of MTB organisms that cause relapse, using new classes of anti-TB drugs is very promising for prevention of TB incidence, because it will markedly reduce the incidence of active TB from persons who are latently infected with MTB. Unfortunately, no new drugs except rifabutin and rifapentine has been marketed for TB in the US and other countries during the 40 years after release of rifampicin. There are a number of constraints that have deterred companies from investing in new anti-TB drugs. The research is expensive, slow and difficult, and requires specialized facilities for handling MTB. There are few animal models that closely mimic the human TB disease. Development time of any anti-TB drug will be long. In fact, clinical trials will require the minimum six-month therapy, with a follow-up period of one year or more. In addition, it is hard to demonstrate obvious benefit of a new anti-TB agents over pre-existing drugs, since clinical trials involve multidrug combination therapy using highly effective ordinary anti-TB drugs. Finaly, there is the perceived lack of commercial return to companies engaged in the development of new anti-TB drugs, because over 95% of TB cases worldwide are in developing countries. In this symposium, we reviewed the following areas. 1. Critical new information on the entire genome of MTB recently obtained and increasing knowledge of various mycobacterial virulence genes are greatly promoting the identification of genes that code for new drug targets. In this context, Dr. Namba reviewed the status of new types of compounds which are being developed as anti-TB drug. He also discussed the development of new antimycobacterial drugs according to new and potential pharmacological targets and the best clinical development plans for new-TB drugs in relation to corporate strategy. 2. Using such findings for mycobacterial genomes, bioinformatics/genomics/proteomics-based drug design and drug development using quantitative structure-activity relationships may be possible in the near future. In this context, Dr. Suwa and Dr. Suzuki reviewed the usefulness of chemical genomics in searching novel drug targets for development of new antituberculous drugs. The authors reviewed (1) the history and present status of chemical genomics that is defined as the systemic search for a selective small molecular modulator for each function of all gene products, (2) recent studies of the authors on profiles of the interactions between various kinds of human proteins and small molecule modulators using the new technology devised by Reverse Proteomics Research Institute, and (3) future prospects of the development of new antituberculous drugs based on chemical genomics. 3. It appears also promising to develop new types of drug administration systems using drug vehicles, which enable efficacious drug delivery to their target in vivo. Dr. Izumikawa, Dr. Ohno and Dr. Kohno reviewed the usefulness of liposome- and polymer-based technologies, which enable efficacious delivery of encapsulated drugs at required doses for prolonged periods of time with only a single shot without toxicity, and also enable highly targeted delivery of drugs to their target in vivo. They indicated that the applications of drug delivery system using conventional anti-mycobacterial agents are challenging to improve the compliance of treatment and better clinical outcome. 4. Immunoadjunctive therapy appears to be promising in improving outcome of clinical control of refractory mycobacterial infections, including MDR-TB and M. avium complex infection. Dr. Shimizu, Dr. Sato and Dr. Tomioka reviewed the present status of immunotherapy of mycobacterial infections in combination with antimycobacterial drugs. They indicated that the development of new classes of immunomodulators other than cytokines (IL-2, IFN-gamma, GM-CSF, IL-12, etc.) particularly those with no severe side-effects, are urgently needed. Their review dealed with some promising immunoadjunctive agents, especially ATP and its analogues, which potentiate macrophage antimycobacterial activity via purinergic P2 receptors. The aim of this symposium is to address the future prospects of the development of new drugs and drug regimens for anti-TB chemotherapy. There are a number of difficulties in drug-design for the development of new drug formulations with increased potential for antimycobacterial effects, excellent pharmacokinetics, and tolerability. It should be emphasized that the most urgent goal of chemotherapy of TB and MAC infections, especially that associated with HIV infection, is to develop highly active, low-cost drugs which can be used not only in industrialized countries but also in developing countries, since the incidences of AIDS-associated intractable TB and MAC infections are rapidly increasing in the latter. We strongly wish a great advance of fundametal and practical studies in developing such kinds of new anti-TB drugs in the near future. 1. Prospects for non-clinical or clinical development of new antituberculous drugs in relation to corporate strategy: Kenji NAMBA (New Product Research Laboratories I, Daiichi Pharmaceutical Co., Ltd.) Tuberculosis (TB) remains one of the deadliest threats to public health. No new anti-TB drugs have been brought into the clinic in the past 40 years. Current non-clinical works with progressed technology and Global Alliance for TB Drug Development, a non-profit organization established in 2000, accelerate research and development of faster-acting anti-TB compounds. We reviewed the status of new types of compounds which are being developed as anti-TB drug, such as diarylquinoline (TMC 207), nitroimidazole (PA-824 and OPC-67683), and moxifloxacin (MFLX). We also discussed the best clinical development plans for new-TB drugs in relation to corporate strategy. 2. Exploring novel drug targets through the chemical genomics approach and its possible application to the development of anti-tuberculosis drugs: Yorimasa SUWA (Reverse Proteomics Research Institute Co., Ltd.), Yohji SUZUKI (Teijin Ltd.) Recently, chemical genomics approach has been focused as an emerging technology for the drug discovery. In advance to a very large scale national project in US started last year, Reverse Proteomics Research Institute Co., Ltd. (REPRORI) has developed the core technologies for chemical genomics. Here we describe the outline of chemical genomics study, especially that of REPRORI, and discuss about its possible application to the development of anti-tuberculosis drugs. 3. Anti-mycobacterial agents and drug delivery: Koichi IZUMIKAWA, Hideaki OHNO, Shigeru KOHNO (Second Department of Internal Medicine, Nagasaki University School of Medicine) Mycobacterium infection is a major clinical concern in whole world. Since the newly developed anti-mycobacterial agents are few and still unavailable in clinical settings, the applications of drug delivery system using conventional anti-mycobacterial agents are challenging to improve the compliance of treatment and better efficacy. The efficacy of anti-mycobacterial agents modified by liposome or polymer based technology have been investigated and reported using various animal models. Drug delivery system increased and prolonged the drug concentrations at the blood and targeted organs and the duration of sustained drug release, respectively. These effects lead to decrease in the frequency of drug administrations dramatically and better efficacy rates. The studies, however, were performed only in animal models, the further investigations and evaluations in human are required for practical use. 4. Adjunctive immunotherapy of mycobacterial infections: Toshiaki SHIMIZU, Katsumasa SATO, Haruaki TOMIOKA (Department of Microbiology and Immunology, Shimane University School of Medicine) There is an urgent need to develop new antimicrobials and protocols for the administration of drugs that are potently efficacious against intractable mycobacterial infections. Unfortunately, development of the new drugs for solving this problem is not progressing. (ABSTRACT TRUNCATED)

Trulson, M. E., & Howell, G. A. (1984). Ontogeny of the behavioral effects of lysergic acid diethylamide in cats. Developmental Psychobiology, 17(4), 329-346. doi:10.1002/dev.420170402

The ontogeny of the behavioral effects of lysergic acid diethylamide (LSD) was examined in cats between the ages of 4 and 112 days postpartum. The kittens showed little LSD-induced behavioral change prior to 14 days of age. By the age of 21 days, however, the kittens exhibited many of the behavioral signs characteristic of LSD-induced behaviors in adult cats. These behaviors include limb-flicking, abortive grooming, head-shakes, grooming, and investigatory responses. In general, these behaviors began at a low frequency of occurrence, then increased rapidly with advancing age, reaching adult values by approximately 35-40 days of age, and remained relatively constant through 112 days postpartum. The time course for the behavioral effects following an acute injection of LSD showed the adult pattern, i.e., persisting for approximately 8 hr post-injection, from their earliest appearance during ontogeny. Young kittens (21-42 days of age) were resistant to the development of tolerance following repeated administration of the drug. LSD was capable of eliciting certain behaviors, such as head-shakes and grooming, well in advance of the age at which they normally appear spontaneously. This indicates that the neuronal and musculature substrata are developed for the performance of these behaviors long before the kitten naturally employs them.

Vacheron-Trystram, M. N., Braitman, A., Cheref, S., & Auffray, L. (2004). Antipsychotics in bipolar disorders. [Antipsychotiques et troubles bipolaires] L'Encephale, 30(5), 417-424.

This article is a review of the various treatments that are currently available, in particular in France, for the treatment of bipolar disorders. This article specifically addresses the use of novel antipsychotic agents as alternative therapy to a lithium therapy and/or the use of conventional antipsychotics. The prevalence of bipolar disorder over a lifetime is around 1% of the general population. Bipolar disorder consists of alternating depressive and manic episodes. It mainly affects younger subjects, and is often associated with alcohol and drug addictions. There are two main subtypes of bipolar disorder. According to the DSM IV-R, type 1 of bipolar disorder is characterised when at least one manic episode (or a mixed episode) has been diagnosed. Type 2 of bipolar disorder is related to patients enduring recurrent depressive episodes but no manic episode. Type 2 affects women more frequently as opposed to type 1 affecting individuals of both sexes. Manic-depressive disorder (or cyclo-thymic disorder) appears in relation to patients who has never suffered manic episode, mixed episode or severe depressive episode but have undergone numerous periods with some symptoms of depression and hypomanic symptoms over a two-year period during which any asymptomatic periods last no longer than two months. The average age of the person going through a first episode (often a depressive one) is 20 years-old. Untreated bipolar patients may endure more than ten manic or depressive episodes. Finally, in relation to 10 to 20% of patients, the bipolar disorder will turn into a fast cycle form, either spontaneously or as a result of certain medical treatments. Psychiatrists are now able to initiate various treating strategies which are most likely to be effective as a result of the identification of clinical subtypes of the bipolar disorder. Lithium therapy has been effectively and acutely used for patients with pure or elated mania and its prophylaxis. However, lithium medication may worsen depressive symptoms when used for a long term maintenance therapy. Additionally, mixed mania, rapid cycling type patients and bipolar disorder associated with substance abuse do not respond well to lithium therapy. In addition to the lithium therapy or in place of a lithium therapy, one can report the frequent use of antipsychotic agents in respect of patients with bipolar disorder during both the acute and maintenance phases of treatment. Antipsychotic agents have been used for almost forty years and may be used in combination with a lithium therapy. Conventional antipsychotics are effective but they may induce late dyskinesia, weight gain, sedation, sexual dysfunction and depression. These adverse side effects often lead to non compliance in particular in circumstances where antipsychotic agents are combined with a lithium therapy. A number of alternative somatic treatment approaches have been reported for patients who do not respond well or who are intolerant to lithium therapy. As such, valproate has received regulatory approval for the acute treatment of mania and carbamazepine has been indicated for this condition in a number of countries. Divalproex (Depakote) has recently obtained the authorization to market in France and may be prescribed for manic states or hypomanic states that do not tolerate lithium therapy or for which lithium therapy is contraindicated. A number of other anticonvulsants (lamotrigine, gabapentin and topiramate) are currently being tested. Because of the side effects of the conventional antipsychotic agents, atypical antipsychotic agents are currently on trial and appear to be of interest in the treatment of bipolar disorders. Currently, a number of prospective studies are available with clozapine, risperidone and olanzapine in the treatment of bipolar disorder. Most are short-term studies. Recent randomised, double-blind, placebo-controlled studies have shown clozapine, risperidone and olanzapine to be effective with antimanic and antidepressive effects, both as monotherapy and as add-on maintenance therapy with lithium or valproate. They also have a favorable side effect profile and a positive effect on overall functioning. Similarly, valproate combined with antipsychotics provides greater improvement in mania than antipsychotic medication alone and results in lower dosage of the antipsychotic medication. There is currently no double-blind study regarding the use of clozapine for bipolar disorders. However, based on the results of a number of open-label studies, clozapine appears to be effective in relation to schizo-affective and bipolar patients including those with rapid cycling or those who respond inadequately to mood stabilizers, carbamazepine, valproate or conventional antipsychotics. Clozapine seems to be more appropriate for bipolar and schizo-affective patients than schizophrenics. In particular, studies show that patients with manic and mixed-psychotic state of illness are better responders than patients with major depressive syndromes. Four open studies suggest the efficacy of clozapine in the maintenance treatment of bipolar disorder and three prospective, open-label studies show the efficacy of clozapine in the manic state of the illness. However, the number of patients in the studies was not important and these studies are not controlled. Clozapine has also adverse side affects, one of which consisting of a major risk of agranulocytosis and, potentially, death. In addition, clozapine has been shown to produce significant weight gain and sialorrhea as well as significant anticholinergic effects. As a result, clozapine should not be prescribed in the first place. As opposed to clozapine, there are open-label reports and controlled studies in respect of risperidone and olanzapine. Two recent double-blind studies of acute mania found olanzapine to be more effective than placebo. Based on these two studies, olanzapine has recently been approved for the indication of mania. The effects of olanzapine and divalproex in the treatment of mania have also been compared in a large randomized clinical trial. The olanzapine treatment group had significantly greater mean improvement of mania ratings and a significantly greater proportion of patients achieving protocol-defined remission. Significantly more weight gain and cases of dry mouth, increased appetite and somnolence were reported with olanzapine while more cases of nausea were reported with divalproex. The comparison of olanzapine with lithium for the treatment of mania has also been the subject of a double-blind randomized controlled trial. That study shows no differences between the two drugs. While these studies support the idea that olanzapine has direct acute anti-manic effects, a number of authors are of the opinion that olanzapine may have specific prophylactic mood-stabilizing properties. Olanzapine would appear to be effective in the maintenance treatment, as it exhibited both antimanic and antidepressant effects. Systematic trials have shown that risperidone may be effective and safe in the treatment of acute mania, as an add-on therapy with lithium or valproate (open studies and two controlled double-blind studies) and as monotherapy (open studies). In an open, multi-center, 6-month study, risperidone seems to be effective and safe as long-term adjunctive therapy in treatment-resistant bipolar and schizo-affective disorders, with no exacerbation of manic symptoms. Risperidone had few adverse side effects (and where there were any, they were mostly mild), mostly consisting of APS and weight gain. A naturalistic comparison of clozapine, risperidone and olanzapine in the treatment of bipolar disorder suggests that the efficacy and tolerability of the three treatments are similar. One major differentiation factor of these drugs appears to be weight gain, particularly between olanzapine and risperidone. However, this may partially be caused by the use of mood-stabilizing agents. Bipolar and schizo-affective patients now require combination therapy approach because of the cyclic nature of these disorders. Many studies report the combination of mood-stabilizing agents with conventional antipsychotics and atypical antipsychotics. Combination therapies produce a number of adverse side effects. Atypical antipsychotics (other than clozapine) are now rated as first-line agents for adjunctive treatment of mania because they produce less adverse side effects. Atypical antipsychotics are also rated as first-line agents for combined treatment of psychotic depression and they are strongly preferred when an antipsychotic is required for long-term maintenance.

van Kleef, M., Lataster, A., Narouze, S., Mekhail, N., Geurts, J. W., & van Zundert, J. (2009). Evidence-based interventional pain medicine according to clinical diagnoses. 2. Cluster headache. Pain Practice : The Official Journal of World Institute of Pain, 9(6), 435-442. doi:10.1111/j.1533-2500.2009.00331.x

Cluster headache is a strictly unilateral headache that is associated with ipsilateral cranial autonomic symptoms and usually has a circadian and circannual pattern. Prevalence is estimated at 0.5 to 1.0/1,000. The diagnosis of cluster headache is made based on the patient's case history. There are two main clinical patterns of cluster headache: the episodic and the chronic. Episodic is the most common pattern of cluster headache. It occurs in periods lasting 7 days to 1 year and is separated by at least a 1-month pain-free interval. The attacks in the chronic form occur for more than 1 year without remission periods or with remission periods lasting less than 1 month. Conservative therapy consists of abortive and preventative remedies. Ergotamines and sumatriptan injections, sublingual ergotamine tartrate administration, and oxygen inhalation are effective abortive therapies. Verapamil is an effective and the safest prophylactic remedy. When pharmacological and oxygen therapies fail, interventional pain treatment may be considered. The effectiveness of radiofrequency treatment of the ganglion pterygopalatinum and of occipital nerve stimulation is only evaluated in observational studies, resulting in a 2 C+ recommendation. In conclusion, the primary treatment is medication. Radiofrequency treatment of the ganglion pterygopalatinum should be considered in patients who are resistant to conservative pain therapy. In patients with cluster headache refractory to all other treatments, occipital nerve stimulation may be considered, preferably within the context of a clinical study.

Vecellio, M., Schopper, C., & Modestin, J. (2003). Neuropsychiatric consequences (atypical psychosis and complex-partial seizures) of ecstasy use: possible evidence for toxicity-vulnerability predictors and implications for preventative and clinical care. Journal of Psychopharmacology (Oxford, England), 17(3), 342-345.

Two case reports of ecstasy abuse and its serious neuropsychiatric complications are presented. The first patient developed a florid paranoid psychosis resembling schizophrenia after repeated long-term recreational ecstasy abuse, and significant alterations with intermittent paroxysmal discharges were found in his electroencephalogram. The second patient showed an atypical paranoid psychosis with Fregoli syndrome and a series of complex-partial epileptic seizures with secondary generalization after a first single ecstasy dose. Both subjects presented considerable vulnerability; the first a minimal brain dysfunction after perinatal asphyxia and a persisting attention deficit/hyperactivity disorder, the second a long-lasting opioid addiction. In vulnerable individuals, dose-independent ecstasy abuse can lead to unpredictable and potentially dangerous neuropsychiatric sequelae which require proper initial assessment and adequate treatment.

Victor, S., & Ryan, S. W. (2003). Drugs for preventing migraine headaches in children. Cochrane Database of Systematic Reviews (Online), (4)(4), CD002761. doi:10.1002/14651858.CD002761

BACKGROUND: It has been estimated that about ten per cent of children between six and 20 years of age suffer from migraine. It is estimated that children with migraine lose one and a half weeks more schooling per year than their peers. Prophylactic drugs can be prescribed when children suffer from frequent or disabling headaches. OBJECTIVES: We aimed to describe and assess the evidence from controlled trials on the efficacy and tolerability of pharmacological agents taken on a regular basis to prevent the occurrence of migraine attacks and/or reduce the intensity of such attacks in children with migraine. SEARCH STRATEGY: The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE were searched from 1966 through 2002. Additional strategies for identifying trials included searching the reference lists of review articles and included studies and searching books related to headache. SELECTION CRITERIA: Prospective randomised controlled trials (RCTs) of self- or parent-administered drug treatments in children (under 18 years of age) who had received a diagnosis of migraine were included. DATA COLLECTION AND ANALYSIS: Two investigators extracted, assessed, and coded separately all data for each study, using a form that was designed specifically for the review. Any disagreement was resolved by discussion. Headache frequency standardised over 28 days was used as the primary outcome measure. Headache intensity, headache duration, amount of symptomatic treatment used, and headache indices were used as secondary outcome measures. Data were extracted from both parallel-group and crossover trials. Continuous and dichotomous data were used to calculate standardised mean differences (SMDs) and odds ratios (ORs), respectively. Numbers-needed-to-treat (NNTs) and numbers-needed-to-harm (NNHs) were also calculated. MAIN RESULTS: Thirty-eight studies were selected. Eighteen were excluded. Eleven preventive drugs were compared with placebo in a total of 15 studies. Drug-drug comparisons were made in just six studies. For only four drugs (L-5-hydroxytryptophan [L-5HTP], flunarizine, clonidine, and propranolol) were two or more studies selected. For only six drugs (trazodone, L-5HTP, propranolol, flunarizine, papaverine, and nimodipine) were data reported for effect on frequency. For no individual drug were comparable data reported in more than one study, thus meta-analysis was not possible.Two placebo-controlled studies showed a beneficial effect on the primary outcome measure, headache frequency. They were for the drugs propranolol and flunarizine. The propranolol study reported a dichotomous outcome (proportion of children responding), and it was possible to calculate a number-needed-to-treat to produce a two-thirds reduction in headache frequency (NNT = 1.5, 95%CI 1.15 to 2.1). The flunarizine study produced a SMD of 1.51 (95% confidence interval, -2.21 to -0.82), which was statistically significant in favour of flunarizine (p < 0.001). Nimodipine, timolol, papaverine, pizotifen, trazodone, L-5HTP, clonidine, metoclopramide, and domperidone showed no efficacy in reduction of frequency of attacks. The available studies on cyproheptadine, phenobarbitone, phenytoin, amitriptyline, carbamazepine, metoprolol, and piracetam were excluded for various reasons. REVIEWER'S CONCLUSIONS: Only one study each for propranolol and flunarizine were identified showing efficacy of these drugs as prophylactics of paediatric migraine. Nimodipine, timolol, papaverine, pizotifen, trazodone, L-5HTP, clonidine, metoclopramide, and domperidone showed no efficacy in reduction of frequency of attacks. Available studies on other commonly used drugs failed to meet our inclusion criteria. The quality of evidence available for the use of drug prophylaxis in paediatric migraine was poor. Studies were generally small, with no planning of sample size, so that for many drugs, despite the negative findings of this review, we do not have conclusive evidence of 'no effect'. There is a clear and urgent need for methodologically sound RCTs for the use of pings of this review, we do not have conclusive evidence of 'no effect'. There is a clear and urgent need for methodologically sound RCTs for the use of prophylactic drugs in paediatric migraine, starting with propranolol. These studies need to be adequately powered to investigate meaningful reductions in pain and suffering from a patient's perspective.

Volz, A., Khorsand, V., Gillies, D., & Leucht, S. (2007). Benzodiazepines for schizophrenia. Cochrane Database of Systematic Reviews (Online), (1)(1), CD006391. doi:10.1002/14651858.CD006391

BACKGROUND: Many people with schizophrenia do not achieve a satisfactory treatment response with ordinary antipsychotic drug treatment. In these cases, various add-on medications are used, among them benzodiazepines. OBJECTIVES: To review the effects of benzodiazepines for the treatment of schizophrenia and schizophrenia-like psychoses. SEARCH STRATEGY: The reviewers searched the Cochrane Schizophrenia Group's register (last search March 2005). This register is compiled by methodical searches of BIOSIS, CINAHL, Dissertation abstracts, EMBASE, LILACS, MEDLINE, PSYNDEX, PsycINFO, RUSSMED, Sociofile, supplemented with hand searching of relevant journals and numerous conference proceedings. We also contacted authors of relevant studies in order to obtain missing data from existing trials. SELECTION CRITERIA: All randomised controlled trials comparing benzodiazepine to antipsychotics or to placebo (or no intervention), whether as sole treatment or as an adjunct to antipsychotic medication for the treatment of schizophrenia and/or schizophrenia-like psychoses. DATA COLLECTION AND ANALYSIS: We independently inspected abstracts, selected studies and re-inspected and quality assessed the full reports. We independently extracted relevant outcomes. Dichotomous data were analysed using relative risks (RR) and the 95% confidence intervals (CI). Continuous data were analysed using weighted mean differences. Where possible the number needed to treat (NNT) or number needed to harm (NNH) statistics were calculated. MAIN RESULTS: The review currently includes 31 studies with over 2000 participants. Most studies were small, of short duration - one to 13 weeks - and inconsistently and incompletely reported.Eight studies compared benzodiazepines as a sole agent with placebo. More participants receiving benzodiazepines showed a clinically significant response (n=222, 4 RCTs, RR 0.54 CI 0.3 to 1.0, NNT 3 CI 2 to 17). Only one small study found a significant group difference in favour of benzodiazepines regarding the improvement in overall BPRS mental state. Different rating scales were used to assess general mental state, and therefore many outcomes could not be pooled and no overall direction of effect emerged. Some adverse events observed in these studies suggested that benzodiazepines were more harmful than placebos but again the data were incompletely reported and without overall effect.Thirteen studies examined the effects of benzodiazepines in comparison to antipsychotics as a sole treatment. Trials that reported on clinical response found no advantage for any treatment group concerning improvement of the participants' global state, except of one small study that analysed the mean CGI severity score at one hour. This comparison is highly limited by the low numbers of studies reporting on global function and the short trial duration. Two studies showed a statistically significant superiority of antipsychotics in terms of relapse prevention at one year. Desired sedation occurred significantly more often among participants in the benzodiazepine group than among participants in the antipsychotic treatment group at 20 (n=301, 1 RCT, RR 1.32 CI 1.2 -1.5, NNT 5, CI 3 to 8) and 40 minutes(n= 301, 1 RCT, RR 1.13 CI 1.0 to 1.2, NNT 9 CI 6 to 33), but not at 30, 60 or 12 minutes. Other outcomes relating to the general or specific mental state revealed no significant differences between groups. As far as adverse events were reported there were no results in favour of any group.Sixteen studies examined whether the augmentation of antipsychotics with benzodiazepines is more effective than antipsychotics as a sole treatment. During the first hour of treatment the combination treatment group benefited from the additional benzodiazepine in terms of the participants global state. This benefit diminished over time and was not reproducible at 2 hours or longer. No superior efficacy of benzodiazepine augmentation could be found regarding the general mental state. Specific aspects of the mental state showed no group difference except for desired sedation at 30 and 60 minutes. Somnolence affected the combination treatment group significantly more than the control group (n=118, 2 RCTs, RR 3.30 CI 1.0 to 10.4, NNH 8 CI 5 to 50). We found use of antiparkinson medication to be less frequently used in the combination treatment group (n=282, RR 0.68 CI 0.5 to 1.0, NNT 9 CI 6 to 48). Adverse events were poorly reported and the results were based on very little data. AUTHORS' CONCLUSIONS: Randomised trial-derived evidence is currently too poor to recommend benzodiazepines neither as a sole nor as an adjunctive agent in schizophrenia or schizophrenia-like psychoses. The only significant effects were seen in terms of short-term sedation, at best. The evidence available on augmentation of antipsychotics with benzodiazepines is inconclusive and justifies large, simple and well-designed future trials focusing on clinical response, mental state, aggressive behaviour and adverse events.

Wang, S. J., Hung, C. W., Fuh, J. L., Lirng, J. F., & Hwu, C. M. (2009). Cranial autonomic symptoms in patients with pituitary adenoma presenting with headaches. Acta Neurologica Taiwanica, 18(2), 104-112.

Different types of symptomatic trigeminal autonomic cephalalgias (TACs) have been reported in patients with pituitary adenoma. We investigated the significance of the presence of cranial autonomic symptoms (CAS) in patients with pituitary adenoma presenting with headaches. The records of patients with pituitary adenoma from 1998 to 2004 in our headache clinic were reviewed including headache profile, presence or absence of CAS, and the characteristics of the pituitary adenoma. CAS were ascertained if one or more autonomic symptoms defined for the diagnosis of TACs in the International Classification of Headache Disorders, 2nd edition (ICHD-2) was identified. Thirty-three patients (24F/9M) with pituitary adenoma presenting with headache were recruited for this study: 18 with CAS (55%) and 15 without. Chronic migraine was the most common headache phenotype (n=16, 48%). Three patients were diagnosed as hemicrania continua-like and three, cluster headache-like. In the group with CAS (CAS+), the sides of the tumor were significantly concordant with the sides of headaches (kappa=0.58, p<0.001) and those of CAS (kappa=0.67, p<0.001). However, this relationship was not demonstrated in those without CAS (CAS-) (kappa=0.07, p=0.61). Compared with the patients in the CAS- group, the patients in the CAS+ group had higher frequencies of macroadenoma (78% vs. 40%, p=0.027) and acromegaly (50% vs. 7%, p=0.009). The presence and absence of CAS in pituitary adenoma-associated headache were associated with different characteristics of the underlying pituitary adenomas including side concordance and incidence of acromegaly and macroadenoma. The pathogeneses for headache might differ between these two groups.

Wardlaw, J. M., Zoppo, G., Yamaguchi, T., & Berge, E. (2003). Thrombolysis for acute ischaemic stroke. Cochrane Database of Systematic Reviews (Online), (3)(3), CD000213. doi:10.1002/14651858.CD000213

BACKGROUND: The majority of strokes are due to blockage of an artery in the brain by a blood clot. Prompt treatment with thrombolytic drugs can restore blood flow before major brain damage has occurred. Successful treatment could mean that the patient is more likely to make a good recovery from their stroke. Thrombolytic drugs however, can also cause serious bleeding in the brain which can be fatal. Thrombolytic therapy has now been evaluated in several randomised trials in acute ischaemic stroke. OBJECTIVES: The objective of this review was to assess the safety and efficacy of thrombolytic agents in patients with acute ischaemic stroke. SEARCH STRATEGY: We searched the Cochrane Stroke Group Trials Register (last searched January 2003), MEDLINE (1966- January 2003) and EMBASE (1980-January 2003). In addition we contacted researchers and pharmaceutical companies, attended relevant conferences and handsearched four Japanese journals. SELECTION CRITERIA: Randomised trials of any thrombolytic agent compared with control in patients with definite ischaemic stroke. DATA COLLECTION AND ANALYSIS: One reviewer applied the inclusion criteria and extracted the data. Trial quality was assessed. The extracted data were verified by the principal investigators of all major trials. Thus published and unpublished data were obtained where available. MAIN RESULTS: Eighteen trials including 5727 patients were included, but not all trials contributed data to each outcome examined in this review. Sixteen trials were double-blind. The trials tested urokinase, streptokinase, recombinant tissue plasminogen activator or recombinant pro-urokinase. Two trials used intra-arterial administration but the rest used the intravenous route. About 50% of the data (patients and trials) come from trials testing intravenous tissue plasminogen activator. There are few data from patients aged over 80 years. Much of the data comes from trials conducted in the first half of the 1990s when, in an effort to reduce delays to trial drug administration, on site randomisation methods were used that, in consequence, limited the ability to stratify randomisation on key prognostic variables. Several trials, because of the biological effects of thrombolysis combined with the follow-up methods used, did not have complete blinding of outcome assessment. Thrombolytic therapy, administered up to six hours after ischaemic stroke, significantly reduced the proportion of patients who were dead or dependent (modified Rankin 3 to 6) at the end of follow-up at three to six months (OR 0.84, 95% CI 0.75 to 0.95). This was in spite of a significant increase in : the odds of death within the first ten days (odds ratio [OR] 1.81, 95% confidence interval [CI] 1.46 to 2.24), the main cause of which was fatal intracranial haemorrhage (OR 4.34, 95% CI 3.14 to 5.99). Symptomatic intracranial haemorrhage was increased following thrombolysis (OR 3.37, 95% CI 2.68 to 4.22). Thrombolytic therapy also increased the odds of death at the end of follow-up at three to six months (OR 1.33, 95% CI 1.15 to 1.53). For patients treated within three hours of stroke, thrombolytic therapy appeared more effective in reducing death or dependency (OR 0.66, 95% CI 0.53 to 0.83) with no statistically significant adverse effect on death (OR 1.13, 95% CI 0.86 to 1.48). There was heterogeneity between the trials that could have been due to many trial features including : thrombolytic drug used, variation in the use of aspirin and heparin, severity of the stroke (both between trials and between treatment groups within trials), and time to treatment. Trials testing intravenous recombinant tissue plasminogen activator suggested that it may be associated with slightly less hazard and more benefit than other drugs when given up to six hours after stroke but these are non-random comparisons - death within the first ten days OR 1.24, 95% CI 0.85 to 1.81, death at the end of follow-up OR 1.17, 95% CI 0.95 to 1.45, dead or dependent at the end of follow-up OR 0.80, 95% CI 0.69 to 0.93. However, no trial has directly comparedup OR 0.80, 95% CI 0.69 to 0.93. However, no trial has directly compared rt-PA with any other thrombolytic agent. There is some evidence that antithrombotic drugs given soon after thrombolysis may increase the risk of death. REVIEWER'S CONCLUSIONS: Overall, thrombolytic therapy appears to result in a significant net reduction in the proportion of patients dead or dependent in activities of daily living. However, this appears to be net of an increase in deaths within the first seven to ten days, symptomatic intracranial haemorrhage, and deaths at follow-up at three to six months. The data from trials using intravenous recombinant tissue plasminogen activator, from which there are the most evidence on thrombolytic therapy so far, suggest that it may be associated with less hazard and more benefit. There was heterogeneity between the trials for some outcomes and the optimum criteria to identify the patients most likely to benefit and least likely to be harmed, the latest time window, the agent, dose, and route of administration, are not clear. The data are promising and may justify the use of thrombolytic therapy with intravenous recombinant tissue plasminogen activator in experienced centres in highly selected patients where a licence exists. However, the data do not support the widespread use of thrombolytic therapy in routine clinical practice at this time, but suggest that further trials are needed to identify which patients are most likely to benefit from treatment and the environment in which it may best be given. To avoid the problem of data missing from some trials for some key outcomes encountered in this review to date, and to assist future metaanalyses, future trialists should try to collect data in such a way as to be compatible with the basic outcome assessments reviewed here (eg early death, fatal intracranial haemorrhage, poor functional outcome).

Weber, P., Ruof, H., & Jourdan, S. (2005). Differential diagnosis of visual hallucinations [Differenzialdiagnose visueller Trugbilder ] Klinische Padiatrie, 217(1), 25-30. doi:10.1055/s-2004-818792

OBJECTIVE: Visual hallucinations in children need a differential diagnostic effort. METHODS AND PATIENTS: In a retrospective cohort study we identified all children, admitted to the Department of Neuropediatrics of a University Hospital between 1.1.2001 and 31.12.2003 suffering from visual hallucinations. All children underwent neurologic examination and electroencephalography (EEG). RESULTS: 14 children with visual hallucinations were identified. Disturbed perception of the size (9 of 14 cases), of the form (5 of 14 cases), and irregular perceptions of movements (5 of 14 cases) were most frequently reported. One child showed a transient hemihypesthesia, the only pathologic finding in the neurologic examination. Three children had features of hypersynchronic activity in EEG: one child undergoing immunosuppressive drug therapy and with a visual hallucination in context of a reversible posterior leucoencephalopathy showed a focal slow background activity, whereas three children had a sharp wave activity. Two of these children fulfilled the criteria for a focal epilepsy, one of them of the frontal lobe, one of the temporal lobe. CONCLUSION: Recurrent visual hallucinations are frequently transient and show clinical and pathophysiologic features reminiscent of infantile migraine. Psychic etiology, focal epilepsy and, under special circumstances, a reversible posterior leucoencephalopathy have to be considered when making a differential diagnosis.

Wesson, D. R., & Smith, D. E. (1976). An analysis of psychedelic drug flashbacks. The American Journal of Drug and Alcohol Abuse, 3(3), 425-438.

Psychedelic drug flashbacks have been a puzzling clinical phenomenon observed by clinicians. Flashbacks are defined as transient, spontaneous recurrences of the psychedelic drug effect appearing after a period of normalcy following an intoxication of psychedelics. The paper traces the evolution of the concept of flashback and gives examples of the varieties encountered. Although many drugs have been advocated for the treatment of flashback, flashbacks generally decrease in intensity and frequency with abstinence from psychedelic drugs.

Wilby, J., Kainth, A., Hawkins, N., Epstein, D., McIntosh, H., McDaid, C., Mason, A., Golder, S., O'Meara, S., Sculpher, M., Drummond, M., & Forbes, C. (2005). Clinical effectiveness, tolerability and cost-effectiveness of newer drugs for epilepsy in adults: a systematic review and economic evaluation. Health Technology Assessment (Winchester, England), 9(15), 1-157, iii-iv.

OBJECTIVES: To examine the clinical effectiveness, tolerability and cost-effectiveness of gabapentin (GBP), lamotrigine (LTG), levetiracetam (LEV), oxcarbazepine (OXC), tiagabine (TGB), topiramate (TPM) and vigabatrin (VGB) for epilepsy in adults. DATA SOURCES: Electronic databases. Internet resources. Pharmaceutical company submissions. REVIEW METHODS: Selected studies were screened and quality assessed. Separate analyses assessed clinical effectiveness, serious, rare and long-term adverse events and cost-effectiveness. An integrated economic analysis incorporating information on costs and effects of newer and older antiepileptic drugs (AEDs) was performed to give direct comparisons of long-term costs and benefits. RESULTS: A total of 212 studies were included in the review. All included systematic reviews were Cochrane reviews and of good quality. The quality of randomised controlled trials (RCTs) was variable. Assessment was hampered by poor reporting of methods of randomisation, allocation concealment and blinding. Few of the non-randomised studies were of good quality. The main weakness of the economic evaluations was inappropriate use of the cost-minimisation design. The included systematic reviews reported that newer AEDs were effective as adjunctive therapy compared to placebo. For newer versus older drugs, data were available for all three monotherapy AEDs, although data for OXC and TPM were limited. There was limited, poor-quality evidence of a significant improvement in cognitive function with LTG and OXC compared with older AEDs. However, there were no consistent statistically significant differences in other clinical outcomes, including proportion of seizure-free patients. No studies assessed effectiveness of AEDs in people with intellectual disabilities or in pregnant women. There was very little evidence to assess the effectiveness of AEDs in the elderly; no significant differences were found between LTG and carbamazepine monotherapy. Sixty-seven RCTs compared adjunctive therapy with placebo, older AEDs or other newer AEDs. For newer AEDs versus placebo, a trend was observed in favour of newer drugs, and there was evidence of statistically significant differences in proportion of responders favouring newer drugs. However, it was not possible to assess long-term effectiveness. Most trials were conducted in patients with partial seizures. For newer AEDs versus older drugs, there was no evidence to assess the effectiveness of LEV, LTG or OXC, and evidence for other newer drugs was limited to single studies. Trials only included patients with partial seizures and follow-up was relatively short. There was no evidence to assess effectiveness of adjunctive LEV, OXC or TPM versus other newer drugs, and there were no time to event or cognitive data. No studies assessed the effectiveness of adjunctive AEDs in the elderly or pregnant women. There was some evidence from one study (GBP versus LTG) that both drugs have some beneficial effect on behaviour in people with learning disabilities. Eighty RCTs reported the incidence of adverse events. There was no consistent or convincing evidence to draw any conclusions concerning relative safety and tolerability of newer AEDs compared with each other, older AEDs or placebo. The integrated economic analysis for monotherapy for newly diagnosed patients with partial seizures showed that older AEDs were more likely to be cost-effective, although there was considerable uncertainty in these results. The integrated analysis suggested that newer AEDs used as adjunctive therapy for refractory patients with partial seizures were more effective and more costly than continuing with existing treatment alone. Combination therapy, involving new AEDs, may be cost-effective at a threshold willingness to pay per quality-adjusted life year (QALY) greater than 20,000 pounds, depending on patients' previous treatment history. There was, again, considerable uncertainty in these results. There were few data available to determine effectiveness of treatments for patients with generalised seizures. LTG and VPA showed similar health benefits when used as monotherapy. VPA was less costly and was likely to be cost-effective. The analysis indicated that TPM might be cost-effective when used as an adjunctive therapy, with an estimated incremental cost-effectiveness ratio of 34,500 pounds compared with continuing current treatment alone. CONCLUSIONS: There was little good-quality evidence from clinical trials to support the use of newer monotherapy or adjunctive therapy AEDs over older drugs, or to support the use of one newer AED in preference to another. In general, data relating to clinical effectiveness, safety and tolerability failed to demonstrate consistent and statistically significant differences between the drugs. The exception was comparisons between newer adjunctive AEDs and placebo, where significant differences favoured newer AEDs. However, trials often had relatively short-term treatment durations and often failed to limit recruitment to either partial or generalised onset seizures, thus limiting the applicability of the data. Newer AEDs, used as monotherapy, may be cost-effective for the treatment of patients who have experienced adverse events with older AEDs, who have failed to respond to the older drugs, or where such drugs are contraindicated. The integrated economic analysis also suggested that newer AEDs used as adjunctive therapy may be cost-effective compared with the continuing current treatment alone given a QALY of about 20,000 pounds. There is a need for more direct comparisons of the different AEDs within clinical trials, considering different treatment sequences within both monotherapy and adjunctive therapy. Length of follow-up also needs to be considered. Trials are needed that recruit patients with either partial or generalised seizures; that investigate effectiveness and cost-effectiveness in patients with generalised onset seizures and that investigate effectiveness in specific populations of epilepsy patients, as well as studies evaluating cognitive outcomes to use more stringent testing protocols and to adopt a more consistent approach in assessing outcomes. Further research is also required to assess the quality of life within trials of epilepsy therapy using preference-based measures of outcomes that generate cost-effectiveness data. Future RCTs should use CONSORT guidelines; and observational data to provide information on the use of AEDs in actual practice, including details of treatment sequences and doses.

Wilhelm, H., & Wilhelm, B. (2003). Clinical Applications of Pupillography. Journal of Neuro-Ophthalmology, 23(1)

colon; The development of personal computer-based infrared video instruments has allowed pupillography to enter the clinical arena. Measuring pupil diameter for refractive surgery, distinguishing Horner syndrome from physiologic anisocoria, quantifying the relative afferent pupillary defect, and plotting visual fields by means of graded pupil constriction to focal light stimuli are recent applications in ophthalmology. Pupillography has also been used to determine sleepiness and autonomic effects of new pharmaceuticals. © 2003 Lippincott Williams & Wilkins, Inc.

Winter, J. C., Kieres, A. K., Zimmerman, M. D., Reissig, C. J., Eckler, J. R., Ullrich, T., Rice, K. C., Rabin, R. A., & Richards, J. B. (2005). The stimulus properties of LSD in C57BL/6 mice. Pharmacology, Biochemistry, and Behavior, 81(4), 830-837. doi:10.1016/j.pbb.2005.05.014

RATIONALE: Drug-induced stimulus control has proven to be a powerful tool for the assessment of a wide range of psychoactive drugs. Although a variety of species has been employed, the majority of studies have been in the rat. However, with the development of techniques which permit the genetic modification of mice, the latter species has taken on new importance. Lysergic acid diethylamide [LSD], the prototypic indoleamine hallucinogen, has not previously been trained as a discriminative stimulus in mice. OBJECTIVE: To demonstrate the feasibility of LSD-induced stimulus control in the mouse and to provide a preliminary characterization of the stimulus properties of LSD in that species. METHODS: Male C57BL/6 mice were trained using a left or right nose-poke operant on a fixed ratio 10, water reinforced task following the injection of lysergic acid diethylamide [LSD, 0.17 or 0.30 mg/kg, s.c.; 15 min pretreatment] or vehicle. RESULTS: Stimulus control was established in 6 of 16 mice at a dose of LSD of 0.17 mg/kg after 39 sessions. An increase in dose to 0.30 mg/kg for the remaining mice resulted in stimulus control in an additional 5 subjects. In the low dose group, subsequent experiments demonstrated an orderly dose-effect relationship for LSD and a rapid offset of drug action with an absence of LSD effects 60 min after injection. When LSD [0.17 mg/kg] was administered in combination with the selective 5-HT2A antagonist, M100907, LSD-appropriate responding was significantly but incompletely reduced to approximately 50%; concurrently, response rates declined significantly. In mice trained with a dose of LSD of 0.30 mg/kg, full generalization to the phenethylamine hallucinogen, [-]-2,5-dimethoxy-4-methylamphetamine [DOM] was observed. CONCLUSIONS: The present data demonstrate the feasibility of LSD-induced stimulus control in the mouse. The general features of stimulus control by LSD in the mouse closely resemble those observed in the rat but the present data suggest that there may be significant differences as well.

Woody, G. E. (1971). Hallucinogens and afterimages. The American Journal of Psychiatry, 128(3), 367.

Yager, J., Crumpton, E., & Rubenstein, R. (1983). Flashbacks among soldiers discharged as unfit who abused more than one drug. The American Journal of Psychiatry, 140(7), 857-861.

Of 280 soldiers discharged from military service in 1971 as unfit, 207 reported the heavy use of at least one drug (most of these abused more than one drug) and 146 (52%) reported having flashbacks. Most flashbacks were of a simple visual nature, but repeat "trips," complex subjective experiences, and persistent difficulties in concentration were often reported. The prevalence and severity of flashbacks increased with drug use, particularly with hallucinogens and marijuana. Because psychological, social, and physiological factors may all contribute to flashback phenomena, other populations need to be studied to determine the extent to which these findings can be generalized.

