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Background Long-term use of cannabis has long been associated with changes in cognition, including memory and learning, particularly verbal learning in man. However, evidence regarding the neurobiological underpinnings of impairments in memory following long-term cannabis use has not been consistent. Furthermore, to our knowledge none of the studies published to date have specifically investigated whether brain function differed between cannabis users and non-users while learning new information as estimated over repeated trials. Therefore, we aimed to investigate this. Methods Twenty-one predominantly cannabis users (CU) who started using cannabis during adolescence and 21 healthy non-using controls (NU), completed a block design verbal paired associates learning task whilst undergoing functional Magnetic Resonance Imaging. The task required participants to learn and recall a set of word-pairs over 4 repeated trials. We examined the interaction between repetition and group (CU vs NU) on brain activation during encoding and recall condition using non-parametric repeated measures analysis of variance. Results There was no significant difference in total recall score between CU and NU. However, there was a significant effect of repetition (p

Background There has been growing interest in the therapeutic potential of Cannabidiol (CBD) stemming from independent evidence that CBD has antipsychotic and anxiolytic properties in patients with mental health disorders. CBD has been found to be non-inferior to antipsychotic medication in a 4-week clinical trial in acute schizophrenia (Leweke et al 2012) and also has been found to reduce anxiety symptoms in social phobia and following public speaking. Human data also suggest that it attenuates the cognitive impairments associated with use of the main psychoactive ingredient in cannabis. However, whether CBD may be useful in relieving symptoms and distress in patients at clinical high-risk of psychosis (CHR) has never been tested. Furthermore, how the beneficial effect of CBD on psychotic and anxiety symptoms may be mediated in the brain remains unclear. The aim of the present study was to investigate whether short-term treatment with CBD was associated with preliminary evidence of therapeutic benefit and understand the neurocognitive mechanisms. Methods We investigated the effects of short-term (21 days) treatment with CBD on psychotic and anxiety symptoms in 33 CHR patients, using a placebo-controlled, double-blind, parallel-arm design (CBD arm- 16; placebo arm- 17). In the subjects who received 21 days of treatment, we used fMRI in conjunction with a verbal memory task to assess the effect of CBD relative to placebo treatment on medial temporal and striatal function. Results Of the 33 CHR patients recruited into the trial, 31 completed treatment for 21 days. Following 21-day treatment (intention-to-treat, last observation carried forward analysis), CBD-treated (n=16) CHR patients showed a significantly greater reduction in anxiety (p=0.02) and in distress associated with psychotic symptoms (p=0.03) and a trend (p=0.14) toward greater reduction in the severity of psychotic symptoms compared to those treated with placebo (n=17) CHR patients (Figure 4). In addition, CBD was tolerated as well as placebo. Consistent with our predictions, treatment with CBD (n=15) attenuated the engagement during verbal encoding of the parahippocampal cortex, but increased activation in the putamen in CHR patients. A similar pattern of activation was evident during verbal recall, with CBD treatment associated with increased engagement in the putamen. Discussion Results from our proof-of-concept study suggest that 3-week treatment with CBD has beneficial effects on anxiety, attenuated psychotic symptoms and the distress associated with psychotic symptoms. They also suggest that short-term treatment with CBD modulates both medial temporal and striatal function in CHR patients, regions that are critically implicated in the CHR state. Coupled with the absence of significant adverse effects associated with CBD, a particularly important issue in relation to the treatment of CHR individuals, not all of whom develop a full-blown psychotic disorder, these data indicate that long-term treatment with CBD is likely to be efficacious in CHR patients.

Background Estrogens, in particular 17β-estradiol (estradiol) have repeatedly been shown to exert powerful influences over cognitive function, and in particular, on a range of cognitive behaviours associated with neurodevelopmental disorders. This includes depressive and anxious behaviours as well as learning and memory (including working memory). These cognitive enhancing effects have been shown to be dependent on increases in the number of dendritic spines as well as alterations in glutamate receptor transmission and regulation of synaptic protein expression. Modulation of these synaptic functions can result in long-term increases in synaptic connectivity. Interestingly, there is growing evidence that estrogenic-based compounds may have a positive effect in the treatment of a number of neuropsychiatric disorders, including schizophrenia. Importantly, recent clinical studies have demonstrated that adjunct treatment with estradiol or the selective estrogen receptor modulator (SERM) raloxifene, ameliorates positive and negative symptoms and improves working memory and attention deficits in male and female schizophrenic patients. However, it has been argued that estrogenic-based compounds are not an effective treatment option owing to potential serve side effects associated with long-term administration. It is, however, of note that the precise mechanisms that underlie the positive effects of estradiol, or estrogenic-based compounds, in this disease are currently unclear. Therefore, determining how estradiol exerts its positive effects in health as well as in disease, will aid in the development of safer and more effective estrogenic-based compounds. Methods Here, we have used human induced pluripotent stem cell (iPSC)-derived from healthy or patients diagnosed schizophrenic but with no common genetic background to study the potential mechanism that may underlie estrogens beneficial effects in disease. iPSCs were differentiated into young, developing, cortical neurons using well established methods. First, we assessed the ability of estrogens to modulate key neuronal and synaptic structures as well as synaptic and inflammatory genes. Next, we assessed the expression and distribution of synaptic proteins were determined in both healthy iPSC-neurons and patient iPSC-neurons (from 3–6 individuals from each group). Subsequently, using a pharmacological approach, we have explored the ability of estrogens to rescue cellular and molecular deficits in iPSC-neurons derived from schizophrenic patients. Results Both healthy and patient iPSC differentiated into neuroepithelium, neural progenitors cells and finally into TBR1- and EMX1-positive neurons efficiently. Assessment of synaptic protein expression revealed reduced expression of key synaptic proteins involved in excitatory transmission compared to control lines. When healthy iPSC-neurons were treated with a range of estrogenic compounds, we observed a robust increase in the expression of key synaptic protein including GRIN1 and DGL4. Consistent with previous reports, patient iPSC-neurons displayed reduced synaptic protein expression compared with healthy iPSC-neurons. Critically, when patient iPSC-neurons were treated with 17β-estradiol or raloxifene, we observed an increase in synaptic protein expression to a level similar to that observed in untreated healthy iPSC-neurons. Discussion These data are the first to demonstrate that estrogens are capable of regulating synaptic proteins in human neurons taken from patients diagnosed with schizophrenia. Collectively, we hope these data will help us understand how estrogens may confer their positive effects in psychiatric disorders.

