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Aim Lack of insight is a cardinal feature of psychosis with crucial implications for outcome. Concerns have been raised regarding a link between insight and suicidality. This study aimed to test the relationship between suicidal behaviour preceding first-episode psychosis (FEP) and insight dimensions at treatment onset. Methods A total of 112 FEP inpatients were recruited. Suicidal events prior to admission were recorded. Insight was assessed multidimensionally with the Schedule for the Assessment of Insight – Expanded version shortly after admission. Suicidal and non-suicidal patients were compared regarding scores on ‘total insight’ and three insight domains: ‘awareness of mental illness’, ‘relabeling of psychotic experiences as abnormal’ and ‘compliance’. This analysis was also adjusted for a set of sociodemographic, clinical, neurocognitive and psychopathological variables. Results Bivariate analyses demonstrated a direct association between previous suicidality and all insight domains. However, these associations did not survive multivariable regression models, which demonstrated gender (female), shorter duration of untreated psychosis (DUP) and psychopathological symptoms – depression and disorganization – to mediate the influence of suicidal history on insight, and therefore to underlie the latter. Conclusions Insight dimensions in FEP patients are influenced by having suicidal antecedents through some mediating variables such as gender, DUP and depression. Further prospective studies are needed to clarify the potential implications of these findings on the management of insight in FEP. As suicidal history is associated with greater levels of both depression and insight at first presentation, these three variables might be useful in predicting further suicidal events.

IMPORTANCE Cannabis use after first-episode psychosis is associated with poor outcomes,but the causal nature of this association is unclear.OBJECTIVE To examine the precise nature of the association between continued cannabis useafter the onset of psychosis and risk of relapse of psychosis.DESIGN, SETTING, AND PARTICIPANTS This prospective cohort study followed up for at least 2 years after the onset of psychosis 220 patients who presented to psychiatric services inSouth London, England, from April 12, 2002, to July 26, 2013, with first-episode psychosis. Longitudinal modeling (fixed-effects analysis, cross-lagged path analysis) was used to examine whether the association between changes in cannabis use and risk of relapse over time is the result of shared vulnerability between psychosis and cannabis use, psychosis increasing the risk of cannabis use (reverse causation), or a causal effect of cannabis use onpsychosis relapse.INTERVENTIONS Exposure to cannabis within the first and second years after onset ofpsychosis.MAIN OUTCOMES AND MEASURES The main outcome measure was relapse of psychosis, defined as subsequent hospitalization for psychosis. Effect of cannabis use status in the first year (Ct1) and second year (Ct2) and pattern of cannabis use continuation in the first year and second year were modeled for risk of relapse in the first year (Rt1) and risk of relapse in the second year (Rt2) after psychosis onset.RESULTS A total of 220 patients with first-episode psychosis were included in the analysis(mean [SD] age, 28.62 [8.58] years; age range, 18-65 years; 90 women [40.9%] and 130 men [59.1%]). Fixed-effects models that adjusted for time-variant (other illicit drug use, antipsychotic medication adherence) and time-invariant (eg, genetic or premorbid environment) unobserved confounders revealed that there was an increase in the odds of experiencing a relapse of psychosis during periods of cannabis use relative to periods of no use (odds ratio, 1.13; 95%CI, 1.03-1.24). Change in the pattern of continuation significantly increased the risk (odds ratio, 1.07; 95%CI, 1.02-1.13), suggesting a dose-dependentassociation. Cross-lagged analysis confirmed that this association reflected an effect of cannabis use on subsequent risk of relapse (Ct1→Rt2: β = 0.44, P = .04) rather than an effect of relapse on subsequent cannabis use (Rt1→Ct2: β = −0.29, P = .59).CONCLUSIONS AND RELEVANCE These results reveal a dose-dependent association between change in cannabis use and relapse of psychosis that is unlikely to be a result of self-medication or genetic and environmental confounding.

The Schizophrenia International Research Society held its first scientific conference in Venice, Italy, June 21 to 25th, 2008. A wide range of controversial topics were presented in overlapping and plenary oral sessions. These included new genetic studies, controversies about early detection of schizophrenia and the prodrome, treatment issues, clinical characteristics, cognition, neuropathology and neurophysiology, other etiological considerations, substance abuse co-morbidity, and animal models for investigating disease etiology and for use as targets in drug studies. Young investigators in the field were awarded travel grants to participate in the congress and one of their roles was to summarize the oral sessions and subsequent discussions. The reports that follow are the culmination of this work produced by 30 young investigators who attended the congress. It is hoped that these summaries will be useful synopses of what actually occurred at the congress for those who did not attend each session or were unable to be present. The abstracts of all presentations, as submitted by the authors a few months prior, were previously published as supplement 2 to volume 102/1-3, June 2008.

Background The outcome of first episode psychosis (FEP) is highly variable and difficult to predict. Cognitive insight measured at illness onset has previously been found to predict psychopathology 12-months later. The aims of this study were to examine whether the prospective relationship between cognitive insight and symptom severity is evident at four-years following FEP and to examine some psychological correlates of cognitive insight. Methods FEP participants (n = 90) completed the Beck Cognitive Insight Scale (BCIS) at illness onset, and associations between BCIS scores with symptom severity outcomes (4-years after FEP) were assessed. The BCIS scales (self-reflectiveness and self-certainty) were examined as a composite score, and individually compared to other cognitive measures (IQ and jumping to conclusions (JTC) bias). Results Regression analyses revealed that the cognitive insight composite did not predict 4-year symptom remission in this study while the self-reflection subscale of the BCIS predicted severity of symptoms at 4-years. Self-certainty items of the BCIS were not associated with symptom severity. Significant correlations between the JTC bias, self-certainty and IQ were found, but self-reflection did not correlate with these other cognitive measures. Conclusions Self-reflective capacity is a more relevant and independent cognitive construct than self-certainty for predicting prospective symptom severity in psychosis. Improving self-reflection may be a useful target for early intervention research.

Cannabis use has been reported to induce long-lasting psychotic disorders and a dose-response relationship has been observed. We performed a systematic review of studies that investigate the association between the degree of cannabis consumption and psychosis and a meta-analysis to quantify the magnitude of effect. Published studies were identified through search of electronic databases, supplemented by manual searches of bibliographies. Studies were considered if they provided data on cannabis consumption prior to the onset of psychosis using a dose criterion (frequency/amount used) and reported psychosis-related outcomes. We performed random effects meta-analysis of individual data points generated with a simulation method from the summary data of the original studies. From 571 references, 18 studies fulfilled inclusion criteria for the systematic review and 10 were inserted in the meta-analysis, enrolling a total of 66 816 individuals. Higher levels of cannabis use were associated with increased risk for psychosis in all the included studies. A logistic regression model gave an OR of 3.90 (95% CI 2.84 to 5.34) for the risk of schizophrenia and other psychosis-related outcomes among the heaviest cannabis users compared to the nonusers. Current evidence shows that high levels of cannabis use increase the risk of psychotic outcomes and confirms a dose-response relationship between the level of use and the risk for psychosis. Although a causal link cannot be unequivocally established, there is sufficient evidence to justify harm reduction prevention programs.

Both substance use and poor medication adherence are associated with poor outcome in psychosis. To clarify the contributions of substance use and poor medication adherence to poor outcome in the year following a first episode of psychosis, 205 patients were evaluated for use of tobacco, alcohol, cannabis and stimulants at their psychosis onset, and in a 1-year follow-up. Data on medication adherence and symptom remission were also collected. Patients had high rates of overall substance use before (37-65%) and after psychosis onset (45-66%). 44% showed poor medication adherence and 55% did not reach remission from psychosis. Nicotine dependence and cannabis use after psychosis onset significantly predicted both poor medication adherence and non-remission, and poor medication adherence mediated the effects of these substances on non-remission. In conclusion, medication adherence lies on the causal pathway between nicotine dependence and cannabis on the one hand and non-remission on the other.