Young, A. H., Geddes, J. R., Macritchie, K., Rao, S. N., Watson, S., & Vasudev, A. (2006). Tiagabine in the treatment of acute affective episodes in bipolar disorder: efficacy and acceptability. Cochrane Database of Systematic Reviews (Online), 3, CD004694. doi:10.1002/14651858.CD004694.pub2

BACKGROUND: Bipolar disorder is a common recurrent illness with high levels of chronicity. Treatment resistance persists despite the use of established medications, such as lithium and valproate. New medications are required for the treatment of refractory cases. Some open-label reports have suggested that the anticonvulsant tiagabine may be efficacious in bipolar disorder. There is a need to clarify the evidence available, in the form of randomised controlled trials, for its use in the treatment of acute affective episodes in bipolar disorder OBJECTIVES: To review the evidence for the efficacy and acceptability of tiagabine in the treatment of acute mood episodes in bipolar disorder. SEARCH STRATEGY: The following databases were searched on 13-10-2005.The Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Registers (CCDANCTR-Studies and CCDANCTR-References),The Cochrane Controlled Clinical Trials Register (CCCTR),EMBASE,MEDLINE,LILACS,PsycLIT andPsyndex.Reference lists of relevant papers and major textbooks of mood disorder were searched. Handsearches were done (specialist journals and conference proceedings). Authors, other experts in the field and pharmaceutical companies were contacted for knowledge of suitable published or unpublished trials. SELECTION CRITERIA: Randomised controlled trials, which compared tiagabine with placebo or with active agents in the treatment of any acute mood episodes in bipolar disorder, were selected. Studies of participants with bipolar disorder were to be included. Subjects could be of either sex and of all ages. DATA COLLECTION AND ANALYSIS: Data extraction and methodological quality assessment were performed independently by two reviewers. For analysis, relative risk was used for binary efficacy outcomes and the weighted mean difference or standardised mean differerence was used for continuously distributed outcomes MAIN RESULTS: We did not find any studies which fulfilled the Cochrane criteria of randomised controlled trials. However, one uncontrolled open label study and one case series were found. There were also three case reports/series of acute treatment which were continued into maintenance therapy, and one open non-randomised study with this design. The results of these studies are inconsistent. AUTHORS' CONCLUSIONS: We found no randomised controlled trials of tiagabine in bipolar disorder. In the reported cases, a significant proportion of patients suffered episodes of syncope or seizure. There is a need for randomised controlled trials examining the efficacy and acceptability of tiagabine in the acute treatment of bipolar disorder, after the nature of these episodes has been clarified.

Young, C. R. (1997). Sertraline treatment of hallucinogen persisting perception disorder. The Journal of Clinical Psychiatry, 58(2), 85.

Young, T. N., Arens, F. J., Kennedy, G. E., Laurie, J. W., & Rutherford, G. (2007). Antiretroviral post-exposure prophylaxis (PEP) for occupational HIV exposure. Cochrane Database of Systematic Reviews (Online), (1)(1), CD002835. doi:10.1002/14651858.CD002835.pub3

BACKGROUND: Populations such as healthcare workers (HCWs), injection drug users (IDUs), and people engaging in unprotected sex are all at risk of being infected with the human immunodeficiency virus (HIV). Animal models show that after initial exposure, HIV replicates within dendritic cells of the skin and mucosa before spreading through lymphatic vessels and developing into a systemic infection (CDC 2001). This delay in systemic spread leaves a "window of opportunity" for post-exposure prophylaxis (PEP) using antiretroviral drugs designed to block replication of HIV (CDC 2001). PEP aims to inhibit the replication of the initial inoculum of virus and thereby prevent establishment of chronic HIV infection. OBJECTIVES: To evaluate the effects of antiretroviral PEP post-occupational exposure to HIV. SEARCH STRATEGY: The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, AIDSearch, and the Database of Abstracts of Reviews of Effectiveness were searched from 1985 to January 2005 to identify controlled trials. There were no language restrictions. Because no controlled clinical trials were retrieved, the search was repeated on 31 May 2005 in MEDLINE, AIDSearch and EMBASE using a search strategy to identify analytic observational studies. Handsearches of the reference lists of all pertinent reviews and studies found were also undertaken. Experts in the field of HIV prevention were contacted. SELECTION CRITERIA: Types of studies: All controlled trials (including randomized clinical trials and controlled clinical trials). If no controlled trials were found, analytic studies (e.g. cohort and case-control studies) were considered. Descriptive studies (i.e. studies with no comparison groups) were excluded.Types of participants included:HCWs exposed to any known or potentially HIV contaminated product;anyone exposed to a needlestick contaminated by known or potentially HIV-infected blood or other bodily fluid in an occupational setting; andanyone exposed through the mucous membranes to an HIV-infected or potentially infected substance in occupational setting.Excluded: Sex workers (PEP post-sexual exposure is addressed in another Cochrane review (Martin 2005)).Types of interventions: Any intervention that administered single or combinations of antiretrovirals as PEP to people exposed to HIV through percutaneous injuries and/or occupational mucous membrane exposures when the HIV status of the source patient was positive or unknown. Studies comparing two types of PEP regimens were considered, as were studies comparing PEP with no intervention.Types of outcome measures:Incidence of HIV infection in those given PEP versus those given placebo or a different PEP regimen; Adherence to PEP; Complications of PEPTypes of outcome measures: Incidence of HIV infection in those given PEP versus those given placebo or a different PEP regimen; Adherence to PEP; Complications of PEP DATA COLLECTION AND ANALYSIS: Data concerning outcomes, details of the interventions, and other study characteristics were extracted by two independent authors (TY and JA) using a standardized data extraction form (Table 04). A third author (GK) resolved disagreements. The following information was gathered from each included study: location of study, date, publication status, demographics (e.g. age, gender, occupation, risk behavior, etc.) of participants/exposure modality, form of PEP used, duration of use, and outcomes.Odds ratios with a 95% confidence interval (CI) were used as the measure of effect. A meta-analysis was performed for adverse events where two-drug regimens were compared with three-drug regimens. Due to overlap between Puro 2000 and Puro 2005, the former was not included in the combined analysis. MAIN RESULTS: Effect of PEP on HIV seroconversionNo randomized controlled trials were identified. Only one case-control study was included. HIV transmission was significantly associated with deep injury (OR 15, 95% CI 6.0 to 41), visible blood on the device (OR 6.2, 95% CI 2.2 to 21), procedures involving a needle placed in the source patient's blood vessel (OR 4.3, 95% CI 1.7 to 12), and terminal illness in the source patient (OR 5.6, 95% CI 2.0 to 16). After controlling for these risk factors, no differences were detected in the rates at which cases and controls were offered post-exposure prophylaxis with zidovudine. However, cases had significantly lower odds of having taken zidovudine after exposure compared to controls (OR 0.19, 95%CI 0.06 to 0.52). No studies were found that evaluated the effect of two or more antiretroviral drugs for occupational PEP.Adherence to and complications with PEPEight reports from observational comparative studies confirmed findings that adverse events were higher with a three-drug regimen, especially one containing indinavir. However, discontinuation rates were not significantly different. AUTHORS' CONCLUSIONS: The use of occupational PEP is based on limited direct evidence of effect. However, it is highly unlikely that a definitive placebo-controlled trial will ever be conducted, and, therefore, on the basis of results from a single case-control study, a four-week regimen of PEP should be initiated as soon as possible after exposure, depending on the risk of seroconversion. There is no direct evidence to support the use of multi-drug antiretroviral regimens following occupational exposure to HIV. However, due to the success of combination therapies in treating HIV-infected individuals, a combination of antiretroviral drugs should be used for PEP. Healthcare workers should be counseled about expected adverse events and the strategies for managing these. They should also be advised that PEP is not 100% effective in preventing HIV seroconversion. A randomized controlled clinical trial is neither ethical nor practical. Due to the low risk of HIV seroconversion, a very large sample size would be required to have enough power to show an effect. More rigorous evaluation of adverse events, especially in the developing world, are required. Seeing that current practice is partly based on results from individual primary animal studies, we recommend a formal systematic review of all relevant animal studies.

Zimmerman, M., McGlinchey, J. B., Young, D., & Chelminski, I. (2006). Diagnosing major depressive disorder introduction: an examination of the DSM-IV diagnostic criteria. The Journal of Nervous and Mental Disease, 194(3), 151-154. doi:10.1097/01.nmd.0000202235.78441.53

During the past 3 decades, more research has been conducted on depression than any other psychiatric disorder. While there are numerous studies on depression in the areas of epidemiology, biopsychosocial correlates, genetics, course, and treatment, remarkably little research has focused on the criteria used to diagnose major depressive disorder. Nearly 10 years ago, we began the Rhode Island Methods to Improve Diagnostic Assessment and Services (MIDAS) project, an integration of a comprehensive assessment protocol into a community-based psychiatry outpatient practice. As part of this clinical-research program, patients have been administered semistructured diagnostic interviews to assess the DSM-IV Axis I and Axis II disorders by well-trained interviewers. One of the goals of the MIDAS project has been to examine issues of nosology. While changes in the successive editions of the American Psychiatric Association's DSM have been increasingly grounded on empirical research, many of the sets of diagnostic criteria have not been subject to empirical scrutiny. During the next 12 months, we will be publishing a series of papers examining varying aspects of the diagnostic criteria for major depression. This series represents the type of methodical psychometric and conceptual analysis that should be conducted when developing or revising diagnostic criteria. We will examine whether the assumptions underlying the DSM's diagnostic rules have empirical support, and examine the impact of these rules on clinical practice. Our goal is not to develop a new definition of depression that would classify some individuals differently than how they are currently classified. That is, we are not seeking to develop a more valid definition of depression. However, our findings sometimes suggest changes that would simplify the criteria, improve their psychometric properties, and enhance their applicability in medical settings. Thus, the focus in the series is on clinical utility rather than validity.

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- Halpern, J. H., - Sherwood, A. R., - Hudson, J. I., - Gruber, S., - Kozin, D., & - Pope, H. G. (- 2010). - Residual Neurocognitive Features of Long-Term Ecstasy Users With Minimal Exposure to Other Drugs - Blackwell Publishing Ltd. doi:- 10.1111/j.1360-0443.2010.03252.x

- ABSTRACT Aims: In field studies assessing cognitive function in illicit ecstasy users, there are several frequent confounding factors that might plausibly bias the findings toward an overestimate of ecstasy-induced neurocognitive toxicity. We designed an investigation seeking to minimize these possible sources of bias. Design: We compared illicit ecstasy users and non-users while 1) excluding individuals with significant lifetime exposure to other illicit drugs or alcohol; 2) requiring that all participants be members of the ?rave? subculture; and 3) testing all participants with breath, urine, and hair samples at the time of evaluation to exclude possible surreptitious substance use. We compared groups with adjustment for age, gender, race/ethnicity, family-of-origin variables, and childhood history of conduct disorder and attention deficit hyperactivity disorder. We provide significance levels without correction for multiple comparisons. Setting: Field study. Participants: Fifty-two illicit ecstasy users and 59 non-users, age 18-45. Measurements: Battery of 15 neuropsychological tests tapping a range of cognitive functions. Findings: We found little evidence of decreased cognitive performance in ecstasy users, save for poorer strategic-self-regulation, possibly reflecting increased impulsivity. However this finding might have reflected a premorbid attribute of ecstasy users, rather than a residual neurotoxic effect of the drug. Conclusions: In a study designed to minimize limitations found in many prior investigations, we failed to demonstrate marked residual cognitive effects in ecstasy users. This finding contrasts with many previous findings?including our own?and emphasizes the need for continued caution in interpreting field studies of cognitive function in illicit ecstasy users.

- Halpern, J. H., - Sherwood, A. R., - Hudson, J. I., - Gruber, S., - Kozin, D., & - Pope, H. G. (- 2010). - Residual Neurocognitive Features of Long-Term Ecstasy Users With Minimal Exposure to Other Drugs - Blackwell Publishing Ltd. doi:- 10.1111/j.1360-0443.2010.03252.x

- Halpern, J. H., - Sherwood, A. R., - Hudson, J. I., - Gruber, S., - Kozin, D., & - Pope, H. G. (- 2010). - Residual Neurocognitive Features of Long-Term Ecstasy Users With Minimal Exposure to Other Drugs - Blackwell Publishing Ltd. doi:- 10.1111/j.1360-0443.2010.03252.x

- ABSTRACT Aims: In field studies assessing cognitive function in illicit ecstasy users, there are several frequent confounding factors that might plausibly bias the findings toward an overestimate of ecstasy-induced neurocognitive toxicity. We designed an investigation seeking to minimize these possible sources of bias. Design: We compared illicit ecstasy users and non-users while 1) excluding individuals with significant lifetime exposure to other illicit drugs or alcohol; 2) requiring that all participants be members of the ?rave? subculture; and 3) testing all participants with breath, urine, and hair samples at the time of evaluation to exclude possible surreptitious substance use. We compared groups with adjustment for age, gender, race/ethnicity, family-of-origin variables, and childhood history of conduct disorder and attention deficit hyperactivity disorder. We provide significance levels without correction for multiple comparisons. Setting: Field study. Participants: Fifty-two illicit ecstasy users and 59 non-users, age 18-45. Measurements: Battery of 15 neuropsychological tests tapping a range of cognitive functions. Findings: We found little evidence of decreased cognitive performance in ecstasy users, save for poorer strategic-self-regulation, possibly reflecting increased impulsivity. However this finding might have reflected a premorbid attribute of ecstasy users, rather than a residual neurotoxic effect of the drug. Conclusions: In a study designed to minimize limitations found in many prior investigations, we failed to demonstrate marked residual cognitive effects in ecstasy users. This finding contrasts with many previous findings?including our own?and emphasizes the need for continued caution in interpreting field studies of cognitive function in illicit ecstasy users.

Abraham, H. D. (1982). A chronic impairment of colour vision in users of LSD. The British Journal of Psychiatry : The Journal of Mental Science, 140, 518-520.

Forty-six users of the hallucinogen lysergic acid diethylamide were compared with 31 controls on a test of colour discrimination an average of two years after their last exposure to the drug. Controls performed better than users, and LSD users without flashbacks performed better than users with flashbacks. An analysis of variance between the three groups was significant at P less than 0.001. This study suggests that some users of LSD may have a sustained or irreversible impairment in colour discrimination.

Abraham, H. D. (1983). L-5-hydroxytryptophan for LSD-induced psychosis. The American Journal of Psychiatry, 140(4), 456-458.

The serotonin precursor L-5-hydroxytryptophan reversed the symptoms of a 23-year-old man suffering from LSD-induced psychosis who participated in a randomized, double-blind crossover study of the drug and a placebo. This finding is compatible with the speculation that some LSD-induced psychotic disorders may be caused by a relative deficiency of CNS serotonin.

Abraham, H. D. (1983). Visual phenomenology of the LSD flashback. Archives of General Psychiatry, 40(8), 884-889.

One hundred twenty-three persons with a history of LSD use were studied for the presence of the LSD flashback phenomenon and compared with 40 control subjects. A syndrome emerged that included ten distance visual disturbances. It had lasted for five years in half of the population, was treatable with benzodiazepines, exacerbated by phenothiazines, and precipitated by 19 different stimuli, most commonly emergence into a dark environment. Sensitivity to LSD as determined by flashbacks appears to divide the study sample into three discrete subgroups. There may be a genetic basis to LSD sensitivity.

Abraham, H. D. (1986). Do psychostimulants kindle panic disorder? The American Journal of Psychiatry, 143(12), 1627-1628.

Abraham, H. D. (1989). Stimulants, panic, and BEAM EEG abnormalities. The American Journal of Psychiatry, 146(7), 947-948.

Abraham, H. D. (1993). Visual hallucinations in macular degeneration. The American Journal of Psychiatry, 150(11), 1758.

Abraham, H. D. (2000). Book reviews. General Hospital Psychiatry, 22(1), 57-58.

Abraham, H. D., & Aldridge, A. M. (1993). Adverse consequences of lysergic acid diethylamide. Addiction (Abingdon, England), 88(10), 1327-1334.

The continued endemic use of hallucinogenic drugs, and of LSD in particular, raises concern regarding their short and long term adverse consequences. The epidemiology of LSD abuse is reviewed suggesting an increase in LSD use among the young as the prevalence rates for other substances continues to fall. Evidence supports the association of LSD use with panic reactions, prolonged schizoaffective psychoses and post-hallucinogen perceptual disorder, the latter being present continually for as long as 5 years. Evidence does not support claims of genetic disorders arising from hallucinogens. In light of the foregoing, current data confirm earlier findings of long lasting psychopathology arising in vulnerable individuals from the use of LSD. A hypothetical long term molecular mechanism of adverse effects is proposed.

Abraham, H. D., Aldridge, A. M., & Gogia, P. (1996). The psychopharmacology of hallucinogens. Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology, 14(4), 285-298. doi:10.1016/0893-133X(95)00136-2

Hallucinogenic drugs have been inhaled, ingested, worshipped, and reviled since prehistory. With the purification and synthesis of bontanical preparations and the ensuing discovery of chemically unique agents, hope was raised regarding their therapeutic potential, but this hope has been clouded by an epidemic of abuse and an inventory of adverse effects. This review examines aspects of that controversy, including the history of hallucinogens, epidemiology of current hallucinogen abuse, the association of LSD use with prolonged psychoses and hallucinogen persisting perception disorder, and the efforts to demonstrate the drug's therapeutic efficacy. Human subject ramifications in hallucinogen experimentation are discussed. Future lines of research are suggested in human, animal, and tissue culture paradigms.

Abraham, H. D., Anderson, C., & Lee, D. (1997). Somatization disorder in sphincter of Oddi dysfunction. Psychosomatic Medicine, 59(5), 553-557.

OBJECTIVE: Sphincter of Oddi dysfunction (SOD) is a biliary disorder with a recognized pathophysiology and demonstrated surgical treatment. We sought to examine whether women with SOD were overrepresented on measures of somatization, sexual and physical abuse, socially compliant attitudes, and familial psychiatric illness. METHOD: We matched 33 women with SOD to 33 normal controls by age, sex, and race, and, with a case-controlled cross-sectional questionnaire, compared the groups on the study variables. Statistics included a chi 2 for categorical variables, t tests for scores of somatization and attitudes of social desirability, and Pearson correlation coefficients for post hoc associations of variables. Bonferroni corrections were used with chi 2 values to reduce capitalization by chance. RESULTS: SOD patients exhibited excessive nongastroenterological somatic complaints compared with controls (p < .0001). There was a statistical increase in reports of childhood sexual, but not physical, abuse in the SOD women (p < .02) compared with controls. The severity of the abuse correlated strongly with the severity of somatic complaints. There were no differences in social desirability attitudes or family psychiatric histories of the two groups. CONCLUSIONS: We conclude that SOD is associated with a high degree of somatization in adulthood, and a mean rate more than four times that of controls in self-reports of sexual abuse in childhood. The severity of childhood sexual abuse is correlated with the severity of somatization in later life. A psychological model for this disorder is suggested by the data. Increased psychiatric attention is indicated in the treatment of women with this disorder.

Abraham, H. D., Degli-Esposti, S., & Marino, L. (1999). Seroprevalence of hepatitis C in a sample of middle class substance abusers. Journal of Addictive Diseases, 18(4), 77-87.

Hepatitis C (HCV) is an indolent and often fatal disease affecting four million Americans commonly associated with low socioeconomic status. We assessed its prevalence in a sample of 334 consecutively admitted middle class substance abusers in a private urban hospital, and ascertained risk factors for its transmission. We found that the point prevalence rate for HCV was 27.7% among all substance abusers, and 76.7% among intravenous drug users. Using logistic regression, we found risk factors associated with HCV were intravenous drug use, needle sharing, prior liver disease, opioid dependence, HIV infection, and benzodiazepine dependence. Not found to increase infective risk were lower social class, male gender, African-American race, male homosexuality, unemployment, and the absence of private health insurance. Multiple viral genotype types were identified in this sample, suggesting diverse sources of transmission in the sample. This study documents an epidemic of HCV in an American middle class sample.

Abraham, H. D., & Duffy, F. H. (1991). Computed EEG abnormalities in panic disorder with and without premorbid drug abuse. Biological Psychiatry, 29(7), 687-690.

Abraham, H. D., & Duffy, F. H. (1996). Stable quantitative EEG difference in post-LSD visual disorder by split-half analysis: evidence for disinhibition. Psychiatry Research, 67(3), 173-187.

Hallucinogen persisting perceptual disorder (HPPD) may follow the ingestion of LSD or other hallucinogens in a subset of users. It is characterized by chronic, intermittent or constant visual hallucinations of many sorts persisting beyond the period of acute drug effects. We studied 44 LSD-induced HPPD subjects and 88 matched controls to search for spectral and evoked potential differences using quantitative EEG (qEEG). HPPD subjects demonstrated faster alpha frequency and shorter VER (visual evoked response) latency, consistent with prior animal and human data on response to acute LSD administration which suggest LSD-induced cortical disinhibition. AER (auditory evoked response) latency was prolonged consistent with a differential LSD effect upon visual and auditory systems. The exploratory T-statistic significance probability mapping (T-SPM) technique demonstrated HPPD-control differences mostly involving temporal and left parietal scalp regions, confirmed by a split-half analysis. Significant variables were all derived from the long latency flash VER and click AER. None were derived from spectral analyzed EEG data. Canonical correlation between SPM-derived measures and variables reflecting disease severity was highly significant. A between-group stepwise discriminant analysis based upon a full set of qEEG measures demonstrated 87% prospective classification success by jackknifing and 88% success in a separate split-half analysis.

Abraham, H. D., & Duffy, F. H. (2001). EEG coherence in post-LSD visual hallucinations. Psychiatry Research, 107(3), 151-163.

LSD use in certain individuals may result in chronic visual hallucinations, a DSM-IV syndrome known as hallucinogen persisting perception disorder (HPPD). We studied 38 HPPD subjects with a mean of 9.7 years of persistent visual hallucinations and 33 control subjects. Measures of local and medium distance EEG spectral coherence were calculated from all subjects. Coherence, a measure of spectral similarity over time, may estimate cortical coupling. In the eyes-open state in HPPD subjects, widespread reduction of coherence was noted. However, upon eye closure, the occipital region demonstrated augmented regional coherence over many frequencies but with reduced coherence of the occipital region to more distant regions. This occipital coherence increase correlated with previously reported shortened occipital visual evoked potential latency for HPPD subjects. We speculate from coherence and known clinical and psychophysical data that, in HPPD, there is widespread cortical inhibition in the eyes-opened state, but localized and isolated occipital disinhibition upon eye closure, a state known to facilitate hallucinatory experiences. An analogy is drawn to findings in the interictal and ictal epileptic focus. In HPPD, we speculate that occipital EEG hypersynchrony resulting from increased regional coherence, when coupled with relative isolation of visual cortex, especially upon eye closure, facilitates hallucinations and illusions.

Abraham, H. D., & Fava, M. (1999). Order of onset of substance abuse and depression in a sample of depressed outpatients. Comprehensive Psychiatry, 40(1), 44-50.

Drug abuse has been thought to cause depression, or to serve as a form of self-medication for depression. Our objective was to examine whether specific types of drug abuse preceded or followed the onset of depression. A retrospective, blinded case-controlled assessment of the drug and depressive history of depressed outpatients was conducted. Three hundred seventy-five patients with major depressive disorder were evaluated for comorbid drug dependence using the Structured Clinical Interview for DSM-III-R (SCID). They were selected from the psychiatric outpatient department of a metropolitan teaching hospital and grouped into homogeneous classes of drug dependence including alcohol, cannabis, cocaine, amphetamine, LSD, hypnosedative, opiate, and polysubstance use. We determined the percent of depressed patients with each specific type of drug abuse, their age of onset of depression and onset of specific drug abuse, and the mean number of lifetime depressive episodes for each patient. We found that alcohol dependence followed the onset of first life depression by 4.7 years (P = .02, two-tailed). Among polydrug-dependent patients, each drug abused followed the onset of depression, except for LSD, which coincided with the onset of depression. Among polydrug users, cocaine dependence occurred 6.8 years after the first major depressive episode (P = .007) and alcohol dependence 4.5 years after the onset of depression (P = .007). Opiate and sedative users had the least number of lifetime depressive episodes (3.7), and LSD and cocaine users had the greatest number (12.2). We conclude that alcohol and cocaine use in this sample of depressed outpatients conformed to a pattern of self-medication.

Abraham, H. D., & Howell, R. R. (1969). Human hepatic uridine diphosphate galactose pyrophosphorylase. Its characterization and activity during development. The Journal of Biological Chemistry, 244(4), 545-550.

Abraham, H. D., & Joseph, A. B. (1986). Bulimic vomiting alters pain tolerance and mood. International Journal of Psychiatry in Medicine, 16(4), 311-316.

Bulimia, a disorder of episodic binging and purging, remains without a known etiology. A case report is presented of a patient who attributed bulimic episodes to efforts at inducing euphoria. Experimental pain tolerance was increased by bulimic vomiting, blocked by naloxone, but not by saline. Vomiting was also associated with falls in depression and anxiety. Plasma ACTH and cortisol, putative markers for beta-endorphin, also rose following vomiting. It is hypothesized that in some bulimics, the disorder arises by virtue of an addiction to one's own internally released endogenous opioid peptides.

Abraham, H. D., & Mamen, A. (1996). LSD-like panic from risperidone in post-LSD visual disorder. Journal of Clinical Psychopharmacology, 16(3), 238-241.

Risperidone, a novel antipsychotic agent, is an antagonist of postsynaptic serotonin-2 and dopamine D2 receptors. In certain individuals, the hallucinogenic drug lysergic acid diethylamide (LSD) is associated with apparently lifelong continuous visual disturbances, characterized in DSM-IV as hallucinogen-persisting perception disorder (HPPD). Because the hallucinogenic mechanism of LSD is known to act in part at postsynaptic serotonin-2 receptors, it is noteworthy that three HPPD patients treated with risperidone reported an exacerbation of LSD-like panic and visual symptoms. We conclude that HPPD may be a relative contraindication for the use of risperidone.

Abraham, H. D., & Wolf, E. (1988). Visual function in past users of LSD: psychophysical findings. Journal of Abnormal Psychology, 97(4), 443-447.

Adamczyk, D. T. (1996). Visual phenomena, disturbances, and hallucinations Optometry Clinics : The Official Publication of the Prentice Society, 5(3-4), 33-52.

The visual system and its processing of sensory information can be affected in a variety of ways that may be either normal or associated with numerous disorders and diseases. Visual images produced by the intrinsic components of the eyes are often normal and are known as entoptic phenomena. In contrast, the visual system may be disrupted by various disorders and pathologic processes, which can result in metamorphopsia, transient loss of vision, and positive scotomas. Such disruptions can be secondary to retinal and optic nerve disease, migraines associated with visual auras, and cerebrovascular and neurologic diseases; they can also be side effects of certain drugs. In addition, the visual system may process incoming sensory information in such a way that what is seen is perceived incorrectly, i.e. illusion; or the visual system may produce images of things not really there, i.e. hallucination. Various types of visual phenomena, disturbances, and hallucinations are discussed. The numerous visual presentations need to be differentiated so that appropriate treatment, management, and patient education can be rendered.

Akerman, S., Holland, P. R., Lasalandra, M. P., & Goadsby, P. J. (2009). Oxygen inhibits neuronal activation in the trigeminocervical complex after stimulation of trigeminal autonomic reflex, but not during direct dural activation of trigeminal afferents. Headache, 49(8), 1131-1143. doi:10.1111/j.1526-4610.2009.01501.x

OBJECTIVE: To understand the mechanism of action of oxygen treatment in cluster headache. BACKGROUND: Trigeminal autonomic cephalalgias, including cluster headache, are characterized by unilateral head pain in association with ipsilateral cranial autonomic features. They are believed to involve activation of the trigeminovascular system and the parasympathetic outflow to the cranial vasculature from the superior salivatory nucleus (SuS) projections through the sphenopalatine ganglion, via the greater petrosal nerve of the VIIth (facial) cranial nerve. Cluster headache is remarkably responsive to treatment with oxygen, and yet our understanding of its mode of action is unknown. METHODS: Combining models of trigeminovascular nociception and a novel approach that activates the trigeminal-autonomic reflex, using SuS/facial nerve stimulation, we explored the effect of oxygen on trigeminal nerve activation as well as on autonomic responses through blood flow observations of the lacrimal duct/sac. RESULTS: Meningeal vasodilation and neuronal firing in the trigeminocervical complex (TCC), in response to dural electrical stimulation, was unaffected by treatment with 100% oxygen. Stimulation of the SuS via the facial nerve caused only marginal changes in dural blood vessel diameter, but did result in evoked firing in the TCC. Two populations of neurons were characterized, those responsive to 100% oxygen treatment, with a maximal inhibition of 33%, 20 minutes after the start of oxygen treatment (t(15) = 4.4, P < .0001). A second population of neurons were not inhibited by oxygen and tended to have shorter latency. Oxygen also inhibited evoked blood flow changes in the lacrimal sac/duct caused by SuS stimulation. CONCLUSIONS: The data provide the first systematic, experimental evidence for a mechanism of action of oxygen in cluster headache. The data show oxygen has no direct effect on trigeminal afferents, acting specifically on the parasympathetic/facial nerve projections to the cranial vasculature to inhibit both evoked trigeminovascular activation and activation of the autonomic pathway during cluster headache attacks. Moreover, the studies begin to characterize a novel laboratory model for the most painful primary headache syndrome known--cluster headache.

Alarcon, R. D., Dickinson, W. A., & Dohn, H. H. (1982). Flashback phenomena. Clinical and diagnostic dilemmas. The Journal of Nervous and Mental Disease, 170(4), 217-223.

The study of flashback phenomena has been neglected in recent years. A case study and a subsequent literature review examine areas about which conflicting opinions exist. Epidemiological studies have not arrived at universally acceptable classificatory schemes. Clinical approaches vary in accounts of phenomenology of the syndrome and the typology of personalities involved. Etiology remains unknown in spite of numerous theories, most of them not experimentally tested. Diagnostic studies may benefit from recent technological advances such as continuous electroencephalogram, computerized axial tomography scan, cerebral blood flow, and neuropsychological tests. The Diagnostic and Statistical Manual of Mental Disorders, 3rd Edition, does not seem to provide an adequate taxonomic niche for this disorder. Therapeutic interventions are examined and their results critically analyzed.

Al-Assmar, S. E. (1999). The seeds of the Hawaiian baby woodrose are a powerful hallucinogen. Archives of Internal Medicine, 159(17), 2090.

Alcantara, A. G. (1998). Is there a role for the alpha2 antagonism in the exacerbation of hallucinogen-persisting perception disorder with risperidone? Journal of Clinical Psychopharmacology, 18(6), 487-488.

Aldurra, G., & Crayton, J. W. (2001). Improvement of hallucinogen persisting perception disorder by treatment with a combination of fluoxetine and olanzapine: case report. Journal of Clinical Psychopharmacology, 21(3), 343-344.

Aouizerate, B., Martin-Guehl, C., & Tignol, J. (2004). Neurobiology and pharmacotherapy of social phobia. [Neurobiologie et pharmacotherapie de la phobie sociale] L'Encephale, 30(4), 301-313.

Social phobia (also known as social anxiety disorder) is still not clearly understood. It was not established as an authentic psychiatric entity until the diagnostic nomenclature of the American Psychiatric Association DSM III in 1980. In recent years, increasing attention among researchers has contributed to provide important information about the genetic, familial and temperamental bases of social phobia and its neurochemical, neuroendocrinological and neuroanatomical substrates, which remain to be further investigated. Up to date, there have been several findings about the possible influence of variables, including particularly genetic, socio-familial and early temperamental (eg behavioral inhibition) factors that represent risk for the later development of social phobia. Clinical neurobiological studies, based on the use of exogenous compounds such as lactate, CO2, caffeine, epinephrine, flumazenil or cholecystokinin/pentagastrin to reproduce naturally occurring phobic anxiety, have shown that patients with social phobia appear to exhibit an intermediate sensitivity between patients with panic disorder and control subjects. No difference in the rate of panic attacks in response to lactate, low concentrations of CO2 (5%), epinephrine or flumazenil was observed between patients with social phobia and normal healthy subjects, both being less reactive compared to patients with panic disorder. However, patients with social phobia had similar anxiety reactions to high concentrations of CO2 (35%), caffeine or cholecystokinin/pentagastrin than those seen in patients with panic disorder, both being more intensive than in controls. Several lines of evidence suggest specific neurotransmitter system alterations in social phobia, especially with regard to the serotoninergic, noradrenergic and dopaminergic systems. Although no abnormality in platelet serotonin transporter density has been found, patients with social phobia appear to show an enhanced sensitivity of both post-synaptic 5HT1A and 5HT2 serotonin receptor subtypes, as reflected by increased anxiety and hormonal responses to serotoninergic probes. Platelet 5HT2 receptor density has also been reported to be positively correlated to symptom severity in patients with social phobia. During anticipation of public speaking, heart rate was elevated in patients with social phobia compared to controls. Norepinephrine response to the orthostatic challenge test or to the Valsalva maneuver was also greater in patients with social phobia. While normal beta-adrenergic receptor number was observed in lymphocytes, a blunted response of growth hormone to clonidine, an a2-adrenergic agonist, was reported. This suggests reduced post-synaptic a2-adrenergic receptor functioning related to norepinephrine overactivity in social phobia. Decreased cerebrospinal fluid levels of the dopamine metabolite homovanillic acid have also been observed. There are relatively few reports of involvement of the adrenal and thyroid functions in social phobia, and all that has been noted is that patients with social phobia show an exaggerated adrenocortical response to a psychological stressor. Recent advances in neuro-imaging have contributed to find low striatal dopamine D2 receptor binding or low dopamine transporter site density in patients with social phobia. They have also demonstrated the involvement of the cortico-limbic pathways, including the prefrontal cortex, hippocampus and amygdala, which show an increased activity in different experimental conditions. These brain regions have extensively been reported to play an important role in the cognitive appraisal in determining the significance of environmental stimuli, in the emotional and mnemonic integration of information, and in the expression of contextual fear-conditioned behaviors, which might be disrupted in the light of the phenomelogical aspects of social phobia. A substantial body of literature based on case reports, open and placebo-controlled trials, has now clearly examined the efficacy of major classes of psychotropic agents including monoamine oxidase inhibitors, beta-blockers, selective serotonin reuptake inhibitors and benzodiazepines in social phobia. Until recently, irreversible non-selective monoamine oxidase inhibitors, of which phenelzine was the most extensively evaluated, were considered as the most efficacious treatment in reducing the symptomatology associated with social phobia in 50-70% of cases after 4 to 6 weeks. However, side effects and dietary restrictions limit their use. This led to the development of reversible inhibitors of monoamine oxidase A, for which careful dietary monitoring is not required. Moclobemide has been the most widely studied but produced unconvincingly therapeutic effects on social phobic symptoms. To date, selective serotonin reuptake inhibitors may be considered as a reasonable first-line pharmacotherapy for social phobia. There is growing evidence for the efficacy of the selective serotonin reuptake inhibitors fluvoxamine, fluoxetine, citalopram, paroxetine and sertraline. They have beneficial effects with response rates ranging from 50 to 80% in social phobia. It has been recommended that the treatment period should be extended at least 6 months beyond the early improvement achieved within the first 4 to 6 weeks. The overall advantages include tolerability with a low risk of adverse events. The benzodiazepines clonazepam and alprazolam have also been proposed for the treatment of social phobia. Symptomatic relief occurred in 40 to 80% of the cases with a relatively rapid onset of action within the first two weeks. Untoward effects, discontinuation-related withdrawal symptoms and abuse or dependence liability constitute major concerns about the use of benzodiazepines, so they should be reserved for cases unresponsive to the safer medications cited above. Beta-blockers such as atenolol and propanolol have commonly been employed in performance anxiety, decreasing autonomic symptoms (eg, tachycardia, sweating and dry mouth). However, they are not effective in the generalized form of social phobia. Other pharmacologic alternatives seem helpful for the management of social phobia, including venlafaxine, gabapentin, bupropion, nefazodone or augmentation with buspirone. Preliminary studies point to promising effects of these agents. Larger controlled clinical trials are now needed to confirm their potential role in the treatment of social phobia.

Appel, N. M., Mitchell, W. M., Garlick, R. K., Glennon, R. A., Teitler, M., & De Souza, E. B. (1990). Autoradiographic characterization of (+-)-1-(2,5-dimethoxy-4-[125I] iodophenyl)-2-aminopropane ([125I]DOI) binding to 5-HT2 and 5-HT1c receptors in rat brain. The Journal of Pharmacology and Experimental Therapeutics, 255(2), 843-857.

The 5-HT2 (serotonin) receptor has traditionally been labeled with antagonist radioligands such as [3H]ketanserin and [3H]spiperone, which label both agonist high-affinity (guanyl nucleotide-sensitive) and agonist low-affinity (guanyl nucleotide-insensitive) states of this receptor. The hallucinogen 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) is an agonist which labels the high-affinity guanyl nucleotide-sensitive state of brain 5-HT2 receptors selectively. In the present study, conditions for autoradiographic visualization of (+/-)-[125I]DOI-labeled 5-HT2 receptors were optimized and binding to slide-mounted sections was characterized with respect to pharmacology, guanyl nucleotide sensitivity and anatomical distribution. In slide-mounted rat brain sections (+/-)-[125I]DOI binding was saturable, of high affinity (KD approximately 4 nM) and displayed a pharmacologic profile typical of 5-HT2 receptors. Consistent with coupling of 5-HT2 receptors in the high-affinity state to a guanyl nucleotide regulatory protein, [125I]DOI binding was inhibited by guanyl nucleotides but not by adenosine triphosphate. Patterns of autoradiographic distribution of [125I]DOI binding to 5-HT2 receptors were similar to those seen with [3H]ketanserin- and [125I]-lysergic acid diethylamide-labeled 5-HT2 receptors. However, the density of 5-HT2 receptors labeled by the agonist [125I]DOI was markedly lower (30-50%) than that labeled by the antagonist [3H]ketanserin. High densities of [125I]DOI labeling were present in olfactory bulb, anterior regions of cerebral cortex (layer IV), claustrum, caudate putamen, globus pallidus, ventral pallidum, islands of Calleja, mammillary nuclei and inferior olive. Binding in hippocampus, thalamus and hypothalamus was generally sparse. Of note, choroid plexus, a site rich in 5-HT1c receptors had a high density of [125I]DOI binding sites but [3H]ketanserin binding in this region was low. Studies in which [125I]DOI binding to 5-HT2 receptors was blocked with spiperone revealed persisting robust [125I]DOI binding in choroid plexus, which was guanyl nucleotide-sensitive and displayed a pharmacologic profile consistent with its binding to 5-HT1c receptors. These studies suggest that [125I]DOI may be useful as a radiolabel for visualizing the agonist high-affinity state of 5-HT2 receptors and for visualizing 5-HT1c receptors.

Assmus, H., & Reimer, F. (1972). Accidental LSD intoxication in three siblings with flashback. [Akzidentelle LSD-Intoxikation bei drei Geschwistern im Kindesalter mit Nachhallpsychose (Flashback] Praxis Der Kinderpsychologie Und Kinderpsychiatrie, 21(6), 207-209.

Atarhouch, N., Hoffmann, E., Adam, S., Titeca, J., Stillemans, E., Fossion, P., . . . Servais, L. (2004). Evaluation of typical psychopathic traits with juvenile offenders. [Evaluation des traits caracteristiques de la psychopathie chez les adolescents delinquants] L'Encephale, 30(4), 369-375.

The concept of psychopathy has received many definitions for the first days of psychiatry. Recently, the Hare's Psychopathy Check List Revised has been created. This scale has the advantage to investigate the classically characteristic traits of the syndrome (need of stimulation, lack of culpability, superficial activity, lack of empathy, impassivity) and to point out the early development of behavior disturbances. In the American classification (DSM IV), oppositional and aggressive behavior in child and adolescent is grouped under the Conduct Disorder diagnostic criteria. This trouble appears to be a strong predictive factor of psychopathy in adult. Identifying the high risk factors of evolution to psychopathic personality would allow an earlier intervention and prevention by multisystemic interventions for example. The present study aims to evaluate in what measure characteristic traits of psychopathy in adults are present in severe juvenile offenders and to point out, in a second time, the differences between adolescents meeting the DSM IV criteria for Conduct Disorder and a control population by a dimensional personality inventory. METHOD: The sample consists in 47 severe juvenile offenders referred for at least 3 months by a Youth Court to a Public Institution for Youth Protection (Belgium, Wauthier-Braine, 1999-2001), who have given an oral contentment and completely fulfilled the Temperament and Character Inventory-TCI. We have collected data about: schooling year by year, number of fails, changes of school; antecedents of oppositional defiant disorder with provocation (ODD, DSM IV criteria); antecedent of Conduct Disorder (CD, DSM IV criteria); penal antecedents (Youth Judge, works of general interest, placements); medico-psychological antecedents (consultation to a psychologist or a psychiatrist, hospitalization, illness, surgical intervention); psychoactive drug use or abuse. We used the TCI--Temperament and Character Inventory. This is a dimensional personality inventory. Based on biological, genetic and clinical hypothesis, it describes 2 types of variables defining personality: Variables of temperament (genetically transmitted and biologically controlled), and Variables of character (learned part of the personality reflecting the degree of adaptation and maturity, varying with environment through development). We have chosen this tool because of its dimensional aspect. Adolescence being a time of psychological and personality changes, such a tool is more useful than a categorical one. We also used this tool to verify the existence of the specific triad described by Cloninger and Svrakic. According to these authors, psychopathic personality in adult is characterized by a specific triad in which novelty seeking is high while harm avoidance and reward dependence are low. These observations are highly correlated to Hare's definition of psychopathy. We give the principal scores for the 7 personality dimensions expressed in global scores (total of the items for each dimension) and pondered ones (global scores divided by the number of items of the dimension x 100). RESULTS: Statistical analysis was performed with the Stateview 5.0 t-test program for data analysis. Statistical results show the absence of a statistically significant difference between the 2 groups for TCI 1, 4.5 and 7 but a statistically significant difference for TCI 2, 3 and 6 (p <.0001). DISCUSSION: The first limitation of our study is linked to the sample composed of young adolescents placed in an Institution for Youth Protection who doesn't reflect the whole population of offenders. A second limitation is correlated to the randomization system: randomization for age but not for sex, ethnical and cultural origin and socioeconomic status. Our results with adolescent offenders don't completely meet the Cloninger's psychopathy triad in adults. Moreover, in literature data, aggressive behavior is correlated to high novelty seeking and associated with low harm avoidance, reward dependence and persistence in children, these items are predictive of antisocial behavior in teenage and young adulthood. In our sample where antisocial behaviors are severe, we should be expecting a high novelty seeking but that is not the case. Our results should be explained by the fact that adolescence in itself is a more powerful factor of high novelty seeking than psychopathic trait. Harm avoidance and reward dependence seem to be a real problem in offending population and reflect aggressive behaviors in adolescents (lack of harm perception, sensitivity and empathy). Another interesting element is the cooperation factor that is significantly lower in the study group. This seems to comfort the hypothesis of a lower social maturity in institutionalized adolescents. CONCLUSION: Regarding to a control group subjects from 15 to 25 years old, adolescent offenders observed in an Institution for Youth Protection show a significantly different profile in the TCI for Harm Avoidance, Reward Dependence and Cooperation. Regarding to adult psychopaths, adolescent offenders partially meet the classical diagnostic triad of psychopathy, what should be indicating that such adolescents already show emotional perturbations: lower harm avoidance, reward dependence and cooperation than control population. This third factor is not characteristic of psychopathy but reflects relational difficulties, which are important in adolescent offenders. So, our study point out the complex psychopathology of adolescent offenders and the coexistence in such adolescents of attachment disorder and the difficulty to treat them because of their multiple lacks (cognitive, psychopathological, familial and scholar). We think important to discuss the necessity of approaches based on the development of personal creative abilities and involving all the professionals concerned in the young's universe. Future researches should compare adolescent offenders and controls randomized for age, sex, socioeconomic, ethnical and cultural status. They also should test specifically the diagnostic triad of psychopathology developed by Cloninger, especially the novelty seeking dimension. Moreover, it would be interesting to integrate these results in a wider protocol and to compare them with clinical, forensic and neurocognitive data, individually and within the familial context.