Background Global neurocognitive impairments are a central feature of psychosis. Deficits in verbal memory in particular are the most consistently reported of these impairments from the first-episode of psychosis (FEP). Neuroimaging studies in psychosis have largely identified reductions in neural activation during various memory and learning related tasks, particularly in the medial temporal lobe, compared to healthy controls. Tetrahydrocannabinol (THC) and cannabidiol (CBD), both components of the cannabis plant that act through the endocannabinoid (eCB) system in the brain, have been found to induce direct and opposite neural effects during similar tasks in healthy samples, when compared to each other. Additionally, CBD has been shown to have antipsychotic properties, and may suppress THC induced psychotic symptoms and their directly associated functional abnormalities in healthy individuals. Thus far, the effects of CBD on the neural substrates implicated in memory and learning, and those underlying psychotic symptoms in FEP cohorts is unknown. Methods 17 FEP patients were initially recruited to the study. A double-blind, randomized, placebo controlled, repeated measures, within subject cross over design, with at least a one-week washout period between scans was employed. Participants were given identical capsules of either CBD (600mg), or placebo (PLB), then scanned using a block design fMRI paradigm, while performing a verbal paired associate learning task. 13 participants completed scanning, and were included in the analysis of the data. An ROI mask of the hippocampus, striatum, and parahippocampal gyrus was used in the data analysis, and all results were thresholded for less than one false positive over the whole map. Results A CBD related decrease in activity was observed in the left hippocampus (p = 0.0024) and the right parahippocampal gyrus (p = 0.0024) during the recall condition, within the FEP group. No significant differences between PLB and CBD functional activity were observed during the encoding condition. No significant differences were observed between FEP participant performances on the CBD and PLB study days. Discussion These findings provide robust evidence of the modulatory effect of an acute dose of CBD on the neural substrates underlying learning and memory, supporting a role for the eCB system in the abnormalities observed in psychosis, and its potential as a target for treatment.

Overall Abstract: While drugs that target the dopaminergic and glutamatergic neurotransmitter systems have been extensively investigated as treatments for psychosis, there has been increasing attention in recent years on the endocannabinoid system as a therapeutic target. The CB1 receptor, the main central cannabinoid receptor is ubiquitous and modulates the function of several neurotransmitters, including dopamine and glutamate. A growing body of evidence suggests that psychosis is associated with alterations in the endocannabinoid system, independent of exposure to cannabis. The CB1 receptor is the main molecular target for delta-9-tetrahydrocannabinol (THC), the major psychoactive ingredient in cannabis. THC is responsible for the psychotogenic effects of cannabis, and is a partial agonist at the CB1 receptor. On the other hand, Cannabidiol (CBD), the second major constituent of cannabis is a non-psychoactive compound that may have an inverse agonist/antagonist effect at CB1 receptors, in addition to a range of other possible mechanisms of action. Interest in the therapeutic potential of CBD stemmed from evidence that it has broadly opposite effects to that of THC, at both the neural and the behavioural level in healthy individuals. Consistent with these results independent evidence that CBD has antipsychotic and anxiolytic properties in patients with mental health disorders has been accumulating. The absence of significant adverse effects associated with CBD, is a critical advantage in relation to the treatment of patients in the various stages of psychosis. Given its tolerability profile, CBD is a treatment of particular interest not just in those with chronic psychosis as in schizophrenia, but also in those in the earlier stages of psychosis. However, published evidence regarding the therapeutic efficacy of CBD as a treatment in psychosis has been limited except a small randomized clinical trial (RCT) some years ago (Leweke et al 2012). Furthermore, the mechanisms that may underlie the beneficial effects of CBD are unclear. This symposium will bring together state of the art evidence regarding the efficacy of CBD in the different stages of psychosis – from those at clinical high-risk (CHR), through early psychosis to chronic schizophrenia. Furthermore, data from animal and human studies will be presented to give an understanding of the potential mechanisms that may underlie the therapeutic effects of CBD. The first speaker (Prof Crippa) will set the scene by presenting evidence regarding the different potential mechanisms of action that may underlie the antipsychotic effect of CBD. The second speaker (Prof McGuire) will present the results of a 6-week placebo-controlled RCT demonstrating the efficacy of CBD as an add-on to existing antipsychotic treatment in schizophrenia. The third speaker (Dr. Ranganathan) will present the results from an ongoing, placebo-controlled RCT using an within-subject, crossover design to show the effects of 4-week CBD treatment on psychotic symptoms, cognition and electrophysiological markers in patients with established psychosis. Finally, the fourth speaker (Dr. Bhattacharyya) will present the results from a recently completed proof-of-concept study demonstrating the efficacy of short-term CBD treatment on symptoms and distress in CHR patients as well as on neurocognitive substrates implicated in the CHR state. Evidence presented here will be discussed by Prof D’Souza, who is an internationally recognized expert in cannabinoid pharmacology and experimental therapeutics development.

What you need to know A general practitioner may support four to eight patients with psychotic disorder and see one new presentation each year.12 Other non-specialist doctors will encounter patients presenting to an emergency department or complicating comorbid illness. Psychosis often emerges for the first time in adolescence and young adulthood.3 In around four out of five patients symptoms remit, but most experience relapses and further difficulties.4 The first two to five years of psychosis are considered a critical period for intervening to improve long term outcome.567 The non-specialist plays a key role in early identification. The challenge is to identify a relatively rare but serious disorder and distinguish this from more common but less severe disorders, occurring in a typically young population experiencing developmental and often stressful transitions. #### Methods We searched the Medline database over 10 years (1 January 2007 to 31 January 2017) for review articles on “early psychotic illness” or “early psychosis.” This yielded 779 including Narrative and Systematic Reviews and Meta-analyses. 125 articles were reviewed for relevance and methodology and analysis of data. Fig 1 Where the soft winds blow by Bryan Charnley (1949-1991), who had schizophrenia (www.bryancharnley.info). ©The estate of Bryan Charnley, reproduced with permission The term psychosis embraces a constellation of symptoms characterised by hallucinations, delusions, or disorganised behaviour or thought (“positive …

What you need to know Fig 1 Puppet Schizophrene by Bryan Charnley (1949-1991), who had schizophrenia (www.bryancharnley.info). © The estate of Bryan Charnley, reproduced with permission Identification of psychotic symptoms in non-specialist settings is key to initiating timely pathways to care. A systematic review of 30 observational studies of pathways to care of first-episode psychosis showed that first contact was more usually through a physician than through emergency services.1 This article is aimed at generalists, primary care physicians, and hospital doctors, who play a critical role and who require a low threshold for referral for specialist assessment, sometimes before diagnosis is certain.2 Prompt intervention is key to improving outcome. However, patients rarely present complaining of hallucinations or delusions. Concerns that something is not quite right may first be raised to the generalist by family members, friends, neighbours, and school teachers.1 In very early stages, perceptual abnormalities and thought disorder may not be apparent, nor delusions well formed. Features may include: Hallmark features are increasing distress and decline in functioning.456 An overview of symptoms is shown in figure 2⇓. Psychosis maybe preceded by …

Background This study examined the effect of Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) on brain activation during a motor inhibition task. Methods Functional magnetic resonance imaging and behavioural measures were recorded while 15 healthy volunteers performed a Go/No-Go task following administration of either THC or CBD or placebo in a double-blind, pseudo-randomized, placebo-controlled repeated measures within-subject design. Results Relative to placebo, THC attenuated activation in the right inferior frontal and the anterior cingulate gyrus. In contrast, CBD deactivated the left temporal cortex and insula. These effects were not related to changes in anxiety, intoxication, sedation, and psychotic symptoms. Conclusions These data suggest that THC attenuates the engagement of brain regions that mediate response inhibition. CBD modulated function in regions not usually implicated in response inhibition.