BACKGROUND: An association between social disadvantage and established psychosis is well documented in the literature, but there remains a lack of data on the social circumstances of patients before they became ill. We investigated whether social disadvantage at, and prior to, first contact with psychiatric services, is associated with psychosis. METHOD: We collected information on social disadvantage in childhood and adulthood from 278 cases presenting with their first episode of psychosis to the South London and Maudsley National Health Service Foundation Trust and from 226 controls recruited from the local population. Three markers of childhood social disadvantage and 3 markers of disadvantage in adulthood were analyzed. RESULTS: Long term separation from, and death of, a parent before the age of 17 years were both strongly associated with a 2- to 3-fold-increased odds of psychosis. Cases were also significantly more likely to report 2 or more markers of adult social disadvantage than healthy controls (OR = 9.03) at the time of the first presentation with psychosis, independent of a number of confounders. When we repeated these analyses for long-standing adult social disadvantage, we found that the strength of the association decreased but still remained significant for 1 year (OR = 5.67) and 5 years (OR = 2.57) prior to the first contact. CONCLUSIONS: Social disadvantage indexes exposure to factors operating prior to onset that increase the risk of psychosis, both during childhood and adulthood.

Abnormalities in hypothalamic-pituitary-adrenal (HPA) axis activity have been reported in patients with psychosis, but it is still unclear how these are related to the clinical symptomatology. Inconsistent findings have emerged from previous studies on the association between cortisol levels and clinical symptoms. Methodological and/or clinical factors, such as patients' diagnosis or illness phase, might partially account for these inconsistencies. The aim of this study was to investigate the association between HPA axis activity and clinical symptoms in first-episode psychosis, taking into account diagnosis and illness phase.Saliva samples were collected in 55 subjects with first-episode psychosis to assess the Cortisol Awakening Response (CAR) and diurnal cortisol levels (AUC-DAY). Severity of symptoms was assessed with the Positive and Negative Syndrome Scale (PANSS). Scores for subscales and symptom dimensions were used as predictors in multivariate analyses in different diagnostic subgroups and in clinically remitted patients. In addition, a systematic review of the literature on this topic was conducted.In subjects with schizophrenia (n=36), the CAR was predicted by the severity of positive symptoms (beta=0.47, p=0.04); in subjects with depressive psychoses (n=8) the CAR was predicted by excitement (beta=0.58, p=0.005), disorganization (beta=0.39, p=0.007) and depressive symptoms (beta=0.32, p=0.005). In patients with bipolar psychoses (n=11) AUC-DAY was predicted negatively by disorganization (beta=-2.82, p=0.009) and positively by excitement (beta=2.06, p=0.009) and positive symptoms (beta=1.28, p=0.02). In the sample in clinical remission (n=9), the CAR was associated with the severity of positive symptoms (beta=1.34, p=0.009) and, negatively, with excitement (beta=-1.05, p=0.04). The systematic review (on a total of 28 papers, including n=1022 patients), found that in patients with psychosis cortisol levels have been associated with the severity of multiple symptom dimensions.HPA axis activity is associated with the severity of multiple types of symptoms in first-episode psychosis. Patients' diagnosis and clinical phase partially influence these associations.

Aim: The study aims to examine whether an extended Theory of Planned Behaviour (TPB) model predicts the frequency of past and intended cannabis use in young adults with psychosis. Methods: A cross-sectional correlational design was used with 32 participants (aged 18–36 years old) within 3 years (mean = 7 months) of their first psychotic episode. TPB variables and a measure of social influence (descriptive norms) were measured. Results: The TPB accounted for a large amount of the variance in both the frequency of past cannabis use (25%) and in the intended frequency of future cannabis use (36%). The addition of descriptive norms (beliefs about the frequency of others' cannabis use) accounted for a significant additional amount of the variance in past use (19%). Adding the ‘friends’ component of descriptive norms only led to a model that accounted for 52% of the variance in past cannabis use. Conclusions: Descriptive social norms should be considered when trying to understand cannabis use in early psychosis. Interventions should take account of the individual's attitude towards cannabis, their perceived control over its use and its social context.

The most important risk factor for schizophrenia is a positive family history, but only a minority of people with schizophrenia have an affected relative and no single gene of large effect has been consistently associated with psychosis risk. Epidemiological research has elucidated putative biological and psychosocial candidate risk factors for schizophrenia. Biological factors include advanced paternal age, exposure to obstetric events and abuse of drugs such as stimulants and cannabis. Recent evidence indicates that social factors such as migration, urban living and victimization also increase the risk. However, neither individual susceptibility genes nor individual environmental risk factors appear sufficient or necessary to cause schizophrenia. Both genetic and environmental risk factors are mostly of small effect, but the latter offer more tangible targets for prevention.

Background The main attempt to prevent the development of psychosis has been through clinics for people at clinical high risk. Such an approach is useful for research but can never reach the majority of individuals who will become psychotic. Biological markers could be used to identify individuals with unusual vulnerabilities e.g. those with copy number variations such as VCFS. However, identifying the with such markers is unlikely to impact on the majority of cases, and as yet no useful interventions are available. How therefore to prevent psychosis? Methods Data will be presented from 3 studies of first onset psychosis (FEP) which used similar methods of ascertainment and assessment of cases and controls; AESOP and GAP from South London and the EU-GEI across 16 sites in 5 European countries. Results The identified risk factors for psychosis were the polygenic risk score for schizophrenia, childhood abuse, living in a city, being from an ethnic minority, drug abuse, adverse life events. Clearly, reducing some of these (e.g. urbanicity or migration) is not within the powers of psychiatrists. The GAP study showed that the polygenic risk score accounted for the greatest variance in caseness; those with scores in the highest quintile were 7 times more likely to be a psychotic case than those in those lowest quintile. The GAP study also gave estimates of the population attributable fraction (PAF): these indicated that if no one was exposed to child abuse and use of high potency cannabis, then 16% and 24% respectively of psychosis in South London could be prevented. The EU-GEI study showed striking differences in the incidence of psychosis between Northern and Southern Europe; data will be prevented concerning the contribution of risk factors, especially cannabis use, to this. Discussion The knowledge that schizophrenia is the extreme of a continuum of psychosis has important implications for prevention. Preventive approaches to hypertension or obesity do not focus on identifying individuals carrying biological markers; rather they encourage members of the general population to take exercise and reduce their calorie intake. A similar approach should be adopted for psychosis. In the long-term attempts to reduce risk factors should be made e.g. addressing psychotogenic aspects of city living or by decreasing discrimination of ethnic minorities. This will be difficult. However, an obvious place to start is by attempting to influence society’s patterns of consumption of high-potency cannabis. Unfortunately, public policy in the US and certain other countries appears to be moving in the opposite direction with increases in consumption and potency. Are these countries sleep-walking to more psychosis?