Aziz, R., Lorberg, B., & Tampi, R. R. (2006). Treatments for late-life bipolar disorder. The American Journal of Geriatric Pharmacotherapy, 4(4), 347-364. doi:10.1016/j.amjopharm.2006.12.007

BACKGROUND: Bipolar affective disorder is not uncommon in the elderly; prevalence rates in the United States range from 0.1% to 0.4%. However, it accounts for 10% to 25% of all geriatric patients with mood disorders and 5% of patients admitted to geropsychiatric inpatient units. These patients often present a tremendous treatment challenge to clinicians. They frequently have differing treatment needs compared with their younger counterparts because of substantial medical comorbidity and age-related variations in response to therapy. Unfortunately, the management of geriatric bipolar disorder has been relatively neglected compared with the younger population. There continues to be a scarcity of published, controlled trials in the elderly, and no treatment algorithms specific to bipolar disorder in the elderly have been devised. OBJECTIVE: The goal of this article was to review the current literature on both the pharmacologic and nonpharmacologic management of late-life bipolar disorder. METHODS: English-language articles written on the treatment of bipolar disorder in the elderly were identified. The first step in data collection involved a search for evidence-based clinical practice guidelines in the Cochrane Database of Systematic Reviews (up until the third quarter of 2006). Systematic reviews were then located in the following databases: MEDLINE (1966-September 2006), EMBASE (1980-2006 [week 36]), and PsycINFO (1967-September 2006 [week 1]). Additional use was made of these 3 databases in searching for single randomized controlled trials, meta-analyses, cohort studies, case-control studies, case series, and case reports. "Elderly," used synonymously with "geriatric," was defined as individuals aged > or =60 years. However, to take into account ambiguity in the nomenclature, the key words aged, geriatric, elderly, and older were combined with words indicating pharmacologic treatments such as pharmacotherapy; classes of medications (eg, lithium, antidepressants, antipsychotics, anticonvulsants, benzodiazepines); and names of selected individual medications (eg, lithium, valproic acid, lamotrigine, carbamazepine, oxcarbazepine, topiramate, gabapentin, zonisamide, clozapine, risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole). These terms were then combined with the diagnostic terms bipolar disorder, mania, hypomania, depression, or bipolar depression. Finally, the terms ECT and psychotherapy were also queried in combination with indicators for age and diagnosis. A few articles on "older adults," usually defined as individuals aged 50 to 55 years, were also included. They may allow for possible extrapolation of data to the geriatric population. Additionally, several mixed-age studies were included for similar considerations. Case reports and case series were described for their potential heuristic value. RESULTS: Unfortunately, there is a considerable dearth of literature involving evidence-based clinical practice guidelines and even randomized controlled trials in elderly individuals with bipolar disorder. Available options for the treatment of bipolar disorder (including those for mania, hypomania, depression, or maintenance) in the elderly include lithium, antiepileptics, antipsychotics, benzodiazepines, antidepressants, electroconvulsive therapy (ECT), and psychotherapy. CONCLUSIONS: The data for the treatment of late-life bipolar disorder are limited, but the available evidence shows efficacy for some commonly used treatments. Lithium, divalproex sodium, carbamazepine, lamotrigine, atypical antipsychotics, and antidepressants have all been found to be beneficial in the treatment of elderly patients with bipolar disorder. Although there are no specific guidelines for the treatment of these patients, monotherapy followed by combination therapy of the various classes of drugs may help with the resolution of symptoms. ECT and psychotherapy may be useful in the treatment of refractory disease. There is a need for more controlled studies in this age group before definitive treatment strategies can be enumerated.

Baethge, C. (2003). Long-term treatment of schizoaffective disorder: review and recommendations. Pharmacopsychiatry, 36(2), 45-56. doi:10.1055/s-2003-39045

OBJECTIVE: To provide an overview of long-term treatment studies in schizoaffective disorder (SAD) and to draw conclusions for clinical decision-making. METHOD: Literature was identified by searches in Medline, Embase, and the Cochrane Controlled Trials Register as well as a hand-search of handbook and journal articles. Studies were considered relevant if they reported on trials of at least 6 months duration and if they presented data for the SAD patients in particular. RESULTS: Thirty-nine studies met the criteria and 18 used modern diagnostic criteria, i. e., RDC, DSM-III-R, -IV, or ICD-10. The studies focused on lithium, anticonvulsants, and antipsychotics. The scientific evidence for prophylactic efficacy of the different substances is poor. Nevertheless, the data encourage the use of lithium and carbamazepine in primarily affective patients and clozapine in primarily schizophrenic patients and possibly in mainly affective patients as well. CONCLUSIONS: There is a considerable need for prospective and controlled studies on the long-term treatment of SAD. However, it seems to be useful to subtype the disorder of the patients into primarily affective vs. schizophrenic schizoaffective disorder and schizodepressive vs. schizobipolar and to treat accordingly.

Ballenger, J. C. (2004). Remission rates in patients with anxiety disorders treated with paroxetine. The Journal of Clinical Psychiatry, 65(12), 1696-1707.

BACKGROUND: Approximately 50% to 60% of patients with depression and/or anxiety respond to treatment, but only a minority achieve remission. The continued presence of subsyndromal symptoms in treated depressed (and probably anxious) patients leads to higher relapse rates and increased utilization of health care resources. It is proposed that remission is the appropriate target in the treatment of both depression and the anxiety disorders. AIMS: Rigorous criteria for remission have been proposed for the anxiety disorders and are currently being applied in clinical studies. Using these criteria, data from the paroxetine clinical study database were retrospectively analyzed to determine remission rates following paroxetine treatment across a range of anxiety disorders in the largest analysis of remission data in the anxiety disorders to date. METHOD: These analyses included data from 16 short-term and 6 long-term, randomized, placebo-controlled studies in panic disorder, social anxiety disorder, obsessive-compulsive disorder, posttraumatic stress disorder (short term only), and generalized anxiety disorder (DSM-III-R or DSM-IV). Separate analyses were performed for each disorder, with short- and long-term data analyzed separately. RESULTS: In general, across the range of anxiety disorders studied, in both short- and long-term studies, remission rates were higher for paroxetine compared with placebo, using disorder-specific, global, and functional remission criteria both individually and combined. Remission occurred in a moderate proportion of paroxetine-treated patients after only 8 to 12 weeks of treatment, and longer-term therapy led to even higher remission rates. CONCLUSION: Paroxetine has demonstrated efficacy in treating patients to remission across the range of anxiety disorders studied. Our findings strongly suggest that continuing treatment with paroxetine (and probably other SSRI antidepressants) for 2 to 12 months increases the proportion of patients achieving clinical remission.

Barlow, H. B., & Sparrock, J. M. B. (1964). The Role of Afterimages in Dark Adaptation. Science, 144(3624), 1309-1314. doi:10.1126/science.144.3624.1309

Barron, S. P., Lowinger, P., & Ebner, E. (1970). A clinical examination of chronic LSD use in the community. Comprehensive Psychiatry, 11(1), 69-79. doi:DOI: 10.1016/0010-440X(70)90206-3

Baucum, A. J.,2nd, Rau, K. S., Riddle, E. L., Hanson, G. R., & Fleckenstein, A. E. (2004). Methamphetamine increases dopamine transporter higher molecular weight complex formation via a dopamine- and hyperthermia-associated mechanism. The Journal of Neuroscience : The Official Journal of the Society for Neuroscience, 24(13), 3436-3443. doi:10.1523/JNEUROSCI.0387-04.2004

Multiple high-dose administrations of methamphetamine (METH) both rapidly (within hours) decrease plasmalemmal dopamine (DA) uptake and cause long-term deficits in DA transporter (DAT) levels and other dopaminergic parameters persisting weeks to months in rat striatum. In contrast, either a single administration of METH or multiple administrations of methylenedioxymethamphetamine (MDMA) cause less of an acute reduction in DA uptake and little or no persistent dopaminergic deficits. The long-term dopaminergic deficits caused by METH have been suggested, in part, to involve the DAT. Hence, this study assessed the impact of METH and MDMA administration on the DAT protein per se. Results revealed that multiple administrations of METH promoted formation of higher molecular weight (>170 kDa) DAT-associated protein complexes 24-48 hr after treatment. This increase was attenuated by either preventing hyperthermia or pretreatment with the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine; notably, each of these manipulations has also been demonstrated previously to prevent the persistent deficits in dopaminergic function caused by METH treatment. In contrast, either a single injection of METH or multiple injections of MDMA caused little or no formation of these DAT complexes. The addition of the reducing agent beta-mercaptoethanol to samples prepared from METH-treated rats diminished the intensity of these complexes. Taken together, these data are the first to demonstrate higher molecular weight DAT complex formation in vivo and that such formation can be altered by both pharmacological and physiological manipulations. The implications of this phenomenon with regard to the neurotoxic potential of these stimulants are discussed.

Bellone, M., Cottencin, O., Rigot, J. M., & Goudemand, M. (2005). Study on psychiatric disorders and defensive process assessed by the "defense style questionnaire" in sterile males SAMPLE consulting in andrology. [Etude des troubles psychiatriques et des modalites defensives evaluees par le "Defense Style Questionnaire" (DSQ) dans un echantillon d'hommes steriles consultant en andrologie] L'Encephale, 31(4 Pt 1), 414-425.

BACKGROUNDS: The literature about artificial insemination and the associated psychological, psychiatric and sexual disorders is relatively rich. But the majority of these studies is made in gynaecology, with a feminine approach of the disorder. There are very few works led in andrology. This justified the investigation of new trails in order to understand better the clinical context of the sterile man. We undertake a study about the psychiatric disorders among sterile men and about the defense styles. These are a clinical entity recently introduced in the quantitative psychopathology research. The defense style questionnaire (DSQ) is a psychometric scale used in common practice in order to measure the defense styles. OBJECTIVES: We made this study in order to examine the psychiatric state of a sterile males sample consulting in andrology; to assess the defense style by means of the Bond and al DSQ-88 ; to look into a difference between the defensive process according to their clinical situation of azoospermic males or as the oligoazoospermic males and finally, to reveal a correlation between the psychiatric disorders developed in this sample of sterile males and the defensive process they used. METHOD: There were 42 people (22 azoospermic males and 20 oligoazoospermic males) aged between 23 and 49 years old in the analysed sample. These have been selected at the surgery of andrology at the RUHC of Lille, depending on their arrival order for 6 months. There was no significant difference between the two groups as far as the age and the education standard are concerned. The selection criteria were medical and somatic. Our sample population were divided into two groups: azoospermia (no spermatozoon found in the semen analysis) and oligoasthenospermia (decrease of the number and the mobility of the spermatozoa and an increase of the percentage of atypical forms). The method first consisted in the DSQ, followed by the analysis of the psychiatric state according to the DSM IV, a hetero questionnaire to collect some general information about infertility and a self questionnaire about the sexual, conjugal and social effects of infertility. The DSQ and the interviews took place in the andrology department with the same investigator trained for this job. RESULTS: We found in our sample 26.2% of psychiatric disorders according to the DSM IV with a significant over-representation of generalized anxious disorder and somatization disorder. The comparison between azoospermic males and oligoazoospermic males patients showed the absence of significative difference as far as psychiatric morbidity rate and the use of defense styles are concerned. DISCUSSION: Our sample defended himself in accordance with modalities similar to the general population and used defense mechanisms preferentially belonging to the mature defense style, such as humor, repression and anticipation. The psychiatric pathology was significantly correlated to the preferential use of withdrawal, consumption, reaction formation and lack of humor use. We also confirm in our study the fact that the subjects using especially neurotic defense styles are more likely to develop a psychiatric disorder than the others. Our male sample is a waiting population and threatened by failure. The situation of wait creates anxiety. We also know that infertility is one of the most stressful situations a couple might face. However, our study did not enable us to know the precise relations between generalized anxious disorder and infertility, especially whether the generalized anxious disorder preceded this pathology or not. The over-representation of a somatization disorder only allows us to acknowledge its existence. We can also deduce from that a possible link between infertility and psychic disorder, even if no research permitted to affirm to date the existence of interrelations linking infertility and psychic life. On the whole, this population was suffering despite 73.8% of the patients had no confirmed psychiatric disorder. It is the reason why a liaison psychiatry more inserted into highly specialized teams is interesting, especially because it includes a medical and psychological approach of such disorders. The defense mechanisms preferentially used by this population were humor, repression and anticipation. Humor can only be considered as a defense mechanism when it is applied to oneself. The population who has no psychiatric disorder more uses humor. Does humor protect against the development of a psychiatric pathology, as certain authors proved it ? On the other hand, is repression really protective? It didn't interfere in our study about the development of a psychiatric pathology. So we can suppose that repression was protective for our whole sample, but we can not prove it. However, we wonder if this mechanism works after the failure of an artificial insemination is announced. In which measure such a stress can be repressed out of the conscience field? As for anticipation, it is used by our population who is for the most part in good health. But the question is to know if our sample really envisaged all the different possible solutions or only the success of artificial insemination. As some other works, we confirm that the, psychiatric, people significantly use the neurotic style. Our psychiatric patients used less humor and more consumption, withdrawal and reaction formation than the sane people. Consumption is rarely considered as a defense mechanism by some other authors. And yet, consumption and the existence of psychiatric disorders were very closely linked. This association is found again with anxiety in other studies. The correlation between psychiatric disorder and withdrawal was veryimportant too. The DSM lV defines withdrawal as an apathetic withdrawal. It is not an apathetic withdrawal in our population because the average scores for the ,, activity >, defense mechanism remained high. In our sample, the use of this defense mechanism would encourage the expression of psychiatric troubles. The reaction formation quoted by Freud and Bergeret are both valorised in our society. What kinds of reaction formations use these men ? Are they pathological ? Our study can not answer to these questions. However, the DSQ items examining the reaction formation present its "socially promoted" aspect and forget the pathological one. It has been showed that the evaluation of the defense modalities in a certain type of population can allow the emergence of specific defense mechanisms. This can be considered as predictive factors of development of a mental pathology. The evaluation of specific mental defenses could permit to define vulnerability and affinity for given affections instead of simple personality traits or profiles. Most part of the works shows results in favour of the capacity of DSQ to assess the different defense mechanisms according to the diagnosis groups. But the insufficient numbers of studies moderate on the whole the hypothesis of the existence of specific defense mechanisms--protective factors and factors of vulnerability--linked to a given psychiatric disorder. CONCLUSION: There is not a difference of psychological effect in terms of degree of sterility. On the other hand, the existence of over-represented psychiatric disorders with sterile males compared with a control group force Consultation-Liaison psychiatrists and andrologists would be able to understand the pain beyond the need of acting by the artificial insemination. In our opinion, this justifies the fact that the patients should have the opportunity of expressing, in the department where they are treated, all the feelings inherent to their personal and conjugal drama as part of a specialized treatment. Our study confirms the difficulty to know whether some defense mechanisms are vulnerability factors for a certain psychiatric disorder or whether the defense mechanisms are an epiphenomenon of a particular psychiatric disorder. This is the reason why a lot of authors having worked with DSQ agree to conclude that additional prospective studies, which would permit to make a link between the defense mechanisms anda certain psychiatric pathology, are necessary. In the case we study, it is important to explore the defensive modalities before the infertility diagnosis and after the birth of a child, with a more important sample population. A better knowledge of the defensive modalities of such a population, used in a psychotherapeutic context could help to prevent the appearance of psychiatric disorders or, if not, to anticipate them.

Benazzi, F. (2007). Bipolar II disorder : epidemiology, diagnosis and management. CNS Drugs, 21(9), 727-740.

Bipolar II disorder (BP-II) is defined, by DSM-IV, as recurrent episodes of depression and hypomania. Hypomania, according to DSM-IV, requires elevated (euphoric) and/or irritable mood, plus at least three of the following symptoms (four if mood is only irritable): grandiosity, decreased need for sleep, increased talking, racing thoughts, distractibility, overactivity (an increase in goal-directed activity), psychomotor agitation and excessive involvement in risky activities. This observable change in functioning should not be severe enough to cause marked impairment of social or occupational functioning, or to require hospitalisation. The distinction between BP-II and bipolar I disorder (BP-I) is not clearcut. The symptoms of mania (defining BP-I) and hypomania (defining BP-II) are the same, apart from the presence of psychosis in mania, and the distinction is based on the presence of marked impairment associated with mania, i.e. mania is more severe and may require hospitalisation. This is an unclear boundary that can lead to misclassification; however, the fact that hypomania often increases functioning makes the distinction between mania and hypomania clearer. BP-II depression can be syndromal and subsyndromal, and it is the prominent feature of BP-II. It is often a mixed depression, i.e. it has concurrent, usually subsyndromal, hypomanic symptoms. It is the depression that usually leads the patient to seek treatment.DSM-IV bipolar disorders (BP-I, BP-II, cyclothymic disorder and bipolar disorder not otherwise classified, which includes very rapid cycling and recurrent hypomania) are now considered to be part of the 'bipolar spectrum'. This is not included in DSM-IV, but is thought to also include antidepressant/substance-associated hypomania, cyclothymic temperament (a trait of highly unstable mood, thinking and behaviour), unipolar mixed depression and highly recurrent unipolar depression.BP-II is underdiagnosed in clinical practice, and its pharmacological treatment is understudied. Underdiagnosis is demonstrated by recent epidemiological studies. While, in DSM-IV, BP-II is reported to have a lifetime community prevalence of 0.5%, epidemiological studies have instead found that it has a lifetime community prevalence (including the bipolar spectrum) of around 5%. In depressed outpatients, one in two may have BP-II. The recent increased diagnosing of BP-II in research settings is related to several factors, including the introduction of the use of semi-structured interviews by trained research clinicians, a relaxation of diagnostic criteria such that the minimum duration of hypomania is now less than the 4 days stipulated by DSM-IV, and a probing for a history of hypomania focused more on overactivity (increased goal-directed activity) than on mood change (although this is still required for a diagnosis of hypomania).Guidelines on the treatment of BP-II are mainly consensus based and tend to follow those for the treatment of BP-I, because there have been few controlled studies of the treatment of BP-II. The current, limited evidence supports the following lines of treatment for BP-II. Hypomania is likely to respond to the same agents useful for mania, i.e. mood-stabilising agents such as lithium and valproate, and the second-generation antipsychotics (i.e. olanzapine, quetiapine, risperidone, ziprasidone, aripiprazole). Hypomania should be treated even if associated with overfunctioning, because a depression often soon follows hypomania (the hypomania-depression cycle). For the treatment of acute BP-II depression, two controlled studies of quetiapine have not found clearcut positive effects. Naturalistic studies, although open to several biases, have found antidepressants in acute BP-II depression to be as effective as in unipolar depression; however, one recent large controlled study (mainly in patients with BP-I) has found antidepressants to be no more effective than placebo. Results from naturalistic studies and clinical observations on mixed depression, while in need of replication in controlled studies, indicate that antidepressants may worsen the concurrent intradepression hypomanic symptoms. The only preventive treatment for both depression and hypomania that is supported by several, albeit older, controlled studies is lithium. Lamotrigine has shown some efficacy in delaying depression recurrences, but there have also been several negative unpublished studies of the drug in this indication.

Bendtsen, L., Bigal, M. E., Cerbo, R., Diener, H. C., Holroyd, K., Lampl, C., . . . Tfelt-Hansen, P. (2009). Guidelines for controlled trials of drugs in tension-type headache: second edition. Cephalalgia : An International Journal of Headache, doi:10.1111/j.1468-2982.2009.01948.x

Guidelines for controlled trials of drugs in tension-type headache: second edition. Cephalalgia 2009. London. ISSN 0333-1024 The Clinical Trials Subcommittee of the International Headache Society published its first edition of the guidelines on controlled trials of drugs in tension-type headache in 1995. These aimed 'to improve the quality of controlled clinical trials in tension-type headache', because 'good quality controlled trials are the only way to convincingly demonstrate the efficacy of a drug, and form the basis for international agreement on drug therapy'. The Committee published similar guidelines for clinical trials in migraine and cluster headache. Since 1995 several studies on the treatment of episodic and chronic tension-type headache have been published, providing new information on trial methodology for this disorder. Furthermore, the classification of the headaches, including tension-type headache, has been revised. These developments support the need for also revising the guidelines for drug treatments in tension-type headache. These Guidelines are intended to assist in the design of well-controlled clinical trials in tension-type headache.

Benemei, S., Appendino, G., & Geppetti, P. (2009). Pleasant natural scent with unpleasant effects: cluster headache-like attacks triggered by Umbellularia californica. Cephalalgia : An International Journal of Headache, doi:10.1111/j.1468-2982.2009.01988.x

Umbellularia californica, a shrub or tree indigenous to southwestern Oregon and northern California, is commonly known as headache tree, probably because it is reported that its scent can cause headache. Here, we report the case of a 69-year-old Italian gardener, affected during his young adult age by cluster headache, who, 10 years from his last cluster episode, developed shorter-lasting cluster-like headache attacks after and at any time he was exposed to U. californica scent. The present case indicates that, even though endogenous mechanisms causing the cluster headache were no longer present, susceptibility to exogenous triggers remains active in this patient, and suggests that identification of the constituent(s) of U. californica responsible for triggering cluster headache-like attacks may help in the understanding of the hitherto elusive mechanism of cluster headache.

Benneyworth, M. A., Smith, R. L., Barrett, R. J., & Sanders-Bush, E. (2005). Complex discriminative stimulus properties of (+)lysergic acid diethylamide (LSD) in C57Bl/6J mice. Psychopharmacology, 179(4), 854-862. doi:10.1007/s00213-004-2108-z

RATIONALE: The drug discrimination procedure is the most frequently used in vivo model of hallucinogen activity. Historically, most drug discrimination studies have been conducted in the rat. With the development of genetically modified mice, a powerful new tool has become available for investigating the mechanisms of drug-induced behavior. The current paper is part of an ongoing effort to determine the utility of the drug discrimination technique for evaluating hallucinogenic drugs in mice. OBJECTIVE: To establish the training procedures and characterize the stimulus properties of (+)lysergic acid diethylamide (LSD) in mice. METHODS: Using a two-lever drug discrimination procedure, C57Bl/6J mice were trained to discriminate 0.45 mg/kg LSD vs saline on a VI30 sec schedule of reinforcement, with vanilla-flavored Ensure serving as the reinforcer. RESULTS: As in rats, acquisition was orderly, but the training dose was nearly five-fold higher for mice than rats. LSD lever selection was dose-dependent. Time-course studies revealed a rapid loss of the LSD stimulus effects. The 5-HT(2A/2C) receptor agonist, 2,5-dimethoxy-4-bromoamphetamine [(-)DOB] (1.0 mg/kg), substituted fully for LSD and the 5-HT(1A) receptor agonist, 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) (1.6 mg/kg), substituted partially for LSD. Pretreatment with the 5-HT(2A) receptor-selective antagonist, MDL 100907, or the 5-HT(1A)-selective antagonist WAY 100635, showed that each antagonist only partially blocked LSD discrimination. Substitution of 1.0 mg/kg (-)DOB for LSD was fully blocked by pretreatment with MDL 100907 but unaltered by WAY 100635 pretreatment. CONCLUSIONS: These data suggest that in mice the stimulus effects of LSD have both a 5-HT(2A) receptor and a 5-HT(1A) receptor component.

Benneyworth, M. A., Smith, R. L., & Sanders-Bush, E. (2008). Chronic phenethylamine hallucinogen treatment alters behavioral sensitivity to a metabotropic glutamate 2/3 receptor agonist. Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology, 33(9), 2206-2216. doi:10.1038/sj.npp.1301600

Recent clinical studies in schizophrenic patients show that a selective agonist of group II metabotropic glutamate (mGlu) receptors has robust efficacy in treating positive and negative symptoms. Group II mGlu receptor agonists also modulate the in vivo activity of psychotomimetic drugs, reducing the ability of psychotomimetic hallucinogens to increase glutamatergic transmission. The use of mouse models provides an opportunity to investigate the dynamic action that mGlu2/3 receptors play in regulating the behavioral effects of hallucinogen-induced glutamatergic neurotransmission using genetic as well as pharmacological strategies. The current study sought to characterize the use of the two-lever drug discrimination paradigm in ICR (CD-1) mice, using the hallucinogenic 5-HT2A/2C receptor agonist (-)-2,5-dimethoxy-4-bromoamphetamine [(-)-DOB)] as a stimulus-producing drug. The (-)-DOB discriminative stimulus was dose-dependent, generalized to the hallucinogen lysergic acid diethylamide, and was potently blocked by the 5-HT2A receptor antagonist M100907. However, contrary to our prediction, the hallucinogen-induced discriminative stimulus was not regulated by mGlu2/3 receptors. In a series of follow-up studies using hallucinogen-induced head twitch response and phencyclidine-induced hyperlocomotion, it was additionally discovered that the repeated dosing regimen required for discrimination training attenuated the behavioral effects of the mGlu2/3 receptor agonist LY379268. Furthermore chronic studies, using a 14 day (-)-DOB treatment, confirmed that repeated hallucinogen treatment causes a loss of behavioral activity of mGlu2/3 receptors, likely resulting from persistent activation of mGlu2/3 receptors by a hallucinogen-induced hyperglutamatergic state.

Bergamin Oliver, Schoetzau Andreas, Sugimoto Keiko, & Zulauf Mario. (1998). The influence of iris color on the pupillary light reflex. Graefe's Archive for Clinical and Experimental Ophthalmology, 236(8), 567-570.

Abstract   · Background: This study was carried out to investigate the effect of iris color on the pupillary light reflex (PLR) in normal healthy volunteers. · Methods: Pupil perimetry was performed on 50 healthy volunteers with the Octopus 1-2-3 automated perimeter. Within the 30-deg visual field 33 test locations were investigated four times. Stimulus parameters were Goldmann size V (1.72°) intensity 1632 cd/m2 stimulus time 200 ms background illumination 0 cd/m2 and interstimulus interval 3 s. Pupillometric parameters studied were initial pupil size amplitude (magnitude of pupillary contraction) latency time contraction time pre-PLR movement contraction velocity parameters were investigated by analysis of variance by the independent variables blue and brown irides. · Results: Iris color (blue vs brown) influenced statistically significantly (P<0.05) amplitude (0.504 mm vs 0.594 mm) contraction time (401 ms vs 407 ms) contraction velocity (13.75 mm2/s vs 16.01 mm2/s) and redilation velocity (4.80 mm2/s vs 5.66 mm2/s). Iris color did not influence initial pupil size (4.78 mm vs 4.83 mm) latency time (520 ms vs 521 ms) (0.328 mm2/s vs 0.325 mm2/s). · Conclusions: Pupillary contraction amplitude and velocity depended on iris color whereas pupil size and latency time were independent of iris color. Therefore iris color might be considered when evaluating pupillary movements in pupil perimetry.

Bøhn, S. K., Smeland, S., Sakhi, A. K., Thoresen, M., Russnes, K. M., Tausjø, J., . . . Blomhoff, R. (2006). Post-radiotherapy plasma total glutathione is associated to outcome in patients with head and neck squamous cell carcinoma. Cancer Letters, 238(2), 240-247. doi:DOI: 10.1016/j.canlet.2005.07.027

Bonavita, V., & De Simone, R. (2009). Redefining primary headaches. Neurological Sciences : Official Journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology, 30 Suppl 1, S1-5. doi:10.1007/s10072-009-0050-x

In the light of the pathophysiologic knowledge acquired in the recent years, a tentative redefinition is now possible of some types of headache until now defined as idiopathic, and indistinctly described as primary headaches. Cluster headache and trigeminal neuralgia are known examples of diseases classified as primary, which are, in contrast, well-defined diseases to be distinguished from headaches without any recognized anatomic site of lesion or pathogenesis. Another still debated condition, chronic migraine, is proposed here as the consequence of "processes" to be ascribed to mechanisms activated by other comorbid conditions. The observations supporting the possibility that allodynia represents the implicit process leading to pain progression, which occurs in some migraineurs, are discussed.

Bone Pina, I., Ramos Gorostiza, P., Villalba Yllan, P., & Valle Fernandez, J. (2000). Persisting and late onset psychotic disorder due to consumption of ecstasy (MDMA). [Trastorno psicotico persistente inducido por consumo de extasis (MDMA)] Actas Espanolas De Psiquiatria, 28(1), 61-65.

Let us present a case of recurrent paranoid psychotic episodes in a patient with a history of abuse of > (MDMA: 3, 4-methylenedioxymethamphetamine), that persisted after a long withdrawal time, that, in our opinion, after an exhaustive differential diagnosis, may be attributed to that consumption. The carachteristics of this case are formally and naturally equivalent to those referred to in other papers about paranoid psychosis after abuse of MDMA, in which the sudden appearance, and the symptomatolgy of an intense feeling of threat and physical violence outstands, accompanied by abnormal corporal perceptions. In the case hereby presented, the withdrawal time is longer than that described in other publications. Even though in some authors' opinion this should be considered as comorbility or dual diagnosis, in our opinion enough facts exist suggesting that this is not a case of functional mental disorder but an organic disorder secondary to the neurotoxic effect of MDMA.

Bonis, P. A., Trikalinos, T. A., Chung, M., Chew, P., Ip, S., DeVine, D. A., & Lau, J. (2007). Hereditary nonpolyposis colorectal cancer: diagnostic strategies and their implications. Evidence report/technology Assessment, (150)(150), 1-180.

OBJECTIVES: Hereditary Nonpolyposis Colorectal Cancer (HNPCC) has been defined clinically and genetically. The disorder has traditionally been recognized in kindreds with a clustering of related cancers in association with mutations in DNA mismatch repair genes. HNPCC is associated with a substantially increased risk for several forms of malignancy but particularly colorectal and endometrial cancer. There were three main objectives of this report: (1) to assess the sensitivity, specificity, and reliability of laboratory and genetic tests commonly used in evaluating patients for HNPCC (analytic validity); (2) to summarize the accuracy of commonly used clinical and laboratory characteristics for predicting the presence of HNPCC in patients with colorectal cancer (clinical validity) and use these estimates to describe the efficiency of various strategies for identifying patients with a mismatch repair mutation; (3) to describe the benefits and harms related to screening and testing patients with colorectal cancer and their family members for HNPCC. DATA SOURCES: Published literature identified through an electronic search (through April 2006), review of relevant bibliographies, and suggestions from technical experts. REVIEW METHODS: We evaluated studies critically and summarized the data qualitatively or by meta-analysis when studies used similar methodology and endpoints. We used decision trees to describe the efficiency of various strategies for identifying patients with HNPCC from a hypothetical population of patients with colorectal cancer. RESULTS: We included a total of 104 studies of which 40 addressed issues related to clinical validity, 3 to analytic validity, and 61 to benefits and harms. We identified only three studies on analytic validity and thus there exists a major gap in the published literature with regard to the accuracy and reliability of specific tests used in the evaluation of HNPCC. Among unselected patients with colorectal cancer who fulfilled the Amsterdam I criteria, 44% (95% CI: 35, 52%) carried pathogenic mismatch repair mutations (mainly in the MLH1 and MSH2 genes). The proportion was somewhat higher (51% [95% CI: 35, 66%]) among studies that performed sequencing on all available samples. The prevalence of MMR mutation carriers may be higher when genetic testing includes evaluation for large genomic deletions/rearrangements and when testing is also performed on MSH6 and PMS2. Approximately 71% (95% CI 63, 78%) of colorectal cancers from patients who fulfilled the Amsterdam I criteria demonstrated microsatellite instability while 40% (95% CI: 28, 53%) demonstrated loss of protein expression by immunohistochemistry. Of nine clinical strategies considered for detecting the presence of mismatch repair mutations in patients with colorectal cancer, the combination of three clinical predictors (age less than 50 years old at diagnosis; or a history of colorectal or endometrial cancer in a first degree family member; or the presence of multiple, synchronous or metachronous colorectal or endometrial cancers in the proband) combined with either immunohistochemistry (IHC) or MSI testing of tumor tissue identified a similar number of patients with mismatch repair mutations as other more complex strategies. There was little published information regarding potential harms associated with screening individuals with HNPCC-related cancers using clinical criteria (e.g. the Amsterdam criteria), MSI or IHC testing. Limited data suggested that testing probands for MMR mutations was not associated with severe psychological impact following formal counseling. Pre-test genetic counseling had good efficacy in improving knowledge about HNPCC and resulted in a high likelihood of proceeding with genetic testing, satisfaction in the decision to undergo genetic testing, and decreasing depression and distress levels among family members of HNPCC probands with cancer and among asymptomatic individuals from HNPCC families. Identification of HNPCC mutations was associated with an increase in the likelihood that family members of probands with CRC would undergo cancer-screening procedures. HNPCC family members who underwent cancer-screening procedures had a lower risk of developing HNPCC-related cancers and lower mortality rates than those who did not take actions. However, all of the relevant studies suggesting these benefits had important limitations. Survival was increased among asymptomatic HNPCC family members who received colonoscopy screening, regardless of their mutation status. There was limited direct evidence related to harms of the cancer-screening procedures in family members of probands with HNPCC. However, complication rates associated with these procedures in other settings are probably similar. CONCLUSIONS: This report characterizes the accuracy of clinical and laboratory predictors of MMR mutations that can be used to identify patients with an increased risk of having MMR mutations. However, the sensitivity, specificity, and reliability of the tests used to evaluate individuals for suspected HNPCC is not known confidently. Data regarding the net benefits and harms associated with predictive genetic testing in patients with HNPCC-related cancers and their families members is incomplete but suggest that such testing improves compliance with screening procedures. At-risk family members who undergo screening colonoscopy have a reduced risk of developing HNPCC-related cancers and lower mortality. However, all studies supporting these benefits had important limitations.

Boyden, J., & Berry, J. d. (2004). Children and youth on the front line : ethnography, armed conflict and displacement. New York: Berghahn Books.

Braga, R. J., Petrides, G., & Figueira, I. (2004). Anxiety disorders in schizophrenia. Comprehensive Psychiatry, 45(6), 460-468. doi:10.1016/j.comppsych.2004.07.009

Data regarding the co-occurrence of anxiety symptoms or syndromes in schizophrenia is scant. Hierarchical assumptions embedded in diagnostic systems and methodologic difficulties hamper the development of studies on accessory symptomatology outside of the core positive-negative-disorganized symptoms. Recent studies have repeatedly challenged these assumptions by presenting data on comorbid disorders in schizophrenia. We review the current knowledge about anxiety comorbidity in schizophrenia, and its relative prevalence, relevance, and treatment. A computerized search of the literature published from 1966 to July 2003 was conducted on Medline using the word "schizophrenia" and the words from the names of each anxiety disorder listed in DSM-IV, one at a time. Only studies including exclusively the diagnosis of schizophrenia were included. Only 15 studies were dedicated to the subject of anxiety comorbidity prevalence in schizophrenia. The most studied comorbidities were obsessive-compulsive disorder (OCD) and panic disorder, and most reports suggested them to be highly prevalent in schizophrenia. Posttraumatic stress disorder (PTSD) was the least studied (N = 2). Except for two pharmacologic studies in OCD, there were no double-blind randomized controlled trials regarding the treatment of anxiety in schizophrenia. Most case reports and open label trials tried conventional treatment for anxiety disorders with some degree of success. The literature indicates that anxiety comorbidities are prevalent in schizophrenia and conventional treatment for anxiety can help alleviate the symptoms in those patients. However, the body of data provided by research so far is still far from allowing evidence-based conclusions. Large studies with operationalized criteria, as well as comprehensive assessments of treatment response and outcome are needed to clarify the relationship between anxiety disorders and schizophrenia.

Bridle, C., Palmer, S., Bagnall, A. M., Darba, J., Duffy, S., Sculpher, M., & Riemsma, R. (2004). A rapid and systematic review and economic evaluation of the clinical and cost-effectiveness of newer drugs for treatment of mania associated with bipolar affective disorder. Health Technology Assessment (Winchester, England), 8(19), iii-iv, 1-187.

OBJECTIVES: To evaluate the clinical and cost-effectiveness of quetiapine, olanzapine and valproate semisodium in the treatment of mania associated with bipolar disorder. DATA SOURCES: Electronic databases; industry submissions made to the National Institute for Clinical Excellence. REVIEW METHODS: Randomised trials and economic evaluations that evaluated the effectiveness of quetiapine, olanzapine or valproate semisodium in the treatment of mania associated with bipolar disorder were selected for inclusion. Data were extracted by one reviewer into a Microsoft Access database and checked for quality and accuracy by a second. The quality of the cost-effectiveness studies was assessed using a checklist updated from that developed by Drummond and colleagues. Relative risk and mean difference data were presented as Forest plots but only pooled where this made sense clinically and statistically. Studies were grouped by drug and, within each drug, by comparator used. Chi-squared tests of heterogeneity were performed for the outcomes if pooling was indicated. A probabilistic model was developed to estimate costs from the perspective of the NHS, and health outcomes in terms of response rate, based on an improvement of at least 50% in a patient's baseline manic symptoms derived from an interview-based mania assessment scale. The model evaluated the cost-effectiveness of the alternative drugs when used as part of treatment for the acute manic episode only. RESULTS: Eighteen randomised trials met the inclusion criteria. Aspects of three of the quetiapine studies were commercial-in-confidence. The quality of the included trials was limited and overall, key methodological criteria were not met in most trials. Quetiapine, olanzapine and valproate semisodium appear superior to placebo in reducing manic symptoms, but may cause side-effects. There appears to be little difference between these treatments and lithium in terms of effectiveness, but quetiapine is associated with somnolence and weight gain, whereas lithium is associated with tremor. Olanzapine as adjunct therapy to mood stabilisers may be more effective than placebo in reducing mania and improving global health, but it is associated with more dry mouth, somnolence, weight gain, increased appetite, tremor and speech disorder. There was little difference between these treatments and haloperidol in reducing mania, but haloperidol was associated with more extrapyramidal side-effects and negative implications for health-related quality of life. Intramuscular olanzapine and lorazepam were equally effective and safe in one very short (24 hour) trial. Valproate semisodium and carbamazepine were equally effective and safe in one small trial in children. Olanzapine may be more effective than valproate semisodium in reducing mania, but was associated with more dry mouth, increased appetite, oedema, somnolence, speech disorder, Parkinson-like symptoms and weight gain. Valproate semisodium was associated with more nausea than olanzapine. The results from the base-case analysis demonstrate that choice of optimal strategy is dependent on the maximum that the health service is prepared to pay per additional responder. For a figure of less than 7179 British pounds per additional responder, haloperidol is the optimal decision; for a spend in excess of this, it would be olanzapine. Under the most favourable scenario in relation to the costs of responders and non-responders beyond the 3-week period considered in the base-case analysis, the incremental cost-effectiveness ratio of olanzapine is reduced to 1236 British pounds. CONCLUSIONS: In comparison with placebo, quetiapine, olanzapine and valproate semisodium appear superior in reducing manic symptoms, but all drugs are associated with adverse events. In comparison with lithium, no significant differences were found between the three drugs in terms of effectiveness, and all were associated with adverse events. Several limitations of the cost-effectiveness analysis exist, which inevitably means that the results should be treated with some caution. There remains a need for well-conducted, randomised, double-blind head-to-head comparisons of drugs used in the treatment of mania associated with bipolar disorder and their cost-effectiveness. Participant demographic, diagnostic characteristics, the treatment of mania in children, the use of adjunctive therapy and long-term safety issues in the elderly population, and acute and long-term treatment are also subjects for further study.

Broggi, G., Messina, G., & Franzini, A. (2009). Cluster headache and TACs: rationale for central and peripheral neuromodulation. Neurological Sciences : Official Journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology, 30 Suppl 1, S75-9. doi:10.1007/s10072-009-0082-2

Cluster headache, the most severe of primary headache conditions for functional and social impairment it provokes, has been recently the object of a great amount of clinical, physiopathological, surgical and functional neuroradiological studies aimed to uncover the real mechanisms which underlie its disabling manifestations. Refinement of methodological and systematic features of multidisciplinary researches in this field has been allowing for more and more precise delineations of the role of both peripheral and central nervous system's contribution in pathophysiology of the disease. Aim of this manuscript is the report of the present knowledge in the role of the different surgical options in the treatment of drug-resistant cluster headache and Short-lasting Unilateral neuralgiform headache attacks with Conjunctival injection and Tearing (SUNCT), which take into account their different hypothesized pathological mechanisms and which comprise central nervous system's approach (Deep Brain Stimulation [DBS] and peripheral approach, namely Occipital Nerve Stimulation (ONS) and Vagal Nerve Stimulation (VNS).

Buhrich, N., Morris, G., & Cook, G. (1983). Bromo-DMA: the Australasian hallucinogen? The Australian and New Zealand Journal of Psychiatry, 17(3), 275-279.

If the frequency of seizures by police of hallucinogens reflects the frequency with which various hallucinogens are ingested in Australasia, most toxic states resulting from hallucinogen abuse are due to Bromo-DMA and not to LSD as is commonly reported by the subjects. Two cases of intoxication with the new hallucinogen, Bromo-DMA, are reported. Both recovered within 24 hours following treatment with haloperidol.

Burstein, S. H., Friderichs, E., Kogel, B., Schneider, J., & Selve, N. (1998). Analgesic effects of 1',1' dimethylheptyl-delta8-THC-11-oic acid (CT3) in mice. Life Sciences, 63(3), 161-168.

The metabolic pathway leading to carboxylic acid derivatives of cannabinoids was discovered more than twenty years ago. While these compounds showed no cannabimimetic activity, subsequent work documented several biological responses both in vitro and in vivo for the THC acids. These include inhibition of eicosanoid synthesis, antiedema effects, antagonism to PAF actions, inhibition of leucocyte adhesion and anti nociception. In this report we present data further characterizing the analgesic properties of the title substance which is a potent synthetic member of this group. CT3 was effective in the mouse hot plate assay at 48 degrees C showing an ED-50 of 4.31 (3.37-5.83) mg/kg when administered i.v (10% Cremophor EL in saline). When given by gavage in peanut oil, it resulted in 30-40% MPE (maximum possible effect) at 10 mg/kg with the effect persisting for up to 5 hours. A more potent response was observed in the mouse p-phenylquinone writhing test. When given i.v., it showed an ED-50 of 1.24 (0.84-1.75) mg/kg. However, no activity was found with oral administration either in peanut oil or Cremophor EL. At 10 mg/kg i.v., a 100% inhibition of the writhing response was seen. The mouse formalin antinociception test was also studied in animals that received CT3 (4.64 mg/kg) i.v. using three behavioral parameters for activity. The drug showed decreases in each category when compared with vehicle/formalin treated mice. The formalin effect showed a typical two phase, time related, response in which CT3 caused a 64% reduction in the early phase and a 48% reduction in the late phase in a composite score of nociception. Interestingly, it did not alter motor function in the rota rod procedure at 4.64 mg/kg i.v.

Busanich, B. M., & Verscheure, S. D. (2006). Does McKenzie therapy improve outcomes for back pain? Journal of Athletic Training, 41(1), 117-119.

CLINICAL QUESTION: What is the clinical evidence base for McKenzie therapy in management of back pain? DATA SOURCES: Studies were identified using a computer-based literature search of 7 databases: MEDLINE, EMBASE, DARE, CINAHL, PEDro, the Cochrane Register of Clinical Trials (CENTRAL), and the Cochrane Database of Systematic Reviews. Search terms included McKenzie therapy, McKenzie treatment, and McKenzie method. Studies published before September 2003 were eligible. STUDY SELECTION: To be included in the review, each study had to fulfill the following criteria: (1) the study was a randomized or quasi-randomized controlled trial, (2) the subjects' primary complaint was nonspecific low back pain or neck pain with or without radiation to the extremities, (3) the authors investigated the efficacy of the McKenzie method/McKenzie treatment in comparison with no treatment, sham treatment, or another treatment, (4) individualized patient treatment and treatment were specified according to McKenzie principles, and (5) the authors reported at least one of the outcome measures of pain, disability, quality of life, work status, global perceived effect, medication use, medical visits, or recurrence. Studies were included with no language restriction and with subjects of all age groups, of either sex, and with any duration of symptoms. Studies were excluded if subjects had any of the following spinal conditions: cauda equina syndrome, cord compression, infection, fracture, neoplasm, inflammatory disease, pregnancy, any form of headache, whiplash-associated disorders, vertigo/dizziness, or vertebrobasilar insufficiency. DATA EXTRACTION: Data were independently extracted from each study by 2 investigators using a standardized data extraction form. The standardized data extraction form and experience level of the investigators were not included in the review. In studies with more than 2 treatment groups, the treatment contrast of more relevance to current Australian physiotherapy was selected. Data were also extracted for short-, intermediate-, and long-term follow-up based on the criteria suggested by the Cochrane Back Review Group. Short-term follow-up was defined as less than 3 months from onset of treatment. Intermediate-term follow-up was defined as at least 3 months and less than 12 months from onset of treatment. Long-term follow-up was defined as equal to or greater than 12 months. All eligible studies were rated for methodologic quality using the PEDro scale. The PEDro scale is a checklist that examines the "believability and the interpretability of trial quality."(1) The 11-item checklist yields a maximum score of 10 if all criteria are satisfied. The first item on the scale (Eligibility Criteria) is not scored. The PEDro scores were extracted from the PEDro database. If a study had not been entered into the database and scored, it was reviewed and scored by an experienced PEDro rater. MAIN RESULTS: Normalized data for pain and disability were given possible total scores of 100. The article's scores on the PEDro scale were average, ranging from 4 to 8 of 10. The most common flaw in the methods, which occurred in all 6 studies, was the failure to blind both the patient and therapist. Four of the 6 did not blind the researcher interpreting the data. For both pain and disability at short-term (12 months) outcomes or outcomes other than pain and disability (eg, quality of life). To date, no authors have compared McKenzie therapy with placebo or no treatment. Also, few data are available on the McKenzie method and its effect on neck pain. Future researchers should focus on these issues.