Summary Background Although the link between cannabis use and development of psychosis is well established, less is known about the effect of continued versus discontinued cannabis use after the onset of psychosis. We aimed to summarise available evidence focusing on the relationship between continued and discontinued cannabis use after onset of psychosis and its relapse. Methods In this systematic review and meta-analysis, we searched MEDLINE for articles published in any language from the database inception date up until April 21, 2015 that included a sample of patients with a pre-existing psychotic disorder with a follow-up duration of at least 6 months. We used a combination of search terms for describing cannabis, the outcome of interest (relapse of psychosis), and the study population. We excluded studies if continued cannabis use or discontinued cannabis use could not be established. We compared relapse outcomes between those who continued (CC) or discontinued (DC) cannabis use or were non-users (NC). We used summary data (individual patient data were not sought out) to estimate Cohen's d, which was entered into random effects models (REM) to compare CC with NC, CC with DC, and DC with NC. Meta-regression and sensitivity analyses were used to address the issue of heterogeneity. Findings Of 1903 citations identified, 24 studies (16 565 participants) met the inclusion criteria. Independent of the stage of illness, continued cannabis users had a greater increase in relapse of psychosis than did both non-users (d CC–NC =0·36, 95% CI 0·22–0·50, p CC–DC =0·28, 0·12–0·44, p=0·0005), as well as longer hospital admissions than non-users (d CC–NC =0·36, 0·13 to 0·58, p=0·02). By contrast, cannabis discontinuation was not associated with relapse (d DC–NC =0·02, −0·12 to 0·15; p=0·82). Meta-regression suggested greater effects of continued cannabis use than discontinued use on relapse (d CC–NC =0·36 vs d DC–NC =0·02, p=0·04), positive symptoms (d CC–NC =0·15 vs d DC–NC =–0·30, p=0·05) and level of functioning (d CC–NC =0·04 vs d DC–NC =–0·49, p=0·008) but not on negative symptoms (d CC–NC =-0·09 vs d DC–NC =–0·31, p=0·41). Interpretation Continued cannabis use after onset of psychosis predicts adverse outcome, including higher relapse rates, longer hospital admissions, and more severe positive symptoms than for individuals who discontinue cannabis use and those who are non-users. These findings point to reductions in cannabis use as a crucial interventional target to improve outcome in patients with psychosis. Funding UK National Institute of Health Research.

A decline in the rate of transition to psychosis in patients presenting with clinical high-risk has been reported in the literature. Several hypotheses have been put forward to explain this decline. In this brief report, we aimed to explore whether the demographic group presenting to clinical high-risk services differs from the 'end-point' population who present with first-episode psychosis (FEP), by focusing on gender.Gender distribution was compared between clinical high-risk (CHR) and FEP using data extracted from published study samples and clinical data from corresponding cohorts within the same catchment area in South London.The proportion of males was significantly higher in FEP compared to CHR services in the literature describing Europe, Australia and North America and in the clinical cohort from South London.Males are under-represented in existing CHR services in Europe, Australia and North America. This could reflect less willingness in males to seek help if experiencing low-level psychological distress and may be related to the declining transition.

Objective Despite an improved quality of life, about 33% of heart transplant recipients will develop depressive symptoms post-operatively. To date, no review has explored the efficacy and safety of pharmacologic or psychologic interventions in this patient group. Methods We conducted a comprehensive Medline, EmBase, Psycinfo search for studies of the treatment of depression in heart transplant recipients. Results We identified 34 studies of variable methodologic quality. Selective serotonin re-uptake inhibitors (SSRIs), particularly citalopram and new-generation anti-depressants (mirtazapine), seem to represent the best therapeutic choices for this population. Tricyclic anti-depressants (TCAs), and electroconvulsive therapy (ECT) should be reserved for severe depression unresponsive to other treatments, whereas monoamine oxidase inhibitors (MAOIs) should be avoided. St John's wort, an alternative herbal drug, has been associated with life-threatening immunosuppression. Psychologic therapy offers further advantages after heart transplantation. Conclusions Further well-conducted, randomized, controlled trials are needed to clarify the efficacy and the safety of pharmacologic (SSRIs and atypical anti-depressants) and psychologic interventions in the management of depression after heart transplantation.

The role of glutamatergic dysfunction in the pathophysiology of OCD has hardly been explored despite recent reports implicating glutamatergic dysfunction in OCD. We decided to investigate CSF glutamate levels in adult OCD probands compared to psychiatrically normal controls. In total, 21 consenting psychotropic drug-naïve adult OCD patients, diagnosed using SCID-IV-CV, and 18 consenting psychiatrically normal controls with age within 10 years of age of the patients, who did not have any history of head injury or neurological illness, were included into the study. Aseptically collected and stored CSF samples obtained from the patients and control subjects were used for glutamate estimation, which was carried out by a modification of the procedure described by Lund (1986). CSF glutamate (micromol/l) level was found to be significantly higher [F(1,31)=6.846, p=0.014] in OCD patients (47.12+/-4.25) compared to control subjects (41.36+/-3.63) on analysis of covariance. There was no effect of gender, age, duration of illness, Y-BOCS score, or CGI-S score on CSF glutamate levels. Our study provides preliminary evidence implicating glutamatergic excess in the pathophysiology of OCD, which needs to be further explored by studies from other centers involving larger sample sets from different age groups.