Background Cognition and more recently social cognition, have been shown to be a strong predictor of clinical and functional outcome in psychosis. Jumping to Conclusions (JTC), which is defined as the proneness to require less information before forming beliefs or making a decision, has been related to the formation and maintenance of delusions. However, its relevance to longer-term outcome is unclear. On the other hand, there is evidence in the literature to suggest differences of patterns in clinical outcome and service based ethnicity. Using data from the GAP case-control study of first-episode psychosis (FEP), we set out to test whether the premorbid IQ, educational level and presence of JTC would predict poor clinical outcome at 4 year controlling for ethnicity. Methods 431 FEP patients were assessed with the positive and negative syndrome scale (PANSS) and Global Assessment of Functioning (GAF). Premorbid IQ was measured by the National Adult Reading Test (NART) scale, probabilistic reasoning “Beads” task was applied and educational levels were recorded alongside with socio-occupational variables at the time of recruitment. Follow-up data over an average period of 4 years were obtained from the electronic psychiatric clinical records in the South London and Maudsley NHS Foundation Trust (SLaM); including items concerning clinical course and outcomes (remission, intervention of police, use of involuntary treatment – the Mental Health Act (MHA) -, and inpatient days). We build different regression models using separately premorbid IQ, education level and JTC as predictors for each clinical outcome, both unadjusted and adjusted by ethnicity, age and gender. Results Higher educational level was predictor of clinical remission [adjusted OR=1.9, 95% confidence interval (CI) 1.2–3, p=0.005]. FEP who presented JTC at baseline were more likely during the follow up period to be detained under the MHA [adjusted OR=11.23, 95% confidence interval (CI) 2.64–47.76, p=0.001], require intervention by the police (adjusted OR=10.76, 95% CI 2.4–48.26, p=0.002) and have longer admissions (adjusted IRR=4.04, 95% CI 1.43–11.36, p=0.008). We couldn’t find any predictor effect for clinical outcome for premorbid IQ. The association with level of education and JTC was not accounted for by socio-demographic variables including ethnicity. Discussion Although we did not find association with premorbid IQ, educational level as indirect proxy of neurocognition showed a predictor effect for clinical remission. JTC in FEP is associated with serious subsequent consequences in terms of social disturbance and a poor therapeutic alliance. Our findings raise the question of whether the implementation of specific interventions to reduce JTC, such as Metacognition Training, may be a useful addition in early psychosis intervention programs.

Background Acute cannabis use stimulates appetite, while general population studies suggest that chronic use is associated with reduced risk of obesity and other cardiometabolic risk factors. Methods In this study, we investigated changes in body mass index (BMI), fasting blood glucose and lipids, and rates of metabolic syndrome risk factors in cannabis users vs. non-users in 109 minimally treated patients with first-episode schizophrenia, schizophreniform or schizo-affective disorder who were treated according to a standardized treatment regime with depot antipsychotic medication over 12 months. Participants underwent repeated urine toxicology tests for cannabis and those testing positive at any time during the study (n=40), were compared with those who tested negative at all time points (n=69). Results There was a significant group*time interaction effect (p=0.002) with the cannabis negative group showing a greater increase in BMI than the cannabis positive group, after adjusting for age, sex, methamphetamine use and modal dose of antipsychotic. There were no group*time interaction effects for fasting blood glucose or lipids. Post hoc tests indicated significant increases in fasting blood glucose and triglycerides and a decrease in high-density lipoprotein cholesterol for the cannabis negative group, with no significant changes in the cannabis positive group. Rates of metabolic syndrome did not differ significantly between groups. However, more cannabis negative patients had elevated waist-circumference at endpoint (p=0.003). Discussion Although other indirect effects such as dietary neglect and smoking may be contributory and could explain our findings, it may be that chronic cannabis use directly suppresses appetite, thereby preventing weight gain in users.

Background According to the gene-environment interaction model the pathogenesis of psychosis relies on an adverse neuro-socio-developmental pathway. Perinatal stress represents an important risk factor for the development of psychosis because it could interfere with socio-neuro-development early in life. We aim to investigate the correlation of perinatal risk factors with the onset of psychosis. Methods Case-control – incidence study. Patients (and their mothers) were eligible if they presented for the first time with first episode psychosis at the Bo West CMHC between 2002 and 2012. The Bo West CMHC serves a catchment area of about 200,000 people. The controls were recruited in the same catchment area and study period. Results 42 patients and 26 controls and their mothers were included. Adjusted logistic regression showed that psychosis onset was significantly associated with: stressful situations during pregnancy; lower level of maternal physical health before or during pregnancy; use of anti-inflammatory drugs during pregnancy; low level of maternal education. Discussion The results of our study suggest that stress during perinatal period increases the risk of developing psychosis. More attention should be given to the containment of perinatal stress and the prevention of its adverse effects on mother and child mental health. Tarricone I, Mimmi S, et al.. First-episode psychosis at the West Bologna Community Mental Health Centre: results of an 8-year prospective study. Psychol Med. 2012 Nov;42(11):2255–64. PubMed PMID: 22404368

Background Treatment-resistant schizophrenia (TRS) is a major cause of disability and functional impairment worldwide. Approximately 30% of patients with schizophrenia will develop TRS at some point during their illness course. Despite the staggering financial and emotional costs associated with TRS, this severe disorder is poorly understood. The pathophysiological basis of TRS is posited in part to have neurodevelopmental roots. If early brain development (

Background Cannabis use remains the most widely used recreational drug worldwide. Following from several USA states legalisation policies, European countries are reconsidering their cannabis laws. While a significant amount of Epidemiological evidence has reported that cannabis use increases the risk of psychosis it is still unclear: 1) what underpins individual differences in developing a psychotic disorder following cannabis use; 2) if variations in availability of cannabis have affected rate of Psychotic disorders across Europe. Methods Using detailed data on lifetime pattern of cannabis use from the EUGEI first episode case-control study (N=2300) and the available Incidence rates of Psychosis calculated for each European site of the same study, we aim 1) to estimate if differences in age at first use, especially of high potency cannabis among cannabis users resulted in differences in their probability to develop psychosis across the study sites; 2) to calculate the proportion of new cases of psychosis attributable to early adolescence-high Potency cannabis in the 5 countries; 3) to relate data on prevalence of cannabis use in each study site with the corresponding Incidence rates for psychotic disorders. Results Cannabis users starting using cannabis at age 15 and younger who live in those EU countries where high potency cannabis is available have the highest probability to develop psychosis, compared to never users (Adj ORs from 2.6–5.9; p

Background Current diagnostic models of psychosis have been questioned since Kraepelin’s original dichotomy of dementia praecox and manic depression. Indeed, increasing evidence has suggested that a dimensional approach might be a valid alternative platform for research. However, while an increasing number of studies have investigated how environmental risk factors for affective and non-affective psychosis map onto symptom dimensions, only a few have examined these dimensions in relation to genetic variants as summarised by Polygenic Risk Score (PRS). Furthermore, no studies have examined the putative effect of PRS for Schizophrenia (SZ), Bipolar Disorder (BP), and Major Depressive Disorder (MDD) on previously identified general and specific symptom dimensions. At the same time, only one study has investigated how symptoms vary according to epidemiological factors such as living in urban neighbourhoods. The objectives of this study were to: 1) test whether a bi-factor model statistically fits the conceptualization of psychosis as composed of general and specific dimensions; 2) examine the extent to which SZ, BP, and MDD PRSs explain the phenotypic variance due to general and specific dimensions; 3) test the hypothesis that the general psychosis dimension would be more severe in highly urban environments. Methods We used clinical and epidemiological data from the EUropean network of national schizophrenia networks studying Gene-Environment Interactions (EUGEI) study, including 2322 First Episode Psychosis (FEP) patients recruited in 17 sites across 6 countries. Genetic variants were collectively analyzed for 800 individuals. The following analysis steps were performed: 1) Psychopathology items were analysed using multidimensional item response modelling in MPlus to estimate unidimensional, multidimensional, and bi-factor models of psychosis. Model fit statistics included Log-Likelihood, and Akaike and Bayesian Information Criteria to compare these models. 2) SZ, BP, and MDD PRSs for general and specific dimensions were built using PRSice. Summary statistics from large case-control mega-analyses from the Psychiatric Genomics Consortium were used as base data sets and general and specific dimension scores were used as discovery data sets. Individuals’ number of risk alleles in the discovery sample was weighted by the log odds ratio from the base samples, accounting for population stratification, and summed into the three PRSs. 3) Multilevel regression analysis was used in STATA 14 to examine the variance in general dimension due to the population density levels across the sites. Results A bi-factor solution, composed of one general and five specific symptom dimensions, showed the best model fit statistics. Higher SZ PRS score was associated with higher scores on positive dimensions (β= 0.27, t=2.11, p