Callahan, S., Rousseau, A., Knotter, A., Bru, V., Danel, M., Cueto, C., . . . Chabrol, H. (2003). Diagnosing eating disorders: presentation of a new diagnostic test and an initial epidemiological study of eating disorders in adolescents. [Les troubles alimentaires: presentation d'un outil de diagnostic et resultats d'une etude epidemiologique chez les adolescents] L'Encephale, 29(3 Pt 1), 239-247.

Precise diagnosis of eating disorders has long been problematic. First off, although the DSM IV provides clear criteria, these are applicable to a very narrow range of disorders. Subclinical disorders, although well defined in the literature, are difficult to diagnose as no tool has been previously available. These subclinical disorders are particularly important if one considers that they are often precursors to more serious and life-threatening eating disorders. In addition, choice of diagnostic tool for eating disorders has also long been the cause of difficulty for both researchers and clinicians. Although interviews are favored for their in-depth approach, they are sometimes difficult to implement and often too long and costly to use on a regular basis. Most available questionnaires are limited by their approach to one or two diagnostic categories, and again, until now, no tool has fully addressed the issue of subclinical disorders. The goal of this work was to translate and use a new questionnaire, The Questionnaire for Eating Disorders (Q-EDD), which was developed in the United States and based on both DSM IV criteria as well as carefully developed subclinical disorder criteria. The Q-EDD can identify the major eating disorder categories while at the same time distinguishing between different qualities in each (for example restricting versus compensatory anorexia). Moreover, the Q-EDD can identify several subclinical disorder categories, providing useful insight into potentially dangerous evolution of these disorders. In collaboration with one of the original authors, the questionnaire was translated into French with careful attention to DSM IV criteria in order to preserve its original validity. The questionnaire was read by several professionals in psychology as well as lay people to assure its face validity and ease of use. Once the questionnaire was adequately translated and corrected, it was used for an epidemiological study with a large sample of adolescents and young adults (n=1 001) from several Junior High and High Schools in the greater metropolitan area of Toulouse, France. The schools were located in a variety of neighborhoods and represented a wide range of population, some of them being more academic oriented, others being more oriented towards practical training. The population was composed of 703 females and 298 males, with an average age of 17.06 years. In addition, the population included several different ethnic categories, all of which are similarly represented in the general French population. The results from the Q-EDD showed levels of various clinical disorders to replicate data from previous epidemiological studies with 1.5% of the population suffering from a serious clinical DSM IV disorder; 7.9% suffering from DSM IV disorders NOS; and 20.9% suffering subclinical disorders. In addition to this finding of 30% of the population with an eating disorder, it was noted that a large number of these young people fell into the severe underweight and low weight categories. Indeed, nearly 10% of this group were within the weight criteria for anorexia, despite the fact that they did not meet the other criteria. This finding seemed to warrant additional investigation, and as a result, a different cut-off for severe underweight was established using literature references; this cut-off was set at the 10(th) percentile for BMI based on age. Yet, even with this new cut-off, 6% of this population still met a severe underweight criteria suggestive of anorexic pathology. These results led to the formulation of 2 hypotheses to explain this finding, the first of which examines morphological differences, the second of which suggests cultural differences in terms of eating habits and diet. The French version of the Q-EDD appears to follow the psychometric properties of the original version, moreover it provides useful and rich data regarding eating disorders in a format that is simple and efficient.

Chessick, C. A., Allen, M. H., Thase, M., Batista Miralha da Cunha, A. B., Kapczinski, F. F., de Lima, M. S., & dos Santos Souza, J. J. (2006). Azapirones for generalized anxiety disorder. Cochrane Database of Systematic Reviews (Online), 3, CD006115. doi:10.1002/14651858.CD006115

BACKGROUND: Azapirones are a group of drugs that work at the 5-HT1A receptor and are used to treat patients suffering from generalized anxiety disorder (GAD). However, several studies have shown conflicting results. Whether azapirones are useful as first line treatment in general anxiety disorders still needs to be answered. OBJECTIVES: To assess the efficacy and the acceptability of azapirones for the treatment of GAD. SEARCH STRATEGY: Initially the Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register (CCDANCTR) and The Cochrane Central Register of Controlled Trials (CENTRAL) were searched, incorporating results of group searches of MEDLINE (1966 to June 2005), EMBASE (1980 to June 2005), CINAHL (1982 to June 2005), PsycLIT (1974 to June 2005), PSYNDEX (1977 to June 2005), and LILACS (1982 to June 2005). Subsequently the revised Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Registers (CCDANCTR-Studies and CCDANCTR-References) were searched on 21-10-2005. Reference lists of relevant papers and major text books of anxiety disorder were examined. Authors, other experts in the field and pharmaceutical companies were contacted for knowledge of suitable trials, published or unpublished. Specialist journals concerning azapirones were handsearched. SELECTION CRITERIA: Randomized controlled trials of azapirones, including buspirone versus placebo and/or other medication and/or psychological treatment, were included. Participants were males and females of all ages with a diagnosis of generalized anxiety disorder. DATA COLLECTION AND ANALYSIS: Data were extracted from the original reports independently by CC, MA and MT. The main outcomes studied were related to the objectives stated above. Data were analysed for generalized anxiety disorder versus placebo, versus other medication and versus psychological treatment separately. Data were analysed using Review Manager Version 4.2.7. MAIN RESULTS: Thirty six trials were included in the review, reporting on 5908 participants randomly allocated to azapirones and/or placebo, benzodiazepines, antidepressants, psychotherapy or kava kava. Azapirones, including buspirone, were superior to placebo in treating GAD. The calculated number needed to treat for azapirones using the Clinical Global Impression scale was 4.4 (95% confidence interval (CI) 2.16 to 15.4). Azapirones may be less effective than benzodiazepines and we were unable to conclude if azapirones were superior to antidepressants, kava kava or psychotherapy. Azapirones appeared to be well tolerated. Fewer participants stopped taking benzodiazepines compared to azapirones. The length of studies ranged from four to nine weeks, with one study lasting 14 weeks. AUTHORS' CONCLUSIONS: Azapirones appeared to be useful in the treatment of GAD, particularly for those participants who had not been on a benzodiazepine. Azapirones may not be superior to benzodiazepines and do not appear as acceptable as benzodiazepines. Side effects appeared mild and non serious in the azapirone treated group. Longer term studies are needed to show that azapirones are effective in treating GAD, which is a chronic long-term illness.

Chronicle, E., & Mulleners, W. (2004). Anticonvulsant drugs for migraine prophylaxis. Cochrane Database of Systematic Reviews (Online), (3)(3), CD003226. doi:10.1002/14651858.CD003226.pub2

BACKGROUND: Anticonvulsant drugs seem to be useful in clinical practice for the prophylaxis of migraine. This might be explained by a variety of actions of these drugs in the central nervous system that are probably relevant to the pathophysiology of migraine. OBJECTIVES: To describe and assess the evidence from controlled trials on the efficacy and tolerability of anticonvulsants for preventing migraine attacks in adult patients with migraine. SEARCH STRATEGY: We searched MEDLINE (from 1966 on) and the Cochrane Central Register of Controlled Trials (CENTRAL). Date of most recent search: April 2003. Additional information was gained from hand-searching specialist headache journals; correspondence with pharmaceutical companies, authors of reports, and experts in the field; and a wide variety of review articles and book chapters. SELECTION CRITERIA: Studies were required to be prospective, controlled trials of self-administered drug treatments taken regularly to prevent the occurrence of migraine attacks and/or to reduce the intensity of those attacks. DATA COLLECTION AND ANALYSIS: Studies were selected and data extracted by two independent reviewers. For migraine frequency data, standardized mean differences (SMDs) were calculated for individual studies and pooled across studies. For dichotomous data on significant reduction in migraine frequency, odds ratios (ORs) and numbers-needed-to-treat (NNTs) were similarly calculated. Adverse events were analyzed by calculating numbers-needed-to-harm (NNHs) for studies using similar agents. MAIN RESULTS: Fifteen papers were included in the review. Of these, 14 reported trials comparing anticonvulsants with placebo, as follows: four trials of divalproex sodium, three trials of topiramate, two trials of sodium valproate, two trials of gabapentin, and one trial each of carbamazepine, clonazepam, and lamotrigine. One paper reported a trial of sodium valproate versus an active comparator, flunarizine, and one trial of divalproex sodium versus placebo included a comparison against propranolol, also an active comparator. Data from 2024 patients were considered. Analysis of data from eight trials (n = 841) demonstrates that anticonvulsants, considered as a class, reduce migraine frequency by about 1.4 attacks per 28 days as compared to placebo (SMD -0.60; 95% confidence interval [CI] -0.93 to -0.26). Data from 10 trials (n = 1341) show that anticonvulsants, considered as a class, also more than double the number of patients for whom migraine frequency is reduced by 50% or more, relative to placebo (OR 3.90; 95% CI 2.61 to 5.82; NNT 3.8; 95% CI 3.2 to 4.6). For seven trials of sodium valproate and divalproex sodium, NNHs for five clinically important adverse events ranged from 6.6 to 16.3. For the three trials of topiramate, NNHs for eight adverse events (100-mg dose) ranged from 2.4 to 32.9. REVIEWERS' CONCLUSIONS: Anticonvulsants appear to be both effective in reducing migraine frequency and reasonably well tolerated. There is noticeable variation among individual agents, but there are insufficient data to know whether this is due to chance or variation in true efficacy. Neither clonazepam nor lamotrigine was superior to placebo (one trial each). Relatively few robust trials are available for agents other than sodium valproate/divalproex sodium. Two recently published and large trials of topiramate demonstrated reasonable efficacy, and one further trial of this agent is anticipated in the near future.

Cittadini, E., & Matharu, M. S. (2009). Symptomatic trigeminal autonomic cephalalgias. The Neurologist, 15(6), 305-312. doi:10.1097/NRL.0b013e3181ad8d67

BACKGROUND: The trigeminal autonomic cephalalgias (TACs) are a group of primary headache syndromes characterized by strictly unilateral head pain that occurs in association with ipsilateral cranial autonomic features. The group includes cluster headache, paroxysmal hemicrania, and short lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing. These syndromes differ in attack duration and frequency as well as the response to therapy. Most of the cases of these syndromes are primary headaches, though numerous symptomatic cases have been described albeit that it is difficult to establish a causal relationship with the underlying pathology in most cases. REVIEW SUMMARY: We reviewed the literature to identify the cases of symptomatic TACs that were likely to be secondary to the reported underlying lesion. We also attempted to identify any clinical features that may be pointers for distinguishing these cases from primary cases and thereby inform the diagnostic workup of these disorders. CONCLUSION: Forty cases of symptomatic TACs were identified. These symptomatic headaches were associated with atypical phenotypes, abnormal examination, and poor treatment response though a significant minority had a typical presentation. A relatively high proportion of all TACs were secondary to pituitary tumors. It is difficult to draw up guidelines for the diagnostic workup required on the basis of this small retrospective case series. It remains unclear whether every TAC patient requires neuroimaging, though if it is considered then magnetic resonance imaging is the preferred modality. In addition, we suggest that all TAC patients should be carefully assessed for pituitary disease related symptoms but further investigations with magnetic resonance imaging of the pituitary gland and pituitary hormonal profile should only be undertaken in patients with atypical features, abnormal examination, or those resistant to the appropriate medical treatment.

Claudino, A. M., Hay, P., Lima, M. S., Bacaltchuk, J., Schmidt, U., & Treasure, J. (2006). Antidepressants for anorexia nervosa. Cochrane Database of Systematic Reviews (Online), (1)(1), CD004365. doi:10.1002/14651858.CD004365.pub2

BACKGROUND: Anorexia Nervosa (AN) is an illness characterised by extreme concern about body weight and shape, severe self-imposed weight loss, and endocrine dysfunction. In spite of its high mortality, morbidity and chronicity, there are few intervention studies on the subject. OBJECTIVES: The aim of this review was to evaluate the efficacy and acceptability of antidepressant drugs in the treatment of acute AN. SEARCH STRATEGY: The strategy comprised of database searches of the Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register, MEDLINE (1966 to April 28th, 2005), EMBASE (1980 to week 36, 2004), PsycINFO (1969 to August week 5, 2004), handsearching the International Journal of Eating Disorders and searching the reference lists of all papers selected. Personal letters were sent to researchers in the field requesting information on unpublished or in-progress trials. SELECTION CRITERIA: All randomised controlled trials of antidepressant treatment for AN patients, as defined by the Diagnostic and Statistical Manual, fourth edition (DSM-IV) or similar international criteria, were selected. DATA COLLECTION AND ANALYSIS: Quality ratings were made giving consideration to the strong relationship between allocation concealment and potential for bias in the results; studies meeting criteria A and B were included. Trials were excluded if non-completion rates were above 50%. The standardised mean difference and relative risk were used for continuous data and dichotomous data comparisons, respectively. Whenever possible, analyses were performed according to intention-to-treat principles. Heterogeneity was tested with the I-squared statistic. Weight change was the primary outcome. Secondary outcomes were severity of eating disorder, depression and anxiety symptoms, and global clinical state. Acceptability of treatment was evaluated by considering non-completion rates. MAIN RESULTS: Only seven studies were included. Major methodological limitations such as small trial size and large confidence intervals decreased the power of the studies to detect differences between treatments, and meta-analysis of data was not possible for the majority of outcomes. Four placebo-controlled trials did not find evidence that antidepressants improved weight gain, eating disorder or associated psychopathology. Isolated findings, favouring amineptine and nortriptyline, emerged from the antidepressant versus antidepressant comparisons, but cannot be conceived as evidence of efficacy of a specific drug or class of antidepressant in light of the findings from the placebo comparisons. Non-completion rates were similar between the compared groups. AUTHORS' CONCLUSIONS: A lack of quality information precludes us from drawing definite conclusions or recommendations on the use of antidepressants in acute AN. Future studies testing safer and more tolerable antidepressants in larger, well designed trials are needed to provide guidance for clinical practice.

Cooper, H. A. (1955). HALLUCINOGENIC DRUGS. The Lancet, 265(6873), 1078-1079. doi:DOI: 10.1016/S0140-6736(55)91156-9

Cranney, A., Horsley, T., O'Donnell, S., Weiler, H., Puil, L., Ooi, D., . . . Mamaladze, V. (2007). Effectiveness and safety of vitamin D in relation to bone health. Evidence report/technology Assessment, (158)(158), 1-235.

OBJECTIVES: To review and synthesize the literature in the following areas: the association of specific circulating 25(OH)D concentrations with bone health outcomes in children, women of reproductive age, postmenopausal women and elderly men; the effect of dietary intakes (foods fortified with vitamin D and/or vitamin D supplementation) and sun exposure on serum 25(OH)D; the effect of vitamin D on bone mineral density (BMD) and fracture or fall risk; and the identification of potential harms of vitamin D above current reference intakes. DATA SOURCES: MEDLINE® (1966-June Week 3 2006); Embase (2002-2006 Week 25); CINAHL (1982-June Week 4, 2006); AMED (1985 to June 2006); Biological Abstracts (1990-February 2005); and the Cochrane Central Register of Controlled Trials (2nd Quarter 2006). REVIEW METHODS: Two independent reviewers completed a multi-level process of screening the literature to identify eligible studies (title and abstract, followed by full text review, and categorization of study design per key question). To minimize bias, study design was limited to randomized controlled trials (RCTs) wherever possible. Study criteria for question one were broadened to include observational studies due to a paucity of available RCTs, and question four was restricted to systematic reviews to limit scope. Data were abstracted in duplicate and study quality assessed. Differences in opinion were resolved through consensus or adjudication. If clinically relevant and statistically feasible, meta-analyses of RCTs on vitamin D supplementation and bone health outcomes were conducted, with exploration of heterogeneity. When meta-analysis was not feasible, a qualitative systematic review of eligible studies was conducted. RESULTS: 167 studies met our eligibility criteria (112 RCTs, 19 prospective cohorts, 30 case-controls and six before-after studies). The largest body of evidence on vitamin D status and bone health was in older adults with a lack of studies in premenopausal women and infants, children and adolescents. The quality of RCTs was highest in the vitamin D efficacy trials for prevention of falls and/or fractures in older adults. There was fair evidence of an association between low circulating 25(OH)D concentrations and established rickets. However, the specific 25(OH)D concentrations associated with rickets is uncertain, given the lack of studies in populations with dietary calcium intakes similar to North American diets and the different methods used to determine 25(OH)D concentrations. There was inconsistent evidence of an association of circulating 25(OH)D with bone mineral content in infants, and fair evidence that serum 25(OH)D is inversely associated with serum PTH. In adolescents, there was fair evidence for an association between 25(OH)D levels and changes in BMD. There were very few studies in pregnant and lactating women, and insufficient evidence for an association between serum 25(OH)D and changes in BMD during lactation, and fair evidence of an inverse correlation with PTH. In older adults, there was fair evidence that serum 25(OH)D is inversely associated with falls, fair evidence for a positive association with BMD, and inconsistent evidence for an association with fractures. The imprecision of 25(OH)D assays may have contributed to the variable thresholds of 25(OH)D below which the risk of fractures, falls or bone loss was increased. There was good evidence that intakes from vitamin D-fortified foods (11 RCTs) consistently increased serum 25(OH)D in both young and older adults. Eight randomized trials of ultraviolet (UV)-B radiation (artificial and solar exposure) were small and heterogeneous with respect to determination of the exact UV-B dose and 25(OH)D assay but there was a positive effect on serum 25(OH)D concentrations. It was not possible to determine how 25(OH)D levels varied by ethnicity, sunscreen use or latitude. Seventy-four trials examined the effect of vitamin D(3) or D(2) on 25(OH)D concentrations. Most trials used vitamin D(3), and the majority enrolled older adults. In three trials, there was a greater response of serum 25(OH)D concentrations to vitamin D(3) compared to vitamin D(2), which may have been due to more rapid clearance of vitamin D(2) in addition to other mechanisms. Meta-analysis of 16 trials of vitamin D(3) was consistent with a dose-response effect on serum 25(OH)D when comparing daily doses of /= 400 IU. An exploratory analysis of the heterogeneity demonstrated a significant positive association comparable to an increase of 1 - 2 nmol/L in serum 25(OH)D for every 100 additional units of vitamin D although heterogeneity remained after adjusting for dose. Vitamin D(3) in combination with calcium results in small increases in BMD compared to placebo in older adults although quantitative synthesis was limited due to variable treatment durations and BMD sites. The evidence for fracture reduction with vitamin D supplementation was inconsistent across 15 trials. The combined results of trials using vitamin D(3) (700 - 800 IU daily) with calcium (500 - 1,200 mg) was consistent with a benefit on fractures although in a subgroup analysis by setting, benefit was primarily in elderly institutionalized women (fair evidence from two trials). There was inconsistent evidence across 14 RCTs of a benefit on fall risk. However, a subgroup analysis showed a benefit of vitamin D in postmenopausal women, and in trials that used vitamin D(3) plus calcium. In addition, there was a reduction in fall risk with vitamin D when six trials that adequately ascertained falls were combined. Limitations of the fall and fracture trials included poor compliance with vitamin D supplementation, incomplete assessment of vitamin D status and large losses to follow-up. We did not find any systematic reviews that addressed the question on the level of sunlight exposure that is sufficient to maintain serum 25(OH)D concentrations but minimizes risk of melanoma and non-melanoma skin cancer. There is little evidence from existing trials that vitamin D above current reference intakes is harmful. In most trials, reports of hypercalcemia and hypercalciuria were not associated with clinically relevant events. The Women's Health Initiative study did report a small increase in kidney stones in postmenopausal women aged 50 to 79 years whose daily vitamin D(3) intake was 400 IU (the reference intake for 50 to 70 years, and below the reference intake for > 70 years) combined with 1000 mg calcium. The increase in renal stones corresponded to 5.7 events per 10,000 person-years of exposure. The women in this trial had higher calcium intakes than is seen in most post-menopausal women. CONCLUSIONS: The results highlight the need for additional high quality studies in infants, children, premenopausal women, and diverse racial or ethnic groups. There was fair evidence from studies of an association between circulating 25(OH)D concentrations with some bone health outcomes (established rickets, PTH, falls, BMD). However, the evidence for an association was inconsistent for other outcomes (e.g., BMC in infants and fractures in adults). It was difficult to define specific thresholds of circulating 25(OH)D for optimal bone health due to the imprecision of different 25(OH)D assays. Standard reference preparations are needed so that serum 25(OH)D can be accurately and reliably measured, and validated. In most trials, the effects of vitamin D and calcium could not be separated. Vitamin D(3) (>700 IU/day) with calcium supplementation compared to placebo has a small beneficial effect on BMD, and reduces the risk of fractures and falls although benefit may be confined to specific subgroups. Vitamin D intake above current dietary reference intakes was not reported to be associated with an increased risk of adverse events. However, most trials of higher doses of vitamin D were not adequately designed to assess long-term harms.

Crino, R., Slade, T., & Andrews, G. (2005). The changing prevalence and severity of obsessive-compulsive disorder criteria from DSM-III to DSM-IV. The American Journal of Psychiatry, 162(5), 876-882. doi:10.1176/appi.ajp.162.5.876

OBJECTIVE: Relative to other mental disorders, the prevalence of obsessive-compulsive disorder (OCD) in the general population is not well established. Some epidemiological surveys have determined the prevalence of DSM-III OCD, but this is one of the first reports, to the authors' knowledge, of DSM-IV OCD's prevalence. METHOD: Data from the Australian National Survey of Mental Health and Well-Being, a nationally representative epidemiological survey of mental disorders, were analyzed. The prevalence and associated characteristics of DSM-IV OCD were identified, and then the data were rescored for DSM-III OCD. Cases defined by each system were compared. RESULTS: The 12-month prevalence of DSM-IV OCD was 0.6%, considerably less than found in surveys employing DSM-III diagnostic criteria. DSM-IV OCD showed significantly higher levels of comorbidity, disability, health service use, and treatment received. CONCLUSIONS: Changes in the reported prevalence and severity of OCD between DSM-III and DSM-IV cases are most likely a function of the differences in diagnostic criteria between DSM-III and DSM-IV.

Cummings, J. L., & Miller, B. L. (1987). Visual hallucinations. Clinical occurrence and use in differential diagnosis The Western Journal of Medicine, 146(1), 46-51.

Visual hallucinations occur in diverse clinical circumstances including ophthalmologic diseases, neurologic disorders, toxic and metabolic disorders and idiopathic psychiatric illnesses. Their content, duration and timing relate to their cause and provide useful differential diagnostic information. Hallucinations must be distinguished from delusions and confabulation. A systematic approach to differentiating among hallucinatory syndromes may improve diagnostic accuracy.

Dawson, K. A. (2001). A case study of space-time distortion during a total lunar eclipse following street use of LSD. Journal of Psychoactive Drugs, 33(3), 301-305.

Although psychedelics can induce "cosmic" consciousness through severe distortions of time and space perceptions, little attention has been given to examination of this psychopharmacological property. With the hope of providing an impetus to further research in this area, a case of cosmic perception under the influence of LSD is reported which included the apparent movement of consciousness to the lunar surface combined with the experience of remote viewing of the Milky Way galaxy. While the possibility of veridical remote viewing is unlikely, it is speculated that the neurocognitive action of LSD can sensitize the user to focused bright light, associated memories, and creative elaborations during actual eclipse events. Experimenters are urged to adopt precautions to avoid potentially detrimental effects of pharmacologically manipulating the space-time continuum.

de Rios, M. D., Grob, C. S., & Baker, J. R. (2002). Hallucinogens and redemption. Journal of Psychoactive Drugs, 34(3), 239-248.

This article examines drug substitution with regard to hallucinogens (ayahuasca, ibogaine, peyote and LSD) set within the concept of redemption. The model examines both religious and secular approaches to the contemporary use of hallucinogens in drug substitution, both by scientists and in religious settings worldwide. The redemptive model posits that the proper use of one psychoactive substance within a spiritual or clinical context helps to free an individual from the adverse effects of their addiction to another substance and thus restores them as functioning members of their community or group. Data is drawn from the U.S., Brazil, Peru, and West Africa. Two principle mechanisms for this are proposed: the psychological mechanism of suggestibility is examined in terms of the individual reaching abstinence goals from addictive substances such as alcohol and opiates. Neurophysiological and neurochemical mechanisms to understand the efficacy of such substitution are highlighted from ongoing research on hallucinogens. Research by two of the authors with the Unaio do Vegetal (UDV) Church in Brazil is examined in terms of the model.

Dependence on LSD and other hallucinogenic drugs. (1967). JAMA : The Journal of the American Medical Association, 202(1), 141-144.

Does risperidone exacerbate hallucinogen-persisting perception disorder? (1998). Brown University Psychopharmacology Update, 9(2), 8.

Reports on the findings of a case study published in a 1997 issue of the `Journal of Clinical Psychopharmacology,' about the effectiveness of risperidone in exacerbating hallucinogen-persisting perception disorder. Patient's medical background; Drug abuse history; Contraindications of risperidone.

Dröge, W. (2002). Aging-related changes in the thiol/disulfide redox state: implications for the use of thiol antioxidants. Experimental Gerontology, 37(12), 1333-1345. doi:DOI: 10.1016/S0531-5565(02)00175-4

Dumortier, G., Welniarz, B., Sauvebois, C., Medjdoub, H., Friche, H., Siad, N., & Degrassat, K. (2005). Prescription of psychotropic drugs in paediatry: approved indications and therapeutic perspectives. [Prescription des psychotropes en pedopsychiatrie: limites des indications officielles et perspectives therapeutiques] L'Encephale, 31(4 Pt 1), 477-489.

In France, psychotropic drugs may be classified in four categories according to their official data. The first category corresponds to psychotropic drugs with an approved indication available in paediatry. Theyare old agents (e.g. haloperidol, amitriptyline, benzodiazepines...) with the exception of methylphenidate (hyperactivity). The second one corresponds to pharmacological agents approved for some indications obtained with adults but not for a1l (i.e. restricted indication: e.g. sertraline approved in paediatry only for OCD but not for depression, risperidone approved only for the treatment of disruptive behaviors in children with subaverage IQs). For the third category, the psychotropic agent is either contraindicated or unadvised under the age of 15 or 18 years, by lack of data (e.g. most of SSRI or atypical antipsychotic drugs). For the last category, official data available in brief summaries offer no information on paediatric use and consequently their administration does not appear possible. Up to now, no approved use has been delivered to injection route (IM or IV) in France, except for an IM formulation of zuclopenthixol. Prescribing psychotropic drug has to respect good practices including close psychological and somatic monitoring that associates the young patient and his relative (psycho-education program). Particular key-points should be taken into consideration (i.e. pharmacokinetic and physiological specificities, risk of false passage under the age of 6 years with capsules or tablets, presence of alcohol in some oral solution or bitter aroma...). Beside these official data, many studies have been published but must be carefully interpreted according to their level of pertinence. Meta-analysis gather all randomised controlled trials published or not, analyse their specific pertinence and thus provide clinically relevant elements. Randomised controlled trials present clinical interest but key-points in study design must be checked (e.g. number of patients, inclusion and exclusion criteria, length of the study and clinical relevance of clinical scales...). Other studies like open trials or clinical cases do not offersufficient guarantees. Some randomised controlled trials of clinical relevance have been carried out in this population with new pharmacological classes (eg SSRI, atypical antipsychotic drugs) and may lead to extended indications in children and adolescents. According to bibliographic and official data, the main criteria in the prescribing choice may take into consideration the following sis stressing a poor benefit/risk ratio. SSRI may offer better prospects but their use has not been approved in this indication, until now. In OCD, sertraline shows great interest to enhance clinical response and represents the molecule of reference. No drug has been approved for mood disorders in children or adolescent, in France, contrary to USA where lithium can be administered over the age of 12 years. In addition, antiepileptic drugs like carbamazepine or divalproate have conducted to clinical improvement in some studies. Benzodiazepines, hydroxyzine and meprobamate use should be strictly restricted in case of anxiety symptoms but are the only agents approved in this indication despise promising results obtained with SSRI. Transitory insomnia may take advantage of alimemazine prescription (approved use over the age of 36 months). Some typical neuroleptics are indicated in tics or in behaviour disorders associated to autism or related syndromes but present clinical limitations and poor tolerability. Promising clinical trials (randomised or not) have been conducted with new atypical antipsychotic drugs like risperidone. In conclusion, present data available for paediatric use of psychotropic agents emphasizes that safety and effectiveness are not always well established in particular for the treatment of chronic disorders (long term tolerability assessment). Moreover, studies should be carried out to specify factors promoting adherence and quality of life for this young population in order to optimise clinical benefit of drug prescription.

Duncan, J. W. (1974). Persisting psychotic states in adolescent drug users. Child Psychiatry and Human Development, 5(1), 51-62.

Dundar, Y., Boland, A., Strobl, J., Dodd, S., Haycox, A., Bagust, A., . . . Walley, T. (2004). Newer hypnotic drugs for the short-term management of insomnia: a systematic review and economic evaluation. Health Technology Assessment (Winchester, England), 8(24), iii-x, 1-125.

OBJECTIVES: To assess the clinical and cost-effectiveness of zaleplon, zolpidem and zopiclone (Z-drugs) compared with benzodiazepines. DATA SOURCES: Electronic databases, reference lists of retrieved articles and pharmaceutical company submissions. REVIEW METHODS: Randomised controlled trials (RCTs) that compared either benzodiazepines to the Z-drugs or any two of the non-benzodiazepine drugs in patients with insomnia were included in the review. Data on the following outcome measures were considered: sleep onset latency, total sleep duration, number of awakenings, quality of sleep, adverse effects and rebound insomnia. A search was also undertaken for any study designs that evaluated issues related to adverse events (e.g. dependency and withdrawal symptoms). Full economic evaluations that compared two or more options and considered both costs and consequences including cost-effectiveness, cost-utility analysis or cost-benefit analysis undertaken in the context of high-quality RCTs were considered for inclusion in the review. RESULTS: Twenty-four studies, involving a total study population of 3909 patients, met the inclusion criteria. These included 17 studies comparing a Z-drug with a benzodiazepine and seven comparing a Z-drug with another Z-drug. The diversity of possible comparisons and the range of outcome measures in the review may be confusing. Outcomes were rarely standardised and, even when reported, differed in interpretation. In addition, variations in assessment and variety in the level of information provided make study comparisons difficult. As a result, meta-analysis has been possible on only a small number of outcomes. However, some broad conclusions might be reached based on the limited data provided. The existing published economic literature in this area is very limited. No relevant economic evaluations were identified for inclusion in the review. The industry submissions did not include detailed evidence of cost-effectiveness. Given the lack of robust clinical evidence, no economic model describing the costs and benefits of the newer hypnotic drugs for insomnia was developed. The systematic review provided in this report suggests that an agnostic approach to cost-effectiveness is required at this stage. In the short-term, no systematic evidence is available concerning significant outcome variations between either the different classes of drugs or between individual drugs within each class. Within this short-term horizon, the one element that does vary significantly is the acquisition cost of the individual drugs. CONCLUSIONS: The short-acting drugs seem equally effective and safe with minor differences that may lead a prescriber to favour one over another in different patients. There is no evidence that one is more cost-effective than any other. Analysis of the additional costs to the NHS, depending on the rate of change from benzodiazepine prescriptions to Z-drug prescriptions, at current levels of hypnotic prescribing, range from GBP2 million to GBP17 million per year. There are clear research needs in this area; in particular, none of the existing trials adequately compare these medications. It is suggested that further consideration should be given to a formal trial to allow head-to-head comparison of some of the key drugs in a double-blind RCT lasting at least 2 weeks, and of sufficient size to draw reasonable conclusions. We would also recommend that any such trial should include a placebo arm. It should also collect good-quality data around sleep outcomes and in particular quality of life and daytime drowsiness. We do not believe that any formal study of risk of dependency is feasible at present. Finally, the management of long-term insomnia is suggested for further investigation: considering the frequency of this symptom and its recurring course, the short-term trial of medication and lack of long-term follow-up undermine attempts to develop evidence-based guidelines for the use of hypnotics in this condition, or indeed for its whole management.

Durham, R. C., Chambers, J. A., Power, K. G., Sharp, D. M., Macdonald, R. R., Major, K. A., . . . Gumley, A. I. (2005). Long-term outcome of cognitive behaviour therapy clinical trials in central Scotland. Health Technology Assessment (Winchester, England), 9(42), 1-174.

OBJECTIVES: To establish the long-term outcome of participants in clinical trials of cognitive behaviour therapy (CBT) for anxiety disorders and psychosis, examining the effectiveness and cost-effectiveness associated with receiving CBT in comparison with alternative treatments. DESIGN: An attempt was made to contact and interview all of the participants in eight randomised, controlled, clinical trials of CBT for anxiety disorders and two randomised, controlled, clinical trials of CBT for schizophrenia conducted between 1985 and 2001. Case note reviews of healthcare resources used in the 2 years prior to entering the trials and the 2 years prior to follow-up interview were undertaken. SETTING: Mixed rural and urban settings in five localities in central Scotland. Anxiety disorder trials were conducted mainly in primary care and included three with generalised anxiety disorder, four with panic disorder and one with post-traumatic stress disorder (PTSD). The psychosis studies (one on relapse prevention and one with chronic disorder) were conducted in secondary care. PARTICIPANTS: Of the 1071 entrants to the 10 studies, 489 agreed to participate (46% of original entrants, 52% of those available to contact). INTERVENTIONS: Follow-up interviews took place between 1999 and 2003, 2-14 years after the original treatment. Interviews for Trials 1-8 were conducted by a research psychologist blind to original treatment condition. Interviews for Trials 9 and 10 were conducted by community psychiatric nurses also blind to treatment condition. Case note reviews were completed following the interview. MAIN OUTCOME MEASURES: For Trials 1-8 the main interview-based outcome measures were: Anxiety Disorders Interview Schedule-DSM-IV for diagnosis and co-morbidity, Clinical Global Severity (0-8) and the Hamilton Anxiety Rating Scale. The main patient-rated measures were: Brief Symptom Inventory, SF-36 II, Clinical Global Improvement (1-7), and the Positive and Negative Affect Scale. For Trials 9 and 10 the primary outcome measure was the interview-based Positive and Negative Syndrome Scale (PANSS). RESULTS: For the anxiety disorder studies (Trials 1-8), over half of the participants (52%) had at least one diagnosis at long-term follow-up, with significant levels of co-morbidity and health status scores comparable to the lowest 10% of the general population. Only 36% reported receiving no interim treatment for anxiety over the follow-up period with 19% receiving almost constant treatment. Patients with PTSD did particularly poorly. There was a 40% real increase in healthcare costs over the two time periods, mainly due to an increase in prescribing. A close relationship was found between poor mental and physical health for those with a chronic anxiety disorder. Treatment with CBT was associated with a better long-term outcome than non-CBT in terms of overall symptom severity but not with regard to diagnostic status. The positive effects of CBT found in the original trials were eroded over longer time periods. No evidence was found for an association between more intensive therapy and more enduring effects of CBT. Long-term outcome was found to be most strongly predicted by the complexity and severity of presenting problems at the time of referral, by completion of treatment irrespective of modality and by the amount of interim treatment during the follow-up period. The quality of the therapeutic alliance, measured in two of the studies, was not related to long-term outcome but was related to short-term outcome. The cost-effectiveness analysis showed no advantages of CBT over non-CBT. The cost of providing CBT in the original trials was only a very small proportion (6.4%) of the overall costs of healthcare for this population, which are high for both physical and mental health problems. In the psychosis studies (Trials 9 and 10), outcome was generally poor with only 10% achieving a 25% reduction in total PANSS scores from pretreatment to long-term follow-up, also cost-effectiveness analysis showed no advantages of CBT over non-CBT, although healthcare costs fell over the two time periods mainly owing to a reduction in inpatient costs. CONCLUSIONS: Psychological therapy services need to recognise that anxiety disorders tend to follow a chronic course and that good outcomes with CBT over the short term are no guarantee of good outcomes over the longer term. Clinicians who go beyond standard treatment protocols of about 10 sessions over a 6-month period are unlikely to bring about greater improvement. Poor outcomes over the long term are related to greater complexity and severity of presenting problems at the time of referral, failure to complete treatment irrespective of modality and the amount of interim treatment during the follow-up period. The relative gains of CBT are greater in anxiety disorders than in psychosis. Longitudinal research designs over extended periods of time (2-5 years), with large numbers of participants (500+), are required to investigate the relative importance of patient characteristics, therapeutic alliance and therapist expertise in determining the cost-effectiveness of CBT in the longer term.

Dyck, E. (2005). Flashback: psychiatric experimentation with LSD in historical perspective. Canadian Journal of Psychiatry.Revue Canadienne De Psychiatrie, 50(7), 381-388.

In the popular mind, d-lysergic acid diethylamide (LSD) research in psychiatry has long been associated with the CIA-funded experiments conducted by Ewen Cameron at the Allen Memorial Institute in Montreal, Quebec. Despite this reputation, a host of medical researchers in the post World War II era explored LSD for its potential therapeutic value. Some of the most widespread trials in the Western world occurred in Saskatchewan, under the direction of psychiatrists Humphry Osmond (in Weyburn) and Abram Hoffer (in Saskatoon). These medical researchers were first drawn to LSD because of its ability to produce a "model psychosis." Their experiments with the drug that Osmond was to famously describe as a "psychedelic" led them to hypothesize and promote the biochemical nature of schizophrenia. This brief paper examines the early trials in Saskatchewan, drawing on hospital records, interviews with former research subjects, and the private papers of Hoffer and Osmond. It demonstrates that, far from being fringe medical research, these LSD trials represented a fruitful, and indeed encouraging, branch of psychiatric research occurring alongside more famous and successful trials of the first generation of psychopharmacological agents, such as chlropromazine and imipramine. Ultimately, these LSD experiments failed for 2 reasons, one scientific and the other cultural. First, in the 1950s and early 1960s, the scientific parameters of clinical trials shifted to necessitate randomized controlled trials, which the Saskatchewan researchers had failed to construct. Second, as LSD became increasingly associated with student riots, antiwar demonstrations, and the counterculture, governments intervened to criminalize the drug, restricting and then terminating formal medical research into its potential therapeutic effects.

Dyer, C. (2002). NHS settles claim of patients treated with LSD. BMJ (Clinical Research Ed.), 324(7336), 501.

EFSA GMO Panel Working Group on Animal Feeding Trials. (2008). Safety and nutritional assessment of GM plants and derived food and feed: the role of animal feeding trials. Food and Chemical Toxicology : An International Journal Published for the British Industrial Biological Research Association, 46 Suppl 1, S2-70. doi:10.1016/j.fct.2008.02.008

In this report the various elements of the safety and nutritional assessment procedure for genetically modified (GM) plant derived food and feed are discussed, in particular the potential and limitations of animal feeding trials for the safety and nutritional testing of whole GM food and feed. The general principles for the risk assessment of GM plants and derived food and feed are followed, as described in the EFSA guidance document of the EFSA Scientific Panel on Genetically Modified Organisms. In Section 1 the mandate, scope and general principles for risk assessment of GM plant derived food and feed are discussed. Products under consideration are food and feed derived from GM plants, such as maize, soybeans, oilseed rape and cotton, modified through the introduction of one or more genes coding for agronomic input traits like herbicide tolerance and/or insect resistance. Furthermore GM plant derived food and feed, which have been obtained through extensive genetic modifications targeted at specific alterations of metabolic pathways leading to improved nutritional and/or health characteristics, such as rice containing beta-carotene, soybeans with enhanced oleic acid content, or tomato with increased concentration of flavonoids, are considered. The safety assessment of GM plants and derived food and feed follows a comparative approach, i.e. the food and feed are compared with their non-GM counterparts in order to identify intended and unintended (unexpected) differences which subsequently are assessed with respect to their potential impact on the environment, safety for humans and animals, and nutritional quality. Key elements of the assessment procedure are the molecular, compositional, phenotypic and agronomic analysis in order to identify similarities and differences between the GM plant and its near isogenic counterpart. The safety assessment is focussed on (i) the presence and characteristics of newly expressed proteins and other new constituents and possible changes in the level of natural constituents beyond normal variation, and on the characteristics of the GM food and feed, and (ii) the possible occurrence of unintended (unexpected) effects in GM plants due to genetic modification. In order to identify these effects a comparative phenotypic and molecular analysis of the GM plant and its near isogenic counterpart is carried out, in parallel with a targeted analysis of single specific compounds, which represent important metabolic pathways in the plant like macro and micro nutrients, known anti-nutrients and toxins. Significant differences may be indicative of the occurrence of unintended effects, which require further investigation. Section 2 provides an overview of studies performed for the safety and nutritional assessment of whole food and feed. Extensive experience has been built up in recent decades from the safety and nutritional testing in animals of irradiated foods, novel foods and fruit and vegetables. These approaches are also relevant for the safety and nutritional testing of whole GM food and feed. Many feeding trials have been reported in which GM foods like maize, potatoes, rice, soybeans and tomatoes have been fed to rats or mice for prolonged periods, and parameters such as body weight, feed consumption, blood chemistry, organ weights, histopathology etc have been measured. The food and feed under investigation were derived from GM plants with improved agronomic characteristics like herbicide tolerance and/or insect resistance. The majority of these experiments did not indicate clinical effects or histopathological abnormalities in organs or tissues of exposed animals. In some cases adverse effects were noted, which were difficult to interpret due to shortcomings in the studies. Many studies have also been carried out with feed derived from GM plants with agronomic input traits in target animal species to assess the nutritive value of the feed and their performance potential. Studies in sheep, pigs, broilers, lactating dairy cows, and fish, comparing the in vivo bioavailability of nutrients from a range of GM plants with their near isogenic counterpart and commercial varieties, showed that they were comparable with those for near isogenic non-GM lines and commercial varieties. In Section 3 toxicological in vivo, in silico, and in vitro test methods are discussed which may be applied for the safety and nutritional assessment of specific compounds present in food and feed or of whole food and feed derived from GM plants. Moreover the purpose, potential and limitations of the 90-day rodent feeding trial for the safety and nutritional testing of whole food and feed have been examined. Methods for single and repeated dose toxicity testing, reproductive and developmental toxicity testing and immunotoxicity testing, as described in OECD guideline tests for single well-defined chemicals are discussed and considered to be adequate for the safety testing of single substances including new products in GM food and feed. Various in silico and in vitro methods may contribute to the safety assessment of GM plant derived food and feed and components thereof, like (i) in silico searches for sequence homology and/or structural similarity of novel proteins or their degradation products to known toxic or allergenic proteins, (ii) simulated gastric and intestinal fluids in order to study the digestive stability of newly expressed proteins and in vitro systems for analysis of the stability of the novel protein under heat or other processing conditions, and (iii) in vitro genotoxicity test methods that screen for point mutations, chromosomal aberrations and DNA damage/repair. The current performance of the safety assessment of whole foods is mainly based on the protocols for low-molecular-weight chemicals such as pharmaceuticals, industrial chemicals, pesticides, food additives and contaminants. However without adaptation, these protocols have limitations for testing of whole food and feed. This primarily results from the fact that defined single substances can be dosed to laboratory animals at very large multiples of the expected human exposure, thus giving a large margin of safety. In contrast foodstuffs are bulky, lead to satiation and can only be included in the diet at much lower multiples of expected human intakes. When testing whole foods, the possible highest concentration of the GM food and feed in the laboratory animal diet may be limited because of nutritional imbalance of the diet, or by the presence of compounds with a known toxicological profile. The aim of the 90-days rodent feeding study with the whole GM food and feed is to assess potential unintended effects of toxicological and/or nutritional relevance and to establish whether the GM food and feed is as safe and nutritious as its traditional comparator rather than determining qualitative and quantitative intrinsic toxicity of defined food constituents. The design of the study should be adapted from the OECD 90-day rodent toxicity study. The precise study design has to take into account the nature of the food and feed and the characteristics of the new trait(s) and their intended role in the GM food and feed. A 90-day animal feeding trial has a large capacity (sensitivity and specificity) to detect potential toxicological effects of single well defined compounds. This can be concluded from data reported on the toxicology of a wide range of industrial chemicals, pharmaceuticals, food substances, environmental, and agricultural chemicals. It is possible to model the sensitivity of the rat subchronic feeding study for the detection of hypothetically increased amount of compounds such as anti-nutrients, toxicants or secondary metabolites. With respect to the detection of potential unintended effects in whole GM food and feed, it is unlikely that substances present in small amounts and with a low toxic potential will result in any observable (unintended) effects in a 90-day rodent feeding study, as they would be below the no-observed-effect-level and thus of unlikely impact to human health at normal intake levels. Laboratory animal feeding studies of 90-days duration appear to be sufficient to pick up adverse effects of diverse compounds that would also give adverse effects after chronic exposure. This conclusion is based on literature data from studies investigating whether toxicological effects are adequately identified in 3-month subchronic studies in rodents, by comparing findings at 3 and 24 months for a range of different chemicals. The 90-day rodent feeding study is not designed to detect effects on reproduction or development other than effects on adult reproductive organ weights and histopathology. Analyses of available data indicate that, for a wide range of substances, reproductive and developmental effects are not potentially more sensitive endpoints than those examined in subchronic toxicity tests. Should there be structural alerts for reproductive/developmental effects or other indications from data available on a GM food and feed, then these tests should be considered. By relating the estimated daily intake, or theoretical maximum daily intake per capita for a given whole food (or the sum of its individual commercial constituents) to that consumed on average per rat per day in the subchronic 90-day feeding study, it is possible to establish the margin of exposure (safety margin) for consumers. Results obtained from testing GM food and feed in rodents indicate that large (at least 100-fold) 'safety' margins exist between animal exposure levels without observed adverse effects and estimated human daily intake. Results of feeding studies with feed derived from GM plants with improved agronomic properties, carried out in a wide range of livestock species, are discussed. The studies did not show any biologically relevant differences in the parameters tested between control and test animals. (ABSTRACT TRUNCATED)

Eisen, M., Kaur, S., Rehema, A., Kullisaar, T., Vihalemm, T., Zilmer, K., . . . Zilmer, M. (2004). Allergic contact dermatitis is accompanied by severe abnormal changes in antioxidativity of blood. Biomedecine & Pharmacotherapy, 58(4), 260-263. doi:DOI: 10.1016/j.biopha.2004.02.005

Ekbom, K., Waldenlind, E., & Tfelt-Hansen, P. (2009). Cluster headache and aura. Headache, 49(5), 786-787. doi:10.1111/j.1526-4610.2009.01417.x

Ellison, G. (1995). The N-methyl-D-aspartate antagonists phencyclidine, ketamine and dizocilpine as both behavioral and anatomical models of the dementias. Brain Research.Brain Research Reviews, 20(2), 250-267.