Smoking cannabis produces a diverse range of effects, including impairments in learning and memory. These effects are exerted through action on the endocannabinoid system, which suggests involvement of this system in human cognition. Learning and memory deficits are core symptoms of psychiatric and neurological disorders such as schizophrenia and Alzheimer's disease, and may also be related to endocannabinoid dysfunction in these disorders. However, before new research can focus on potential treatments that work by manipulating the endocannabinoid system, it needs to be elucidated how this system is involved in symptoms of psychiatric disorders. Here we review neuroimaging studies that investigated acute and non-acute effects of cannabis on human learning and memory function, both in adults and in adolescents. Overall, results of these studies show that cannabis use is associated with a pattern of increased activity and a higher level of deactivation in different memory-related areas. This could reflect either increased neural effort ('neurophysiological inefficiency') or a change in strategy to maintain good task performance. However, the interpretation of these findings is significantly hampered by large differences between study populations in cannabis use in terms of frequency, age of onset, and time that subjects were abstinent from cannabis. Future neuroimaging studies should take these limitations into account, and should focus on the potential of cannabinoid compounds for treatment of cognitive symptoms in psychiatric disorders.

Accumulating evidence suggests involvement of the endocannabinoid system in the pathophysiology of schizophrenia, which signifies a potential application for this system in the treatment of this disorder. However, before new research can focus on potential treatments that work by manipulating the endocannabinoid system, it needs to be elucidated how this system is involved in symptoms of schizophrenia. Here we review human studies that investigated acute effects of cannabis or ∆9-tetrahydrocannabinol (THC) on brain functions that are implicated in schizophrenia. Results suggest that the impact of THC administration depends on the difficulty of the task performed. Impaired performance of cognitive paradigms is reported on more challenging tasks, which is associated with both activity deficits in temporal and prefrontal areas and a failure to deactivate regions of the default mode network. Comparable reductions in prefrontal activity and impairments in deactivation of the default mode network are seen in patients during performance of cognitive paradigms. Normal performance levels after THC administration demonstrated for less demanding tasks are shown to be related to either increased neural effort in task-specific regions ('neurophysiological inefficiency'), or recruitment of alternative brain areas, which suggests a change in strategy to meet cognitive demands. Particularly a pattern of performance and brain activity corresponding with an inefficient working memory system is consistently demonstrated in patients. These similarities in brain function between intoxicated healthy volunteers and schizophrenia patients provide an argument for a role of the endocannabinoid system in symptoms of schizophrenia, and further emphasize this system as a potential novel target for treatment of these symptoms.

The endocannabinoid system (ECS) is now recognised as an important modulator of various central nervous system processes. More recently, an increasing body of evidence has accumulated to suggest antioxidant, anti-inflammatory and neuroprotective roles of ECS. In this review we discuss the role and therapeutic potential of ECS in neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease, multiple sclerosis, Huntington’s disease, Tourette’s syndrome, brain ischemia and amyotrophic lateral sclerosis (ALS). Elements of the ECS, such as fatty acid amide hydrolase or the cannabinoid receptors are now considered as promising pharmacological targets for some diseases. Although still preliminary, recent reports suggest that modulation of the ECS may constitute a novel approach for the treatment of AD. There are windows of opportunity in conditions caused by acute events such as trauma and ischemia as well in conditions that may involve altered functionality of the target receptors of the ECS, such as in AD. The ECS changes in Parkinson’s disease could be compensatory as well as pathogenic of the illness process and needs further understanding and clinical studies are still in the preliminary stage. There is not enough evidence to support use of cannabinoids in treating Huntington’s disease, tics and obsessive compulsive behaviour in Tourette's syndrome. Evidence on therapeutic use of cannabinoids in multiple sclerosis and ALS is currently limited. A major challenge for future research is the development of novel compounds with more selectivity for various components of the ECS which could target different neurotoxic pathways and be used in combination therapy.

Background: The growing concern about cannabis use, the most commonly used illicit drug worldwide, has led to a significant increase in the number of human studies using neuroimaging techniques to determine the effect of cannabis on brain structure and function. We conducted a systematic review to assess the evidence of the impact of chronic cannabis use on brain structure and function in adults and adolescents. Methods: Papers published until August 2012 were included from EMBASE, Medline, PubMed and LILACS databases following a comprehensive search strategy and pre-determined set of criteria for article selection. Only neuroimaging studies involving chronic cannabis users with a matched control group were considered. Results: One hundred and forty-two studies were identified, of which 43 met the established criteria. Eight studies were in adolescent population. Neuroimaging studies provide evidence of morphological brain alterations in both population groups, particularly in the medial temporal and frontal cortices, as well as the cerebellum. These effects may be related to the amount of cannabis exposure. Functional neuroimaging studies suggest different patterns of resting global and brain activity during the performance of several cognitive tasks both in adolescents and adults, which may indicate compensatory effects in response to chronic cannabis exposure. Limitations: However, the results pointed out methodological limitations of the work conducted to date and considerable heterogeneity in the findings. Conclusion: Chronic cannabis use may alter brain structure and function in adult and adolescent population. Further studies should consider the use of convergent methodology, prospective large samples involving adolescent to adulthood subjects, and data-sharing initiatives.

Neuroimaging studies have shown that chronic consumption of cannabis may result in alterations in brain morphology. Recent work focusing on the relationship between brain structure and the catechol-O-methyltransferase (COMT) gene polymorphism suggests that functional COMT variants may affect brain volume in healthy individuals and in schizophrenia patients. We measured the influence of COMT genotype on the volume of four key regions: the prefrontal cortex, neostriatum (caudate-putamen), anterior cingulate cortex and hippocampus-amygdala complex, in chronic early-onset cannabis users and healthy control subjects. We selected 29 chronic cannabis users who began using cannabis before 16 years of age and matched them to 28 healthy volunteers in terms of age, educational level and IQ. Participants were male, Caucasians aged between 18 and 30 years. All were assessed by a structured psychiatric interview (PRISM) to exclude any lifetime Axis-I disorder according to Diagnostic and Statistical Manual for Mental Disorders-Fourth Edition. COMT genotyping was performed and structural magnetic resonance imaging data was analyzed by voxel-based morphometry. The results showed that the COMT polymorphism influenced the volume of the bilateral ventral caudate nucleus in both groups, but in an opposite direction: more copies of val allele led to lesser volume in chronic cannabis users and more volume in controls. The opposite pattern was found in left amygdala. There were no effects of COMT genotype on volumes of the whole brain or the other selected regions. Our findings support recent reports of neuroanatomical changes associated with cannabis use and, for the first time, reveal that these changes may be influenced by the COMT genotype.