Background Little is known about the impact of different forms of childhood adversity (CA) on outcomes in first episode psychosis (FEP) patients beyond the first year of treatment. We investigated associations between different types of CA and 5-year outcomes in a well-characterised sample of FEP patients. Methods A total of 237 FEP cases aged 18–65 years were followed on average for 5 years after first presentation to psychiatric services in South-London, UK. CA was assessed at service entry using the Childhood Experience of Care and Abuse Questionnaire. Using electronic clinical notes, extensive information was collected on clinical and social outcomes, service use, and self-injurious behaviours. As case analysis with missing data provides the most severely biased results we conducted multiple imputations to handle the missing data. We imputed the missing values using multiple imputations by chained equations (MICE). MICE has been shown to be a robust method for dealing with missing data across empirical and longitudinal studies. Results 72.1% of the sample reported at least one form of CA. Childhood parental separation was associated with greater likelihood of non-compliance with antipsychotic medications (OR=2.44, 95% CI=1.11–5.39), compulsory admission (OR=2.40, 95% CI=1.32–4.37), and living alone (OR=1.99, 95% CI=1.04–3.81) by the end of the follow-up. Institutional care was associated with longer total length of inpatient stay (IRR=1.34, 95% CI=1.01–1.79); parental death was associated with compulsory admissions (OR=2.87, 95% CI=1.02–8.05) during the follow-up. Discussion Our findings suggest some specificity in the detrimental impact of CA on service use and social functioning over a 5-year period following first contact with mental health services for psychosis. Clinicians should screen patients for CA and tailor interventions accordingly to improve outcomes.

First-episode psychosis (FEP) patients show hyperactivity of the hypothalamic–pituitary–adrenal (HPA) axis, but the mechanisms leading to this are still unclear. The aim of this study was to investigate the role of stress and antipsychotic treatment on diurnal cortisol levels, and on cortisol awakening response, in FEP. Recent stressful events, perceived stress and childhood trauma were collected in 50 FEP patients and 36 healthy controls using structured instruments. Salivary cortisol was obtained at awakening, at 15, 30, and 60 min after awakening, and at 12 and 8 pm. Patients experienced more recent stressful events, perceived stress and childhood trauma than controls (p < 0.001). Patients had a trend for higher diurnal cortisol levels (p=0.055), with those with less than two weeks of antipsychotics showing significantly higher cortisol levels than both patients with more than two weeks of antipsychotics (p=0.005) and controls (p=0.002). Moreover, patients showed a blunted cortisol awakening response compared with controls, irrespectively of antipsychotic treatment (p=0.049). These abnormalities in patients were not driven by the excess of stressors: diurnal cortisol levels were negatively correlated with the number of recent stressful events (r=−0.36, p=0.014), and cortisol awakening response was positively correlated with a history of sexual childhood abuse (r=0.33, p=0.033). No significant correlations were found between perceived stress or severity of symptoms and cortisol levels, either diurnal or in the awakening response. Our study shows that antipsychotics normalize diurnal cortisol hyper-secretion but not the blunted cortisol awakening response in FEP; factors other than the excess of psychosocial stress explain HPA axis abnormalities in FEP.

Two major theories of schizophrenia are respectively, the neurodevelopmental hypothesis and the dopamine hypothesis. Each of these has recently been revised. Firstly, the classical neurodevelopmental hypothesis has been modified to include the pathogenic effects of psychostimulants and cannabis abuse, and also of chronic social adversity; it is perhaps now more appropriately termed, the developmental hypothesis. Secondly, recent amendments to the dopamine hypothesis suggest that excess striatal dopamine is responsible for increased salience being given to insignificant events and thoughts, and that this underpins the development of psychotic symptoms. Traditionally, it has been thought that this striatal dopamine dysregulation might be secondary to frontal dysfunction. However, recent animal research shows that over-expression of striatal D(2) receptors results in frontal dysfunction manifesting as cognitive difficulties and animal equivalents of so-called negative symptoms. This raises the question whether early intervention may prevent the development of these latter problems. Finally, the two theories are beginning to be integrated through the growing evidence that all the developmental risk factors which increase risk of schizophrenia appear to act by facilitating dopamine dysregulation.

Cannabis has been known for at least 4,000 years to have profound effects on the mind--effects that have provoked dramatically divergent attitudes towards it. Some societies have regarded cannabis as a sacred boon for mankind that offers respite from the tribulations of everyday life, whereas others have demonized it as inevitably leading to 'reefer madness'. The debate between the protagonists and prohibitionists has recently been re-ignited, but unfortunately this debate continues mainly in ignorance of our new understanding of the effects of cannabis on the brain and of studies that have quantified the extent of the risks of long-term use.

Cannabis is the world's most commonly used illicit drug. In this review, we consider the recent literature on the effects of cannabis on mental health and on cognition.Cannabis use in adolescence increases the risk of later schizophrenia-like psychoses, especially in genetically vulnerable individuals. Not surprisingly, patients already suffering from psychosis who use cannabis have a worse outcome than those who do not. These effects of cannabis may be consequent on its impact on the dopamine system. There is less evidence of cannabis playing an aetiological role in other mental disorders including depression, but there have been far fewer studies. Heavy cannabis use has also been shown to affect memory and learning performance, both in healthy individuals and in patients suffering from psychosis. Combined cognitive-behavioural therapy and motivational interviewing seems a promising psychological intervention to achieve a cessation of cannabis use in patients suffering from schizophrenia.Further research is needed to understand the biological mechanisms underlying the effects of cannabis on mental health, but intervention strategies to help patients abstain should currently be implemented in psychiatric services, and public education campaigns should be directed at increasing awareness of the health risks of cannabis.

Not all individuals who smoke cannabis report psychotic-like experiences. Given that risk factors for psychotic disorders are multifaceted, precipitating factors to psychotic-like experiences after cannabis are likely to be equally complex. Reduced neurocognitive performance is associated with both psychosis risk and cannabis use. Therefore, it is possible cognitive performance may differentiate those who report psychotic-like experiences after cannabis from those who do not. We determined whether those reporting psychotic/dysphoric experiences after cannabis had reduced neurocognitive performance compared to those reporting primarily euphoric experiences.Participants were recruited on the basis of responses to the cannabis high captured by the Psychosis-Dysphoric and Euphoric experiences subscales from the Cannabis Experiences Questionnaire (CEQ).Compared to participants reporting primarily euphoric cannabis experiences (n = 36; 44% male; mean age (SD) = 28 (9) years), those who reported psychotic/dysphoric experiences (n = 40; 45% male; mean age (SD) = 26 (5) years) demonstrated significantly faster responses to a trial and error learning task. In the presence of distracters, those with psychotic/dysphoric experiences after cannabis made more errors on a Continuous Performance Task.Those who report psychotic/dysphoric experiences after cannabis have subtle inefficiencies in their cognitive processes. The multiple factors which predict vulnerability to psychotic-like experiences after cannabis require further investigation.