Phencyclidine (PCP) and ketamine can induce a model psychosis in drug addicts and exacerbate the symptoms of chronic schizophrenics. The model psychoses these drugs induce mimic a variety of schizophrenic symptoms, including flattened affect, dissociative thought disorder, depersonalization and catatonic states. These symptoms can persist for prolonged periods and chronic PCP and ketamine addicts have persisting memory deficits. Dizocilpine (MK-801) is a simpler drug than PCP or ketamine in its actions, but it shares with both the property of blocking in a non-competitive manner the N-methyl-D-aspartate (NMDA) ion-channel. Behavioral observations and drug-discrimination studies in animals indicate that PCP and dizocilpine are similar in their effects and they both have a neurotoxic effect on neurons in posterior cingulate cortex. Recent studies have indicated that both of these drugs, when given continuously for several days, further induce neuronal degeneration in other limbic structures. These include brain regions of rats related to olfaction, associated limbic structures such as piriform cortex and posterior regions of entorhinal cortex and in it's projections, through the perforant pathway, to dentate gyrus and other cells in ventral hippocampus. These degenerative consequences may be excitatory neurotoxic effects, for these compounds also induce an elevation in glucose metabolism maximal in just those structures where degeneration is observed and the degeneration involves entire cells, with all of their processes. It has been suggested these non-competitive NMDA antagonists induce an increase in firing rate in a limbic circuit which includes the perforant pathway. At least some competitive NMDA antagonists induce the same pattern of degeneration and altered glucose utilization. There is anatomical and functional evidence that alterations in these same limbic structures are present in the dementia syndrome manifested by some schizophrenics and most Alzheimer's patients. This suggests that these non-competitive NMDA antagonists may provide a more complete model of psychoses and memory disturbances than previously recognized, in that they can mimic both persisting symptomatology and neuroanatomical abnormalities. While the neurochemical underpinnings of this effect remain elusive, it appears to be both age and sex dependent. Further studies of the mechanisms by which NMDA antagonists induce increased glucose utilization and neurotoxicity in these limbic structures may clarify these alterations in this simplified Papez-like circuit.

Ellison, G. D., & Keys, A. S. (1996). Persisting changes in brain glucose uptake following neurotoxic doses of phencyclidine which mirror the acute effects of the drug. Psychopharmacology, 126(3), 271-274.

Phencyclidine (PCP) can induce a model psychosis which has a number of similarities to dementias and schizophrenia. In some cases the psychosis persists for prolonged periods after drug discontinuation. N-Methyl-D-aspartate (NMDA) antagonists such as PCP induce increases in glucose metabolism in a variety of brain structures but most notably in limbic regions such as retrosplenial, piriform, and entorhinal cortex, hippocampus, and olfactory tubercle. When given continuously for several days, these NMDA antagonists induced neural degeneration in these same critical limbic areas. In the present study regional 2-fluorodeoxyglucose (FDG) uptake was measured in rats at both 24 h and 10 days after neurotoxic, 5-day "binge" PCP administration. At 24 h after minipump removal there were persisting and large increases in glucose uptake in many brain regions, with maximal changes in the same limbic structures in which neurotoxicity has been observed. Surprisingly, many of these regions still showed elevated glucose metabolism after 10 days of recovery. These findings suggest an anatomical and neurochemical substrate for the persisting psychosis which can occur following PCP.

El-Mallakh, R. S., & Abraham, H. D. (2007). MDMA (Ecstasy). Annals of Clinical Psychiatry : Official Journal of the American Academy of Clinical Psychiatrists, 19(1), 45-52. doi:10.1080/10401230601163592

BACKGROUND: 3,4-Methylenedioxymethamphetamine (MDMA or Ecstasy) is a synthetic amphetamine analogue that is recreationally used to obtain a psychological effect of enhanced affiliative emotional response. Its use in Western countries appears to be increasing, particularly among young individuals. METHODS: Pertinent basic and clinical literature is critically reviewed. RESULTS: A significant body of literature suggests that the patterns of MDMA use differ from traditional drugs of abuse, with relatively uncommon dependence and escalation of dosage. Nonetheless, MDMA is also neurotoxic with significant deleterious effects on serotonergic neurons, memory, and mood. Despite this, there is a dearth of treatment strategies for both acute intoxication and consequences of longer term use. CONCLUSIONS: MDMA is an important drug of abuse that has a wide range of adverse consequences.

Espiard, M., Lecardeur, L., Abadie, P., Halbecq, I., & Dollfus, S. (2005). Hallucinogen persisting perception disorder after psilocybin consumption: a case study. European Psychiatry, 20(5-6), 458-460. doi:DOI: 10.1016/j.eurpsy.2005.04.008

Favazza, A. R., & Domino, E. F. (1969). Recurrent LSD experience (flashbacks) triggered by marihuana. University of Michigan Medical Center Journal, 35(4), 214-216.

Ferrari, A., Spaccapelo, L., Gallesi, D., & Sternieri, E. (2009). Focus on headache as an adverse reaction to drugs. The Journal of Headache and Pain, 10(4), 235-239. doi:10.1007/s10194-009-0127-1

There are a large number of drugs inducing headache as an adverse reaction. Nevertheless, headaches as adverse reactions to drugs have received limited attention. Non-serious adverse reactions, such as headache, are not quantified and described as accurately as serious, life threatening ones. However, non-serious reactions can also be extremely troublesome, above all when they are chronic: they can affect patients' quality of life and contribute to non-compliance. It is absolutely possible that the number of patients with headache as an adverse reaction, which is going to increase, considering the growing use of medications. Physicians should, therefore, be aware of this issue. Indeed, it is difficult to attribute the diagnosis of adverse drug reaction to a condition, headache, which is also a very common symptom in general population.

Fontaine, D., Lazorthes, Y., Mertens, P., Blond, S., Geraud, G., Fabre, N., . . . Lanteri-Minet, M. (2009). Safety and efficacy of deep brain stimulation in refractory cluster headache: a randomized placebo-controlled double-blind trial followed by a 1-year open extension. The Journal of Headache and Pain, doi:10.1007/s10194-009-0169-4

Chronic cluster headache (CCH) is a disabling primary headache, considering the severity and frequency of pain attacks. Deep brain stimulation (DBS) has been used to treat severe refractory CCH, but assessment of its efficacy has been limited to open studies. We performed a prospective crossover, double-blind, multicenter study assessing the efficacy and safety of unilateral hypothalamic DBS in 11 patients with severe refractory CCH. The randomized phase compared active and sham stimulation during 1-month periods, and was followed by a 1-year open phase. The severity of CCH was assessed by the weekly attacks frequency (primary outcome), pain intensity, sumatriptan injections, emotional impact (HAD) and quality of life (SF12). Tolerance was assessed by active surveillance of behavior, homeostatic and hormonal functions. During the randomized phase, no significant change in primary and secondary outcome measures was observed between active and sham stimulation. At the end of the open phase, 6/11 responded to the chronic stimulation (weekly frequency of attacks decrease >50%), including three pain-free patients. There were three serious adverse events, including subcutaneous infection, transient loss of consciousness and micturition syncopes. No significant change in hormonal functions or electrolytic balance was observed. Randomized phase findings of this study did not support the efficacy of DBS in refractory CCH, but open phase findings suggested long-term efficacy in more than 50% patients, confirming previous data, without high morbidity. Discrepancy between these findings justifies additional controlled studies (clinicaltrials.gov number NCT00662935).

Fotiou, D. F., Stergiou, V., Tsiptsios, D., Lithari, C., Nakou, M., & Karlovasitou, A. (2009). Cholinergic deficiency in Alzheimer's and Parkinson's disease: Evaluation with pupillometry. International Journal of Psychophysiology, 73(2), 143-149. doi:DOI: 10.1016/j.ijpsycho.2009.01.011

The aim of the study was to evaluate the cholinergic deficiency in Alzheimer's (AD) and Parkinson's disease (PD). For this purpose, pupil size changes and mobility were assessed using a fast-video pupillometer (263 frames/s). Twenty-three (23) patients with probable AD and twenty-two (22) patients with PD (eleven with cognitive impairment and eleven without) entered the study. A full record of the pupil's reaction to light was registered. From this data ten (10) parameters were measured and reported. Comparison of those parameters in both group of subjects followed. Patients with probable AD had abnormal pupillary function compared to healthy ageing. All the Pupil Light Reflex (PLR) variables significantly differed between the two groups (p < 0.005) except the Baseline Pupil Diameter after 2-min dark adaptation (D1) and the Minimum Pupil Diameter (D2). Maximum Constriction Acceleration (ACmax) was the best predictor in classifying a subject as normal or as an AD with a perfect classification ability (AUC = 1, p < 0.001). ACmax and Maximum Constriction Velocity (VCmax) were significantly lower in PD patients without and with coexisting cognitive impairment compared to normal subjects (p < 0.001). Patients with cognitive impairment had significantly lower levels of ACmax, VCmax and amplitude (AMP = D1–D2) than patients with no cognitive deficits. ACmax and secondarily VCmax were the best predictors in classifying a subject as normal or as a PD patient with or without cognitive impairment. Cognitive and memory impairment, which reflects a cholinergic deficit, may be a crucial pathogenetic factor for the decrease in the aforementioned pupillometric parameters. VCmax and ACmax can be considered as the most sensitive indicators of this cholinergic deficiency.

Frankel, F. H. (1994). The concept of flashbacks in historical perspective. The International Journal of Clinical and Experimental Hypnosis, 42(4), 321-336.

A computer search of the literature for papers indexed under "flashbacks" produced a list of 70 references, many found in publications on the topics of substance abuse and trauma. Several of these were letters or papers written in languages other than English. In all, the author reviewed 55 papers. Although most of these papers contained comments that addressed the subject matter to some extent as recurrences or reminiscences of past happenings, the variability in the use of the term leaves many unresolved questions regarding the veridicality of the imagery. Nothing in the presentations reviewed by the author clearly demonstrates the unidimensional nature of flashbacks nor any recognizable neurophysiological correlate. The content of a flashback appears to be at least as likely to be the product of imagination as it is of memory.

Frecska, E., & Luna, L. E. (2006). The adverse effects of hallucinogens from intramural perspective. Neuropsychopharmacologia Hungarica : A Magyar Pszichofarmakologiai Egyesulet Lapja = Official Journal of the Hungarian Association of Psychopharmacology, 8(4), 189-200.

Very recently, after a long-lasting, worldwide moratorium on research of hallucinogenic agents, a good number of advanced countries have been revising their position, and start to approve testing the physiological and therapeutic effects of hallucinogens in human subjects. The purpose of this article is to review safety information available in the literature on hallucinogen use, and sort out those data from the reported complications of their abuse. Because of prohibitory regulations of the last 35 years, there are difficulties in achieving this kind of evaluation. Our approach has to be broad, and at times retrospective, in contrast to the well-controlled, focused, prospective design of the premarketing trials of legal drugs. The article summarizes the analyses in anticipation of supportive regulatory changes for the use of hallucinogens in well controlled studies and strictly supervised clinical trials. Keywords: adverse effects, ayahuasca, N,N-dimethyltryptamine, hallucinogenic agents, ibogaine, lysergic acid diethylamide, N-methyl-3,4-methylenedioxyamphetamine, psilocybin, therapeutic use.

Frenzilli, G., Ferrucci, M., Giorgi, F. S., Blandini, F., Nigro, M., Ruggieri, S., . . . Fornai, F. (2007). DNA fragmentation and oxidative stress in the hippocampal formation: a bridge between 3,4-methylenedioxymethamphetamine (ecstasy) intake and long-lasting behavioral alterations. Behavioural Pharmacology, 18(5-6), 471-481. doi:10.1097/FBP.0b013e3282d518aa

Intake of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) in humans leads to marked behavioral alterations. In a recent paper, we demonstrated that chronic MDMA intake produces a latent hippocampal hyperexcitability that parallels a reduced threshold for limbic seizures and a slowing of electroencephalographic activity. These phenomena suggest an alteration in hippocampal function. So far, only a few studies have focused on the hippocampal formation as a potential target for the effects induced by MDMA. In this study we sought to evaluate whether the intrinsic cells of the hippocampus might be modified chronically by ecstasy intake. In particular, we examined whether administration of MDMA, at doses producing hippocampal hyperexcitability also produces rearrangements of DNA strands measured by the comet assay. We found that MDMA, at very low doses, comparable with those self-administered by humans, produces acute oxidative stress and DNA single and double-strand breaks, which persist together with long-lasting metabolic changes in the hippocampal formation. These persisting effects are accompanied by behavioral sensitization, reduced seizure threshold and long-lasting slowing of electroencephalographic activity, and hyperexcitability of the hippocampus, without affecting the basal ganglia. The present data indicate that the intake of very low doses of MDMA, comparable to those consumed by humans, produces selective hippocampal alterations which may underlie cognitive impairment and seizure susceptibility.

Fujiwara, M. (2001). Characteristics of abnormal behavior induced by delta 9-tetrahydrocannabinol in rats. Nippon Yakurigaku Zasshi.Folia Pharmacologica Japonica, 117(1), 35-41.

delta 9-Tetrahydrocannabinol (THC), one of the active compounds of marihuana, is known to induce drug dependence and tolerance, and its action is weaker than those of other abused drugs in humans and animals. Acute effects of THC, "high", "irritable" and "cognitive deficits" are more important than the drug dependence and tolerance. For this reason, we examined characteristics of abnormal behavior such as catalepsy-like immobilization, aggressive behavior including irritable aggression and muricide, and spatial cognition impairment induced by acute and chronic treatments of THC in rats. The catalepsy-like immobilization is related to a decrease in catecholaminergic and serotonergic neurons in the nucleus accumbens and amygdaloid nucleus and thus serves as a useful model for amotivational syndrome, one of cannabis psychoses. In aggressive behavior, muricide was determined by the housing condition. Muricide was induced if the rat was placed under an isolated housing condition within the period of the effect of single injection of THC. The behavioral change resembles exacerbation and flashback in humans. Spatial cognition is impaired by the interaction between cannabinoid (CB1) and 5-HT2 receptor in the dorsal raphe-hippocampal serotonergic neurons. Thus the abnormal behavior induced by THC can be a useful model for investigating mental function in humans and new drugs for the treatment of mental disorders.

Gaillard, M. C., & Borruat, F. X. (2003). Persisting visual hallucinations and illusions in previously drug-addicted patients. Klinische Monatsblatter Fur Augenheilkunde, 220(3), 176-178. doi:10.1055/s-2003-38173

BACKGROUND: Tetrahydrocannabinol (cannabis) and lysergic acid diethylamide (LSD) are psychomimetic agents that induce impairment of sensory perception. Illusions and hallucinations are mostly visual. Most frequently the visual phenomena occur in conjunction with drug abuse. PATIENTS AND METHODS: Three previously drug-addicted patients were examined for either persisting or spontaneously recurrent visual phenomena. Two patients complained of persisting visual illusions (vibrations, dyskinetopsia and impaired depth perception) during more than 12 months after an excessive use of cannabis. The third patient was a multiple drug abuser (LSD for 6 years) and complained of visual hallucinations and palinopsia following heavy ethanol intake, 20 years after stopping the use of any drug. RESULTS: Results from neuro-ophthalmic and neurological examinations were normal for the first two patients. The third patient presented abnormal visual fields with preserved visual acuity; electroencephalography was abnormal, suggesting an underlying toxic encephalopathy. CONCLUSIONS: Persistent visual illusions or hallucinations can occur during several months after an intake of cannabis. Flash-back phenomena are frequent amongst LSD abusers. They rarely occur at long times after the last intake (20 years in the present case); when they do so, precipitating factors are often present (ethanol, medication, anesthesia). Such phenomena reflect the cortical dysfunctions that can be induced by illegal substances.

Gaillard, R., Ouanas, A., Spadone, C., Llorca, P. M., Loo, H., & Bayle, F. J. (2006). Benzodiazepines and schizophrenia, a review of the literature. [benzodiazepines et schizophrenie, revue de la litterature] L'Encephale, 32(6 Pt 1), 1003-1010.

AIn this work, the authors have analysed the principal studies on the interest in the use of benzodiazepines in schizophrenia. The first double-controlled study concerning this question was conducted in 1961. The results of the first studies are criticisable due to the variability of the diagnostic and clinical assessment criteria, as well as to the divergences between the different conclusions. Through this review of literature, the authors wish to clarify the questions and hypothesis raised specify certain therapeutic strategies. MECHANISM OF GABA-ERGIC TREATMENTS: The analysis of the principle works on this question provides evidence on the use of benzodiazepines in schizophrenia. By fixing on their receptors, benzodiazepines facilitate GABA-ergic transmission. GABA is an inhibitor neurotransmitter. The GABA stimulation induced by benzodiazepines may be at the origin of a reduction of the pre-synaptic release of dopamine in the mesolimbic region. The GABA stimulation may also delay the post-synaptic adaptation of the dopaminergic neurons to neuroleptics. This phenomenon may enhance the activity of neuroleptics in resistant schizophrenia. Benzodiazepines would also have an effect on the mesoprefrontocortical regions where neuroleptics may be less efficient. It is interesting to note that this cerebral region is particularly sensitive to stress. This effect of benzodiazepines on the mesoprefrontocortical region might explain a preferentially beneficial effect in patients who have radiographic signs consistent with prefroncortical atrophy, although this observation remains preliminary. BENZODIAZEPINES IN MONOTHERAPY: In monotherapy their action on productive and deficient psychotic symptoms is greatly discussed and not very convincing. The main studies in the use of benzodiazepines alone ) are heterogeneous for their diagnosis criteria, their methodology and their results. The conclusions of the publications are not totally clear, and different points are to be criticized: heterogeneity of assessment criteria, heterogeneity and variability of methodology, use of non standardized scales, most of the studies are open studies, variability of benzodiazepines dose. BENZODIAZEPINES IN ASSOCIATION WITH NEUROLEPTICS: In few controlled studies, most authors have underlined ) the advantage of the association of benzodiazepines with neuroleptics. This association may act either on positive symptoms (hallucinations, delusions) or on negative symptoms. The latent period and the length of the effect of benzodiazepines in the treatment of psychotic patients remain unclear. According to certain studies, the therapeutic effect may appear in a short time, and then disappear within the fourth week. The association of benzodiazepines with neuroleptics is particularly helpful for patients with great anxiety, whether they have neuroleptic intolerance or not. There is no robust convergence about the type of benzodiazepines and their optimal dose in the treatment of schizophrenia. Their use may permit a reduction in the neuroleptic dose. They could increase the plasma concentration of neuroleptics and they might act on the mesoprefrontocortical regions where there are fewer dopaminergic auto receptors. BENZODIAZEPINES AND ANXIETY IN SCHIZOPHRENIA: States of anxiety, and in particular panic disorders that would participate in the exacerbation of psychotic symptoms, would benefit from the use of benzodiazepines. Anxiety can be considered as a major symptom of schizophrenia: insecure feelings and impressions of threatening events are frequent during schizophrenia. Interpretations or brutal hallucinations can lead to the feeling of imminent catastrophe or anxiety. Nevertheless, anxious phenomenons are under-estimated for many reasons: on the one hand, positive symptoms may hide anxiety, and on the other, the symptoms that are observed in patients treated with neuroleptics are often attributed to the neuroleptic side effects rather than linked to anxiety. Benzodiazepines and catatonia - Lorazepam has demonstrated its efficacy on catatonia. This effect seems to be specific of small doses of lorazepam (<5 mg/day). It should be compared to the effect of zolpidem in the same conditions. This prescription should be limited to acute catatonia, with no effect on chronic catatonia. Benzodiazepines and neuroleptic side effects - The use of benzodiazepines to treat some side effects of neuroleptics such as akathesia is reported by certain authors but remains little explained. They may have no effect or only small effects on tardive dyskinesia, but could reduce their incidence with the use of the smallest doses of neuroleptics in association with benzodiazepines. Safety of use - The safety of use of benzodiazepines in schizophrenia, particularly in association with neuroleptics is admitted, however recommended precautions with clozapine are to be noted. Benzodiazepine combined with clozapine clearly increases the frequency of cardiovascular and respiratory accidents. Some studies point out the risk of behavioural desinhibition and dysphoria. Their use should also be limited to patients with good compliancy, in order to avoid exacerbation of symptoms in the case of brutal interruption of the treatment. Dependency, which is an important issue in the use of benzodiazepines, seems much lesser in schizophrenia than in personality disorders and anxiety. Conversely, some studies point out the benefits of benzodiazepine use in schizophrenia, with their efficacy in the treatment and prevention of drug abuse. Finally, benzodiazepines contribute to the establishment of a good patient-doctor relationship, and may guarantee enhanced treatment compliancy.

Gao, K., Muzina, D., Gajwani, P., & Calabrese, J. R. (2006). Efficacy of typical and atypical antipsychotics for primary and comorbid anxiety symptoms or disorders: a review. The Journal of Clinical Psychiatry, 67(9), 1327-1340.

OBJECTIVE: The efficacy of antipsychotics in the treatment of primary or comorbid anxiety disorders or anxiety symptoms in major depressive disorder or bipolar disorder was reviewed. DATA SOURCES: English-language literature cited in MEDLINE from January 1, 1968, to December 31, 2005, was searched with the keywords anxiety disorder, anxiety symptoms, generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, posttraumatic stress disorder, social phobia, bipolar disorder, major depressive disorder, Hamilton Rating Scale for Anxiety, antipsychotics, typical antipsychotics, atypical antipsychotics, fluphenazine, haloperidol, perphenazine, pimozide, thiothixene, trifluoperazine, loxapine, molindone, chlorpromazine, mesoridazine, thioridazine, fluspirilene, penfluridol, pipothiazine, flupenthixol, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, aripiprazole, amisulpride, and clinical trial. Randomized, double-blind, placebo-controlled trials and open-label studies with a minimum of 20 subjects with a DSM-III/IV or ICD-10 diagnosis of anxiety disorder and studies without a DSM-III/IV or ICD-10 diagnosis of anxiety disorder but with Hamilton Rating Scale for Anxiety (HAM-A) scores as an outcome were prioritized. Studies on bipolar disorder or major depressive disorder with the analysis of changes in anxiety symptoms were reviewed. Early studies on neurosis/ anxiety or anxious depression without a HAM-A component were also reviewed. DATA SYNTHESIS: Six trials in primary generalized anxiety disorder (GAD), 15 in refractory obsessive-compulsive disorder (OCD), 8 in posttraumatic stress disorder (PTSD), 6 in neurosis with the HAM-A, 1 in social phobia, and 2 in anxiety symptoms in bipolar depression were identified. Low doses of trifluoperazine were superior to placebo in the treatment of GAD. Most of the less well-designed studies showed that other typical antipsychotics might be superior to placebo or as effective as benzodiazepines in the treatment of GAD and other anxiety conditions. In most studies, risperidone, olanzapine, and quetiapine augmentation to antidepressants was superior to placebo in treating refractory OCD and PTSD. Both olanzapine and quetiapine significantly reduced anxiety compared to placebo in studies of bipolar depression. CONCLUSION: Except for trifluoperazine, there is no large, well-designed study of antipsychotics in the treatment of primary or comorbid anxiety symptoms or disorders. The efficacy of these agents in various anxiety conditions needs to be further investigated with large, well-designed comparison studies.

Gensichen, J., Torge, M., Peitz, M., Wendt-Hermainski, H., Beyer, M., Rosemann, T., . . . Gerlach, F. M. (2005). Case management for the treatment of patients with major depression in general practices--rationale, design and conduct of a cluster randomized controlled trial--PRoMPT (PRimary care Monitoring for depressive Patient's Trial) [iSRCTN66386086]--study protocol. BMC Public Health, 5, 101. doi:10.1186/1471-2458-5-101

BACKGROUND: Depression is a disorder with high prevalence in primary health care and a significant burden of illness. The delivery of health care for depression, as well as other chronic illnesses, has been criticized for several reasons and new strategies to address the needs of these illnesses have been advocated. Case management is a patient-centered approach which has shown efficacy in the treatment of depression in highly organized Health Maintenance Organization (HMO) settings and which might also be effective in other, less structured settings. METHODS/DESIGN: PRoMPT (PRimary care Monitoring for depressive Patients Trial) is a cluster randomised controlled trial with General Practice (GP) as the unit of randomisation. The aim of the study is to evaluate a GP applied case-management for patients with major depressive disorder. 70 GPs were randomised either to intervention group or to control group with the control group delivering usual care. Each GP will include 10 patients suffering from major depressive disorder according to the DSM-IV criteria. The intervention group will receive treatment based on standardized guidelines and monthly telephone monitoring from a trained practice nurse. The nurse investigates the patient's status concerning the MDD criteria, his adherence to GPs prescriptions, possible side effects of medication, and treatment goal attainment. The control group receives usual care--including recommended guidelines. Main outcome measure is the cumulative score of the section depressive disorders (PHQ-9) from the German version of the Prime MD Patient Health Questionnaire (PHQ-D). Secondary outcome measures are the Beck-Depression-Inventory, self-reported adherence (adapted from Moriskey) and the SF-36. In addition, data are collected about patients' satisfaction (EUROPEP-tool), medication, health care utilization, comorbidity, suicide attempts and days out of work. The study comprises three assessment times: baseline (T0) , follow-up after 6 months (T1) and follow-up after 12 months (T2). DISCUSSION: Depression is now recognized as a disorder with a high prevalence in primary care but with insufficient treatment response. Case management seems to be a promising intervention which has the potential to bridge the gap of the usually time-limited and fragmented provision of care. Case management has been proven to be effective in several studies but its application in the private general medical practice setting remains unclear.

Giesbrecht, T., Merckelbach, H., van Oorsouw, K., & Simeon, D. (2010). Skin conductance and memory fragmentation after exposure to an emotional film clip in depersonalization disorder Psychiatry Research, doi:10.1016/j.psychres.2010.03.010

It is often assumed that when confronted with an emotional event, patients with DPD inhibit information processing. It is also thought that this fosters memory fragmentation. This hypothesis has not been tested in chronic depersonalization. The aim of this study was to investigate the temporal pattern of autonomic responding to emotional material in depersonalization disorder, along with concomitant deficits in subjective and objective memory formation (i.e., difficulties to form a coherent narrative consisting of an ordered sequence of events). Participants with depersonalization disorder (n=14) and healthy control participants (n=14) viewed an emotional video clip while their skin conductance (SC) levels were measured. Peritraumatic dissociation was measured before and after the clip, and memory performance was measured 35min after viewing. Compared to controls, depersonalized participants exhibited a distinctly different temporal pattern of autonomic responding, characterized by an earlier peak and subsequent flattening of SCLs. Maximum SCLs did not differ between the two groups. Moreover, unlike the control group, depersonalized participants showed no SC recovery after clip offset. In terms of memory performance, patients exhibited objective memory fragmentation, which they also reported subjectively. However, they did not differ from controls in free recall performance. Apparently, emotional responding in DPD is characterized by a shortened latency to peak with subsequent flattening and is accompanied by memory fragmentation in the light of otherwise unremarkable memory functioning.

Giesbrecht, T., Merckelbach, H., van Oorsouw, K., & Simeon, D. (2010). Skin conductance and memory fragmentation after exposure to an emotional film clip in depersonalization disorder Psychiatry Research, 177(3), 342-349. doi:10.1016/j.psychres.2010.03.010

It is often assumed that when confronted with an emotional event, patients with DPD inhibit information processing. It is also thought that this fosters memory fragmentation. This hypothesis has not been tested in chronic depersonalization. The aim of this study was to investigate the temporal pattern of autonomic responding to emotional material in depersonalization disorder, along with concomitant deficits in subjective and objective memory formation (i.e., difficulties to form a coherent narrative consisting of an ordered sequence of events). Participants with depersonalization disorder (n=14) and healthy control participants (n=14) viewed an emotional video clip while their skin conductance (SC) levels were measured. Peritraumatic dissociation was measured before and after the clip, and memory performance was measured 35 min after viewing. Compared to controls, depersonalized participants exhibited a distinctly different temporal pattern of autonomic responding, characterized by an earlier peak and subsequent flattening of SCLs. Maximum SCLs did not differ between the two groups. Moreover, unlike the control group, depersonalized participants showed no SC recovery after clip offset. In terms of memory performance, patients exhibited objective memory fragmentation, which they also reported subjectively. However, they did not differ from controls in free recall performance. Apparently, emotional responding in DPD is characterized by a shortened latency to peak with subsequent flattening and is accompanied by memory fragmentation in the light of otherwise unremarkable memory functioning.

Giesbrecht, T., Merckelbach, H., van Oorsouw, K., & Simeon, D. (2010). Skin conductance and memory fragmentation after exposure to an emotional film clip in depersonalization disorder Psychiatry Research, 177(3), 342-349. doi:10.1016/j.psychres.2010.03.010

It is often assumed that when confronted with an emotional event, patients with DPD inhibit information processing. It is also thought that this fosters memory fragmentation. This hypothesis has not been tested in chronic depersonalization. The aim of this study was to investigate the temporal pattern of autonomic responding to emotional material in depersonalization disorder, along with concomitant deficits in subjective and objective memory formation (i.e., difficulties to form a coherent narrative consisting of an ordered sequence of events). Participants with depersonalization disorder (n=14) and healthy control participants (n=14) viewed an emotional video clip while their skin conductance (SC) levels were measured. Peritraumatic dissociation was measured before and after the clip, and memory performance was measured 35 min after viewing. Compared to controls, depersonalized participants exhibited a distinctly different temporal pattern of autonomic responding, characterized by an earlier peak and subsequent flattening of SCLs. Maximum SCLs did not differ between the two groups. Moreover, unlike the control group, depersonalized participants showed no SC recovery after clip offset. In terms of memory performance, patients exhibited objective memory fragmentation, which they also reported subjectively. However, they did not differ from controls in free recall performance. Apparently, emotional responding in DPD is characterized by a shortened latency to peak with subsequent flattening and is accompanied by memory fragmentation in the light of otherwise unremarkable memory functioning.

Gilman, S. E., & Abraham, H. D. (2001). A longitudinal study of the order of onset of alcohol dependence and major depression. Drug and Alcohol Dependence, 63(3), 277-286.

Alcohol dependence and major depression commonly occur together; however, few studies have assessed prospectively the magnitude of the risk that one disorder imparts on the subsequent occurrence of the other. We used data from the first two waves of the Epidemiologic Catchment Area community survey (n=14480) to estimate the odds of either major depression or alcohol dependence being followed by the other disorder after 1 year of follow-up. The odds of developing major depression associated with low, medium, and high levels of alcoholic symptoms at baseline were 1.66, 3.98, and 4.32 for females (P<0.001), and 1.19, 2.49, and 2.12 for males (P=0.026). Conversely, odds ratios indicating the 1-year follow-up risk of incident alcohol dependence within low, medium, and high categories of baseline depressive symptomatology were 2.75, 3.52, and 7.88 for females (P<0.001) and 1.50, 1.41, and 1.05 for males (P=0.091). Individuals with alcohol dependence appeared more likely to meet lifetime diagnostic criteria for both disorders after 1 year than individuals with depression. These results suggest that both alcohol dependence and major depression pose a significant risk for the development of the other disorder at 1 year.

Giorgi, F. S., Lazzeri, G., Natale, G., Iudice, A., Ruggieri, S., Paparelli, A., . . . Fornai, F. (2006). MDMA and seizures: a dangerous liaison? Annals of the New York Academy of Sciences, 1074, 357-364. doi:10.1196/annals.1369.035

In the past decades, there was a massive increase in the abuse of methylenedioxymethamphetamine (MDMA) in the Western countries. Seizure onset after MDMA is considered to be related mainly to its acute systemic effects (e.g., hyponatremia and hyperthermia). However, additional mechanisms might concur to it as well. Experiments aimed at disclosing the basis for such an acute effect have the advantage of profiting of controlled conditions and the "pure" compounds, as opposed to the limits of clinical data which are biased by several confounding factors. Amphetamines exert profound effect on different monoaminergic systems, which might participate to lowering of seizure threshold. Chronic effects of MDMA abuse on seizure threshold have not been explored in detail so far. Recent data showed that in mice receiving small, repeated doses of MDMA, a persisting pro-convulsant effect toward limbic seizures and metabolic hyperexcitability can be observed. In the present article, we reviewed these studies and we report our preliminary experimental data documenting the lack of mossy fiber sprouting at short time intervals following MDMA, when seizure susceptibility is already present.

Giuliani, D., Ferrari, F., & Ottani, A. (2000). The cannabinoid agonist HU 210 modifies rat behavioural responses to novelty and stress. Pharmacological Research : The Official Journal of the Italian Pharmacological Society, 41(1), 47-53. doi:10.1006/phrs.1999.0560

Experiments were performed on groups of rats after acute and sub-chronic treatment (once daily for 9 days) with the cannabinoid agonist HU 210 (25-100 microg kg(-1), i.p.) as well as 24 h and 7 days after the last drug injection. The animals underwent three behavioural tests in novel environments. In the observation cages (Test 1), rat locomotor activity was found to be dose-dependently reduced after acute and sub-chronic treatment at all doses and virtually unchanged during abstinence; grooming was potently inhibited by acute treatment but potentiated by the sub-chronic one at doses of 50 and 100 microg kg(-1), the effect of the higher dose persisting after 24 h and 7 days abstinence. Vocalization in animals in response to a tactile stimulus was highest after HU 210 at 100 microg kg(-1) in all experimental modes except after 7 days abstinence. In the X-maze (Test 2), sub-chronic HU 210 dose- dependently enhanced rat natural aversion for open arms, and this behaviour persisted during abstinence after the highest dose. Grooming in the X-maze was completely absent in rats acutely injected with HU 210 but potentiated in those sub-chronically treated or abstinent. In the swimming test (Test 3) rats sub-chronically treated at 50 and 100 pg kg(-1) displayed relevant wall-hugging and the same occurred 24 h after last injection. On the whole, our results are indicative of an anxiogenic-like effect of sub-chronic HU 210 at high doses and reflect the persistence of enhanced emotional response to novel environments when the treatment is discontinued.

Glauser, T., Ben-Menachem, E., Bourgeois, B., Cnaan, A., Chadwick, D., Guerreiro, C., . . . Tomson, T. (2006). ILAE treatment guidelines: evidence-based analysis of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia, 47(7), 1094-1120. doi:10.1111/j.1528-1167.2006.00585.x

PURPOSE: To assess which antiepileptic medications (AEDs) have the best evidence for long-term efficacy or effectiveness as initial monotherapy for patients with newly diagnosed or untreated epilepsy. METHODS: A 10-member subcommission of the Commission on Therapeutic Strategies of The International League Against Epilepsy (ILAE), including adult and pediatric epileptologists, clinical pharmacologists, clinical trialists, and a statistician evaluated available evidence found through a structured literature review including MEDLINE, Current Contents and the Cochrane Library for all applicable articles from 1940 until July 2005. Articles dealing with different seizure types (for different age groups) and two epilepsy syndromes were assessed for quality of evidence (four classes) based on predefined criteria. Criteria for class I classification were a double-blind randomized controlled trial (RCT) design, >or=48-week treatment duration without forced exit criteria, information on >or=24-week seizure freedom data (efficacy) or >or=48-week retention data (effectiveness), demonstration of superiority or 80% power to detect a <or=20% relative difference in efficacy/effectiveness versus an adequate comparator, and appropriate statistical analysis. Class II studies met all class I criteria except for having either treatment duration of 24 to 47 weeks or, for noninferiority analysis, a power to only exclude a 21-30% relative difference. Class III studies included other randomized double-blind and open-label trials, and class IV included other forms of evidence (e.g., expert opinion, case reports). Quality of clinical trial evidence was used to determine the strength of the level of recommendation. RESULTS: A total of 50 RCTs and seven meta-analyses contributed to the analysis. Only four RCTs had class I evidence, whereas two had class II evidence; the remainder were evaluated as class III evidence. Three seizure types had AEDs with level A or level B efficacy and effectiveness evidence as initial monotherapy: adults with partial-onset seizures (level A, carbamazepine and phenytoin; level B, valproic acid), children with partial-onset seizures (level A, oxcarbazepine; level B, None), and elderly adults with partial-onset seizures (level A, gabapentin and lamotrigine; level B, None). One adult seizure type [adults with generalized-onset tonic-clonic (GTC) seizures], two pediatric seizure types (GTC seizures and absence seizures), and two epilepsy syndromes (benign epilepsy with centrotemporal spikes and juvenile myoclonic epilepsy) had no AEDs with level A or level B efficacy and effectiveness evidence as initial monotherapy. CONCLUSIONS: This evidence-based guideline focused on AED efficacy or effectiveness as initial monotherapy for patients with newly diagnosed or untreated epilepsy. The absence of rigorous comprehensive adverse effects data makes it impossible to develop an evidence-based guideline aimed at identifying the overall optimal recommended initial-monotherapy AED. There is an especially alarming lack of well-designed, properly conducted RCTs for patients with generalized seizures/epilepsies and for children in general. The majority of relevant existing RCTs have significant methodologic problems that limit their applicability to this guideline's clinically relevant main question. Multicenter, multinational efforts are needed to design, conduct and analyze future clinically relevant RCTs that can answer the many outstanding questions identified in this guideline. The ultimate choice of an AED for any individual patient with newly diagnosed or untreated epilepsy should include consideration of the strength of the efficacy and effectiveness evidence for each AED along with other variables such as the AED safety and tolerability profile, pharmacokinetic properties, formulations, and expense. When selecting a patient's AED, physicians and patients should consider all relevant variables and not just efficacy and effectiveness.

Glick, S. D., Rossman, K., Wang, S., Dong, N., & Keller, R. W.,Jr. (1993). Local effects of ibogaine on extracellular levels of dopamine and its metabolites in nucleus accumbens and striatum: interactions with D-amphetamine. Brain Research, 628(1-2), 201-208.

Systemic administration of ibogaine (40 mg/kg, i.p.) has been reported to induce both acute (1-3 h) and persistent (19-20 h) changes in extracellular levels of dopamine and its metabolites in the nucleus accumbens and striatum. In the present study, local administration of ibogaine to the striatum and nucleus accumbens produced effects that mimicked both the acute and persistent effects of systemic administration: perfusion with high concentrations (200 and 400 microM) of ibogaine mimicked the acute effects (decreased extracellular dopamine levels and increased extracellular metabolite levels) whereas perfusion with a low concentration (10 microM) of ibogaine mimicked the persistent effects (decreased extracellular levels of DOPAC). These results indicate that ibogaine acts directly in brain regions containing dopaminergic nerve terminals and that long-lasting effects of systemically administered ibogaine might be mediated by persisting low levels of ibogaine. Locally administered ibogaine (10 microM) was also found to enhance the effects of systemically administered D-amphetamine (1.25 mg/kg, i.p.) on extracellular dopamine levels, and conversely, systemically administered ibogaine (40 mg/kg, i.p.; 19 h pretreatment) enhanced the effects of locally administered D-amphetamine (1-10 microM). These results indicate that, in addition to a metabolic mechanism implicated previously, a pharmacodynamic mechanism contributes to the interaction between ibogaine and D-amphetamine. The relevance of such mechanisms to claims regarding ibogaine's anti-addictive properties is unclear.