BackgroundCannabis can induce transient psychotic symptoms, but not all users experience these adverse effects. We compared the neural response to Δ9-tetrahydrocannabinol (THC) in healthy volunteers in whom the drug did or did not induce acute psychotic symptoms.MethodIn a double-blind, placebo-controlled, pseudorandomized design, 21 healthy men with minimal experience of cannabis were given either 10 mg THC or placebo, orally. Behavioural and functional magnetic resonance imaging measures were then recorded whilst they performed a go/no-go task.ResultsThe sample was subdivided on the basis of the Positive and Negative Syndrome Scale positive score following administration of THC into transiently psychotic (TP; n = 11) and non-psychotic (NP; n = 10) groups. During the THC condition, TP subjects made more frequent inhibition errors than the NP group and showed differential activation relative to the NP group in the left parahippocampal gyrus, the left and right middle temporal gyri and in the right cerebellum. In these regions, THC had opposite effects on activation relative to placebo in the two groups. The TP group also showed less activation than the NP group in the right middle temporal gyrus and cerebellum, independent of the effects of THC.ConclusionsIn this first demonstration of inter-subject variability in sensitivity to the psychotogenic effects of THC, we found that the presence of acute psychotic symptoms was associated with a differential effect of THC on activation in the ventral and medial temporal cortex and cerebellum, suggesting that these regions mediate the effects of the drug on psychotic symptoms.

Background Dhat syndrome is a widely recognized clinical condition often seen on the Indian subcontinent that is characterized by a preoccupation with semen loss in urine and other symptoms such as fatigue or depressed mood. Although it has been considered to be a culture-bound syndrome, it may also be regarded as a distinct manifestation of depression or another medical illness. Objective The purpose of this paper was to carry out a systematic review on Dhat syndrome. Methods A review of the literature published up until February 2012 was conducted using the key words [Dhat syndrome] or [semen-loss anxiety] or [semen-loss syndrome]. We included only original studies. Review The majority of studies reported patients from the Indian subcontinent. There was a high degree of heterogeneity among the studies. Dhat was a common condition in young people from certain cultures and origins. Depressive and anxiety symptoms were common, including fatigue, sleepiness, and sexual dysfunction. Good clinical engagement, social support, and sexual education were useful in some cases. Given the high rate of comorbid depressive symptoms, antidepressant has been used. Discussion In an increasingly globalized world, clinicians must be able to properly diagnose and treat patients from other cultures, who may report symptoms that are influenced by their beliefs, culture, or place of origin. Dhat may be a common manifestation of a depressive or anxiety disorder in certain cultures. Further research is needed to improve our understanding of this condition, to clarify its nosologic status, and to offer appropriate treatment to affected individuals.

Synchronised neural oscillations preceding speech generation are reduced in patients with schizophrenia, this deficit being implicated in symptom formation. We measured synchronisation of neural oscillations preceding vocalisation in the presence of delta-9 tetrahydrocannabinol (THC) and found they were significantly disrupted. Furthermore, the degree of disruption was related to THC-induced symptoms, suggesting THC may modulate a similar neural substrate to schizophrenia.

Cannabinoid receptors (CB1 and CB2) are ubiquitous within the brain (Wilson and Nicoll, 2002; Eggan and Lewis, 2007). Their distribution and role in the modulation of different neurotransmitter systems (Pertwee and Ross, 2002; Pertwee, 2008a) clearly indicate that cannabinoids are involved in the modulation of different cognitive and emotional processes (Solowij and Michie, 2007). The role of the endocannabinoid system in this has attracted the attention of basic scientists for decades (Zanettini et al., 2011). The modulation of cognitive and emotional processes in man by the extracts of Cannabis sativa (C sativa), the most commonly used illicit drug consumed by an estimated 4% of the adult population worldwide (Copeland and Swift, 2009), has also been known for a long time and extensively investigated in experimental and observational studies (Solowij, 1998; Ranganathan and D'Souza, 2006; Solowij and Michie, 2007; Crippa et al., 2009; D'Souza et al., 2009). However, only over the last 20 years has it been possible to precisely investigate the neural basis of the acute effects of cannabinoids on cognition by employing sophisticated neuroimaging techniques (Bhattacharyya et al., 2009a, 2012a; Martin-Santos et al., 2010). A renewed interest in the link between regular cannabis use and development of psychotic disorders has provided further impetus, coupled with interest in the therapeutic potential of certain cannabinoids. Pharmacological challenge studies involving the administration of cannabinoids present in the extract of C sativa or their synthetic counterparts in combination with neuroimaging have served to complement current understanding regarding the role of the endocannabinoid system in regulating human cognitive and emotional processes (Zanettini et al., 2011), to model aspects of various psychiatric illnesses in man and understand their neural underpinnings (Bhattacharyya et al., 2009a). Among the more than 60 different cannabinoids (Mechoulam and Gaoni, 1967) present in the extract of C sativa, delta-9-tetrahydrocanabinol (THC) is thought to be responsible for most of the psychotropic effects of cannabis (Mechoulam et al., 1970) and modulation of cognitive domains such as learning and memory (Hall and Solowij, 1998; Curran et al., 2002; Ranganathan and D'Souza, 2006), psychomotor control (Hart et al., 2001; McDonald et al., 2003; Ramaekers et al., 2006, 2009), and attention (Hall and Solowij, 1998; Ilan et al., 2004), as evident from systematic acute experimental studies. The purpose of this article is to provide a brief critical overview of current neuroimaging evidence of the acute effects of THC in man as evident from neuroimaging studies. The studies are organized into groups based on neuroimaging domains examined.

Background Using positron emission tomography (PET), we previously observed increases in 3,4-dihydroxy-6-[ 18 F]fluoro-L-phenylalanine ( 18 F-DOPA) uptake in the striatum of subjects at ultra-high risk (UHR) for psychosis, indicating elevated presynaptic dopamine synthesis capacity. The purpose of this study was to test if this finding would be replicated in a second UHR cohort. Methods 18 F-DOPA PET was used to estimate dopamine synthesis capacity in the striatum of an entirely new cohort of 26 individuals at UHR for psychosis (14 males, mean±SD age=22.7±4.7 years) and 20 healthy volunteers matched for age and gender (11 males, mean±SD age=24.5±4.5 years). Results Dopamine synthesis capacity was elevated in the whole [ t (44) = 2.6; p = .01, effect size=.81] and associative striatum [ t (44) = 2.6; p = .01, effect size=.73] of UHR compared with control subjects. When the two samples were combined to give a final sample of 32 control and 50 UHR subjects, the higher levels of dopamine synthesis capacity in the UHR group reached significance across the whole [ F (1,81) = 11.0; p = .001], associative [ F (1,81) = 12.7; p = .001], and sensorimotor [ F (1,81) = 4.7; p = .03], but not the limbic [ F (1,81) = 2.1; p = .2], striatum. Conclusions The findings indicate that elevated dopamine synthesis capacity in the dorsal striatum is a robust feature of individuals at UHR for psychosis and provide further evidence that dopaminergic abnormalities precede the onset of psychosis.