Prisoners exhibit high rates of substance use and mental health problems. In the present study, we sought to gain a detailed understanding of substance use amongst young prisoners to inform early detection and early intervention strategies in a prison setting.This is a cross-sectional study of 2102 prisoners who were screened by the London Early Detection and Prevention in Prison Team (LEAP). Data on the use of substances were collected including age of first use, recent use, duration of use and poly-drug use. The Prodromal Questionnaire - Brief Version was used to screen for the at-risk mental state.We found high rates of lifetime and recent use and low age of first use of a number of substances. We also found strong associations between substance use and screening positive for an at-risk mental state. Logistic regression analysis confirmed that use of any drug in the last year, poly-drug and early use, as well as heavy alcohol use, were related to an increased risk of screening positive.Substance use in the prison population is not only widespread and heavy but is also strongly linked with a higher risk of developing mental health problems. The need for early detection and early intervention in prison is discussed.

While the role of childhood adversity in increasing the risk of psychosis has been extensively investigated, it is not clear what the impact of early adverse experiences is on the outcomes of psychotic disorders. Therefore, we investigated associations between childhood adversity and 1-year outcomes in 285 first-presentation psychosis patients. Exposure to childhood adversity prior to 17 years of age was assessed using the Childhood Experience of Care and Abuse Questionnaire. Data on illness course, symptom remission, length of psychiatric hospitalization, compliance with medication, employment, and relationship status were extracted from clinical records for the year following first contact with mental health services for psychosis. Seventy-one percent of patients reported exposure to at least 1 type of childhood adversity (physical abuse, sexual abuse, parental separation, parental death, disrupted family arrangements, or being taken into care). No robust associations were found between childhood adversity and illness course or remission. However, childhood physical abuse was associated with almost 3-fold increased odds of not being in a relationship at 1-year follow-up compared to patients who did not report such adverse experiences. There was also evidence of a significant association between parental separation in childhood and longer admissions to psychiatric wards during 1-year follow-up and 2-fold increased odds of noncompliance with medication compared to those not separated from their parents. Therefore, our findings suggest that there may be some specificity in the impact of childhood adversity on service use and social functioning among psychosis patients over the first year following presentation to mental health services.

Background Cognitive biases may contribute to delusion persistence. We tested this in a longitudinal study of first episode psychosis (FEP). Methods 34 FEP patients completed assessments of delusions and Jumping to Conclusions (JTC) at baseline and 12-month follow-up. Results JTC was associated with baseline delusion severity (t(32) = 2.7, p = 0.01). Baseline delusions persisted at follow-up for 8/20 participants (40%), who all jumped to conclusions (8/8, 100%), compared to half of those with no or changeable delusions (14/26, 54%; χ2 (df = 1) = 5.7, p = 0.03; Phi = 0.4). Conclusion Findings implicate cognitive biases in delusion persistence, and support the potential to reduce delusions through reasoning-focused interventions.

BACKGROUND: Cortisol and inflammatory markers have been increasingly reported as abnormal at psychosis onset. The main aim of our study was to investigate the ability of these biomarkers to predict treatment response at 12 weeks follow-up in first episode psychosis.METHODS: In a longitudinal study, we collected saliva and blood samples in 68 first episode psychosis patients (and 57 controls) at baseline and assessed response to clinician-led antipsychotic treatment after 12 weeks. Moreover, we repeated biological measurements in 39 patients at the same time we assessed the response. Saliva samples were collected at multiple time points during the day to measure diurnal cortisol levels and cortisol awakening response (CAR); interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-8, IL-10, tumor necrosis factor-α, and interferon-γ (IFN-γ) levels were analyzed from serum samples. Patients were divided into Non-Responders (n = 38) and Responders (n = 30) according to the Remission symptom criteria of the Schizophrenia Working Group Consensus.RESULTS: At first onset, Non-Responders had markedly lower CAR (d = 0.6, P = .03) and higher IL-6 and IFN-γ levels (respectively, d = 1.0, P = .003 and d = 0.9, P = .02) when compared with Responders. After 12 weeks, Non-Responders show persistent lower CAR (P = .01), and higher IL-6 (P = .04) and IFN-γ (P = .05) when compared with Responders. Comparison with controls show that these abnormalities are present in both patients groups, but are more evident in Non-Responders.CONCLUSIONS: Cortisol and inflammatory biomarkers at the onset of psychosis should be considered as possible predictors of treatment response, as well as potential targets for the development of novel therapeutic agents.

Both cannabis use and the dopamine receptor (DRD2) gene have been associated with schizophrenia, psychosis-like experiences, and cognition. However, there are no published data investigating whether genetically determined variation in DRD2 dopaminergic signaling might play a role in individual susceptibility to cannabis-associated psychosis. We genotyped (1) a case-control study of 272 patients with their first episode of psychosis and 234 controls, and also from (2) a sample of 252 healthy subjects, for functional variation in DRD2, rs1076560. Data on history of cannabis use were collected on all the studied subjects by administering the Cannabis Experience Questionnaire. In the healthy subjects' sample, we also collected data on schizotypy and cognitive performance using the Schizotypal Personality Questionnaire and the N-back working memory task. In the case-control study, we found a significant interaction between the rs1076560 DRD2 genotype and cannabis use in influencing the likelihood of a psychotic disorder. Among cannabis users, carriers of the DRD2, rs1076560, T allele showed a 3-fold increased probability to suffer a psychotic disorder compared with GG carriers (OR = 3.07; 95% confidence interval [CI]: 1.22-7.63). Among daily users, T carrying subjects showed a 5-fold increase in the odds of psychosis compared to GG carriers (OR = 4.82; 95% CI: 1.39-16.71). Among the healthy subjects, T carrying cannabis users had increased schizotypy compared with T carrying cannabis-naïve subjects, GG cannabis users, and GG cannabis-naïve subjects (all P ≤ .025). T carrying cannabis users had reduced working memory accuracy compared with the other groups (all P ≤ .008). Thus, variation of the DRD2, rs1076560, genotype may modulate the psychosis-inducing effect of cannabis use.

Background: The risk of individuals having adverse effects from drug use (eg, alcohol, tobacco) generally depends on the frequency of use and potency of the drug used. The risk of individuals having a psychotic disorder showed a roughly 3 times increase in users of skunk-like/high potency cannabis and over 5 times in daily users of high potency cannabis compared with those who never used cannabis.

Background: While the relationship between cannabis and psychosis is well established, there is a lack of studies into whether cannabis use is associated with a particular pattern of symptoms at psychosis onset. Moreover, there is much evidence that psychotic experiences are common in the healthy population, and again their relationship with exposure to cannabis has been scarcely studied. We hypothesized that psychopathology in first-episode psychosis patients (FEP), and psychotic experiences in controls, would be qualitatively and quantitatively affected by pattern of cannabis use.

Background: A history of childhood adversity is associated with psychotic disorder, with an increase in risk according to number or severity of exposures. However, it is not known why only some exposed individuals go on to develop psychosis. One possibility is preexisting genetic vulnerability. Research on gene–environment interaction in psychosis has primarily focused on candidate genes, although the genetic effects are now known to be polygenic. This pilot study investigated whether the effect of childhood adversity on psychosis is moderated by the polygenic risk score for schizophrenia (PRS).

Background: Prognostic biomarkers for psychosis are still unknown and there is a substantial proportion of patients that fails to respond to antipsychotic medications. Neurocognitive functioning, as an intermediate phenotype of psychosis, might have a prognostic role in identifying subgroups of patients with different pathophysiological profiles accountable for treatment response. This study explored whether neurocognitive performance in first-episode psychosis (FEP) patients can predict clinical response after 12 weeks of treatment with antipsychotics.