Goadsby, P. J. (2009). Lacrimation, conjunctival injection, nasal symptoms... cluster headache, migraine and cranial autonomic symptoms in primary headache disorders -- what's new? Journal of Neurology, Neurosurgery, and Psychiatry, 80(10), 1057-1058. doi:10.1136/jnnp.2008.162867

Goodwin, G. M., Anderson, I., Arango, C., Bowden, C. L., Henry, C., Mitchell, P. B., . . . Wittchen, H. U. (2008). ECNP consensus meeting. Bipolar depression. Nice, March 2007. European Neuropsychopharmacology : The Journal of the European College of Neuropsychopharmacology, 18(7), 535-549. doi:10.1016/j.euroneuro.2008.03.003

DIAGNOSIS AND EPIDEMIOLOGY: DSM-IV, specifically its text revision DSM-IV-TR, remains the preferred diagnostic system. When employed in general population samples, prevalence estimates of bipolar disorder are relatively consistent across studies in Europe and USA. In community studies, first onset of bipolar mood disorder is usually in the mid-teenage years and twenties, and the occurrence of a major depressive episode or hypomania is usually its first manifestation. Since reliable criteria for delineating unipolar (UP) and bipolar (BI) depression cross-sectionally are currently lacking, there is a longitudinal risk - probably over 10% - that initial UP patients ultimately turn out as BP in the longer run. Its early onset implies a severe potential burden of disease in terms of impaired social and neuropsychological development, most of which is attributable to depression. BIPOLAR DEPRESSION IN CHILDREN: Bipolar I disorder is rare in prepubertal children, when defined according to unmodified DSM-IV-TR criteria. A broad diagnosis of bipolar disorder risks confounding with other childhood psychopathology and has less predictive value for bipolar disorder in adulthood than the conservative definition. Nevertheless, empirical studies of drug and other treatments and longitudinal studies to assess validity of the broadly defined phenotype in children and adolescents are desirable, rather than extrapolation from adult bipolar practice. The need for an increased capacity to conduct reliable trials in children and adolescents is a challenge to Europe, whose healthcare system should allow greater participation and collaboration than other regions, via clinical networks. ECNP will aspire to facilitate such developments. BIPOLAR DEPRESSION IN ADULTS - UNIPOLAR/BIPOLAR CONTRAST: Despite some differences in symptom profiles and severity measures, a cross-sectional categorical distinction between bipolar (BP) and unipolar (UP) depression is currently impossible. For regulatory purposes, a major depressive episode, meeting DSM-IV-TR criteria, remains the same diagnosis, irrespective of the overall course of the disorder. However, in refining diagnosis in future studies and DSM-V, a probabilistical approach to the UP/BP distinction is more likely to be informative as recommended by the International Society for Bipolar Disorders (ISBD). Anxiety is a commonly present, often at syndromal levels, in bipolar populations. Thus, RCT inclusion criteria for trials not targeting anxiety, should accept co-morbid anxiety disorders as part of the history and even current anxiety symptoms, where these are not dominating the mental state at recruitment to a study. Rapid cycling patients defined as those suffering from 4 or more episodes per year, may also be recruited into trials of bipolar depression without impairing assay sensitivity. Illness severity critically affects assay sensitivity. The minimum scores for entry into a bipolar depression trials should be >20 on HAM-D (17 item scale). However, efficacy is best detected in patients with HAM-D >24 at baseline. THE USE OF RATING SCALES IN BIPOLAR DEPRESSION: There is some dissatisfaction with the HAM-D or MADRS as the preferred primary outcome for trials, although they probably capture global severity adequately. Secondary measures to capture so-called atypical symptoms (such as hypersomnia or hyperphagia), or specific psychopathology more common in bipolar participants (such as lability of mood), could be informative as secondary measures. TREATMENT STUDIES IN BIPOLAR DEPRESSION: Monotherapy trials against placebo remain the gold-standard design for determining efficacy in bipolar depression. The confounding effects of co-medication are emerging from the literature on antidepressant studies in bipolar depression, often conducted in combination with antimanic agents to avoid possible switch to mood elevation. Three arm trials, including the compound to be tested, placebo, and a standard comparator, are generally preferred in order to ensure assay sensitivity and a better picture of benefit-risk ratio. However, in the absence of any gold-standard, two-arm trials may be enough. If efficacy happens to be proven as monotherapy, new compounds may be tested in adjunctive-medication placebo-controlled designs. Younger adults, without an established need for long-term medication, may be particularly suitable for clinical trials requiring placebo controls. The conversion rate of initial UP depression, converting to become BP in the long run is estimated to be 10%. Switch to mania or hypomania may be the consequence of active treatment for bipolar depression. Some medicines such as the tricyclic antidepressants and venlafaxine may be more likely to provoke switch than others, but this increased rate of switch may not be seen until about 10 weeks of treatment. Twelve week trials against placebo are necessary to determine the risk of switch and to establish continuing effects. Careful assessment at 6-8 weeks is required to ensure that patients who are failing to respond do not continue in a study for unacceptable periods of time. To capture a switch event, studies should include scales to define the phenomenology of the event (e.g. hypomania or mania) and its severity. These may be best applied shortly after the clinical decision that switch is occurring. Long-term treatment is commonly required in bipolar disorder. Trials to detect maintenance of effect or continued response in bipolar depression should follow a 'relapse prevention' design: i.e. patients are treated in an index episode with the medicine of interest and then randomized to either continue the active treatment or placebo. However, acute withdrawal of active medication after treatment response might artificially enhance effect size due to active drug withdrawal effects. A short taper is usually desirable. Longer periods of stabilisation are also desirable for up to 3 months: protocol compliance may then be difficult to achieve in practice and so will certainly make studies more difficult and expensive to conduct. The addition of a medicine to other agents during or after the resolution of a depressive or manic episode, and its subsequent investigation as monotherapy against placebo to prevent further relapse (as in the lamotrigine maintenance trials) is clinically informative. Assay sensitivity and patient acceptability are enhanced if the outcome in long-term studies is 'time to intervention for a new episode' for discontinuation designs.

Gouzoulis-Mayfrank, E., Daumann, J., & Sass, H. (2002). Chronic neurotoxic damage in ecstasy (MDMA) users. Review of the current state of research. [Neurotoxische Langzeitschaden bei Ecstasy (MDMA)-Konsumenten. Uberblick uber den aktuellen Wissensstand] Der Nervenarzt, 73(5), 405-421.

The popular dance drug ecstasy (3,4-methylenedioxymethamphetamine, or MDMA, and some analogues) causes selective and persistent neurotoxic damage of the central serotonergic system in laboratory animals. Serotonin plays a role in numerous functional systems in the CNS. Consequently, various abnormalities including psychiatric, vegetative, neuroendocrine, and cognitive disorders might be expected in humans following damage of the central serotonergic system. In recent years, the questions of possible functional disorders following ecstasy-induced neurotoxicity were addressed in several cross-sectional studies with drug users. In this review we summarize and evaluate the quality of design of these studies. Despite large methodological problems, evidence accumulates in favor of persisting brain damage in ecstasy users resulting in subtle cognitive deterioration. Findings of relatively low memory performance associated with heavy ecstasy use are highly consistent across different studies and user populations. In addition, low performance in tests of higher executive function were reported in some but not all studies. The important questions about progression, persistence, or reversibility of damage after long periods of abstinence have to be addressed in future studies with longitudinal design.

Green, S., Buchbinder, R., & Hetrick, S. (2003). Physiotherapy interventions for shoulder pain. Cochrane Database of Systematic Reviews (Online), (2)(2), CD004258. doi:10.1002/14651858.CD004258

BACKGROUND: The prevalence of shoulder disorders has been reported to range from seven to 36% of the population (Lundberg 1969) accounting for 1.2% of all General Practitioner encounters in Australia (Bridges Webb 1992). Substantial disability and significant morbidity can result from shoulder disorders. While many treatments have been employed in the treatment of shoulder disorders, few have been proven in randomised controlled trials. Physiotherapy is often the first line of management for shoulder pain and to date its efficacy has not been established. This review is one in a series of reviews of varying interventions for shoulder disorders, updated from an earlier Cochrane review of all interventions for shoulder disorder. OBJECTIVES: To determine the efficacy of physiotherapy interventions for disorders resulting in pain, stiffness and/or disability of the shoulder. SEARCH STRATEGY: MEDLINE, EMBASE, the Cochrane Clinical Trials Regiter and CINAHL were searched 1966 to June 2002. The Cochrane Musculoskeletal Review Group's search strategy was used and key words gained from previous reviews and all relevant articles were used as text terms in the search. SELECTION CRITERIA: Each identified study was assessed for possible inclusion by two independent reviewers. The determinants for inclusion were that the trial be of an intervention generally delivered by a physiotherapist, that treatment allocation was randomised; and that the study population be suffering from a shoulder disorder, excluding trauma and systemic inflammatory diseases such as rheumatoid arthritis. DATA COLLECTION AND ANALYSIS: The methodological quality of the included trials was assessed by two independent reviewers according to a list of predetermined criteria, which were based on the PEDro scale specifically designed for the assessment of validity of trials of physiotherapy interventions. Outcome data was extracted and entered into Revman 4.1. Means and standard deviations for continuous outcomes and number of events for binary outcomes were extracted where available from the published reports. All standard errors of the mean were converted to standard deviation. For trials where the required data was not reported or not able to be calculated, further details were requested from first authors. If no further details were provided, the trial was included in the review and fully described, but not included in the meta-analysis. Results were presented for each diagnostic sub group (rotator cuff disease, adhesive capsulitis, anterior instability etc) and, where possible, combined in meta-analysis to give a treatment effect across all trials. MAIN RESULTS: Twenty six trials met inclusion criteria. Methodological quality was variable and trial populations were generally small (median sample size = 48, range 14 to 180). Exercise was demonstrated to be effective in terms of short term recovery in rotator cuff disease (RR 7.74 (1.97, 30.32), and longer term benefit with respect to function (RR 2.45 (1.24, 4.86). Combining mobilisation with exercise resulted in additional benefit when compared to exercise alone for rotator cuff disease. Laser therapy was demonstrated to be more effective than placebo (RR 3.71 (1.89, 7.28) for adhesive capsulitis but not for rotator cuff tendinitis. Both ultrasound and pulsed electromagnetic field therapy resulted in improvement compared to placebo in pain in calcific tendinitis (RR 1.81 (1.26, 2.60) and RR 19 (1.16, 12.43) respectively). There is no evidence of the effect of ultrasound in shoulder pain (mixed diagnosis), adhesive capsulitis or rotator cuff tendinitis. When compared to exercises, ultrasound is of no additional benefit over and above exercise alone. There is some evidence that for rotator cuff disease, corticosteroid injections are superior to physiotherapy and no evidence that physiotherapy alone is of benefit for Adhesive Capsulitis REVIEWER'S CONCLUSIONS: The small sample sizes, variable methodological quality and heterogeneity in terms of population studied, physiotherapy intervention employed and length of follow up of randomised controlled trials of physiotherapy interventions results in little overall evidence to guide treatment. There is evidence to support the use of some interventions in specific and circumscribed cases. There is a need for trials of physiotherapy interventions for specific clinical conditions associated with shoulder pain, for shoulder pain where combinations of physiotherapy interventions, as well as, physiotherapy interventions as an adjunct to other, non physiotherapy interventions are compared. This is more reflective of current clinical practice. Trials should be adequately powered and address key methodological criteria such as allocation concealment and blinding of outcome assessor.

Gresch, P. J., Smith, R. L., Barrett, R. J., & Sanders-Bush, E. (2005). Behavioral tolerance to lysergic acid diethylamide is associated with reduced serotonin-2A receptor signaling in rat cortex. Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology, 30(9), 1693-1702. doi:10.1038/sj.npp.1300711

Tolerance is defined as a decrease in responsiveness to a drug after repeated administration. Tolerance to the behavioral effects of hallucinogens occurs in humans and animals. In this study, we used drug discrimination to establish a behavioral model of lysergic acid diethylamide (LSD) tolerance and examined whether tolerance to the stimulus properties of LSD is related to altered serotonin receptor signaling. Rats were trained to discriminate 60 microg/kg LSD from saline in a two-lever drug discrimination paradigm. Two groups of animals were assigned to either chronic saline treatment or chronic LSD treatment. For chronic treatment, rats from each group were injected once per day with either 130 microg/kg LSD or saline for 5 days. Rats were tested for their ability to discriminate either saline or 60 microg/kg LSD, 24 h after the last chronic injection. Rats receiving chronic LSD showed a 44% reduction in LSD lever selection, while rats receiving chronic vehicle showed no change in percent choice on the LSD lever. In another group of rats receiving the identical chronic LSD treatment, LSD-stimulated [35S]GTPgammaS binding, an index of G-protein coupling, was measured in the rat brain by autoradiography. After chronic LSD, a significant reduction in LSD-stimulated [35S]GTPgammaS binding was observed in the medial prefrontal cortex and anterior cingulate cortex. Furthermore, chronic LSD produced a significant reduction in 2,5-dimethoxy-4-iodoamphetamine-stimulated [35S]GTPgammaS binding in medial prefrontal cortex and anterior cingulate cortex, which was blocked by MDL 100907, a selective 5-HT2A receptor antagonist, but not SB206553, a 5-HT2C receptor antagonist, indicating a reduction in 5-HT2A receptor signaling. 125I-LSD binding to 5-HT2A receptors was reduced in cortical regions, demonstrating a reduction in 5-HT2A receptor density. Taken together, these results indicate that adaptive changes in LSD-stimulated serotonin receptor signaling may mediate tolerance to the discriminative stimulus effects of LSD.

Griffiths, R. R., Richards, W. A., McCann, U., & Jesse, R. (2006). Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance. Psychopharmacology, 187(3), 268-83; discussion 284-92. doi:10.1007/s00213-006-0457-5

RATIONALE: Although psilocybin has been used for centuries for religious purposes, little is known scientifically about its acute and persisting effects. OBJECTIVES: This double-blind study evaluated the acute and longer-term psychological effects of a high dose of psilocybin relative to a comparison compound administered under comfortable, supportive conditions. MATERIALS AND METHODS: The participants were hallucinogen-naive adults reporting regular participation in religious or spiritual activities. Two or three sessions were conducted at 2-month intervals. Thirty volunteers received orally administered psilocybin (30 mg/70 kg) and methylphenidate hydrochloride (40 mg/70 kg) in counterbalanced order. To obscure the study design, six additional volunteers received methylphenidate in the first two sessions and unblinded psilocybin in a third session. The 8-h sessions were conducted individually. Volunteers were encouraged to close their eyes and direct their attention inward. Study monitors rated volunteers' behavior during sessions. Volunteers completed questionnaires assessing drug effects and mystical experience immediately after and 2 months after sessions. Community observers rated changes in the volunteer's attitudes and behavior. RESULTS: Psilocybin produced a range of acute perceptual changes, subjective experiences, and labile moods including anxiety. Psilocybin also increased measures of mystical experience. At 2 months, the volunteers rated the psilocybin experience as having substantial personal meaning and spiritual significance and attributed to the experience sustained positive changes in attitudes and behavior consistent with changes rated by community observers. CONCLUSIONS: When administered under supportive conditions, psilocybin occasioned experiences similar to spontaneously occurring mystical experiences. The ability to occasion such experiences prospectively will allow rigorous scientific investigations of their causes and consequences.

Gury, C. (2004). Schizophrenia, diabetes mellitus and antipsychotics. [schizophrenie, diabete et antipsychotiques] L'Encephale, 30(4), 382-391.

During the last years, a contribution of antipsychotic drugs in the increase of diabetes prevalence in schizophrenic population has been repetitively suggested. The debate focused mainly on the second-generation antipsychotics. The analysis of the scientific literature indicates however that this discussion is not recent and an increase of diabetes prevalence in schizophrenic populations was already described before the introduction of neuroleptics. Then, after the introduction of the first neuroleptics in the 1950s, an increase of diabetes prevalence was reported among treated patients and the same alarms occurred in the 1990s after the introduction of second-generation antipsychotics. These treatments were related to an increase of glucose tolerance impairment, type II diabetes and diabetic acidoketosis. Recent epidemiological studies have confirmed the increase prevalence of diabetes in schizophrenic patients, particularly in schizophrenic patients before any antipsychotic treatment. Among the suggested mechanisms, there are sedentary life (due to hospitalisation and sedative effects of neuroleptics), food imbalance, shared genetic factors for diabetes and schizophrenia. Moreover, the frequency of the metabolic syndrome is increased in schizophrenic populations. This syndrome associates blood glucose increase, lipid metabolism disorders and android obesity. This could explain--via an increase of the cortisol production--the increase of mortality due to cardiovascular diseases observed in schizoprhenic patients. Thus, it seems well established that schizophrenia is associated with an increased risk for diabetes. It is however more difficult to evaluate the role of antipsychotic treatment as a causative factor of diabetes. Indeed, there are many published case reports or diabetes or diabetic acidoketosis after an antipsychotic treatment, but the level of evidence in controlled trials is low. Many studies were performed on large databases, but were retrospective and subjected to many flaws: concomitant diseases not taken into account, diabetes status evaluated by drug consumption, unknown diabetes status before antipsychotic treatment, etc. In the few prospective studies performed, no significant differences between the atypical versus typical antipsychotics were evidenced for new cases of diabetes. Moreover, in general population, the glucose tolerance impairment is underdiagnosed and it is estimated that people with a glucose tolerance impairment have a 5-10% annual risk of type II diabetes. Thus, this concern has to be replaced among the world epidemic increase of diabetes and in a population of patients whose the disease itself and life style are risk factors for diabetes. Some studies have explored the pathophysiological mechanisms that could support a diabetogenic effect of antipsychotics. Although it does not seem to be a direct effect of antipsychotics on insulin secretion by pancreatic cells, body weight increase has been evidence for both typical and atypical antipsychotics. However, it remains unclear whether this weight increase is responsible for a visceral adiposity, which is a risk factor better fitted to the cardiovascular mortality tha the body weight itself. Other hypotheses involving an effect on the leptin, which regulates the appetite, have been proposed. In waiting of new prospective controlled studies, and without denying the impact of antipsychotics on the glucose and lipid metabolisms (on the weight increase, for example), it should be recognized that the benefit/risk ratio remains largely in favour of the treatment, particularly for the atypical antipsychotics, more effective and better tolerated at the neurological level than the conventional antipsychotics. One of the benefits of the mainly articles in professional media about this concern is to draw attention on the metabolism disorders in schizophrenic patients, which are important risk factor of their frequent cardiovascular surmortality whatever the causes. Consequently, it is advised to monitor glucose and lipid metabolisms of schizophrenic patients before and during their treatment (body weight, fast blood glucose, blood cholesterol and triglycerides). In conclusion, schizophrenic patients are a population with an increased metabolic risk, which is a cause of their increased mortality. Although these data are known since a long time ago, this population does not benefit from the same metabolic follow-up than the non-schizophrenic population. The debate on the possible relationship between diabetes and antipsychotics should be also taken as a helpful recall of the necessity to follow simple rules of prevention and monitoring in this at-risk population. This should make it possible to preserve the benefit of the antipsychotics, the contribution of which in the treatment of schizophrenia is not any more to demonstrate.

Halpern, A. L., Halpern, J. H., & Doherty, S. B. (2008). "Enhanced" interrogation of detainees: do psychologists and psychiatrists participate? Philosophy, Ethics, and Humanities in Medicine : PEHM, 3, 21. doi:10.1186/1747-5341-3-21

After revelations of participation by psychiatrists and psychologists in interrogation of prisoners at Guantanamo Bay and Central Intelligence Agency secret detention centers, the American Psychiatric Association and the American Psychological Association adopted Position Statements absolutely prohibiting their members from participating in torture under any and all circumstances, and, to a limited degree, forbidding involvement in interrogations. Some interrogations utilize very aggressive techniques determined to be torture by many nations and organizations throughout the world. This paper explains why psychiatrists and psychologists involved in coercive interrogations violate the Geneva Conventions and the laws of the United States. Whether done with ignorance of professional ethical obligations or not, these psychiatrists and psychologists have crossed an ethical barrier that may best be averted from re-occurring by teaching medical students and residents in all medical specialties about the ethics principles stemming from the 1946-1947 Nuremberg trials and the Geneva Conventions, together with the Ethics Codes of the World Medical Association and the American Medical Association; and, with regard to psychiatric residents and psychological trainees, by the teaching about The Principles of Medical Ethics With Annotations Especially Applicable to Psychiatry and the Ethical Principles of Psychologists and Code of Conduct, respectively. In this way, all physicians and psychologists will clearly understand that they have an absolute moral obligation to "First, do no harm" to the human beings they professionally encounter.

Halpern, J. H., & Pope, H. G.,Jr. (2003). Hallucinogen persisting perception disorder: what do we know after 50 years? Drug and Alcohol Dependence, 69(2), 109-119.

'Flashbacks' following use of hallucinogenic drugs have been reported for decades; they are recognized in DSM-IV as 'Hallucinogen Persisting Perception Disorder (Flashbacks)', or HPPD. We located and analyzed 20 quantitative studies between 1955 and 2001 examining this phenomenon. However, many of these studies were performed before operational criteria for HPPD were published in DSM-III-R, so they are difficult to interpret in the light of current diagnostic criteria. Overall, current knowledge of HPPD remains very limited. In particular (1) the term 'flashbacks' is defined in so many ways that it is essentially valueless; (2) most studies provide too little information to judge how many cases could meet DSM-IV criteria for HPPD; and consequently (3) information about risk factors for HPPD, possible etiologic mechanisms, and potential treatment modalities must be interpreted with great caution. At present, HPPD appears to be a genuine but uncommon disorder, sometimes persisting for months or years after hallucinogen use and causing substantial morbidity. It is reported most commonly after illicit LSD use, but less commonly with LSD administered in research or treatment settings, or with use of other types of hallucinogens. There are case reports, but no randomized controlled trials, of successful treatment with neuroleptics, anticonvulsants, benzodiazepines, and clonidine. Although it may be difficult to collect large samples of HPPD cases, further studies are critically needed to augment the meager data presently available regarding the prevalence, etiology, and treatment of HPPD.

Halpern, J. H., Sholar, M. B., Glowacki, J., Mello, N. K., Mendelson, J. H., & Siegel, A. J. (2003). Diminished interleukin-6 response to proinflammatory challenge in men and women after intravenous cocaine administration. The Journal of Clinical Endocrinology and Metabolism, 88(3), 1188-1193.

Cocaine abuse is associated with increased rates of infections, including human immunodeficiency virus, and cocaine has immunomodulatory effects in experimental animal and cellular models. When challenged by antigens, tissues release cytokine polypeptides that signal a complex balance of cellular and humoral immune responses. Placement of indwelling venous catheters also leads to surrounding tissue inflammation, mediated partially by local production and release of the proinflammatory cytokine, IL-6. Thus, catheter placement provides a model for examination of cocaine's immunological effects. Thirty healthy men and women with a history of cocaine use participated in this study of neuroendocrine and immunological responses to iv injection of 0.4 mg/kg cocaine or saline placebo. After injection, blood samples were collected from the antecubital vein of the opposite arm via an indwelling venous catheter at 2, 4, 8, 12, 16, 20, 30, 40, 60, 80, 120, 180, and 240 min. Cocaine, ACTH, cortisol, and dehydroepiandrosterone concentrations peaked at 8, 12, 40, and 20 min, respectively. Stimulation of IL-6 at 240 min was markedly reduced in subjects receiving cocaine compared with subjects receiving placebo (3.85 +/- 0.49 vs. 11.64 +/- 2.21 pg/ml; P = 0.0019, by two-tailed t test). Gender and menstrual cycle phase did not significantly influence most endocrine or IL-6 measures, although the small number of subjects limits the power of these comparisons. Because cocaine stimulates the hypothalamic-pituitary-adrenal axis, IL-6 suppression may be a consequence of corticosteroid release. Cocaine-induced suppression of proinflammatory IL-6 may mediate impaired host defenses to infections.

Hasse, H. E., & Waldmann, H. (1971). "Flashback": spontaneous psychotic episodes in adolescence resulting from psychedelic drug use. ["Flashback": Spontane psychotische Episoden als Folgeerscheinung des Phantasticagebrauchs Jugendlicher] Archiv Fur Psychiatrie Und Nervenkrankheiten, 214(4), 399-439.

Hay, P., Bacaltchuk, J., Claudino, A., Ben-Tovim, D., & Yong, P. Y. (2003). Individual psychotherapy in the outpatient treatment of adults with anorexia nervosa. Cochrane Database of Systematic Reviews (Online), (4)(4), CD003909. doi:10.1002/14651858.CD003909

BACKGROUND: Anorexia nervosa is a disorder of high morbidity and significant mortality. It is commonest in young adult women, in whom the incidence may be increasing. The focus of treatment has moved to an outpatient setting and a number of differing psychotherapies are presently used in treatment. OBJECTIVES: The aim of the present review was to evaluate the evidence from randomised controlled trials for the efficacy of outpatient psychotherapies used in the treatment of older adolescents and adults with anorexia nervosa SEARCH STRATEGY: The strategy comprised database searches of MEDLINE, EXTRAMED, EMBASE,PSYCLIT, CURRENT CONTENTS, Cochrane Collaboration Controlled Trials Register and the Depression and Anxiety Neuroses Cochrane Group (CCDAN), a hand-search of The International Journal of Eating Disorders, and he reference lists of all papers selected. Personal letters were sent to identified notable researchers published in the area, requesting information on trials that are unpublished or in progress. SELECTION CRITERIA: All randomised controlled trials of adult individual outpatient therapy for anorexia nervosa as defined by the DSM-IV or similar international criterion. Quality ratings were made according to the CCDAN criteria and in addition, whether the trial had examined treatment integrity. DATA COLLECTION AND ANALYSIS: A range of outcome variables were selected, including physical state, severity of eating disorder attitudes and beliefs, interpersonal function, and general psychiatric symptom severity. Continuous outcome data comparisons were made with the standardized mean difference statistic, and binary outcome comparisons made with the relative risk statistic. Reliability of data extraction and quality ratings were made with the kappa statistic. Sensitivity analyses to evaluate the effects of trial quality and subgroup analyses to explore specific questions of treatment effects from different settings, frequency and duration of therapies were planned. MAIN RESULTS: Six small trials only, two of which included children or adolescents, were identified from the search and aggregation of data was not possible. Bias was possible due particularly to lack of blinding of outcome assessments. The results in two trials suggested that 'treatment as usual' or similar may be less efficacious than a specific psychotherapy. No specific treatment was consistently superior to any other specific approach. Dietary advice as a control arm had a 100% non-completion rate in one trial. REVIEWER'S CONCLUSIONS: No specific approach can be recommended from this review. It is unclear why 'treatment as usual' performed so poorly or why dietary advice alone appeared so unacceptable as the reasons for non-completion were not reported. There is an urgent need for large well-designed trials in his area.

Haynes, J. (2009). Decoding visual consciousness from human brain signals. Trends in Cognitive Sciences, 13(5), 194-202. doi:DOI: 10.1016/j.tics.2009.02.004

Hay-Smith, E. J., Bo, K., Berghmans, L. C., Hendriks, H. J., de Bie, R. A., & van Waalwijk van Doorn, E. S. (2007). WITHDRAWN: Pelvic floor muscle training for urinary incontinence in women. Cochrane Database of Systematic Reviews (Online), (1)(1), CD001407. doi:10.1002/14651858.CD001407.pub2

BACKGROUND: Pelvic floor muscle training is the most commonly recommended physical therapy treatment for women with stress leakage of urine. It is also used in the treatment of women with mixed incontinence, and less commonly for urge incontinence. Adjuncts, such as biofeedback or electrical stimulation, are also commonly used with pelvic floor muscle training. The content of pelvic floor muscle training programmes is highly variable. OBJECTIVES: To determine the effects of pelvic floor muscle training for women with symptoms or urodynamic diagnoses of stress, urge and mixed incontinence, in comparison to no treatment or other treatment options. SEARCH STRATEGY: Search strategy: We searched the Cochrane Incontinence Group trials register (May 2000), Medline (1980 to 1998), Embase (1980 to 1998), the database of the Dutch National Institute of Allied Health Professions (to 1998), the database of the Cochrane Rehabilitation and Related Therapies Field (to 1998), Physiotherapy Index (to 1998) and the reference lists of relevant articles. We handsearched the proceedings of the International Continence Society (1980 to 2000). We contacted investigators in the field to locate studies. Date of the most recent searches: May 2000. SELECTION CRITERIA: Randomised trials in women with symptoms or urodynamic diagnoses of stress, urge or mixed incontinence that included pelvic floor muscle training in at least one arm of the trial. DATA COLLECTION AND ANALYSIS: Two reviewers assessed all trials for inclusion/exclusion and methodological quality. Data were extracted by the lead reviewer onto a standard form and cross checked by another. Disagreements were resolved by discussion. Data were processed as described in the Cochrane Handbook. Sensitivity analysis on the basis of diagnosis was planned and undertaken where appropriate. MAIN RESULTS: Forty-three trials met the inclusion criteria. The primary or only reference for 15 of these was a conference abstract. The pelvic floor muscle training programs, and comparison interventions, varied markedly. Outcome measures differed between trials, and methods of data reporting varied, making the data difficult to combine.Many of the trials were small. Allocation concealment was adequate in five trials, and nine trials used assessors masked to group allocation. Thirteen trials reported that there were no losses to follow up, seven trials had dropout rates of less than 10%, but in the remaining trials the proportion of dropouts ranged from 12% to 41%.Pelvic floor muscle training was better than no treatment or placebo treatments for women with stress or mixed incontinence. 'Intensive' appeared to be better than 'standard' pelvic floor muscle training. PFMT may be more effective than some types of electrical stimulation but there were problems in combining the data from these trials. There is insufficient evidence to determine if pelvic floor muscle training is better or worse than other treatments.The effect of adding pelvic floor muscle training to other treatments (e.g. electrical stimulation, behavioural training) is not clear due to the limited amount of evidence available. Evidence of the effect of adding other adjunctive treatments to PFMT (e.g. vaginal cones, intravaginal resistance) is equally limited. The effectiveness of biofeedback assisted PFMT is not clear, but on the basis of the evidence available there did not appear to be any benefit over PFMT alone at post treatment assessment.Long-term outcomes of pelvic floor muscle training are unclear. Side effects of pelvic floor muscle training were uncommon and reversible. A number of the formal comparisons should be viewed with caution due to statistical heterogeneity, lack of statistical independence, and the possibility of spurious confidence intervals in some instances. AUTHORS' CONCLUSIONS: Pelvic floor muscle training appeared to be an effective treatment for adult women with stress or mixed incontinence. Pelvic floor muscle training was better than no treatment or placebo treatments. The limitations of the evidence available mean that is difficult to judge if pelvic floor muscle training was better or worse than other treatments. Most trials to date have studied the effect of treatment in younger, premenopausal women. The role of pelvic floor muscle training for women with urge incontinence alone remains unclear. Many of the trials were small with poor reporting of allocation concealment and masking of outcome assessors. In addition there was a lack of consistency in the choice and reporting of outcome measures that made data difficult to combine. Methodological problems limit the confidence that can be placed in the findings of the review. Further, large, high quality trials are necessary.

Hedlund, C., Rapoport, A. M., Dodick, D. W., & Goadsby, P. J. (2009). Zolmitriptan nasal spray in the acute treatment of cluster headache: a meta-analysis of two studies. Headache, 49(9), 1315-1323. doi:10.1111/j.1526-4610.2009.01518.x

OBJECTIVE: To conduct an individual subject meta-analysis of available controlled studies of zolmitriptan nasal spray in the acute treatment of cluster headache. BACKGROUND: Two double-blind, placebo-controlled, randomized, crossover studies of zolmitriptan nasal spray in the acute treatment of cluster headache, with similar patient populations, protocol designs, doses, and clinical endpoints have been published. METHODS: In both double-blind studies, each patient was to treat 3 attacks, 1 with placebo, 1 with zolmitriptan 5 mg, and 1 with zolmitriptan 10 mg in a randomized, crossover manner. Headache intensity was rated on a 5-point scale (none to very severe). The primary endpoint was headache relief at 30 minutes post dose: reduction from moderate, severe, or very severe pain to mild or none. A multilevel, random-effects, logistic regression model was used to analyze the data. RESULTS: A total of 121 patients (100 male; 64.5% with episodic cluster headache) provided efficacy data for at least 1 attack. Zolmitriptan 5 mg and 10 mg were significantly more effective at providing headache relief at 30 minutes post treatment than placebo (odds ratio 3.48; 95% confidence interval 1.49-8.10 and odds ratio 8.68; 95% confidence interval: 3.35-22.5, respectively). For episodic cluster headache, response rates were 35.6%, 51.7%, and 73.7% for placebo, zolmitriptan 5 mg (odds ratio 2.5; P = .06 vs placebo), and 10 mg (odds ratio 9.9; P < .001 vs placebo), respectively. For chronic cluster headache, response rates were 17.2%, 41.9%, and 40.7% for placebo, zolmitriptan 5 mg (odds ratio 8.1; P = .035), and 10 mg (odds ratio 7.6; P = .046), respectively. Zolmitriptan was well tolerated in both studies with no serious adverse events reported. CONCLUSION: Zolmitriptan nasal spray at a dose of 5 mg and 10 mg is efficacious in the acute treatment of episodic and chronic cluster headache.

Heinrich, S. P., Mell, D., & Bach, M. (2009). Frequency-domain analysis of fast oddball responses to visual stimuli: A feasibility study. International Journal of Psychophysiology, 73(3), 287-293. doi:DOI: 10.1016/j.ijpsycho.2009.04.011

Event-related potential responses to oddball stimuli, including the P300 component, have been proposed as a diagnostic tool for discerning psychiatric or higher-level neural disorders from malingering, for instance in cases of unexplained visual loss. For clinical use, short recording durations and easy statistical assessment are highly desirable. With this aim, we investigated the feasibility of recording oddball responses in a fast steady-state regime. We used gratings with two possible orientations in a rapid oddball paradigm with an inter-stimulus interval of 214 ms. Six consecutive presentations of one stimulus type (frequent) were followed by a single presentation of the other (infrequent) stimulus type. Subjects were attending to the rare stimulus type. The electroencephalographic recordings were analyzed in the frequency domain. All subjects produced significant harmonic responses related to the processing of the rare stimulus, demonstrating the feasibility of the technique, with the potential of reducing recording times substantially compared to conventional slow stimulation. We furthermore found that the regularity of the occurrence of infrequent stimuli, which is necessary for frequency-domain analysis, does not per se reduce the P300 responses, as would have been expected in the framework of some hypotheses regarding the role of the P300.

Hermle, L., Kovar, K. A., Hewer, W., & Ruchsow, M. (2008). Hallucinogen-induced psychological disorders. [Halluzinogen-induzierte psychische Storungen] Fortschritte Der Neurologie-Psychiatrie, 76(6), 334-342. doi:10.1055/s-2008-1038191

OBJECTIVE: The purpose of this article is to provide an overview of the current research on hallucinogen induced psychiatric disorders. In addition to LSD and psilocybin hallucinogens of biologic origin are increasingly used by adolescents and young adults. METHODS: Relevant literature and related articles were identified by means of a computerized MEDLINE search including the years 1997 - 2007. As keywords "hallucinogen induced psychosis", "hallucinogen induced flashback", "hallucinogen persisting perception disorder (HPPD)" were used. Finally, 64 journal articles and books out of 103 were included in the review. RESULTS: Acute psychotic syndromes in adolescents are rarely due to intoxications with hallucinogenic drugs. However, clinical relevance of flashback phenomena as post-hallucinogenic psychiatric disorder has to be disputed. Because of the high popularity of biogenic hallucinogens and LSD knowledge of intoxications and resulting psychiatric disorders as well as medical complications and therapeutical approaches are clinically important. Especially intoxications with drugs of herbal origin like tropanalcaloids play an important role in emergency situations.

Herr, B. E., Abraham, H. D., & Anderson, W. (1991). Length of stay in a general hospital psychiatric unit. General Hospital Psychiatry, 13(1), 68-70.

Fifty psychiatric inpatients with a prolonged length of stay were compared to 50 control admissions for factors associated with prolonged hospitalizations in a general hospital. Seven variables were found to be significantly overrepresented among the long stayers, including treatment with electroconvulsive therapy, medical consultations, underemployment, dementia, disposition to a place other than home, absence of alcohol or drug abuse, and presence of psychosis without affective symptoms. The clinical and policy implications of these finding are discussed.

Higashida, R. T., Furlan, A. J., Roberts, H., Tomsick, T., Connors, B., Barr, J., . . . Technology Assessment Committee of the Society of Interventional Radiology. (2003). Trial design and reporting standards for intra-arterial cerebral thrombolysis for acute ischemic stroke. Stroke; a Journal of Cerebral Circulation, 34(8), e109-37. doi:10.1161/01.STR.0000082721.62796.09

BACKGROUND AND PURPOSE: The National Institutes of Health (NIH) estimates that stroke costs now exceed 45 billion dollars per year. Stroke is the third leading cause of death and one of the leading causes of adult disability in North America, Europe, and Asia. A number of well-designed randomized stroke trials and case series have now been reported in the literature to evaluate the safety and efficacy of thrombolytic therapy for the treatment of acute ischemic stroke. These stroke trials have included intravenous studies, intra-arterial studies, and combinations of both, as well as use of mechanical devices for removal of thromboemboli and of neuroprotectant drugs, alone or in combination with thrombolytic therapy. At this time, the only therapy demonstrated to improve outcomes from an acute stroke is thrombolysis of the clot responsible for the ischemic event. There is room for improvement in stroke lysis studies. Divergent criteria, with disparate reporting standards and definitions, have made direct comparisons between stroke trials difficult to compare and contrast in terms of overall patient outcomes and efficacy of treatment. There is a need for more uniform definitions of multiple variables such as collateral flow, degree of recanalization, assessment of perfusion, and infarct size. In addition, there are multiple unanswered questions that require further investigation, in particular, questions as to which patients are best treated with thrombolysis. One of the most important predictors of clinical success is time to treatment, with early treatment of <3 hours for intravenous tissue plasminogen activator and <6 hours for intra-arterial thrombolysis demonstrating significant improvement in terms of 90-day clinical outcome and reduced cerebral hemorrhage. It is possible that improved imaging that identifies the ischemic penumbra and distinguishes it from irreversibly infarcted tissue will more accurately select patients for therapy than duration of symptoms. There are additional problems in the assessment of patients eligible for thrombolysis. These include being able to predict whether a particular site of occlusion can be successfully revascularized, predict an individual patient's prognosis and outcome after revascularization, and in particular, to predict the development of intracerebral hemorrhage, with and without clinical deterioration. It is not clear to assume that achieving immediate flow restoration due to thrombolytic therapy implies clinical success and improved outcome. There is no simple correlation between recanalization and observed clinical benefit in all ischemic stroke patients, because other interactive variables, such as collateral circulation, the ischemic penumbra, lesion location and extent, time to treatment, and hemorrhagic conversion, are all interrelated to outcome. METHODS: This article was written under the auspices of the Technology Assessment Committees for both the American Society of Interventional and Therapeutic Neuroradiology and the Society of Interventional Radiology. The purpose of this document is to provide guidance for the ongoing study design of trials of intra-arterial cerebral thrombolysis in acute ischemic stroke. It serves as a background for the intra-arterial thrombolytic trials in North America and Europe, discusses limitations of thrombolytic therapy, defines predictors for success, and offers the rationale for the different considerations that might be important during the design of a clinical trial for intra-arterial thrombolysis in acute stroke. Included in this guidance document are suggestions for uniform reporting standards for such trials. These definitions and standards are mainly intended for research trials; however, they should also be helpful in clinical practice and applicable to all publications. This article serves to standardize reporting terminology and includes pretreatment assessment, neurologic evaluation with the NIH Stroke Scale score, imaging evaluation, occlusion sites, perfusion grades, follow-up imaging studies, and neurologic assessments. Moreover, previously used and established definitions for patient selection, outcome assessment, and data analysis are provided, with some possible variations on specific end points. This document is therefore targeted to help an investigator to critically review the scales and scores used previously in stroke trials. This article also seeks to standardize patient selection for treatment based on neurologic condition at presentation, baseline imaging studies, and utilization of standardized inclusion/exclusion criteria. It defines outcomes from therapy in phase I, II, and III studies. Statistical approaches are presented for analyzing outcomes from prospective, randomized trials with both primary and secondary variable analysis. A discussion on techniques for angiography, intra-arterial thrombolysis, anticoagulation, adjuvant therapy, and patient management after therapy is given, as well as recommendations for posttreatment evaluation, duration of follow-up, and reporting of disability outcomes. Imaging assessment before and after treatment is given. In the past, noncontrast CT brain scans were used as the initial screening examination of choice to exclude cerebral hemorrhage. However, it is now possible to quantify the volume of early infarct by using contiguous, discrete (nonhelical) images of 5 mm. In addition, CT angiography by helical scanning and 100 mL of intravenous contrast agent can be used expeditiously to obtain excellent vascular anatomy, define the occlusion site, obtain 2D and 3D reformatted vascular images, grade collateral blood flow, and perform tissue-perfusion studies to define transit times of a contrast bolus through specific tissue beds and regions of interest in the brain. Dynamic CT perfusion scans to assess the whole dynamics of a contrast agent transit curve can now be routinely obtained at many hospitals involved in these studies. The rationale, current status of this technology, and potential use in future clinical trials are given. Many hospitals are also performing MR brain studies at baseline in addition to, or instead of, CT scans. MRI has a high sensitivity and specificity for the diagnosis of ischemic stroke in the first several hours from symptom onset, identifies arterial occlusions, and characterizes ischemic pathology noninvasively. Case series have demonstrated and characterized the early detection of intraparenchymal hemorrhage and subarachnoid hemorrhage by MRI. Echo planar images, used for diffusion MRI and, in particular, perfusion MRI are inherently sensitive for the susceptibility changes caused by intraparenchymal blood products. Consequently, MRI has replaced CT to rule out acute hemorrhage in some centers. The rationale and the potential uses of MR scanning are provided. In addition to established criteria, technology is continuously evolving, and imaging techniques have been introduced that offer new insights into the pathophysiology of acute ischemic stroke. For example, a better patient stratification might be possible if CT and/or MRI brain scans are used not only as exclusion criteria but also to provide individual inclusion and exclusion criteria based on tissue physiology. Imaging techniques might also be used as a surrogate outcome measure in future thrombolytic trials. The context of a controlled study is the best environment to validate emerging imaging and treatment techniques. The final section details reporting standards for complications and adverse outcomes; defines serious adverse events, adverse events, and unanticipated adverse events; and describes severity of complications and their relation to treatment groups. Recommendations are made regarding comparing treatment groups, randomization and blinding, intention-to-treat analysis, quality-of-life analysis, and efficacy analysis. This document concludes with an analysis of general costs associated with therapy, a discussion regarding entry criteria, outcome measures, and the variability of assessment of the different stroke scales currently used in the literature is also featured. CONCLUSIONS: In summary, this article serves to provide a more uniform set of criteria for clinical trials and reporting outcomes used in designing stroke trials involving intra-arterial thrombolytic agents, either alone or in combination with other therapies. It is anticipated that by having a more uniform set of reporting standards, more meaningful analysis of the data and the literature will be able to be achieved.

Hofmann, S. G., & Smits, J. A. (2008). Cognitive-behavioral therapy for adult anxiety disorders: a meta-analysis of randomized placebo-controlled trials. The Journal of Clinical Psychiatry, 69(4), 621-632.

OBJECTIVE: Cognitive-behavioral therapy (CBT) is frequently used for various adult anxiety disorders, but there has been no systematic review of the efficacy of CBT in randomized placebo-controlled trials. The present study meta-analytically reviewed the efficacy of CBT versus placebo for adult anxiety disorders. DATA SOURCES: We conducted a computerized search for treatment outcome studies of anxiety disorders from the first available date to March 1, 2007. We searched MEDLINE, PsycINFO, PubMed, Scopus, the Institute of Scientific Information, and Dissertation Abstracts International for the following terms: random*, cognitive behavior*therap*, cognitive therap*, behavior*therap*, GAD, generalized anxiety disorder, OCD, obsessive compulsive disorder, social phobia, social anxiety disorder, specific phobia, simple phobia, PTSD, post-traumatic stress disorder, and acute stress disorder. Furthermore, we examined reference lists from identified articles and asked international experts to identify eligible studies. STUDY SELECTION: We included studies that randomly assigned adult patients between ages 18 and 65 years meeting DSM-III-R or DSM-IV criteria for an anxiety disorder to either CBT or placebo. Of 1165 studies that were initially identified, 27 met all inclusion criteria. DATA EXTRACTION: The 2 authors independently identified the eligible studies and selected for each study the continuous measures of anxiety severity. Dichotomous measures reflecting treatment response and continuous measures of depression severity were also collected. Data were extracted separately for completer (25 studies for continuous measures and 21 studies for response rates) and intent-to-treat (ITT) analyses (6 studies for continuous measures and 8 studies for response rates). DATA SYNTHESIS: There were no significant differences in attrition rates between CBT and placebo. Random-effects models of completer samples yielded a pooled effect size (Hedges' g) of 0.73 (95% CI = 0.88 to 1.65) for continuous anxiety severity measures and 0.45 (95% CI = 0.25 to 0.65) for depressive symptom severity measures. The pooled odds ratio for completer treatment response rates was 4.06 (95% CI = 2.78 to 5.92). The strongest effect sizes were observed in obsessive-compulsive disorder and acute stress disorder, and the weakest effect size was found in panic disorder. The advantage of CBT over placebo did not depend on placebo modality, number of sessions, or study year. CONCLUSIONS: Our review of randomized placebo-controlled trials indicates that CBT is efficacious for adult anxiety disorders. There is, however, considerable room for improvement. Also, more studies need to include ITT analyses in the future.

Holsten, F. (1974). Flashbacks--late reactions after LSD and cannabis use among 78 drug addicts. ["Flashbacks"--senreaksjoner etter bruk av LSD og cannabis hos 78 stoffbrukere] Tidsskrift for Den Norske Laegeforening : Tidsskrift for Praktisk Medicin, Ny Raekke, 94(30), 2070-2077.