Δ(9)-tetrahydrocannabinol (Δ(9)-THC) is the main compound of the Cannabis Sativa responsible for most of the effects of the plant. Another major constituent is cannabidiol (CBD), formerly regarded to be devoid of pharmacological activity. However, laboratory rodents and human studies have shown that this cannabinoid is able to prevent psychotic-like symptoms induced by high doses of Δ(9)- THC. Subsequent studies have demonstrated that CBD has antipsychotic effects as observed using animal models and in healthy volunteers. Thus, this article provides a critical review of the research evaluating antipsychotic potential of this cannabinoid. CBD appears to have pharmacological profile similar to that of atypical antipsychotic drugs as seem using behavioral and neurochemical techniques in animal models. Additionally, CBD prevented human experimental psychosis and was effective in open case reports and clinical trials in patients with schizophrenia with a remarkable safety profile. Moreover, fMRI results strongly suggest that the antipsychotic effects of CBD in relation to the psychotomimetic effects of Δ(9)-THC involve the striatum and temporal cortex that have been traditionally associated with psychosis. Although the mechanisms of the antipsychotic properties are still not fully understood, we propose a hypothesis that could have a heuristic value to inspire new studies. These results support the idea that CBD may be a future therapeutic option in psychosis, in general and in schizophrenia, in particular.

Individuals with an at risk mental state (ARMS) are at greatly increased risk of developing a psychotic illness. Risk of transition to psychosis is associated with regionally reduced cortical gray matter volume. There has been considerable interest in the interaction between psychosis risk and substance use. In this study we investigate the relationship between alcohol, cannabis and nicotine use with gray matter volume in ARMS subjects and healthy volunteers. Twenty seven ARMS subjects and 27 healthy volunteers took part in the study. All subjects underwent volumetric MRI imaging. The relationship between regional gray matter volume and cannabis use, smoking, and alcohol use in controls and ARMS subjects was analysed using voxel-based morphometry. In any region where a significant relationship with drug was present, data were analysed to determine if there was any group difference in this relationship. Alcohol intake was inversely correlated with gray matter volume in cerebellum, cannabis intake was use was inversely correlated with gray matter volume in prefrontal cortex and tobacco intake was inversely correlated with gray matter volume in left temporal cortex. There were no significant interactions by group in any region. There is no evidence to support the hypothesis of increased susceptibility to harmful effects of drugs and alcohol on regional gray matter in ARMS subjects. However, alcohol, tobacco and cannabis at low to moderate intake may be associated with lower gray matter in both ARMS subjects and healthy volunteers-possibly representing low-level cortical damage or change in neural plasticity.

Rationale: Animal and humans studies suggest that the two main constituents of cannabis sativa, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) have quite different acute effects. However, to date the two compounds have largely been studied separately. Objective: To evaluate and compare the acute pharmacological effects of both THC and CBD in the same human volunteers. Methods: A randomised, double-blind, cross-over, placebo controlled trial was conducted in 16 healthy male subjects. Oral THC 10 mg or CBD 600 mg or placebo was administered in three consecutive sessions, at one-month interval. Physiological measures and symptom ratings were assessed before, and at 1, 2 and 3 hours post drug administration. The area under the curve (AUC) between baseline and 3 hours, and the maximum absolute change from baseline at 2 hours were analysed by one-way repeated measures analysis of variance, with drug condition (THC or CBD or placebo) as the factor. Results: Relative to both placebo and CBD, administration of THC was associated with anxiety, dysphoria, positive psychotic symptoms, physical and mental sedation, subjective intoxication (AUC and effect at 2 hours: p

Animal and human studies indicate that cannabidiol (CBD), a major constituent of cannabis, has anxiolytic properties. However, no study to date has investigated the effects of this compound on human pathological anxiety and its underlying brain mechanisms. The aim of the present study was to investigate this in patients with generalized social anxiety disorder (SAD) using functional neuroimaging. Regional cerebral blood flow (rCBF) at rest was measured twice using (99m)Tc-ECD SPECT in 10 treatment-naïve patients with SAD. In the first session, subjects were given an oral dose of CBD (400 mg) or placebo, in a double-blind procedure. In the second session, the same procedure was performed using the drug that had not been administered in the previous session. Within-subject between-condition rCBF comparisons were performed using statistical parametric mapping. Relative to placebo, CBD was associated with significantly decreased subjective anxiety ( p

Background Both medial temporal cortical dysfunction and perturbed glutamatergic neurotransmission are regarded as fundamental pathophysiological features of psychosis. However, although animal models of psychosis suggest that these two abnormalities are interrelated, their relationship in humans has yet to be investigated. Methods We used a combination of functional magnetic resonance imaging and magnetic resonance spectroscopy to investigate the relationship between medial temporal activation during an episodic memory task and local glutamate levels in 22 individuals with an at-risk mental state for psychosis and 14 healthy volunteers. Results We observed a significant between-group difference in the coupling of medial temporal activation with local glutamate levels. In control subjects, medial temporal activation during episodic encoding was positively associated with medial temporal glutamate. However, in the clinical population, medial temporal activation was reduced, and the relationship with glutamate was absent. Conclusions In individuals at high risk of psychosis, medial temporal dysfunction seemed related to a loss of the normal relationship with local glutamate levels. This study provides the first evidence that links medial temporal dysfunction with the central glutamate system in humans and is consistent with evidence that drugs that modulate glutamatergic transmission might be useful in the treatment of psychosis.

Delta-9-tetrahydrocannabinol (Delta-9-THC) and Cannabidiol (CBD), the two main ingredients of the Cannabis sativa plant have distinct symptomatic and behavioral effects. We used functional magnetic resonance imaging (fMRI) in healthy volunteers to examine whether Delta-9-THC and CBD had opposite effects on regional brain function. We then assessed whether pretreatment with CBD can prevent the acute psychotic symptoms induced by Delta-9-THC. Fifteen healthy men with minimal earlier exposure to cannabis were scanned while performing a verbal memory task, a response inhibition task, a sensory processing task, and when viewing fearful faces. Subjects were scanned on three occasions, each preceded by oral administration of Delta-9-THC, CBD, or placebo. BOLD responses were measured using fMRI. In a second experiment, six healthy volunteers were administered Delta-9-THC intravenously on two occasions, after placebo or CBD pretreatment to examine whether CBD could block the psychotic symptoms induced by Delta-9-THC. Delta-9-THC and CBD had opposite effects on activation relative to placebo in the striatum during verbal recall, in the hippocampus during the response inhibition task, in the amygdala when subjects viewed fearful faces, in the superior temporal cortex when subjects listened to speech, and in the occipital cortex during visual processing. In the second experiment, pretreatment with CBD prevented the acute induction of psychotic symptoms by Delta-9-tetrahydrocannabinol. Delta-9-THC and CBD can have opposite effects on regional brain function, which may underlie their different symptomatic and behavioral effects, and CBD's ability to block the psychotogenic effects of Delta-9-THC.