Background: The endocannabinoid system (ECS) has been implicated in the pathophysiology of psychosis and epidemiological studies demonstrate an association between exposure to exogenous cannabinoids and acute as well as delayed psychosis outcomes. Family history of psychosis represents a nonmodifiable risk factor for psychosis, while cannabis exposure is a modifiable one. Individuals with a family history of psychosis (FHP) are at a greater risk for a psychotic disorder such as schizophrenia, psychosis associated with cannabis use, and enhanced sensitivity to the acute psychotomimetic effects of THC. In fact, it has been suggested that enhanced sensitivity to cannabis’ psychotomimetic effects may be a marker of familial risk for psychosis. Methods: Data will be presented from ongoing studies systematically examining the ECS in FHP individuals compared to those without a family history of psychosis (FHN) using a multidimensional approach. Cannabinoid 1 receptor (CB1R) availability was measured using the reversible ligand [11C]OMAR and High Resolution Research Tomography PET. The acute response to delta-9-tetrahydrocannabinol (THC) was measured in randomized, placebo-controlled, double-blind, acute pharmacological challenge study designed to examine the effects of intravenous THC on a wide range of subjective, cognitive, and electrophysiological biomarkers of psychosis. FHP and FHN subjects were matched on a number of relevant variables such as age, education, BMI, cannabis use histories, other substance exposure, and so on. Results: Data will be presented demonstrating that compared to FHN, FHP have (A) ↓ CB1R availability ([11C]OMAR VT)), (B) ↑ THC-induced psychotomimetic effects (Positive And Negative Syndrome Scale [PANSS] positive subscale), and (C) ↑ THC-induced cortical noise (Lempel-Ziev complexity scores) compared to FHN. Conclusion: These data are the very first to examine the confluence of the endocannabinoid and exogenous cannabinoid hypotheses in the risk for psychosis. Preliminary data suggest that a family history of psychosis is associated with lower CB1R availability and altered response to THC, a pattern of effects similar to that observed in individuals with a psychotic disorder. Future studies should aim to develop a stratification of the risk of exposure to cannabinoids in individuals with a family history of psychosis and inform public health policies. This is particularly important given that cannabis exposure is the main modifiable risk factor for psychosis.

Summary Background The risk of individuals having adverse effects from drug use (eg, alcohol) generally depends on the frequency of use and potency of the drug used. We aimed to investigate how frequent use of skunk-like (high-potency) cannabis in south London affected the association between cannabis and psychotic disorders. Methods We applied adjusted logistic regression models to data from patients aged 18–65 years presenting to South London and Maudsley NHS Foundation Trust with first-episode psychosis and population controls recruited from the same area of south London (UK) to estimate the effect of the frequency of use, and type of cannabis used on the risk of psychotic disorders. We then calculated the proportion of new cases of psychosis attributable to different types of cannabis use in south London. Findings Between May 1, 2005, and May 31, 2011, we obtained data from 410 patients with first-episode psychosis and 370 population controls. The risk of individuals having a psychotic disorder showed a roughly three-times increase in users of skunk-like cannabis compared with those who never used cannabis (adjusted odds ratio [OR] 2·92, 95% CI 1·52–3·45, p=0·001). Use of skunk-like cannabis every day conferred the highest risk of psychotic disorders compared with no use of cannabis (adjusted OR 5·4, 95% CI 2·81–11·31, p=0·002). The population attributable fraction of first-episode psychosis for skunk use for our geographical area was 24% (95% CI 17–31), possibly because of the high prevalence of use of high-potency cannabis (218 [53%] of 410 patients) in our study. Interpretation The ready availability of high potency cannabis in south London might have resulted in a greater proportion of first onset psychosis cases being attributed to cannabis use than in previous studies. Funding UK National Institute of Health Research (NIHR) Specialist Biomedical Research Centre for Mental Health, SLaM and the Institute of Psychiatry at King's College London, Psychiatry Research Trust, Maudsley Charity Research Fund, and th European Community's Seventh Framework Program grant (agreement No. HEALTH-F2-2009-241909 [Project EU-GEI]).

BACKGROUND: Failure to account for the etiological diversity that typically occurs in psychiatric cohorts may increase the potential for confounding as a proportion of genetic variance will be specific to exposures that have varying distributions in cases. This study investigated whether minimizing the potential for such confounding strengthened the evidence for a genetic candidate currently unsupported at the genome-wide level. METHODS: Two hundred and ninety-one first-episode psychosis cases from South London, UK and 218 unaffected controls were evaluated for a functional polymorphism at the rs1360780 locus in FKBP5. The relationship between FKBP5 and psychosis was modeled using logistic regression. Cannabis use (Cannabis Experiences Questionnaire) and parental separation (Childhood Experience of Care and Abuse Questionnaire) were included as confounders in the analysis. RESULTS: Association at rs1360780 was not detected until the effects of the two environmental factors had been adjusted for in the model (OR = 2.81, 95% CI 1.23-6.43, p = 0.02). A statistical interaction between rs1360780 and parental separation was confirmed by stratified tests (OR = 2.8, p = 0.02 vs. OR = 0.89, p = 0.80). The genetic main effect was directionally consistent with findings in other (stress-related) clinical phenotypes. Moreover, the variation in effect magnitude was explained by the level of power associated with different cannabis constructs used in the model (r = 0.95). CONCLUSION: Our results suggest that the extent to which genetic variants in FKBP5 can influence susceptibility to psychosis may depend on other etiological factors. This finding requires further validation in large independent cohorts. Potentially this work could have translational implications; the ability to discriminate between genetic etiologies based on a case-by-case understanding of previous environmental exposures would confer an important clinical advantage that would benefit the delivery of personalizable treatment strategies.

Objectives Substance abuse is a well established risk factor for First-Episode Psychosis (FEP), but its influence on FEP course is less clear. Starting from our baseline observation that substance users were younger than non-users at the psychosis onset, we hypothesized that substance use at baseline could be an independent risk factor for a worse clinical course. Methods An incidence cohort of patients with FEP collected in an 8 year period (2002–2009) at the Bologna West Community Mental Health Centers (CMHCs) was assessed at baseline and at 12 month follow-up. Drop-out, hospitalizations and service utilization were used as clinical outcomes. Results Most of the patients were still in contact with CMHC at 12 month follow up. Substance users had a significantly higher rate of hospitalizations during the follow-up after adjusting for age, gender and other potential confounders (OR 5.84, 95% CI 2.44–13.97, p ≤ 0.001). Conclusions This study adds to previous evidence showing the independent effect of substance use on FEP course. The identification of a “potentially modifiable” environmental predictor of the course of the illness such as substance use at psychosis onset allows us to envisage the possibility of ameliorating the course of the illness by managing this factor.