Holsten, F. (1976). Flashbacks: a personal follow-up. Archiv Fur Psychiatrie Und Nervenkrankheiten, 222(4), 293-304.

During the period 1971-1973, it was found that 53 out of 91 young drug abusers in a psychiatric hospital had experienced flashbacks. This applied to as many as 50 out of the 65 patients who had used LSD, but also to abusers of organic solvents and cannabis. As many as 38% of the patients were found to be severely incapacitated by their flashbacks. On a personal follow-up 1 1/2-4 years after the first therapeutic contact, 35 patients were still troubled by flashbacks. On the whole reactions were less intense than at the time of the first contact. No relation between the flashbacks and protracted psychotic development could be established. The overall clinical and social course was worse for patients with flashbacks than for the rest of the population. Patients still bothered by flashbacks used drugs and alcohol as sedatives to a greater extent than the rest.

Horowitz, M. J. (1969). Flashbacks: recurrent intrusive images after the use of LSD. The American Journal of Psychiatry, 126(4), 565-569.

Hoshi, R., Cohen, L., Lemanski, L., Piccini, P., Bond, A., & Curran, H. V. (2007). Ecstasy (MDMA) does not have long-term effects on aggressive interpretative bias: a study comparing current and ex-ecstasy users with polydrug and drug-naive controls. Experimental and Clinical Psychopharmacology, 15(4), 351-358. doi:10.1037/1064-1297.15.4.351

+/-3, 4-methylenedioxymethamphetamine (MDMA or ecstasy) remains a widely used recreational drug, which, in animals, can produce long-lasting changes to the brain's serotonergic system. As serotonin has been implicated in human aggression, it is possible that ecstasy users are at risk of increased aggression even after prolonged abstention from the drug. The objective of this study was to indirectly assess aggression in current and abstinent ecstasy users using an information-processing paradigm that measures cognitive bias toward material with aggressive content. The task employed has previously shown increased aggressive bias 3-4 days after ecstasy use. An interpretative bias task was administered to 105 male participants: 26 ex-ecstasy users, 25 current ecstasy users, 29 polydrug using controls, and 25 drug-naive controls. Accuracy and response times to process and recognize ambiguous sentences were tested. There were no group differences in aggressive interpretative bias. All 4 groups processed neutral sentences faster than aggressive sentences and were subsequently faster and more confident in recognizing neutral compared with aggressive sentences. Further, self-ratings of aggression also showed no group differences, even though self-rated impulsivity was significantly higher in current ecstasy users than in drug-naive controls. The findings that all groups were biased toward neutral and away from aggressive interpretations of ambiguous sentences add to the existing body of knowledge in suggesting that increased aggression found in ecstasy users a few days after taking the drug is a transient phenomenon and not a long-term, persisting effect.

Ikeda, A., Sekiguchi, K., Fujita, K., Yamadera, H., & Koga, Y. (2005). 5-methoxy-N,N-diisopropyltryptamine-induced flashbacks. The American Journal of Psychiatry, 162(4), 815. doi:10.1176/appi.ajp.162.4.815

Imai, N., Yagi, N., Konishi, T., Serizawa, M., & Kobari, M. (2009). Websites offer helpful information concerning consultation with headache specialists. Cephalalgia : An International Journal of Headache, doi:10.1111/j.1468-2982.2009.01915.x

Patients with severe primary headache may benefit from consultation with headache specialists, but doctor attendance rates in Japan are very low. More headache patients might consult headache specialists if these specialists were more widely recognized by the public. To determine what information prompted patients to seek consultation with a headache specialist, we questioned 256 primary headache patients about the source of the helpful information concerning consultation with headache specialists. From 191 patients, a total of 235 responses to the questionnaire were obtained. The most common response was 'websites' (33.2%), followed by 'professionals' (23.8%), 'acquaintances' (20.9%), 'print media' (6.8%) and 'TV/radio' (3.4%). Patients who indicated websites showed the most severe pain and highest impact of headache, and accounted for 52.4% of those with cluster headaches. Development of websites concerning headache specialists would seem likely to increase doctor attendance rates for patients with primary headache.

International journal of psychophysiology : official journal of the International Organization of Psychophysiology (1983). . Amsterdam ;New York: Elsevier Science Publishers.

Jebelli, A. K., Doan, N., & Ellison, G. (2002). Prenatal phencyclidine induces heightened neurodegeneration in rats in some brain regions, especially during 2nd trimester, but possible anti-apoptotic effects in others. Pharmacology & Toxicology, 90(1), 20-25.

Phencyclidine administered to the developing rat brain at high doses for a few hours during late foetal life induces apoptotic neurodegeneration in several brain regions. We sought to investigate whether prolonged, low level foetal exposure to phencyclidine during different gestational periods (2nd trimester versus 3rd trimester) would have different effects on several brain regions showing neurodegeneration as assessed using silver stains. Pregnant rats were treated with phencyclidine (5.45 mg/day) continuously for 5 days via minipumps, and the pups were either perfused immediately after birth and silver-stained for degeneration, or allowed to mature and then tested for behavioural deficits. In the newborn pups, there was a substantial increase in the number of agrophilic cells in entorhinal cortex and subiculum; this effect was greater when the drug was given during 2nd trimester. However, in the ventromedial nucleus of the hypothalamus, both the 2nd and 3rd trimester phencyclidine pups had significantly fewer degenerating cells than the controls. Behavioural tests of rotorod and open field performance in the pups allowed to mature indicated decreased motor coordination and hyperactivity in the 3rd trimester phencyclidine pups, but minimal alterations in the 2nd trimester pups. Thus, prenatal exposure to phencyclidine can have either neurodegenerative or antiapototic effects depending upon brain region, and there is a discrepancy between persisting behavioural deficits and amount of cell loss for time of maximal prenatal effect of the drug.

Johnson, M., Richards, W., & Griffiths, R. (2008). Human hallucinogen research: guidelines for safety. Journal of Psychopharmacology (Oxford, England), 22(6), 603-620. doi:10.1177/0269881108093587

There has recently been a renewal of human research with classical hallucinogens (psychedelics). This paper first briefly discusses the unique history of human hallucinogen research, and then reviews the risks of hallucinogen administration and safeguards for minimizing these risks. Although hallucinogens are relatively safe physiologically and are not considered drugs of dependence, their administration involves unique psychological risks. The most likely risk is overwhelming distress during drug action ('bad trip'), which could lead to potentially dangerous behaviour such as leaving the study site. Less common are prolonged psychoses triggered by hallucinogens. Safeguards against these risks include the exclusion of volunteers with personal or family history of psychotic disorders or other severe psychiatric disorders, establishing trust and rapport between session monitors and volunteer before the session, careful volunteer preparation, a safe physical session environment and interpersonal support from at least two study monitors during the session. Investigators should probe for the relatively rare hallucinogen persisting perception disorder in follow-up contact. Persisting adverse reactions are rare when research is conducted along these guidelines. Incautious research may jeopardize participant safety and future research. However, carefully conducted research may inform the treatment of psychiatric disorders, and may lead to advances in basic science.

Jurgens, T. P., Leone, M., Proietti-Cecchini, A., Busch, V., Mea, E., Bussone, G., & May, A. (2009). Hypothalamic deep-brain stimulation modulates thermal sensitivity and pain thresholds in cluster headache. Pain, 146(1-2), 84-90. doi:10.1016/j.pain.2009.07.006

Deep-brain stimulation (DBS) of the posterior hypothalamus has been shown to be clinically effective for drug-resistant chronic cluster headache, but the underlying mechanism is still not understood. The hypothalamus as an important centre of homeostasis is connected among others to the trigeminal system via the trigeminohypothalamic tract. We aimed to elucidate whether hypothalamic stimulation affects thermal sensation and pain perception only in the clinically affected region (the first trigeminal branch) or in other regions as well. Thus, we examined three groups: chronic cluster headache patients with unilateral DBS of the posterior hypothalamus (n = 11), chronic cluster headache patients without DBS (n = 15) and healthy controls (n = 29). Perception and pain thresholds for hot and cold stimuli were determined bilaterally in all subjects supraorbitally, at the forearm, and in the lower leg. In DBS patients, thresholds were determined with the stimulator activated and inactivated. Cold pain thresholds at the first trigeminal branch were increased on the stimulated side in the DBS group compared to healthy subjects (p = .015). The DBS group also had higher cold detection thresholds compared to non-implanted cluster headache patients (p < .05). Short-term interruption of stimulation did not induce any changes in DBS patients. Clinically relevant differences were found neither between non-stimulated cluster headache patients and healthy controls nor between the affected and the non-affected sides in the chronic cluster headache patients without DBS. These results support the notion that neurostimulation of the posterior hypothalamus is specific for cluster headache and only affects certain aspects of pain sensation.

Juve, J. L. (1972). Bad drug trips and flashbacks. Child Welfare, 51(1), 41-50.

Kang, J. K., Ryu, J. W., Choi, J. H., Merrill, R. L., & Kim, S. T. (2009). Application of ICHD-II criteria for headaches in a TMJ and orofacial pain clinic. Cephalalgia : An International Journal of Headache, doi:10.1111/j.1468-2982.2009.01866.x

Kang J-K, Ryu J-W, Choi J-H, Merrill RL & Kim ST. Application of ICHD-II criteria for headaches in a TMJ and orofacial pain clinic. Cephalalgia 2009. London. ISSN 0333-1024The aim of this study was to identify and diagnose headache in a temporomandibular joint and orofacial pain clinic population using the second edition of The International Classification of Headache Disorder criteria. In 502 temporomandibular disorder and orofacial pain patients, 246 patients (49%) were diagnosed with tension-type headache (TTH), followed by migraine without aura (14.5%), probable migraine (12.9%), migraine with aura (7%), probable TTH (4.8%) and cluster headache (0.2%). The prevalence of headaches was compared between male and female patients, and the prevalence of migraine was found to be higher in women than in men. In evaluating by age, the prevalence of migraine was highest in patients in their 20s and 30s and declined as age increased above 40. TTH showed the highest rate throughout all age groups, but it also decreased as age increased. In this study, the prevalence of migraine was lower than that reported in Dr Kim et al.'s study, and the prevalence of TTH much higher than that reported in the previous study. Of the headache patients, 81.1% presented with masseter muscle pain and 47.8% with temporal muscle pain. This finding suggests that pericranial muscle pain may be an inducing factor of primary headache.

Katzenschlager, R., Sampaio, C., Costa, J., & Lees, A. (2003). Anticholinergics for symptomatic management of Parkinson's disease. Cochrane Database of Systematic Reviews (Online), (2)(2), CD003735. doi:10.1002/14651858.CD003735

BACKGROUND: Anticholinergics were the first drugs available for the symptomatic treatment of Parkinson's disease and they are still widely used today, both as monotherapy and as part of combination regimes. They are commonly believed to be associated with a less favourable side effect profile than other antiparkinsonian drugs, in particular with respect to neuropsychiatric and cognitive adverse events. They have been claimed to exert a better effect on tremor than on other parkinsonian features. OBJECTIVES: To determine the efficacy and tolerability of anticholinergics in the symptomatic treatment of Parkinson's disease compared to placebo or no treatment. SEARCH STRATEGY: The literature search included electronic searches of the Cochrane Controlled Trials Register (The Cochrane Library, Issue 4, 2001), MEDLINE (1966 to 2001), Old Medline (1960-1965), Index Medicus (1927 - 1959), as well as handsearching the neurology literature including the reference lists of identified articles, other reviews and book chapters. SELECTION CRITERIA: Randomised controlled trials of anticholinergic drugs versus placebo or no treatment in de-novo or advanced Parkinson's disease, either as monotherapy or as an add-on to other antiparkinsonian drugs were included. Trials of anticholinergic drugs that were never in general clinical use were excluded. DATA COLLECTION AND ANALYSIS: Data was abstracted independently by two authors. Differences were settled by discussion among all authors. Data collected included patient characteristics, disease duration and severity, concomitant medication, interventions including duration and dose of anticholinergic treatment, outcome measures, rates of and reasons for withdrawals, and neuropsychiatric and cognitive adverse events. MAIN RESULTS: The initial search yielded 14 potentially eligible studies, five of which were subsequently excluded. In three cases this was because they dealt with substances that had never been marketed or had not been licensed for as far as could be traced back. One trial had been published twice in different languages. One study was excluded based on the assessment of its methodological quality. The remaining nine studies were all of double-blind cross-over design and included 221 patients. Trial duration was between five and 20 weeks and drugs investigated were benzhexol (mean doses: 8 to 20 mg/d), orphenadrine (mean dose not reported), benztropine (mean dose not reported), bornaprine (8 to 8.25 mg/d), benapryzine (200 mg/d), and methixine (45 mg/d). Only one study involved two anticholinergic drugs. Outcome measures varied widely across studies and in many cases, the scales applied were the authors' own and were not defined in detail. Incomplete reporting of methodology and results was frequent. The heterogeneous study designs as well as incomplete reporting precluded combined statistical analysis. Five studies used both tremor and other parkinsonian features as outcome measures. Outcome measures in these five studies were too different for a combined analysis and results varied widely, from a significant improvement in tremor only to significant improvement in other features but not in tremor. All studies except one (dealing with methixine) found a significant improvement from baseline on the anticholinergic drug in at least one outcome measure. The difference between placebo and active drug was reported in four studies and was found to be significant in all cases. No study failed to show superiority of the anticholinergic over placebo. The occurrence of neuropsychiatric and cognitive adverse events was reported in all but three studies (in 35 patients on active drug versus 13 on placebo). The most frequently reported reason for drop-outs from studies was in patients on placebo due to withdrawal from pre-trial anticholinergic treatment. REVIEWER'S CONCLUSIONS: As monotherapy or as an adjunct to other antiparkinsonian drugs, anticholinergics are more effective than placebo in improving motor function in Parkinson's disease. Neuropsychiatric and cognitive adverse events occur more frequently on anticholinergics than on placebo and are a more common reason for withdrawal than lack of efficacy. Results regarding a potentially better effect of the anticholinergic drug on tremor than on other outcome measures are conflicting and data do not strongly support a differential clinical effect on individual parkinsonian features. Data is insufficient to allow comparisons in efficacy or tolerability between individual anticholinergic drugs.

Kawasaki, A., & Purvin, V. (1996). Persistent palinopsia following ingestion of lysergic acid diethylamide (LSD). Archives of Ophthalmology, 114(1), 47-50.

OBJECTIVE: To identify a distinctive chronic visual complication of lysergic acid diethylamide (LSD) use. DESIGN: Description of the clinical findings in three patients with this disorder. SETTING: A neuro-ophthalmology referral center. RESULTS: All three patients experienced prolonged afterimages (palinopsia) during LSD intoxication and have continued to be symptomatic up to 3 years after they ceased to ingest the drug. Results of neuro-ophthalmologic and neurologic examinations and neuroimaging and electrophysiologic studies were normal. CONCLUSIONS: We have described three patients in whom persistent palinopsia developed following ingestion of LSD. Clinicians should inquire about past LSD use in all patients who initially have seemingly spontaneous, isolated palinopsia. Recognition of this distinctive clinical syndrome associated with LSD use might avoid unnecessary anxiety and excessive diagnostic tests for patients with this disorder.

King, W.,Jr, & Ellison, G. (1989). Long-lasting alterations in behavior and brain neurochemistry following continuous low-level LSD administration. Pharmacology, Biochemistry, and Behavior, 33(1), 69-73.

Groups of rats were administered either 80 micrograms LSD-25 continuously over seven days using subcutaneous minipumps, or were given the same total amount of drug in seven daily injections, or were administered vehicle. When tested long after cessation of drug administration, persisting alterations in behavior and brain were found in the continuous LSD groups. In social open-field tests, this consisted of decreased social distance between animals; this effect increased upon repeated testing. In uptake of labeled ligands, this was reflected predominantly by decreased 3H-LSD binding in several limbic regions. LSD appears to have especially persisting neurotoxic effects when administered in a continuous, low-level fashion.

Kolmel, H. W. (1985). Complex visual hallucinations in the hemianopic field Journal of Neurology, Neurosurgery, and Psychiatry, 48(1), 29-38.

From 120 patients with an homonymous hemianopia 16 experienced complex visual hallucinations in the hemianopic field. The brain lesion was located in the occipital lobe, though damage was not limited to this area. Complex hallucinations appeared after a latent period. They were weak in colour and stereotypical in appearance, which allowed differentiation from visual hallucinations of other causes. Different behaviour after saccadic eye movement differentiated between complex visual hallucinations in the hemianopic field and visual auras of an epileptic origin.

Lambru, G., Castellini, P., Manzoni, G. C., & Torelli, P. (2009). Post-traumatic cluster headache: from the periphery to the central nervous system? Headache, 49(7), 1059-1061. doi:10.1111/j.1526-4610.2009.01456.x

A correlation between head trauma and cluster headache is believed to exist. We report a case of post-traumatic episodic cluster headache that fulfills the criteria of the International Classification of Headache Disorders, 2nd edition. The distinctive features of this case are: a close temporal relation between head trauma and headache onset; pain ipsilateral to the side of trauma; mild severity of trauma; episodic course well-responsive to low doses of verapamil. Given the close temporal relation between the 2 events, multiple hypotheses can be advanced about a possible role of head trauma in the pathogenesis of cluster headache.

Landray, M., Nuttall, S., Lydakis, C., Martin, U., Maxwell, S., & Lip, G. (1998). Oxidative stress after thrombolysis. The Lancet, 352(9132), 960-960. doi:DOI: 10.1016/S0140-6736(05)61514-0

Larbi, A., Kempf, J., & Pawelec, G. (2007). Oxidative stress modulation and T cell activation. Experimental Gerontology, 42(9), 852-858. doi:DOI: 10.1016/j.exger.2007.05.004

Lauterbach, E. C., Abdelhamid, A., & Annandale, J. B. (2000). Posthallucinogen-like visual illusions (palinopsia) with risperidone in a patient without previous hallucinogen exposure: possible relation to serotonin 5HT2a receptor blockade. Pharmacopsychiatry, 33(1), 38-41.

BACKGROUND: Previous reports document visual illusions resembling hallucinogen persisting perception disorder (HPPD) after risperidone treatment in patients with histories of previous LSD exposure. METHODS: We report a case with visual disturbances resembling HPPD after each of three consecutive risperidone dose increases. RESULTS: Contrasting with previous reports, our patient lacked any history of substance abuse, particularly hallucinogen exposure. She lacked neurologic or other contributory illnesses. Illusions generally remitted within 48 hours each time. Coadministration of trazodone and clonazepam may have contributed to these phenomena, although clonazepam has been used to treat this condition. She had been unusually sensitive to the side-effects of many psychotropics. CONCLUSIONS: This case is unique due to the absence of substance abuse. This and another report note heightened sensitivity to medication side-effects. Visual phenomena resembling HPPD evidently can occur with risperidone and, possibly, other atypical antipsychotics and certain antidepressants regardless of previous hallucinogen use. Several lines of evidence implicate reduced 5HT2a serotonin receptor stimulation rather than increased 5HT2c stimulation.

Lefort, G., Moyen, B., Beaufils, P., de Billy, B., Breda, R., Cadilhac, C., . . . Versier, G. (2006). Osteochondritis dissecans of the femoral condyles: report of 892 cases. [L'osteochondrite dissequante des condyles femoraux] Revue De Chirurgie Orthopedique Et Reparatrice De l'Appareil Moteur, 92(5 Suppl), 2S97-2S141.

PURPOSE OF THE STUDY: Osteochondritis rarely involves the femoral condyles. Discovery in this localization raises several questions concerning the nature of the articular cartilage, the potential for spontaneous healing, and, in the event of a free fragment, the outcome after its loss or repair. MATERIAL AND METHODS: This multicentric study included 892 pediatric and adult cases, the cutoff between two series being defined by fusion of the inferior growth plate. We excluded medical or surgical osteochondritis, cases involving the patella, osteochondral fractures, juvenile polyosteochondrosis, adult osteonecrosis, and osteochondritis beginning after the age of 50 years. RESULTS: Mean age at diagnosis was 16.5 years. Mean age at treatment onset was 22 years. Pain was the predominant symptom. 80% of cases were unilateral and 70% involved the medial condyle. The anatomic lesions were different in adults, showing more advanced degradation. At diagnosis, Bedouelle stages Ia and IIb constituted 80% of the cases observed among children while in adults, 66% were Bedouelle stages IIb to IV. Outcome was very good for the majority of children with Hughston clinical stage 4 while half of the x-rays were Hughston stage 3 and 4. There were thus a large percentage of children with abnormal xrays whose disease history was not yet terminated. In the adult series, the percentages of Hughston 3 and 4 was about the same as clinically. The x-rays were rarely perfectly normal since half of the clinical stage 3 patients were noted in stage 4. An abnormal x-ray with a very good clinical presentation was observed in a very large proportion of patients. DISCUSSION: It is difficult to interpret the plain x-ray and identify patients with a potentially unfavorable prognosis. We defined three radiographic classes: defect, nodule and empty notch. The Bedouelle classification uses information from all available explorations, particularly MRI and arthroscopy. Numerous therapeutic methods are used. Interruption of sports activities is the first intention treatment for children. Data in the literature and the findings of this symposium do not demonstrate any beneficial effect of immobilization on healing compared with simple abstention from sports activities. Transchondral perforation is a simple operation with low morbidity. In 85% of cases, it was used for lesions with an intact joint cartilage considered stable in 96% of cases. Healing was achieved in six months for 48% if the growth plate had not fused. The fragment was fixed in 43% of the cases with a loose cartilage fragment. Outcome was fair but degraded with the state of the joint cartilage and thus the stability of the fragment. Fixation must stabilize the fragment but not prevent further consolidation via osteogenesis. This is why deep perforations are drilled beyond the ossified area and additional osteochondral grafts are used. The Wagner operation gives less satisfactory results than more complicated procedures. Removal of a sequestrum is a simple, minimally invasive procedure with an uneventful postoperative period, but in the long term it favors osteoarthritic degradation, especially when performed in adults. Mosaic grafts give good mid term results. Morbidity is low especially if the grafts are harvested above the notch. The question of chondrolysis around the grafts was beyond the scope of this study. Chondrocyte grafting is difficult to accomplish and is expensive. The mid term results are good for large lesions. Osteotomy is logical only in the event of early stage osteoarthritic degradation. DECISION ALGORITHM IN CHILDREN AND ADOLESCENTS: If the plain x-ray reveals a defect (class I), simple interruption of sports activities should be proposed. Two situations can then develop. First, in a certain number of patients, the pain disappears as the defective zone ossifies progressively. Complete cure is frequent before the age of 12 years. In the second situation, the knee remains painful and the x-ray does not change or worsens to a class II nodular formation. In this case an MRI must be obtained to determine whether the joint cartilage is normal. There are two possibilities. First, the osteochondral fragment is viable and most probably will become completely re-integrated, particularly if the lesion is far from the growth plate. Necrosis is the other possibility. Transchondral perforations are needed in this case. If on the contrary the cartilage is altered, there is little hope for spontaneous cure. Arthroscopy may be needed to complete the exploration. Fragments, especially if there is a large surface area, must be fixed. Perforations to favor revascularization are certainly useful here. In the last situation (class III), the fragment wobbles on a thin attachment or has already fallen into the joint space. This is the type of problem generally observed in adults. The decision algorithm in adults is the same as in children for the rare nodular aspects (class II). There could be a discussion between transcartilage perforation and fixation. If there are a large number of fragments, fixation may not be fully successful and the lesion might be considered class III. For class III lesions, three operations can be used: removal of the sequestrum, mosaic bone-cartilage grafts, or autologous chondrocyte grafts. At the same follow-up, mosaic grafts give better results than excision of sequestra. It may be useful to remove sequestra in a limited number of situations: if there is just a small area of osteochondritis, the lesion is old and partially healed, or the zone is non weight-bearing. For other lesions, we favor mosaic grafts. We still do not have enough follow-up to assess the long-term outcome with these mosaic grafts, but simple excision clearly favors osteoarthritic degradation. Can chondrocytes grafts be compared with mosaic grafts? Chondrocyte grafts have been used for very large lesions and have given results similar to mosaic grafts. It might also be possible to combine fixation of a loose fragment and a mosaic graft. LESSONS FROM THIS STUDY: 1) The prognosis of osteochondritis is better before than after fusion of the growth plate but the lesion does not always heal in children. 2) Presence of osteochondritis requires complementary anatomic and functional exploration to determine the stability and the vitality of the fragment. 3) Attention must be taken to perform transchondral perforations early enough, particularly in children. 4) Screw fixation is not always sufficient. The trophicity of the fragment and its blood supply must be improved. 5) Mosaic grafts are preferable to excision of the fragment. 6) Chondrocyte grafts will be more widely used in the future.

Leikin, J. B., Krantz, A. J., Zell-Kanter, M., Barkin, R. L., & Hryhorczuk, D. O. (1989). Clinical features and management of intoxication due to hallucinogenic drugs. Medical Toxicology and Adverse Drug Experience, 4(5), 324-350.

Hallucinogenic drugs are unique in that they produce the desired hallucinogenic effects at what are considered non-toxic doses. The hallucinogenic drugs can be categorised into 4 basic groups: indole alkaloid derivatives, piperidine derivatives, phenylethylamines and the cannabinols. The drugs reviewed include lysergic acid diethylamide (LSD), phencyclidine (PCP), cocaine, amphetamines, opiates, marijuana, psilocybin, mescaline, and 'designer drugs.' Particularly noteworthy is that each hallucinogen produces characteristic behavioural effects which are related to its serotonergic, dopaminergic or adrenergic activity. Cocaine produces simple hallucinations, PCP can produce complex hallucinations analogous to a paranoid psychosis, while LSD produces a combination of hallucinations, pseudohallucinations and illusions. Dose relationships with changes in the quality of the hallucinatory experience have been described with amphetamines and, to some extent, LSD. Flashbacks have been described with LSD and alcohol. Management of the intoxicated patient is dependent on the specific behavioural manifestation elicited by the drug. The principles involve differentiating the patient's symptoms from organic (medical or toxicological) and psychiatric aetiologies and identifying the symptom complex associated with the particular drug. Panic reactions may require treatment with a benzodiazepine or haloperidol. Patients with LSD psychosis may require an antipsychotic. Patients exhibiting prolonged drug-induced psychosis may require a variety of treatments including ECT, lithium and l-5-hydroxytryptophan.

Leipsic, J. S., Abraham, H. D., & Halperin, P. (1995). Neuroleptic malignant syndrome in the elderly. Journal of Geriatric Psychiatry and Neurology, 8(1), 28-31.

Four cases of neuroleptic malignant syndrome (NMS) were identified in a general hospital over a 5-year period. Two cases presented to the psychiatric consultation liaison service, and two were found by a computerized review of discharge diagnoses. Cases were examined for age, sex, administered neuroleptic potency and dose, premorbid history, prodromal symptoms, methods of treatment, and clinical outcome. The mean age of cases was found to be 14 years greater than the age of the non-NMS patient population. All NMS cases had premorbid neuropsychiatric disorders and recognizable prodromal symptoms. The mean neuroleptic dose was significantly lower than in previously reported cases. A systems model integrating premorbid factors, intercurrent illness, and drug effects in pathogenesis is presented.

Leone, M., & Bussone, G. (2009). Pathophysiology of trigeminal autonomic cephalalgias. Lancet Neurology, 8(8), 755-764. doi:10.1016/S1474-4422(09)70133-4

Cluster headache, paroxysmal hemicrania, and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) are primary headaches recently classified together as trigeminal autonomic cephalalgias (TACs). The causes of these headaches have long been debated, with "peripheral" hypotheses in opposition to "central" hypotheses. The available information indicates that the pain originates from within the brain in cluster headache. The hypothalamic activation observed during TAC attacks by use of functional neuroimaging, and the success of hypothalamic stimulation as a treatment, confirm that the posterior hypothalamus is crucial in the pathophysiology of these headaches. The posterior hypothalamus is now known to modulate craniofacial pain, and hypothalamic activation occurs in other pain disorders, suggesting that this brain area is likely to have a more complex role in the pathophysiology of TACs than that of a mere trigger. Hypothalamic activation might play a part in terminating rather than triggering attacks, and might also give rise to a central permissive state, allowing attacks to take place.

Leone, M., Franzini, A., Cecchini, A. P., Mea, E., Broggi, G., & Bussone, G. (2009). Costs of hypothalamic stimulation in chronic drug-resistant cluster headache: preliminary data. Neurological Sciences : Official Journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology, 30 Suppl 1, S43-7. doi:10.1007/s10072-009-0057-3

In about 20% of chronic cluster headache (CH) cases, drugs may become ineffective. Under these circumstances, steroids and triptans are frequently employed leading to fearful side effects in one and high costs in the other. The direct costs of drug-resistant chronic CH are mainly due to frequent medical consultations and frequent use of expensive drugs. In recent years, hypothalamic stimulation has been employed to treat drug-resistant chronic CH patients suffering multiple daily attacks and long-term results from different centres show a 60% overall benefit. Nine years since the introduction of this technique, we attempt a preliminary analysis of the direct costs of hypothalamic stimulation based on patients treated at our centre. We estimated the following direct costs as follows: cost of neurosurgery plus cost of equipment (electrode, connection and impulse generator = 25,000 euro), cost of hospital admissions in long-term follow-up (2,000 euro per admission), cost of single sumatriptan injection (25 euro). Number of daily sumatriptan injections in the year before and for each year after hypothalamic implantation was obtained from headache diaries. To estimate the saving due to the reduction in sumatriptan consumption following hypothalamic stimulation, we calculated the following for each year of follow-up after surgery: number of sumatriptan injections in the year before surgery minus number of sumatriptan injections in each year, updated to December 2008. In our 19 implanted patients, the costs of neurosurgery plus cost of equipment were 475,000 euro; the costs of hospital admissions during follow up were 250,000 euro. Reduction in sumatriptan consumption resulted in a total saving of 3,573,125 euro. Hence, in our 19 patients, the sumatriptan saving (3,573,125 euro) minus the direct costs due to operation and follow up hospitalisations (475,000 + 250,000) euro is equal to 2,848,125 euro. These preliminary results indicate that hypothalamic stimulation is associated with marked reduction of direct costs in the management of complete drug-resistant chronic CH.

Lerner, A. G., Finkel, B., Oyffe, I., Merenzon, I., & Sigal, M. (1998). Clonidine treatment for hallucinogen persisting perception disorder. The American Journal of Psychiatry, 155(10), 1460.

Lerner, A. G., Gelkopf, M., Oyffe, I., Finkel, B., Katz, S., Sigal, M., & Weizman, A. (2000). LSD-induced hallucinogen persisting perception disorder treatment with clonidine: an open pilot study. International Clinical Psychopharmacology, 15(1), 35-37.

A pilot open study was conducted in order to evaluate the efficacy of clonidine in the treatment of LSD-induced hallucinogen persisting perception disorder (HPPD). Eight patients fulfilled entrance criteria. All complained of HPPD for at least 3 months and were drug free at least 3 months. They received fixed low doses of clonidine, 0.025 mg, three times a day for 2 months. They were evaluated by the Clinical Global Impression Scale (CGI) and a self-report scale on the severity of symptoms (graded 0-5). Patients scored an average of 5.25 (SD = 0.46) on the CGI and 4 on the self-report scale at baseline, indicating marked psychopathology. One patient dropped out at week 3 and a second patient dropped out at week 5. Of the six patients remaining at the end of 2 months, the average CGI score was 2.5 (SD = 0.55) and the self-report scale score was 2, indicating mild symptomatology. LSD-related flashbacks associated with excessive sympathetic nervous activity may be alleviated with clonidine in some patients.

Lerner, A. G., Gelkopf, M., Skladman, I., Oyffe, I., Finkel, B., Sigal, M., & Weizman, A. (2002). Flashback and Hallucinogen Persisting Perception Disorder: clinical aspects and pharmacological treatment approach. The Israel Journal of Psychiatry and Related Sciences, 39(2), 92-99.

One unique characteristic of lysergic acid diethylamide (LSD) and LSD-like substances is the recurrence of some of the symptoms which appeared during the intoxication after the immediate effect of the hallucinogen has worn off. This recurring syndrome, mainly visual, has not been clearly understood, appreciated or distinguished from other clinical entities by clinicians. The terms Flashback and Hallucinogen Persisting Perception Disorder (HPPD) are used interchangeably in the professional literature. Flashback is a usually short-term, non-distressing, spontaneous, recurrent, reversible and benign condition accompanied by a pleasant affect. In contrast, HPPD is a generally long-term, distressing, spontaneous, recurrent, pervasive, either slowly reversible or irreversible, non-benign condition accompanied by an unpleasant dysphoric affect. Flashback and HPPD appear to be part of a vast and broad spectrum of non-psychopathological and psychopathological states reported by hallucinogen users. Pharmacological agents such as clonidine, perphenazine and clonazepan have been shown to ameliorate this syndrome in some of the individuals seeking treatment.

Lerner, A. G., Gelkopf, M., Skladman, I., Rudinski, D., Nachshon, H., & Bleich, A. (2003). Clonazepam treatment of lysergic acid diethylamide-induced hallucinogen persisting perception disorder with anxiety features. International Clinical Psychopharmacology, 18(2), 101-105. doi:10.1097/01.yic.0000053665.88477.46

An unique and intriguing characteristic of lysergic acid diethylamide (LSD) and LSD-like substances is the recurrence of some of the symptoms which appear during the intoxication, in the absence of recent intake of hallucinogens. Hallucinogen persisting perception disorder (HPPD) is a condition in which the re-experiencing of one or more perceptual symptoms causes significant distress or impairment in social, occupational or other important areas of functioning and may be extremely debilitating. Benzodiazepines are one of the recommended agents for the treatment of HPPD but it is unclear which of them may be more helpful. The goal of our investigation was to assess the efficacy of clonazepam in the treatment of LSD-induced HPPD. Sixteen patients fulfilled entrance criteria. All complained of HPPD with anxiety features for at least 3 months and were drug free at least 3 months. They received clonazepam 2 mg/day for 2 months. Follow-up was continued for 6 months. They were weekly evaluated during the 2 months of clonazepam administration and monthly during the follow-up period using the Clinical Global Impression Scale, a Self-report Scale and Hamilton Anxiety Rating Scale. Patients reported a significant relief and the presence of only mild symptomatology during the clonazepam administration. This improvement was clearly sustained and persisted during a 6-month follow-up period. This study suggests that high potency benzodiazepines like clonazepam, which has serotonergic properties, may be more effective than low-potency benzodiazepines in the treatment of some patients with LSD-induced HPPD.

Lerner, A. G., Oyefe, I., Isaacs, G., & Sigal, M. (1997). Naltrexone treatment of hallucinogen persisting perception disorder. The American Journal of Psychiatry, 154(3), 437.

Lerner, A. G., Shufman, E., Kodesh, A., Kretzmer, G., & Sigal, M. (2002). LSD-induced Hallucinogen Persisting Perception Disorder with depressive features treated with reboxetine: case report. The Israel Journal of Psychiatry and Related Sciences, 39(2), 100-103.

We would like to present the case of a patient who had a prior history of cannabis, ecstasy (MDMA) and LSD abuse and who developed both Hallucinogen Persisting Perception Disorder (HPPD) and a major depressive episode. Following two unsuccessful SSRIs trials, reboxetine was prescribed. During a six-month follow-up period on reboxetine 6 mg./day, no exacerbation of the visual disturbance or recurrence of the depressive features were reported. Reboxetine may have an alpha 2 adrenoreceptor modulating effect on both noradrenaline and serotonin release, thus reboxetine's alpha 2 adrenoreceptor modulating effect on noradrenaline release may affect sympathetic activity and be involved in the recovery process.

Lerner, A. G., Skladman, I., Kodesh, A., Sigal, M., & Shufman, E. (2001). LSD-induced Hallucinogen Persisting Perception Disorder treated with clonazepam: two case reports. The Israel Journal of Psychiatry and Related Sciences, 38(2), 133-136.

Benzodiazepines are recommended for the treatment of Hallucinogen Persisting Perception Disorder (HPPD), although it is unclear which may be more helpful. Two out-patients with LSD-induced HPPD were successfully treated with clonazepam. They had not responded to low potency benzodiazepines or low doses of classic antipsychotics. After clonazepam discontinuation they reported a marked improvement and only mild symptomatology which persisted during a six month follow-up period. High potency benzodiazepines like clonazepam, which has serotonergic properties, may be superior to low-potency benzodiazepines in the treatment of some patients with LSD-induced HPPD.

Lethaby, A. E., Cooke, I., & Rees, M. (2005). Progesterone or progestogen-releasing intrauterine systems for heavy menstrual bleeding. Cochrane Database of Systematic Reviews (Online), (4)(4), CD002126. doi:10.1002/14651858.CD002126.pub2

BACKGROUND: Heavy menstrual bleeding (HMB) is an important cause of ill health in women and it accounts for 12% of all gynaecology referrals in the UK. Heavy menstrual bleeding is clinically defined as greater than or equal to 80 ml of blood loss per menstrual cycle. However, women may complain of excessive bleeding when their blood loss is less than 80 ml. Hysterectomy is often used to treat women with this complaint but medical therapy may be a successful alternative.The intrauterine coil device was originally developed as a contraceptive but the addition of uterine relaxing hormones, progestogens, to these devices resulted in a large reduction in menstrual blood loss. Case studies of two types of progesterone or progestogen-releasing systems, Progestasert and Mirena, reported reductions of up to 90% and that dysmenorrhoea may be improved. Insertion, however, may be regarded as invasive by some women, which affects its acceptability as a treatment. Frequent intermenstrual bleeding and spotting is also likely during the first few months. OBJECTIVES: To determine the effectiveness and acceptability of progesterone or progestogen-releasing intrauterine devices in achieving a reduction in heavy menstrual bleeding. SEARCH STRATEGY: All studies which might describe randomised controlled trials of progesterone or progestagen-releasing intrauterine devices for the treatment of heavy menstrual bleeding were obtained by electronic searches of The Cochrane Library, MEDLINE (1966 to 2005) and EMBASE (1980 to 2005). Companies producing progestogen-releasing intrauterine devices and experts in the field were contacted for information on published and unpublished trials. SELECTION CRITERIA: Randomised controlled trials in women of reproductive age treated with progesterone or progestogen-releasing intrauterine devices versus no treatment, placebo, or other medical or surgical therapy for heavy menstrual bleeding within primary care, family planning or specialist clinic settings were eligible for inclusion. Women with postmenopausal bleeding, intermenstrual or irregular bleeding, or pathological causes of heavy menstrual bleeding were excluded. DATA COLLECTION AND ANALYSIS: Potential trials were independently assessed by three review authors and nine trials met the criteria for inclusion in the review. The reviewers extracted the data independently and data were pooled where appropriate. Odds ratios (OR) were estimated from the data for dichotomous outcomes and weighted mean differences (WMD) for continuous outcomes. The primary outcome was reduction in menstrual blood loss but incidence of side effects, changes in quality of life, satisfaction and acceptability measures were also assessed. MAIN RESULTS: Progesterone or progestogen-releasing intrauterine systems have not been compared to placebo or no treatment. Progestasert has been compared to a number of different medical therapies in one small study but no conclusions can be made about its effectiveness. The levonorgestrel-releasing intrauterine device (LNG IUS) has been compared to oral cyclical norethisterone (NET) administered on days 5 to 26 of the menstrual cycle in one trial and was significantly more effective although there was a large reduction in loss from baseline in both groups. Some short term side effects were more common in the LNG IUS group but a significantly greater proportion of women in this group were satisfied and willing to continue with their treatment. In one trial of women awaiting hysterectomy, where the LNG IUS was compared with a control group taking their existing medical therapy, a higher proportion of the women in the intrauterine device group cancelled their planned surgery after six months of treatment.The LNG IUS has been compared to an endometrial ablation: either transcervical resection of the endometrium (TCRE) (two trials) or balloon ablation (three trials). There was a significantly greater mean reduction in menstrual bleeding in one trial in those undergoing balloon ablation (WMD -45.2 units, 95% CI -56.9 to -33.5), a lower score on the pictorial blood loss chart (PBAC) (WMD 33.2 units, 95% CI 27.2 to 39.2) and higher rates of successful treatment in 3 trials including both balloon and TCRE (OR 0.28, 95% CI 0.14 to 0.58) but the rates of satisfaction with treatment was were similar. There was no conclusive evidence of changes in quality of life between groups but women with the LNG IUS had a greater incidence of progestogenic side effects within one year. The LNG IUS has been compared to hysterectomy in one trial. There was no evidence of a change in quality of life scores but the LNG IUS treatment had lower costs than with hysterectomy, both at one and five-years follow up. AUTHORS' CONCLUSIONS: The levonorgestrel-releasing intrauterine device (LNG IUS) is more effective than cyclical norethisterone (for 21 days) as a treatment for heavy menstrual bleeding. Women with an LNG IUS are more satisfied and willing to continue with treatment but experience more side effects, such as intermenstrual bleeding and breast tenderness.The LNG IUS results in a smaller mean reduction in menstrual blood loss (as assessed by the PBAC chart) than endometrial ablation but there is no evidence of a difference in the rate of satisfaction with treatment. Women with an LNG IUS experience more progestogenic side effects compared to women having TCRE for treatment of their heavy menstrual bleeding but there is no evidence of a difference in their perceived quality of life.The LNG IUS treatment costs less than hysterectomy but there is no evidence of a difference in quality of life measures between these groups.There are no data available from randomised controlled trials comparing progesterone-releasing intrauterine systems to either placebo or other commonly used medical therapies for heavy menstrual bleeding.

Linszen, D., & van Amelsvoort, T. (2007). Cannabis and psychosis: an update on course and biological plausible mechanisms. Current Opinion in Psychiatry, 20(2), 116-120. doi:10.1097/YCO.0b013e32803577fb

PURPOSE OF REVIEW: Cannabis use is the most commonly abused illicit substance. Its relation with psychosis remains a topic of debate. Epidemiological studies suggest that cannabis is a component cause accounting for approximately 10% of cases. An increasing number of studies have been published on neurobiological effects of cannabis and vulnerability of psychosis. RECENT FINDINGS: Acute cannabis administration can induce memory impairments, sometimes persisting months following abstinence. There is no evidence that residual effects on cognition remain after years of abstinence. The scarce literature on neuro-imaging mainly done in nonpsychotic populations, show little evidence that cannabis has effects on brain anatomy. Acute effects of cannabis include increases of cerebral blood flow, whereas long-term effects of cannabis include attenuation of cerebral blood flow. In animals Delta9-tetrahydrocannabinol enhances dopaminergic neurotransmission in brain regions known to be implicated in psychosis. Studies in humans show that genetic vulnerability may add to increased risk of developing psychosis and cognitive impairments following cannabis consumption. Delta9-tetrahydrocannabinol induces psychotic like states and memory impairments in healthy volunteers. SUMMARY: Simultaneously with increasing understanding of neurobiological cannabis effects, there is a lack of studies in people with psychosis. There are plausible mechanisms that might explain the psychotogenic effects of cannabis.

Llorca, P. M., Miadi-Fargier, H., Lancon, C., Jasso Mosqueda, G., Casadebaig, F., Philippe, A., . . . Durand-Zaleski, I. (2005). Cost-effectiveness analysis of schizophrenic patient care settings: impact of an atypical antipsychotic under long-acting injection formulation. [Analyse cout-efficacite des strategies de prise en charge des patients schizophrenes: place d'un antipsychotique atypique sous forme injectable a liberation prolongee] L'Encephale, 31(2), 235-246.