Cannabis sativa, the most widely used illicit drug, has profound effects on levels of anxiety in animals and humans. Although recent studies have helped provide a better understanding of the neurofunctional correlates of these effects, indicating the involvement of the amygdala and cingulate cortex, their reciprocal influence is still mostly unknown. In this study dynamic causal modelling (DCM) and Bayesian model selection (BMS) were used to explore the effects of pure compounds of C. sativa [600 mg of cannabidiol (CBD) and 10 mg Delta 9-tetrahydrocannabinol (Delta 9-THC)] on prefrontal-subcortical effective connectivity in 15 healthy subjects who underwent a double-blind randomized, placebo-controlled fMRI paradigm while viewing faces which elicited different levels of anxiety. In the placebo condition, BMS identified a model with driving inputs entering via the anterior cingulate and forward intrinsic connectivity between the amygdala and the anterior cingulate as the best fit. CBD but not Delta 9-THC disrupted forward connectivity between these regions during the neural response to fearful faces. This is the first study to show that the disruption of prefrontal-subocritical connectivity by CBD may represent neurophysiological correlates of its anxiolytic properties.

Background: The glutamate model of schizophrenia proposes that altered glutamatergic neurotransmission is fundamental to the development of the disorder. In addition, its potential to mediate neurotoxicity raises the possibility that glutamate dysfunction could underlie neuroanatomic changes in schizophrenia. Here we determine whether changes in brain glutamate are present in subjects at ultra high risk of developing psychosis and whether these changes are related to reductions in cortical gray matter volume.Methods: Twenty-seven individuals with an at-risk mental state and a group of 27 healthy volunteers underwent proton magnetic resonance spectroscopy and volumetric proton magnetic resonance imaging using a 3-Tesla scanner. Glutamate and glutamine levels were measured in anterior cingulate, left hippocampus, and left thalamus. These measures were then related to cortical gray matter volume.Results: At-risk mental state (ARMS) subjects had significantly lower levels of glutamate than control subjects in the thalamus (p Conclusions: This study provides the first evidence that brain glutamate function is perturbed in people with prodromal signs of schizophrenia and that glutamatergic dysfunction is associated with a reduction in gray matter volume in brain regions thought to be critical to the pathogenesis of the disorder. These findings support the hypothesis that drugs affecting the glutamate system may be of benefit in the early stages of psychotic illness.

Background Anxiety reactions and panic attacks are the acute symptoms most frequently associated with cannabis use. Understanding the relationship between cannabis and anxiety may clarify the mechanism of action of cannabis and the pathophysiology of anxiety. Aims of the present study were to review the nature of the relationship between cannabis use and anxiety, as well as the possible clinical, diagnostic and causal implications. Method Systematic review of the Medline, PsycLIT and EMBASE literature. Results Frequent cannabis users consistently have a high prevalence of anxiety disorders and patients with anxiety disorders have relatively high rates of cannabis use. However, it is unclear if cannabis use increases the risk of developing long-lasting anxiety disorders. Many hypotheses have been proposed in an attempt to explain these relationships, including neurobiological, environmental and social influences. Conclusions The precise relationship between cannabis use and anxiety has yet to be established. Research is needed to fully clarify the mechanisms of such the association. Copyright # 2009 John Wiley & Sons, Ltd.

Although serum autoantibodies directed against basal ganglia (BG) implicate autoimmunity in the pathogenesis of obsessive-compulsive disorder (OCD), it is unclear whether these antibodies can cross the blood-brain barrier to bind against BG or other components of the OCD circuit. It is also unclear how they might lead to hyperactivity in the OCD circuit. We examined this by investigating the presence of autoantibodies directed against the BG or thalamus in the serum as well as CSF of 23 OCD patients compared with 23 matched psychiatrically normal controls using western blot. We further investigated CSF amino acid (glutamate, GABA, taurine, and glycine) levels and also examined the extent to which these levels were related to the presence of autoantibodies. There was evidence of significantly more binding of CSF autoantibodies to homogenate of BG as well as to homogenate of thalamus among OCD patients compared with controls. There was no significant difference in binding between patient and control sera except for a trend toward more bands to BG and thalamic protein corresponding to 43 kD among OCD patients compared with controls. CSF glutamate and glycine levels were also significantly higher in OCD patients compared with controls, and further multivariate analysis of variance showed that CSF glycine levels were higher in those OCD patients who had autoantibodies compared with those without. The results of our study implicate autoimmune mechanisms in the pathogenesis of OCD and also provide preliminary evidence that autoantibodies against BG and thalamus may cause OCD by modulating excitatory neurotransmission.

BackgroundWe conducted a systematic review to assess the evidence for specific effects of cannabis on brain structure and function. The review focuses on the cognitive changes associated with acute and chronic use of the drug.MethodWe reviewed literature reporting neuroimaging studies of chronic or acute cannabis use published up until January 2009. The search was conducted using Medline, EMBASE, LILACS and PsycLIT indexing services using the following key words: cannabis, marijuana, delta-9-tetrahydrocannabinol, THC, cannabidiol, CBD, neuroimaging, brain imaging, computerized tomography, CT, magnetic resonance, MRI, single photon emission tomography, SPECT, functional magnetic resonance, fMRI, positron emission tomography, PET, diffusion tensor MRI, DTI-MRI, MRS and spectroscopy.ResultsSixty-six studies were identified, of which 41 met the inclusion criteria. Thirty-three were functional (SPECT/PET/fMRI) and eight structural (volumetric/DTI) imaging studies. The high degree of heterogeneity across studies precluded a meta-analysis. The functional studies suggest that resting global and prefrontal blood flow are lower in cannabis users than in controls. The results from the activation studies using a cognitive task are inconsistent because of the heterogeneity of the methods used. Studies of acute administration of THC or marijuana report increased resting activity and activation of the frontal and anterior cingulate cortex during cognitive tasks. Only three of the structural imaging studies found differences between users and controls.ConclusionsFunctional neuroimaging studies suggest a modulation of global and prefrontal metabolism both during the resting state and after the administration of THC/marijuana cigarettes. Minimal evidence of major effects of cannabis on brain structure has been reported.