European Community Recent years have seen considerable progress in epidemiological and molecular genetic research into environmental and genetic factors in schizophrenia, but methodological uncertainties remain with regard to validating environmental exposures, and the population risk conferred by individual molecular genetic variants is small. There are now also a limited number of studies that have investigated molecular genetic candidate gene-environment interactions (G x E), however, so far, thorough replication of findings is rare and G x E research still faces several conceptual and methodological challenges. in this article, we aim to review these recent developments and illustrate how integrated, large-scale investigations may overcome contemporary challenges in G x E research, drawing on the example of a large, international, multi-center study into the identification and translational application of G x E in schizophrenia. While such investigations are now well underway, new challenges emerge for G x E research from late-breaking evidence that genetic variation and environmental exposures are, to a significant degree, shared across a range of psychiatric disorders, with potential overlap in phenotype. 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Psychiat, New Haven, CT USA Middle E Tech Univ, Dept Psychol, TR-06531 Ankara, Turkey Diskapi YB Res & Training Hosp, Ankara, Turkey Turkish Federat Schizophrenia Assoc, Ankara, Turkey Ataturk Training & Res Hosp, Psychiat Clin, Ankara, Turkey Manisa Mental Hlth Hosp, Manisa, Turkey Istanbul Univ, Expt Med Res Inst, Dept Adv Neurol Sci, Istanbul Fac Med, Istanbul, Turkey Univ Complutense, IiSGM CIBERSAM, Dept Child & Adolescent Psychiat, Hosp Gen Univ Gregorio Maranon,Sch Med, E-28040 Madrid, Spain Univ Barcelona, Dept Psychiat, Hosp Clin, IDIBAPS,Ctr Invest Biomed Red Salud Mental CIBERS, Barcelona, Spain Univ Valencia, Sch Med, Dept Psychiat, Ctr Invest Biomed Red Salud Mental CIBERSAM, Valencia, Spain Univ Oviedo, Sch Med, Dept Med,Psychiat Area, Ctr Invest Biomed Red Salud Mental CIBERSAM, Oviedo, Spain Univ Santiago de Compostela, Dept Mental Hlth & Drug Addit Assistance, Hlth Serv Galicia,Psychiat Genet Grp IDIS, Hosp Clin,Ctr Invest Biomedica Red Salud Mental C, Santiago de Compostela 15706, Spain Hosp Virgen de la Luz, Serv Psiquiat, Dept Psychiat, Cuenca, Spain Hosp Univ Infanta Leonor Hosp Virgen Torre, Villa de Vallecas Mental Hlth Ctr, Villa de Vallecas Mental Hlth Dept, Madrid, Spain Hosp Univ Infanta Leonor Hosp Virgen Torre, Puente de Vallecas Mental Hlth Dept, Ctr Salud Mental Puente Vallecas, Madrid, Spain Hosp Clin Univ, Fdn Publ Galega Med Xenomica, Santiago de Compostela, Spain Univ Complutense, Sch Med, Hosp Gen Univ Gregorio Maranon, Dept Psychiat, E-28040 Madrid, Spain Hosp Psiquiatr Conxo, Santiago de Compostela, Spain Univ Amsterdam, Acad Med Ctr, Early Psychosis Sect, Dept Psychiat, NL-1105 AZ Amsterdam, Netherlands Vrije Univ Amsterdam, Dept Clin Psychol, Amsterdam, Netherlands EMGO Inst Hlth & Care Res, Amsterdam, Netherlands Parnassia Psychiat Inst, Dept Psychosis Res, the Hague, Netherlands Rivierduinen Psychiat Inst, Leiden, Netherlands Grp Hosp Mondor, AP HP, Creteil, France Hop Henri Mondor, INSERM, U955, Equipe 15, F-94010 Creteil, France Univ Paris Est, Fac Med, Creteil, France Fdn Fondamental, Creteil, France CMP B CHU, F-63003 Clermont Ferrand 1, France Univ Auvergne, EA 7280, Clermont Ferrand, France EPS Maison Blanche, Paris, France UPC KU Leuven, Dept Neurosci, UPC, Kortenberg, Belgium UPC, Dept Neurosci, Res Grp Psychiat, Leuven, Belgium Katholieke Univ Leuven, Univ Hosp Gasthuisberg, Dept Human Genet, Leuven, Belgium Assoc Sci Res Multiple Births, Ghent, Belgium Univ Ghent, Dept Neurol, Ghent Univ Hosp, B-9000 Ghent, Belgium Univ Athens, Sch Med, Eginit Hosp, Athens 11528, Greece Med Univ Vienna, Dept Psychiat & Psychotherapy, Vienna, Austria Psychiat Univ Clin Basel, Ctr Gender Res & Early Detect, Basel, Switzerland Psychiat Univ Clin Basel, Diagnost & Crisis Intervent Ctr, Basel, Switzerland Univ Cologne, Dept Psychiat & Psychotherapy, D-50931 Cologne, Germany Univ Hong Kong, Li Ka Shing Fac Med, Ctr Genom Sci, State Key Lab Brain & Cognit Sci, Hong Kong, Hong Kong, Peoples R China Univ Hong Kong, Li Ka Shing Fac Med, Dept Psychiat, Hong Kong, Hong Kong, Peoples R China Univ Hong Kong, Queen Mary Hosp, Li Ka Shing Fac Med, State Key Lab Brain & Cognit Sci, Hong Kong, Hong Kong, Peoples R China Univ Hong Kong, Queen Mary Hosp, Li Ka Shing Fac Med, Dept Psychiat, Hong Kong, Hong Kong, Peoples R China Univ Basque Country, Univ Deusto, Interuniv Chair Law & Human Genome Prov Govt Bisk, Bilbao, Bizkaia, Spain Univ Zaragoza, Zaragoza, Spain Univ Cambridge, Dept Psychiat, Cambridge, England UCL, Div Psychiat, London, England Royal Coll Surgeons Ireland, Beaumont Hosp, Educ & Res Ctr, Dept Psychiat, Dublin 9, Ireland Univ Munich, Dept Psychiat, Div Mol & Clin Neurobiol, Munich, Germany Univ Bologna, Alma Mater Studiorium, Psychiat Unit, Dept Med & Surg Sci, Bologna, Italy Univ Bologna, Alma Mater Studiorium, Genet Unit, Dept Med & Surg Sci, Bologna, Italy Local Hlth Trust, Dept Mental Hlth & Pathol Addict, Bologna, Italy Univ Palermo, Sect Psychiat, Dept Expt Biomed & Clin Neurosci, Palermo, Italy P Giaccone Gen Hosp, Unit Psychiat, Palermo, Italy Univ Melbourne, Ctr Youth Mental Hlth, Parkville, Vic 3052, Australia Univ Melbourne, Melbourne Neuropsychiat Ctr, Carlton, Vic, Australia Univ São Paulo, Fac Med, Dept Med Prevent, BR-01246903 São Paulo, Brazil Univ São Paulo, Nucleo Pesquina Saude Mental Populac, São Paulo, Brazil Univ São Paulo, Fac Med Ribeirao Preto, Dept Neurociencias & Ciencias Comportamento, BR-14049 Ribeirao Preto, Brazil Univ Verona, Sect Psychiat, Dept Publ Hlth & Community Med, I-37100 Verona, Italy Copenhagen Univ Hosp, Res Unit, Mental Hlth Ctr Copenhagen, Copenhagen, Denmark Univ Paris 05, Fac Med, Serv Hosp Univ, Hop St Anne, Paris, France Univ Autonoma Barcelona, Dept Psicol Clin & Salut, E-08193 Barcelona, Spain St Pere Claver Fundacio Sanitaria, Dept Salut Mental, Barcelona, Spain Univ N Carolina, Dept Psychol, Greensboro, NC 27412 USA CIBERSAM, Spanish Mental Hlth Res Network, Barcelona, Spain Universidade Federal de São Paulo, Dept Psychiat, PRISMA Early Intervent Program, São Paulo, Brazil Univ Belgrade, Sch Med, Beograd, Serbia Universidade Federal de São Paulo, Dept Psychiat, PRISMA Early Intervent Program, São Paulo, Brazil European Community: HEALTH-F2-2009-241909 Web of Science

UNLABELLED: Cannabis use is associated with an earlier age of onset of psychosis (AOP). However, the reasons for this remain debated. METHODS: We applied a Cox proportional hazards model to 410 first-episode psychosis patients to investigate the association between gender, patterns of cannabis use, and AOP. RESULTS: Patients with a history of cannabis use presented with their first episode of psychosis at a younger age (mean years = 28.2, SD = 8.0; median years = 27.1) than those who never used cannabis (mean years = 31.4, SD = 9.9; median years = 30.0; hazard ratio [HR] = 1.42; 95% CI: 1.16-1.74; P < .001). This association remained significant after controlling for gender (HR = 1.39; 95% CI: 1.11-1.68; P < .001). Those who had started cannabis at age 15 or younger had an earlier onset of psychosis (mean years = 27.0, SD = 6.2; median years = 26.9) than those who had started after 15 years (mean years = 29.1, SD = 8.5; median years = 27.8; HR = 1.40; 95% CI: 1.06-1.84; P = .050). Importantly, subjects who had been using high-potency cannabis (skunk-type) every day had the earliest onset (mean years = 25.2, SD = 6.3; median years = 24.6) compared to never users among all the groups tested (HR = 1.99; 95% CI: 1.50- 2.65; P < .0001); these daily users of high-potency cannabis had an onset an average of 6 years earlier than that of non-cannabis users. CONCLUSIONS: Daily use, especially of high-potency cannabis, drives the earlier onset of psychosis in cannabis users.