Schizophrenia is a disease affecting the young adults and amounts to approximately 300,000 people in France. The French public psychiatric sector takes care of approximately 150,000 adults schizophrenics: 50% benefit from ambulatory care, 50% are in partial or full-time hospitalization care. Schizophrenia represents the first diagnosis that psychiatric sectors take in charge. The costs associated with schizophrenia, mainly hospital costs, are important and were estimated at 2% of the total medical costs in France. In the French social welfare system, the social costs (pensions, allowances, managements of custody or guardianship by social workers) are also to be taken into account: it amounts to a third of the global direct cost. Schizophrenia also generates indirect costs (losses of productivity and premature deaths) which would be at least equal, or even more important, than direct medical costs. The non-compliance to the antipsychotic treatment is a major problem with people suffering from schizophrenia. Indeed the lack of compliance to the treatment, estimated at 20 to 40%, is a major handicap for schizophrenic patient stabilization. The poor level of compliance is due to many various causes: adverse effects that are considered unbearable, medicine viewed as persecutory, negation of the disease, nostalgia for the productive phases of the disease, lack of social support, complexity of the prescription, relapse itself. Compliance is thus influenced by the patient's clinical features, local provision of health care and the specific nature of the drug (adverse effects, pharmaceutical formulation). The atypical antipsychotics present fewer extrapyramidal side effects and reduce the cognitive deficits associated with the disease, which results in improved compliance. Long-acting injectable antipsychotics allow a better therapeutic compliance and thus better efficacy of the treatment. Several studies have shown a significant improvement in compliance related to the pharmaceutical formulation of antipsychotics. Hospitalization and relapse risks are lower in compliant than in non-compliant patients. OBJECTIVES: The main objective of this pharmacoeconomic analysis is to evaluate the impact in terms of medical benefits and costs of the following strategies: 1. Risperidone long-acting injection: first long-acting injectable atypical antipsychotic; 2. Haloperidol depot: long-acting injectable conventional neuroleptic; 3. Olanzapine: atypical antipsychotic available commercially in oral formulation. METHODS: The target population defined for the study are young schizophrenic patients treated for at least 1 year and whose disorder has not been diagnosed for longer than 5 years. The time horizon is 2 years. A cost-effectiveness analysis is performed. The perspective adopted is the French Health System. The main hypothesis of the model is that an increase in compliance linked to the use of long-acting injectable formulation could lead to an increased efficacy and a modification of the cost-effectiveness ratio. A decision tree was built. Six periods of follow-up are identified with a duration of 4-months per period. The tree contains 3 principal arms, each one corresponding to a specific treatment: risperidone LA injection, haloperidol decanoate and olanzapine. For each arm, at the chance node, two health states are identified: either the patient responds favourably to the treatment or does not respond favourably and requires a switch to another drug treatment. After a period of response, the patient can either remain in the same state or experiences a clinical deterioration. If the patient presents a clinical deterioration, he can either go back to a positive response state after a period of intensive follow-up or remain in an insufficient response state; in this case, a change of antipsychotic treatment is necessary. In the model, a patient should receive four different treatments before a long-term hospitalization takes put in place. According to the market authorization labelling, clozapine is proposed only as a 2nd or 3rd line therapeutic option, so when at least one or two successive neuroleptics have failed. The efficacy data used in the model are provided by clinical research recently published. These studies estimate the efficacy of oral risperidone, LA risperidone, olanzapine, and treatment by haloperidol. When available data in the literature were insufficient, the opinion of experts was sought. The effectiveness criteria is the rate of patients treated successfully: patients responding to the initial treatment with the possibility of experiencing one or two episodes of clinical deterioration but without requiring a switch to another drug during 2 years of follow-up. The base case is as follows: efficacy for oral risperidone is used for the LA risperidone strategy, increased by 10% within the first 4 months of follow-up; efficacy for oral haloperidol is used for haloperidol depot, increased by 5% within the first 4 months of follow-up; for olanzapine, observed data in clinical trials were applied. The hypotheses for long acting forms are rather conservative because the increase of efficacy which can be expected for the long-acting injectable formulations varies between 5% to more than 30% according to the literature data. The analysis of sensibility includes three scenarios: scenario 1: for LA risperidone, 5% of patients treated successfully improvement in regard to oral risperidone instead of 10% in the base case; scenario 2: for haloperidol depot, 10% of patients treated successfully improvement in regard of oral haloperidol instead of 5% in the base case; scenario 3: the results of an open trial conducted within the framework of the LA risperidone license are used, leading to an increase of up to 13,3% of the rate of successfully treated patients, compared to oral risperidone literature data. As for the side effects, only extrapyramidal symptoms were considered. Other side effects are described in the literature such as the obesity or the occurrence of a diabetes; these effects were not taken into account in the model, their impact on the cove-rage of schizophrenic patients and on resources utilisation being poorly known. Only direct medical costs were considered in the pharmaco-economic analysis. Two types of costs were identified: hospital costs and community care costs. The stays in overnight hospitalisation and day hospitalisation were derived from the Disease Related Groups (DRG) and valued from the data of the National Cost Study (Etude Nationale de Couts; 1999). The DRGs corresponding to the diagnosis of schizophrenia are the DRG 627 (complete hospitalization) and DRG 819 (day hospitalisation). Ambulatory care: procedures and visits, were valued in euros in reference with the tariffs for reimbursement issued in the Naming General of the Professional Acts (NGAP) and published by the French National Health Insurance (Year 2001). Medication consumption was quantified by using the daily dosage specified in the the MAA and the French prescription database IMS-Dorema. The cost of medicines was valued from tariffs 2001 (SEMPEX). LA risperidone price being not fixed to date, the reserved hypothesis is a 141,62 Euro retail price. As schizophrenia is listed among the diseases reimbursed at a 100% rate by the Health insurance, out of pocket expenses by patient are not considered in the analysis. The cost for the extrapyramidal effects was attributed to all the strategies. This cost was calculated according to the rates of extrapyramidal effects occurrence collected in the literature. Globally, in the published studies, the incidence of the side effects for the patients treated by olanzapine or risperidone is similar. It was thus decided by the experts to use the same rate of occurrence for extrapyramidal effects for olanzapine and risperidone (20%). This rate is 40% for haloperidol decanoate, 10% for oral clozapine. For the cost estimation, the expenses for treating a schizophrenic patient for two years were taken into account. RESULTS: The results show that in two years, LA risperidone is more effective than the two other antipsychotics. After 2 years, the rate of patients treated successfully is 82,7% for LA risperidone, 74,8% for olanzapine and 57,3% for haloperidol depot. The 2 year-cost per patient treated by LA risperidone is 14,055 Euro. This cost is 14,351 Euro and 17,203 Euro respectively for the strategies olanzapine and haloperidol depot. The cost-efficacy ratios per patient successfully treated are 16,995 Euro for the strategy LA risperidone, 19,186 Euro for olanzapine and 30,023 Euro for haloperidol depot. LA risperidone is a dominant strategy compared with both olanzapine and haloperidol depot. Scenario 1 shows that LA risperidone strategy remains the most effective. Indeed, this strategy allows a response increase of 3,5% regarding olanzapine strategy and of 21% regarding haloperidol depot strategy. Under the hypothesis tested in scenario 1, LA risperidone is a partial dominant strategy against olanzapine and a total dominant strategy against haloperidol depot. In scenario 2, as efficacy is improved for haloperidol decanoate (61,10%), a decrease of 1,763 Euro in the cost per patient treated is observed for this strategy. Cost per patient treated successfully and efficacy for LA risperidone and olanzapine are the same than in the base case. LA risperidone is a total dominant strategy against olanzapine and haloperidol decanoate. In scenario 3, the rate of patients treated successfully at 2 years is 88,6% for LA risperidone with a cost per patient of 12,347 Euro. LA risperidone is dominant against olanzapine and haloperidol depot. DISCUSSION AND CONCLUSION: The schizophrenia is a relatively frequent disease. (ABSTRACT TRUNCATED)

Lostumbo, L., Carbine, N., Wallace, J., & Ezzo, J. (2004). Prophylactic mastectomy for the prevention of breast cancer. Cochrane Database of Systematic Reviews (Online), (4)(4), CD002748. doi:10.1002/14651858.CD002748.pub2

BACKGROUND: Breast cancer is the most common cancer and the second most common cause of cancer-related death among North American and Western European women. Recent progress in understanding the genetic basis of breast cancer, along with rising incidence rates, have resulted in increased interest in prophylactic mastectomy as a method of preventing breast cancer, particularly in those with familial susceptibility. OBJECTIVES: The primary objective was to determine whether prophylactic mastectomy reduces death from any cause in women who have never had breast cancer and in women who have a history of breast cancer in one breast. The secondary objective was to examine the effect of prophylactic mastectomy on other endpoints including breast cancer incidence, breast cancer mortality, disease-free survival, physical morbidity, and psychosocial outcomes. SEARCH STRATEGY: Electronic searches were performed in the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Cancerlit, and the Science Citation Index. SELECTION CRITERIA: Inclusion criteria were studies in English of any design type including randomized or nonrandomized controlled trials, cohort studies, case-control studies, and case series with at least ten participants. Participants included women at risk for breast cancer in at least one breast. Interventions included all types of mastectomy performed for the purpose of preventing breast cancer, including subcutaneous mastectomy, total or simple mastectomy, modified radical mastectomy, and radical mastectomy. DATA COLLECTION AND ANALYSIS: Information on patients, interventions, methods, and results were extracted by at least two independent reviewers. Methodological quality was assessed based on how well each study minimized potential selection bias, performance bias, detection bias, and attrition bias. Data for each study were summarized descriptively; quantitative meta-analysis was not feasible due to heterogeneity of study designs and insufficient reporting. Data were analyzed separately for bilateral prophylactic mastectomy (BPM) and contralateral prophylactic mastectomy (CPM). MAIN RESULTS: Twenty-three studies, including more than 4,000 patients, met inclusion criteria. No randomized or nonrandomized controlled trials were found. Most studies were either case series or cohort studies. All studies had methodological limitations, with the most common source of potential bias being systematic differences between the intervention and comparison groups that could potentially be associated with a particular outcome. Thirteen studies assessed the effectiveness of BPM. No study assessed all-cause mortality after BPM. All studies reporting on incidence of breast cancer and disease-specific mortality reported reductions after BPM. Nine studies assessed psychosocial measures; most reported high levels of satisfaction with the decision to have prophylactic mastectomy (PM) but more variable satisfaction with cosmetic results. Only one study assessed satisfaction with the psychological support provided by healthcare personnel during risk counseling and showed that more women were dissatisfied than satisfied with the support they received in the healthcare setting. Worry over breast cancer was significantly reduced after BPM when compared both to baseline worry levels and to the groups who opted for surveillance rather than BPM. Three studies reported body image/feelings of femininity outcomes, and all reported that a substantial minority (about 20%) reported BPM had adverse effects on those domains. Six studies assessed contralateral prophylactic mastectomy. Studies consistently reported reductions in contralateral incidence of breast cancer but were inconsistent about improvements in disease-specific survival. Only one study attempted to control for multiple differences between intervention groups, and this study showed no overall survival advantage for CPM at 15 years. Two case series were exclusively focused on adverse events from prophylactic mastectomy with reconstruction, and both reported rates of unanticipated re-operations from 30% to 49%. REVIEWERS' CONCLUSIONS: While published observational studies demonstrated that BPM was effective in reducing both the incidence of, and death from, breast cancer, more rigorous prospective studies (ideally randomized trials) are needed. The studies need to be of sufficient duration and make better attempts to control for selection biases to arrive at better estimates of risk reduction. The state of the science is far from exact in predicting who will get or who will die from breast cancer. By one estimate, most of the women deemed high risk by family history (but not necessarily BRCA 1 or 2 mutation carriers) who underwent these procedures would not have died from breast cancer, even without prophylactic surgery. Therefore, women need to understand that this procedure should be considered only among those at very high risk of the disease.For women who had already been diagnosed with a primary tumor, the data were particularly lacking for indications for contralateral prophylactic mastectomy. While it appeared that contralateral mastectomy may reduce the incidence of cancer in the contralateral breast, there was insufficient evidence about whether, and for whom, CPM actually improved survival.Physical morbidity is not uncommon following PM, and many women underwent unanticipated re-operations (usually due to problems with reconstruction); however, these data need to be updated to reflect changes in surgical procedures and reconstruction.Regarding psychosocial outcomes, women generally reported satisfaction with their decisions to have PM but reported satisfaction less consistently for cosmetic outcomes, with diminished satisfaction often due to surgical complications. Therefore, physical morbidity and post-operative surgical complications were areas that should be considered when deciding about PM. With regard to emotional well-being, most women recovered well postoperatively, reporting reduced cancer worry and showing reduced psychological morbidity from their baseline measures; exceptions also have been noted. Of the psychosocial outcomes measured, body image and feelings of femininity were the most adversely affected.

Lous, J., Burton, M. J., Felding, J. U., Ovesen, T., Rovers, M. M., & Williamson, I. (2005). Grommets (ventilation tubes) for hearing loss associated with otitis media with effusion in children. Cochrane Database of Systematic Reviews (Online), (1)(1), CD001801. doi:10.1002/14651858.CD001801.pub2

BACKGROUND: Otitis media with effusion (OME), or 'glue ear', is very common in children, especially between the ages of one and three years with a prevalence of 10% to 30% and a cumulative incidence of 80% at the age of four years. OME is defined as middle ear effusion without signs or symptoms of an acute infection. OME may occur as a primary disorder or as a sequel to acute otitis media. The functional effect of OME is a conductive hearing level of about 25 to 30 dB associated with fluid in the middle ear. Both the high incidence and the high rate of spontaneous resolution suggest that the presence of OME is a natural phenomenon, its presence at some stage in childhood being a normal finding. Notwithstanding this, some children with OME may go on to develop chronic otitis media with structural changes (tympanic membrane retraction pockets, erosion of portions of the ossicular chain and cholesteatoma), language delays and behavioural problems. It remains uncertain whether or not any of these findings are direct consequences of OME. The most common medical treatment options include the use of decongestants, mucolytics, steroids, antihistamines and antibiotics. The effectiveness of these therapies has not been established. Surgical treatment options include grommet (ventilation or tympanostomy tube) insertion, adenoidectomy or both. Opinions regarding the risks and benefits of grommet insertion vary greatly. The management of OME therefore remains controversial. OBJECTIVES: To assess the effectiveness of grommet insertion compared with myringotomy or non-surgical treatment in children with OME. The outcomes studied were (i) hearing level, (ii) duration of middle ear effusion, (iii) well-being (quality of life) and (iv) prevention of developmental sequelae possibly attributable to the hearing loss (for example, impairment in impressive and expressive language development (measured using standardised tests), verbal intelligence, and behaviour). SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 1, 2003), MEDLINE (1966 to 2003), EMBASE (1973 to 2003) and reference lists of all identified studies. The date of the last systematic search was March 2003, and personal non-systematic searches have been performed up to August 2004. SELECTION CRITERIA: Randomised controlled trials (RCTs) evaluating the effect of grommets on hearing, duration of effusion, development of language, cognition, behaviour or quality of life. Only studies using common types of grommets (mean function time of 6 to 12 months) were included. DATA COLLECTION AND ANALYSIS: Data from studies were extracted by two reviewers and checked by the other reviewers. MAIN RESULTS: Children treated with grommets spent 32% less time (95% confidence interval (CI) 17% to 48%) with effusion during the first year of follow-up. Treatment with grommets improved hearing levels, especially during the first six months. In the randomised controlled trials that studied the effect of grommet insertion alone, the mean hearing levels improved by around 9 dB (95% CI 4 dB to 14 dB) after the first six months, and 6 dB (95% CI 3 dB to 9 dB) after 12 months. In the randomised controlled trials that studied the combined effect of grommets and adenoidectomy, the additional effect of the grommets on hearing levels was improvement by 3 to 4 dB (95% CI 2 dB to 5 dB) at six months and about 1 to 2 dB (95% CI 0 dB to 3 dB) at 12 months. Ears treated with grommets had an additional risk for tympanosclerosis of 0.33 (95% CI 0.21 to 0.45) one to five years later. In otherwise healthy children with long-standing OME and hearing loss, early insertion of grommets had no effect on language development or cognition. One randomised controlled trial in children with OME more than nine months, hearing loss and disruptions to speech, language, learning or behaviour showed a very marginal effect of grommets on comprehensive language. AUTHORS' CONCLUSIONS: The benefits of grommets in children appear small. The effect of grommets on hearing diminished during the first year. Potentially adverse effects on the tympanic membrane are common after grommet insertion. Therefore an initial period of watchful waiting seems to be an appropriate management strategy for most children with OME. As no evidence is yet available for the subgroups of children with speech or language delays, behavioural and learning problems or children with defined clinical syndromes (generally excluded from the primary studies included in this review), the clinician will need to make decisions regarding treatment for such children based on other evidence and indications of disability related to hearing impairment.This review does not resolve the discrepancy between parental and clinical observation of a beneficial treatment effect and the results in the reviewed RCT showing only a short-term effect on hearing and virtually no effect on development. Is the perceived, often dramatic, effect of grommets only a short-term one? Are some children more sensitive to OME-related hearing loss than others? If so, how do we identify them?Further research should focus upon indications. Studies should use sufficiently large sample sizes to show significant interactions. There is a need to determine the most suitable variables and appropriate "softer" outcomes to be the subject of these interaction tests. Interesting options include measures of speech-in-noise and binaural hearing.The generally modest results in the trials which are included in this review should make it easier to justify randomisation of more severely affected and higher-risk children in appropriately constructed trials. Randomised controlled trials are necessary in these children before more detailed conclusions about the effectiveness of grommets can be drawn.

Mackinnon, A., & Mulligan, R. (2005). The estimation of premorbid intelligence levels in French speakers. [Estimation de l'intelligence premorbide chez les francophones] L'Encephale, 31(1 Pt 1), 31-43.

Knowledge of cognitive performance earlier in life is essential in order to characterize precisely the extent to which these abilities have declined when an individual is diagnosed as having a dementing illness. The National Adult Reading Test (NART) was developed by Nelson and O'Connell to estimate premorbid intellectual ability in patients suffering from intellectual deterioration due to dementia. The test consists of 50 words, graded in difficulty, whose pronunciation cannot be determined from their spelling. The ability to successfully read irregularly spelt words is relatively robust in the face of current cognitive impairment and is a sensitive marker of intellectual attainment. Because the NART relies on orthographic irregularities in the English language, the construction of analogues of the test in other languages is not simply a matter of translation of the test content. Rather, words in the target language that have comparable properties to those in the NART must be sought. A French adaptation of the NART--the fNART--was developed by Bovet and calibrated on a small French-speaking Swiss sample. In a sample of 30 nondemented subjects, number of words pronounced correctly correlated highly with WAIS-R verbal and total IQ scores and less strongly with performance IQ (r = 0.43). Data available from an epidemiological survey undertaken in Geneva, Switzerland provided an opportunity to establish the measurement properties and construct validity of the fNART in a large sample unselected with respect to cognitive decline. In addition to the fNART, the survey incorporated a brief test battery assessing the domains of crystallized intelligence, memory and cognitive speed. An interview that enabled the diagnosis of dementia according to DSM IV criteria, the Mini Mental State Examination and the Psychogeriatric Assessment Scales (PAS) were also administered. If the fNART measures intellectual ability, substantial correlations between it and the test battery would be expected. Further validation of the test was sought by exploring its relation with years of education. The stability of the fNART was assessed by comparing the scores of subjects with and without dementia, and by examining the relationship of fNART scores to an informant-based report of change in cognitive performance from earlier in life assessed in the PAS. If the fNART is stable in the face of cognitive deterioration, no between-group differences or association with reported cognitive change would be expected. METHOD: Subjects were randomly selected from residents of the canton of Geneva aged over 65 years. The analyses reported here were undertaken on a sample of 368 persons who gave codable responses to at least 90% of the fNART items. They ranged in age from 65 to 94 years. Subjects were interviewed in their homes by trained lay interviewers. RESULTS: Cronbach's alpha for the forty-item scale was high (0.89). The percentage of subjects correctly pronouncing words ranged from 7.3% for "chamsin" to 96.7% for "agenda". Item response theory (IRT) models were fitted to the data. In a three-parameter model the value of the guessing (asymptote) parameter was vanishing small for all items. Accordingly, a two-parameter model was adopted. The discriminating power (slope) of items ranged considerably from 0.281 (rebus) to 1.192 (beotien). The average slope was 0.656. This corresponds to average factor loading of 0.528 (range 0.270 to 0.766.) The items measure a broad range of ability (mean threshold--0.719, sd = 1.540). Most items, however, discriminate at moderate levels. The parameter values obtained in the current study were compared to those estimated in a French sample of persons at risk of dementia . The correlation between item pairs for slope and parameter estimates was 0.53 and 0.70 respectively. This indicated substantial concordance between the samples regarding the difficulty of the items, but some differences in the power of groups to differentiate ability. In particular, a small number of words that performed very well in the "at risk" sample showed more moderate discrimination in the current study. Scores on the fNART were correlated with measures of crystallised intelligence, memory and cognitive speed. All correlations were statistically significant. With all tests entered a regression equation the multiple correlation coefficient was 0.63. Mean fNART scores of those suffering from DSM IV dementia and those meeting only Criterion A (multiple cognitive deficits) were lower than those of subjects meeting neither set of criteria. However subjects in the first two groups were older than subjects in the undemented group and had significantly lower educational attainment. When these two factors were controlled in an analysis of covariance, the magnitude of the differences between the groups, while still overall significantly different, was substantially reduced. A similar pattern of results applied when psychometric measures of cognitive state--the MMSE and the PAS Cognitive Impairment Scale--were used instead of diagnostic categories. The partial correlations of the fNART with the MMSE and PAS cognitive impairment scale controlling for age and education were 0.25 (P < 0.01) and -0.33 (P < 0.01) respectively. fNART scores did not differ between the sexes, nor were they significantly correlated with PAS Depression, Stroke or Behaviour Change scales. There was a small but significant correlation between the fNART and informant-assessed Cognitive Decline on the PAS. DISCUSSION: This study demonstrated the excellent measurement properties of a French adaptation of the National Adult Reading Test in a large probability sample of elderly native speakers and provided the first large-sample evidence to support the validity of the fNART as a test of intellectual functioning relatively robust to dementia status. The negligible values of the pseudo-guessing parameters suggest that the goal of choosing words whose pronunciation is not susceptible to guessing has been achieved. The average item discriminability was high and the words used covered the spectrum of ability. The finding of substantial relationships of cognitive performance and educational attainment with fNART scores is important in validating the test as a measure of premorbid cognitive ability. The low correlations of the fNART with informant-based assessment of cognitive decline and age support the fNART as being relative robust to decline in ability. The relationships observed in this French adaptation are comparable to those reported for the English instrument . However, subjects meeting DSM IV criteria for dementia or Criterion A only had lower scores than other subjects. Decline in NART scores with dementia has been observed, particularly in moderate and severe cases. Given that the mechanism of the fNART is the same as the NART it is to be expected that while generally robust to current dementia status, some decline in performance will occur with the progression of the disease. The relationships between the fNART and PAS scales was remarkably similar to those reported by Jorm et al. in an English-speaking sample between the PAS and NART. Although small, the correlation between the fNART and the PAS Cognitive Decline scale might have been expected to be non-significant if the measure were truly stable in the face of intellectual deterioration. However this correlation is mirrored in the original English instruments and may reflect the higher risk of dementia in persons of lower intellectual ability. CONCLUSION: Further research is desirable to improve the precision of the calibration of the scale against the WAIS-R. Nevertheless, this study has demonstrated that the fNART is a reliable and valid method of assessing premorbid intellectual ability in French speakers.

Madden, J. S. (1994). LSD and post-hallucinogen perceptual disorder. Addiction (Abingdon, England), 89(6), 762-763.

Maddison, P., & Newsom-Davis, J. (2003). Treatment for Lambert-Eaton myasthenic syndrome. Cochrane Database of Systematic Reviews (Online), (2)(2), CD003279. doi:10.1002/14651858.CD003279

BACKGROUND: Lambert-Eaton myasthenic syndrome is an autoimmune presynaptic disorder of neuromuscular transmission. Treatments have attempted to overcome the harmful autoimmune process, or to improve residual neuromuscular transmission, in order to reverse the principal neurological symptom of muscle weakness. OBJECTIVES: The objective was to examine the efficacy of all forms of treatment in Lambert-Eaton myasthenic syndrome. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group specialised trials register (September 2002), MEDLINE (January 1966 to November 2002) and EMBASE (January 1980 to November 2002). We checked the bibliographies in reports of the randomised trials and contacted authors to identify additional published or unpublished data. SELECTION CRITERIA: Types of studies: all randomised or quasi-randomised trials. Types of participants: all adults and children with a diagnosis of Lambert-Eaton myasthenic syndrome, with or without small-cell lung cancer. Types of interventions: any form of medical (pharmacological or physical) treatment. Types of outcome measures: Primary: change in the muscle strength scale score (Quantitative Myasthenia Gravis score), or limb muscle strength measured by myometry. Secondary: improvement in the mean amplitude of the resting compound muscle action potentials. The mean amplitude used was the mean of all muscles tested. DATA COLLECTION AND ANALYSIS: We identified three randomised controlled trials. Individual patient data were only available for one trial. MAIN RESULTS: The three eligible trials included two controlled trials of the effects of 3,4-diaminopyridine compared with placebo in a total of 38 patients with Lambert-Eaton myasthenic syndrome, one of which was of crossover design. A third crossover trial compared intravenous immunoglobulin treatment to placebo in nine patients with Lambert-Eaton myasthenic syndrome. A meta-analysis of the primary endpoint results of these trials was not possible because of differences in comparisons and endpoints and, in two trials, lack of individual patient data. EFFECTS OF 3,4-DIAMINOPYRIDINE: Two trials of 3,4-diaminopyridine reported a significant improvement in the primary endpoint of muscle strength score, or myometric limb measurement following treatment. Both trials also reported a significant improvement in the secondary endpoint of resting compound muscle action potential amplitude following 3,4-diaminopyridine, compared with placebo. A meta-analysis of the primary endpoint results was not possible because of marked differences in these two trials regarding primary outcome measures. However, a meta-analysis of the secondary endpoint (improvement in the amplitude of the mean resting compound muscle action potential) was possible. It was necessary to assume a known correlation (similarity) of the paired responses for each individual in the two treatment periods in order to properly allow for the crossover design of one of the two trials (the correlation coefficient was assumed to be 0.5 in calculations). Using this approach, meta-analysis revealed a significant overall benefit in compound muscle action potential amplitude after 3,4-diaminopyridine treatment. The overall weighted mean difference was 1.80 mV (95% confidence interval 0.82 to 2.78), favouring treatment. These results were not sensitive to the assumption made because the overall benefit estimated was still significant when the correlation was assumed to be less than 0.1. EFFECTS OF INTRAVENOUS IMMUNOGLOBULIN: A crossover trial reported a significant improvement in the primary outcome measure of myometric limb strength when patients received intravenous immunoglobulin compared to placebo infusions. This trial also demonstrated an improvement in the secondary outcome measure of change in the mean resting compound muscle action potential amplitude following intravenous immunoglobulin, but this improvement did not reach significance. Clinical improvement lasted for up to eight weeks. REVIEWER'S CONCLUSIONS: Limited evidence from randomised controlled trials showed that either 3,4-diaminopyridine or intravenous immunoglobulin improved muscle strength scores and compound muscle action potential amplitudes in patients with Lambert-Eaton myasthenic syndrome. There are insufficient data at present to quantify this treatment effect. Other possible treatments, such as plasma exchange, steroids and immunosuppressive agents have not been tested in randomised controlled trials.

Mainardi, F., Trucco, M., Maggioni, F., Palestini, C., Dainese, F., & Zanchin, G. (2009). Cluster-like headache. A comprehensive reappraisal. Cephalalgia : An International Journal of Headache, doi:10.1111/j.1468-2982.2009.01993.x

Among the primary headaches, cluster headache (CH) presents very particular features allowing a relatively easy diagnosis based on criteria listed in Chapter 3 of the International Classification of Headache Disorders (ICHD-II). However, as in all primary headaches, possible underlying causal conditions must be excluded to rule out a secondary cluster-like headache (CLH). The observation of some cases with clinical features mimicking primary CH, but of secondary origin, led us to perform an extended review of CLH reports in the literature. We identified 156 CLH cases published from 1975 to 2008. The more frequent pathologies in association with CLH were the vascular ones (38.5%, n = 57), followed by tumours (25.7%, n = 38) and inflammatory infectious diseases (13.5%, n = 20). Eighty were excluded from further analysis, because of inadequate information. The remaining 76 were divided into two groups: those that satisfied the ICHD-II diagnostic criteria for CH, 'fulfilling' group (F), n = 38; and those with a symptomatology in disagreement with one or more ICHD-II criteria, 'not fulfilling' group (NF), n = 38. Among the aims of this study was the possible identification of clinical features leading to the suspicion of a symptomatic origin. In the differential diagnosis with CH, red flags resulted both for F and NF, older age at onset; for NF, abnormal neurological/general examination (73.6%), duration (34.2%), frequency (15.8%) and localization (10.5%) of the attacks. We stress the fact that, on first observation, 50% of CLH presented as F cases, perfectly mimicking CH. Therefore, the importance of accurate, clinical evaluation and of neuroimaging cannot be overestimated.

Mampreso, E., Maggioni, F., Viaro, F., Disco, C., & Zanchin, G. (2009). Efficacy of oxygen inhalation in sumatriptan refractory "high altitude" cluster headache attacks. The Journal of Headache and Pain, doi:10.1007/s10194-009-0160-0

We describe the case of a 40-year-old woman, affected by episodic cluster headache, who presented with a cluster headache triggered by exposure to high altitude. Her attacks were refractory to sumatriptan, very effective at sea level, but responded to oxygen. A pathophysiological mechanism is proposed.

Mangini, M. (1998). Treatment of alcoholism using psychedelic drugs: a review of the program of research. Journal of Psychoactive Drugs, 30(4), 381-418.

Following Albert Hofmann's discovery of LSD's psychoactive properties in 1943, and previous to their scheduling as controlled substances, the psychedelic drugs were widely studied--six international conferences and hundreds of papers discussed their potential therapeutic usefulness. The observation that the frightening experience of delirium tremens sometimes led alcoholics to moderate their alcohol intake suggested to early psychedelic researchers that the "psychotomimetic" experience thought to be produced by LSD could be used to treat alcoholism. A number of hypothesis-generating studies employing a variety of research designs to examine this premise were completed, but relatively few controlled trials attempted hypothesis testing. After twenty-five years of study, a combination of flawed methodology, uneven results and social reprehension led to the abandonment of research on the therapeutic use of psychedelic drugs, leaving many avenues of inquiry unexplored and many questions unanswered. Today, after a thirty-year hiatus, this research is gradually being resumed, and there is renewed interest in the findings of previous studies. This article explores the history of one branch of psychedelic research, the therapeutic use of LSD in the treatment of alcoholism, and of the events that led to the relabeling of the "hallucinogens" as drugs of abuse.

Marais, B. J., Gie, R. P., Hesseling, A. C., Schaaf, H. S., Lombard, C., Enarson, D. A., & Beyers, N. (2006). A refined symptom-based approach to diagnose pulmonary tuberculosis in children. Pediatrics, 118(5), e1350-9. doi:10.1542/peds.2006-0519

BACKGROUND: Tuberculosis control programs place an almost exclusive emphasis on adults with sputum smear-positive tuberculosis, because they are most infectious. However, children contribute a significant proportion of the global tuberculosis caseload and experience considerable tuberculosis-related morbidity and mortality, but few children in endemic areas have access to antituberculosis treatment. The diagnostic difficulty experienced in endemic areas with limited resources has been identified as a major factor contributing to poor treatment access. In general, there is a sense of scepticism regarding the potential value of symptom-based diagnostic approaches, because current clinical diagnostic approaches are often poorly validated. The natural history of childhood tuberculosis demonstrates that symptoms may offer good diagnostic value if they are well defined and if appropriate risk stratification is applied. This study aimed to determine the value of well-defined symptoms to diagnose childhood pulmonary tuberculosis in a tuberculosis-endemic area. METHODS: A prospective, community-based study was conducted in Cape Town, South Africa. Specific well-defined symptoms were documented in all children 2 weeks' duration; study participants were thoroughly evaluated for tuberculosis. In addition, all of the children who received antituberculosis treatment during the study period were reviewed by the investigator, irrespective of study inclusion. This concurrent disease surveillance provided a comprehensive overview of all of the childhood tuberculosis cases, allowing accurate assessment of the possible disadvantages associated with this symptom-based diagnostic approach. In the absence of an acceptable gold standard test, optimal case definition is an important consideration. Children were categorized as "bacteriologically confirmed tuberculosis," "radiologically certain tuberculosis," "probable tuberculosis," or "not tuberculosis." Bacteriologically confirmed tuberculosis was defined as the presence of acid-fast bacilli on sputum microscopy and/or Mycobacterium tuberculosis cultured from a respiratory specimen. Radiologically certain tuberculosis was defined as agreement between both independent experts that the chest radiograph indicated certain tuberculosis in the absence of bacteriologic confirmation. Probable tuberculosis was defined as the presence of suggestive radiologic signs and good clinical response to antituberculosis treatment in the absence of bacteriologic confirmation or radiologic certainty. Good clinical response was defined as complete symptom resolution and weight gain of > or = 10% of body weight at diagnosis, within 3 months of starting antituberculosis treatment. Not tuberculosis was defined as spontaneous symptom resolution or no response to antituberculosis therapy in the absence of bacteriologic confirmation or radiologic signs suggestive of tuberculosis. Pulmonary tuberculosis was defined as a symptomatic child with: (1) bacteriologically confirmed tuberculosis, (2) radiologically confirmed tuberculosis, or (3) probable tuberculosis (as defined), excluding isolated pleural effusion. RESULTS: In total, 1024 children were referred for evaluation. Resolving symptoms were reported in 596 children (58.2%); 428 (41.8%) children with persistent, nonremitting symptoms at evaluation were investigated for tuberculosis. Pulmonary tuberculosis was diagnosed in 197 children; 96 were categorized as bacteriologically confirmed tuberculosis, 75 as radiologically certain tuberculosis, and 26 as probable tuberculosis. Combining a persistent nonremitting cough of > 2 weeks' duration, documented failure to thrive (in the preceding 3 months), and fatigue provided reasonable diagnostic accuracy in HIV-uninfected children (sensitivity: 62.6%; specificity: 89.8%; positive predictive value: 83.6%); the performance was better in the low-risk group (> or = 3 years; sensitivity: 82.3%; specificity: 90.2%; positive predictive value: 82.3%) than in the high-risk group ( 2 weeks' duration; study participants were thoroughly evaluated for tuberculosis. In addition, all of the children who received antituberculosis treatment during the study period were reviewed by the investigator, irrespective of study inclusion. This concurrent disease surveillance provided a comprehensive overview of all of the childhood tuberculosis cases, allowing accurate assessment of the possible disadvantages associated with this symptom-based diagnostic approach. In the absence of an acceptable gold standard test, optimal case definition is an important consideration. Children were categorized as "bacteriologically confirmed tuberculosis," "radiologically certain tuberculosis," "probable tuberculosis," or "not tuberculosis." Bacteriologically confirmed tuberculosis was defined as the presence of acid-fast bacilli on sputum microscopy and/or Mycobacterium tuberculosis cultured from a respiratory specimen. Radiologically certain tuberculosis was defined as agreement between both independent experts that the chest radiograph indicated certain tuberculosis in the absence of bacteriologic confirmation. Probable tuberculosis was defined as the presence of suggestive radiologic signs and good clinical response to antituberculosis treatment in the absence of bacteriologic confirmation or radiologic certainty. Good clinical response was defined as complete symptom resolution and weight gain of > or = 10% of body weight at diagnosis, within 3 months of starting antituberculosis treatment. Not tuberculosis was defined as spontaneous symptom resolution or no response to antituberculosis therapy in the absence of bacteriologic confirmation or radiologic signs suggestive of tuberculosis. Pulmonary tuberculosis was defined as a symptomatic child with: (1) bacteriologically confirmed tuberculosis, (2) radiologically confirmed tuberculosis, or (3) probable tuberculosis (as defined), excluding isolated pleural effusion. RESULTS: In total, 1024 children were referred for evaluation. Resolving symptoms were reported in 596 children (58.2%); 428 (41.8%) children with persistent, nonremitting symptoms at evaluation were investigated for tuberculosis. Pulmonary tuberculosis was diagnosed in 197 children; 96 were categorized as bacteriologically confirmed tuberculosis, 75 as radiologically certain tuberculosis, and 26 as probable tuberculosis. Combining a persistent nonremitting cough of > 2 weeks' duration, documented failure to thrive (in the preceding 3 months), and fatigue provided reasonable diagnostic accuracy in HIV-uninfected children (sensitivity: 62.6%; specificity: 89.8%; positive predictive value: 83.6%); the performance was better in the low-risk group (> or = 3 years; sensitivity: 82.3%; specificity: 90.2%; positive predictive value: 82.3%) than in the high-risk group ( 2 weeks' duration; objective weight loss [documented failure to thrive] during the preceding 3 months; and reported fatigue) provided good diagnostic accuracy in HIV-uninfected children > or = 3 years of age, with clinical follow-up providing additional value. The approach performed less well in children < 3 years. However, the presence of a persistent, nonremitting cough together with documented failure to thrive still provided a fairly accurate diagnosis (sensitivity: 68.3%; specificity: 80.1%; positive predictive value: 82.1%), illustrating the importance of regular weight monitoring in young children. Clinical follow-up also offered additional diagnostic value, but caution is required, because very young children have an increased risk of rapid disease progression. The approach performed poorly in HIV-infected children. Recent household contact with an adult index case seemed to provide more diagnostic value than a positive tuberculin skin test, but novel T-cell-based assays may offer the only real improvement in sensitivity to diagnose M. tuberculosis infection in HIV-infected children. The variable diagnostic value offered by this symptom-based diagnostic approach illustrates the importance of risk stratification, as demonstrated by the fact that 11 (91.7%) of 12 children with severe disease manifestations who failed to meet the entry criteria were < 3 years of age or HIV infected. Particular emphasis should be placed on the provision of preventive chemotherapy after documented exposure and/or infection in these high-risk children. Study limitations include the small number of HIV-infected children, but on the positive side, the large number of HIV-uninfected children permitted adequate evaluation in this important group. It is often forgotten that HIV-uninfected children constitute the majority of child tuberculosis cases, even in settings where HIV is endemic. This study demonstrates the importance of ascertaining a child's HIV status before symptom-based diagnosis is attempted. Because children were recruited at both the clinic and hospital level, some selection bias may have been introduced; however, the only significant difference between the 2 groups was the proportion of HIV-infected children. Pulmonary tuberculosis was diagnosed with different levels of certainty, but no significant differences were recorded between these groups. CONCLUSIONS: Pulmonary tuberculosis can be diagnosed with a reasonable degree of accuracy in HIV-uninfected children using a simple symptom-based approach. This offers the exciting prospect of improving treatment access for children, particularly in resource-limited settings where current access to antituberculosis treatment is poor.

Markel, H., Lee, A., Holmes, R. D., & Domino, E. F. (1994). LSD flashback syndrome exacerbated by selective serotonin reuptake inhibitor antidepressants in adolescents. The Journal of Pediatrics, 125(5 Pt 1), 817-819.

Two adolescents with a long history of abuse of lysergic acid diethylamide (LSD) and symptoms consistent with major depressive disorder, on initiation of antidepressant therapy with selective serotonin reuptake inhibitor agents, had the new onset or worsening of LSD flashback syndrome. The similarity in neuroreceptor physiology for both LSD and serotonin suggests that the LSD flashback syndrome may be induced by these drugs in patients with a history of LSD abuse.

Matefy, R. E., & Krall, R. G. (1974). An initial investigation of the psychedelic drug flashback phenomena. Journal of Consulting and Clinical Psychology, 42(6), 854-860.

Mathet, F., Martin-Guehl, C., Maurice-Tison, S., & Bouvard, M. P. (2003). Prevalence of depressive disorders in children and adolescents attending primary care. A survey with the Aquitaine Sentinelle Network. [Prevalence des troubles depressifs chez l'enfant et l'adolescent consultant en medecine generale] L'Encephale, 29(5), 391-400.

Since depressive disorders in children and adolescents have not been widely studied in the context of gene-ral medicine, we conducted an epidemiological survey among general practitioners (GP's) consulted by young subjects aged 7 to 17 years for various reasons. OBJECTIVE: The aims were the following: to estimate the prevalence of depressive disorders in general practice, to detect the eventual existence of particular clinical forms, to assess the frequency of comorbid disorders and to determine to what degree these disorders were diagnosed by GP's. METHOD: The study was conducted over 6 months in concert with 45 practitioners of the Aquitaine Sentinelle Network because of their strong experience in the field of epidemiological surveys, especially regarding psychiatric disorders. The population included all consecutive attenders aged 7 to 17 years. Consent to participate was obtained from children and adolescents and their parents. Finally 155 patients took part. A two-stage epidemiologic strategy was used, including screening tests in the first stage and semi structured interview by clinician in the second stage for diagnostic confirmation. During the first stage, information was obtained from children and adolescents and general practitioners using three questionnaires. The self-report questionnaire Center for Epidemiological Studies Depression (CES-D) was used for screening depression in 13 to 17 years old adolescents and the 20 items of the scale were modified to make it more comprehensible and relevant for children aged 7 to 12. The cut-off of 21 used in France appeared to be the more appropriate in both males and females and was taken to indicate high likelihood of depressive disorder. Therefore people with score 21 or more were approached for the second stage. The Child Behavior Checklist (CBCL), an instrument of well-established validity and reliability, provided information from parents about the child's behavior and competencies. Demographic and environmental data, as well as the reason for the visit and the presence of associated psychological factors were collected from a questionnaire devised for the study and completed by the practitioner. The 21 patients initially detected were invited to take part in the second stage. A total of 18 agreed to meet the psychiatrist. Sex-ratio female/male of this sample was 1,25 and mean age was 12,5 years. All of them underwent the Schedule for Affective Disorders and Schizophrenia for School Aged Children (Kiddie-SADS), a semi structured research interview of established validity. Diagnoses were made according to the DSM IV criteria (American Psychiatric Association). RESULTS: Results showed that more than one child out of 10 aged less than 13 years had a depressive disorder, and that the prevalence in the adolescent sub-group was 5%. Major depressive episode was present in 6% of the children sample, dysthymia in 4% and maladjustment disorder with depressive mood in about 1%. All depressive disorders were moderate. Atypical depression (in the Anglosaxon sense of the term) was present in half of the depressed adolescents. Other disorders included anxiety disorders with a rate of about 4% overanxious in the adolescent sample, obsessive compulsive disorder, panic disorder. Disruptive disorders were considerably less common. Psychiatric comorbidity, usually involving different types of emotional disorders, was present in about 50% of psychiatric cases, with a prevalence of anxiety disorders. The reasons why depressed subjects consulted were not specific. The most common reasons for visiting the GP were the somatic complaints with a rate of 50% in both populations, whatever the CES-D's score was. A few per cent of patients attending primary care presented with mental health complaints, and the rate was similar in the two populations. Frequency of consultation was not a discriminant factor of depression. Familial cohesion and school performance were not associated with the CES-D's score, nor familial psychiatric history. Personal psychiatric history was related to depression, whereas the occurrence of bereavement made the CES-D score positive but was not significantly associated with fully- blown depression. Finally, we estimated that 70% of diagnoses of depression were not made during the consultation with GP's. CONCLUSION: No particular characteristic of depressed children consulting GP's could be established. These findings underline the importance of training GP's in the screening of depressive disorders in children and adolescents. A better knowledge that young general practice attenders have high rates of depressive disorders may facilitate more rapid referral for psychiatric assessment and treatment.

Mathias, S., Lubman, D. I., & Hides, L. (2008). Substance-induced psychosis: a diagnostic conundrum. The Journal of Clinical Psychiatry, 69(3), 358-367.

OBJECTIVE: To critically examine the DSM-IV-TR criteria for substance-induced psychotic disorder (SIPD). DATA SOURCES: Leading electronic databases (such as MEDLINE, PubMed) were searched for the years 1992 through 2007, using combinations of the following key search terms: substance abuse/dependence, alcohol, marijuana, cannabis, methamphetamine, crack, cocaine, amphetamine, ecstasy, ketamine, phencyclidine, LSD, mental health, drug-induced psychosis, substance-induced psychosis, psychosis, and schizophrenia. References identified from bibliographies of pertinent articles and books in the field were also collected and reviewed. DATA EXTRACTION: Only research studies or case reports/series that presented data on populations diagnosed with SIPD by using clinical or structured diagnostic interviews and that were published in English were used to assess the validity of the current SIPD criteria. DATA SYNTHESIS: We identified 49 articles that presented clinical data on SIPD. Almost half of these publications were case reports, with 18 articles specifically focusing on delineating the clinical characteristics or outcomes of individuals diagnosed with SIPD. While several large studies have recently been conducted to ass