Context Cannabis sativa use can impair verbal learning, provoke acute psychosis, and increase the risk of schizophrenia. It is unclear where C sativa acts in the human brain to modulate verbal learning and to induce psychotic symptoms. Objectives To investigate the effects of 2 main psychoactive constituents of C sativa , Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol, on regional brain function during verbal paired associate learning. Design Subjects were studied on 3 separate occasions using a block design functional magnetic resonance imaging paradigm while performing a verbal paired associate learning task. Each imaging session was preceded by the ingestion of Δ9-THC (10 mg), cannabidiol (600 mg), or placebo in a double-blind, randomized, placebo-controlled, repeated-measures, within-subject design. Setting University research center. Participants Fifteen healthy, native English-speaking, right-handed men of white race/ethnicity who had used C sativa 15 times or less and had minimal exposure to other illicit drugs in their lifetime. Main Outcome Measures Regional brain activation (blood oxygen level–dependent response), performance in a verbal learning task, and objective and subjective ratings of psychotic symptoms, anxiety, intoxication, and sedation. Results Δ9-Tetrahydrocannabinol increased psychotic symptoms and levels of anxiety, intoxication, and sedation, whereas no significant effect was noted on these parameters following administration of cannabidiol. Performance in the verbal learning task was not significantly modulated by either drug. Administration of Δ9-THC augmented activation in the parahippocampal gyrus during blocks 2 and 3 such that the normal linear decrement in activation across repeated encoding blocks was no longer evident. Δ9-Tetrahydrocannabinol also attenuated the normal time-dependent change in ventrostriatal activation during retrieval of word pairs, which was directly correlated with concurrently induced psychotic symptoms. In contrast, administration of cannabidiol had no such effect. Conclusion The modulation of mediotemporal and ventrostriatal function by Δ9-THC may underlie the effects of C sativa on verbal learning and psychotic symptoms, respectively.

Despite widespread use and validation of their efficacy, about 40-60% of obsessive compulsive disorder (OCD) sufferers do not respond to appropriate courses of treatment with serotonin reuptake inhibitors (SRI) and even with the combination of pharmacotherapy and cognitive behaviour therapy a substantial number of patients remain dramatically symptomatic. Recently, there has been increasing interest in investigating glutamatergic dysfunction in OCD. Multiple lines of evidence point toward glutamatergic dysfunction being related to the pathophysiology of OCD, with glutamate modulating drugs being an alternative pharmacological strategy for treating OCD. In this article we focus in detail on the rationale for targeting glutamatergic agents as well as review the recent important patents for compounds that have emerged from these studies.

Background Cannabis is frequently used among individuals with first episode psychosis and is associated with poor clinical outcomes. However, little is known about the effect of cannabis use on the response to antipsychotic medications and how use could affect outcomes. Using natural language processing on clinical data from a large electronic case register, we sought to investigate whether resistance to antipsychotic treatment mediated poor clinical outcomes associated with cannabis use. Methods Data were obtained from 2026 people with first episode psychosis in south London, UK. Cannabis use documented in free text clinical records was identified with natural language processing. Data for age, sex, ethnicity, marital status, psychotic disorder diagnosis, subsequent hospital admission, and number of unique antipsychotic medications prescribed were obtained using the Clinical Record Interactive Search instrument. The association of these variables with cannabis use was analysed with multivariable regression and mediation analysis. Findings 939 people (46·3%) with first episode psychosis were using cannabis at first presentation. Cannabis use was most strongly associated with being 16–25 years old, male, and single, and was also associated with an increase in number of hospital admissions (incidence rate ratio 1·50, 95% CI 1·25–1·80), compulsory hospital admission (odds ratio 1·55, 1·16–2·08), and number of days spent in hospital (β coefficient 35·1 days, 12·1–58·1) over 5 years' follow-up. An increase in number of unique antipsychotic medications mediated an increase in number of hospital admissions (natural indirect effect 1·11, 1·04–1·17; total effect 1·41, 1·22–1·64), compulsory hospital admission (1·27, 1·10–1·45; 1·71, 1·05–2·78), and number of days spent in hospital (16·1, 6·7–25·5; 19·9, 2·5–37·3). Interpretation We showed that a substantial number of people with first episode psychosis used cannabis and that its use was associated with increased likelihood of hospital admission and number of days spent in hospital. These associations were partly mediated by an increase in number of unique antipsychotic medications prescribed. These findings suggest that cannabis might reduce response to conventional antipsychotic treatment and highlight the importance of strategies to reduce its use. Funding National Institute for Health Research, UK Medical Research Council.

OBJECTIVE The results of various family studies of obsessive-compulsive disorder have varied widely, possibly because of heterogeneity in the obsessive-compulsive disorder phenotype. The current study was conducted to determine familiality of checker and washer subtypes of obsessive-compulsive disorder compared with normal controls. METHODS In this study, all available first-degree relatives of 25 checker, 34 washer and 40 psychiatrically normal control probands were interviewed directly, using structured interviews. RESULTS The morbid risk of syndromal and subsyndromal obsessive-compulsive disorder was significantly greater among the relatives of checker probands (19.4%) than in the relatives of washer (8.7%) or control probands (5.4%), while the morbid risk for the relatives of washer and control probands was not significantly different. In all, 67% of the checker relatives with syndromal and subsyndromal obsessive-compulsive disorder were checkers, while 54% of the washer relatives with syndromal and subsyndromal obsessive-compulsive disorder were washers. CONCLUSIONS Our study provides preliminary evidence of familiality of the checker subtype of obsessive-compulsive disorder. Future studies using patients subtyped on the basis of symptom dimensions, in larger obsessive-compulsive disorder samples, are needed, to further validate the genetic basis of obsessive-compulsive disorder.

Background: Depressive and other anxiety disorders are commonly found to coexist with obsessive compulsive disorder (OCD). Although western studies have looked at this issue, there are no reports from India investigating anxiety and depressive comorbidity in adult OCD. Methods: Between January and December 2001, charts of 218 OCD patients seen in the OCD clinic at the National Institute of Mental Health and Neurosciences, Bangalore, were evaluated using the OPCRIT criteria for ICD-10 for the presence of comorbid depressive and anxiety disorders. Results: There were 146 males and 72 females; their mean age at OCD onset was 21.32 ± 0.64 years. Thirty-six (16.5%) patients had depressive episodes, 12 (5.5%) dysthymia and 15 (6.9%) any anxiety disorder. No significant difference in terms of age, sex, marital status or age at onset was found between the OCD patients with and without comorbid anxiety disorder, major depression or dysthymia, except that female OCD patients were more likely than males to have comorbid major depressive disorder. Conclusions: The results of our study are in keeping with previous data from other parts of the world, though the actual rates of comorbidity in our sample appear to be much lower. It remains to be seen whether the differences in rates are a result of methodological issues or different characteristics of sample populations. Further long-term, prospective, methodologically sound studies investigating the comorbidity of depressive and other anxiety disorders in OCD patients are needed to clarify this issue.