In recent years, research into gene x environment (GXE) interactions has provided a better understanding of a number of complex diseases including cancer and diabetes. Furthermore, it has opened up the possibility of screening programmes to promote primary prevention and public education campaigns. Recently, psychiatric researchers have also begun to investigate GXE interactions. This review describes the literature on GXE interactions in psychiatry and its potential contribution to future understanding of mental disorders.

Context Cross-sectional studies of the signs and symptoms of psychosis yield dimensional phenotypes. However, the validity and clinical utility of such dimensions remain debated. This study investigated the structure of psychotic symptomatology, the stability of the structure over time, and the concordance between symptom dimensions and categorical diagnoses. Methods Sample consisted of 500 first-episode psychotic patients. A cross-sectional study (N = 500) investigated the organizational structure of symptom dimensions at the onset of psychosis and its concordance with categorical diagnoses; next, a nested longitudinal study (N = 100) examined the stability of the symptom dimensions structure after 5-10 years of follow-up. Results Factor analyses identified 6 first-order factors (mania, negative, disorganization, depression, hallucinations, and delusions) and 2 high-order factors (affective and nonaffective psychoses). Cumulative variance accounted for by the first and high-order factors was 63%: 31% by the first-order factors and 32% by the high-order factors. The factorial structure of psychotic symptoms during first episode remained stable after 5-10 years of follow-up. The overall concordance between 4 categorical diagnostic groups (schizophrenia, mania with psychosis, psychotic depression and schizoaffective disorder) and dimensional symptom ranged from 62.2% to 73.1% (when the schizoaffective group was excluded). Conclusions Symptoms of psychosis assume a multidimensional hierarchical structure. This hierarchical model was stable over time and showed good concordance with categorical diagnoses. The combined use of dimensional and categorical approach to psychotic disorders would be of clinical and research utility.

Background: A number of studies have reported that patients with psychosis who use cannabis have better cognitive performance than those who do not. This is surprising as cannabis can impair cognition in healthy subjects. An obvious question is whether the better current performance of psychotic patients who have used cannabis is a reflection of their having a higher premorbid IQ than those psychotic patients who haven't used cannabis. Aim: In a sample of patients at their first episode of psychosis, we tested the hypothesis that patients who smoked cannabis would have a higher premorbid IQ than patients who did not. Methodology: 279 participants (119 patients and 160 healthy controls) were assessed in order to obtain current and premorbid IQ measures and detailed information on cannabis use. We examined the association between cannabis use and both premorbid and current IQ in patients and controls. Results: Patients who had ever smoked cannabis had significantly higher current (p < .001) and premorbid IQ (p = .004) compared to patients who had never used cannabis. This difference was not found among controls. Conclusions: These findings suggest that the better cognitive performance of patients with their first episode of psychosis who have used cannabis compared with those who haven't is due to the better premorbid IQ of the former.

Lack of insight is a cardinal feature of psychosis with crucial implications for outcome. Concerns have been raised regarding a link between insight and suicidality. This study aimed to test the relationship between suicidal behaviour preceding first-episode psychosis (FEP) and insight dimensions at treatment onset.A total of 112 FEP inpatients were recruited. Suicidal events prior to admission were recorded. Insight was assessed multidimensionally with the Schedule for the Assessment of Insight - Expanded version shortly after admission. Suicidal and non-suicidal patients were compared regarding scores on 'total insight' and three insight domains: 'awareness of mental illness', 'relabeling of psychotic experiences as abnormal' and 'compliance'. This analysis was also adjusted for a set of sociodemographic, clinical, neurocognitive and psychopathological variables.Bivariate analyses demonstrated a direct association between previous suicidality and all insight domains. However, these associations did not survive multivariable regression models, which demonstrated gender (female), shorter duration of untreated psychosis (DUP) and psychopathological symptoms - depression and disorganization - to mediate the influence of suicidal history on insight, and therefore to underlie the latter.Insight dimensions in FEP patients are influenced by having suicidal antecedents through some mediating variables such as gender, DUP and depression. Further prospective studies are needed to clarify the potential implications of these findings on the management of insight in FEP. As suicidal history is associated with greater levels of both depression and insight at first presentation, these three variables might be useful in predicting further suicidal events.

Background Cannabis use is associated with an increased risk of psychosis. One study has suggested that genetic variation in the AKT1 gene might influence this effect. Methods In a case-control study of 489 first-episode psychosis patients and 278 control subjects, we investigated the interaction between variation at the AKT1 rs2494732 single nucleotide polymorphism and cannabis use in increasing the risk of psychosis. Results The rs2494732 locus was not associated with an increased risk of a psychotic disorder, with lifetime cannabis use, or with frequency of use. We did, however, find that the effect of lifetime cannabis use on risk of psychosis was significantly influenced by the rs2494732 locus (likelihood ratio statistic for the interaction=8.54; p = .014). Carriers of the C/C genotype with a history of cannabis use showed a greater than twofold increased likelihood of a psychotic disorder (odds ratio=2.18 [95% confidence interval: 1.12, 4.31]) when compared with users who were T/T carriers. Moreover, the interaction between the rs2494732 genotype and frequency of use was also significant at the 5% level (likelihood ratio=13.39; p = .010). Among daily users, C/C carriers demonstrated a sevenfold increase in the odds of psychosis compared with T/T carriers (odds ratio=7.23 [95% confidence interval: 1.37, 38.12]). Conclusions Our findings provide strong support for the initial report that genetic variation at rs2494732 of AKT1 influences the risk of developing a psychotic disorder in cannabis users.

Highlight ► First-episode psychosis is characterised by a pro-inflammatory state supported partly by activation of leukocytes. Stress contributes to this pro-inflammatory state., An inflammatory syndrome has been previously reported in chronic schizophrenia. The aims of this study were to investigate: (1) serum levels and leukocyte gene expression of cytokines in patients with first-episode psychosis and controls; and (2) possible causes of abnormal cytokine levels in first-episode psychosis, testing their association with psychosocial stressors, current nicotine and cannabis use, and duration of antipsychotic treatment. We recruited 24 first-episode psychosis patients and 24 healthy controls matched for age, gender, ethnicity and body mass index. Serum interleukin(IL)-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, Tumour Necrosis Factor- α (TNF-α), Interferon- γ (IFN-γ), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), and monocyte chemotactic protein-1 (MCP-1) were analysed in all subjects. Leukocyte gene expression analyses were conducted only for those cytokines that were different between-groups in the serum analyses. Patients had significantly higher serum levels of IL-1α (effect size d = 0.6, p = 0.03), IL-1β (d = 0.4, p = 0.01), IL-8 (d = 0.6, p = 0.01) and TNF-α (d = 0.7, p = 0.05) and a trend for higher IL-6 serum levels (d = 0.3, p = 0.09) when compared with controls. Leukocyte m-RNA levels of IL-1α (d = 0.6, p = 0.04), IL-6 (d = 0.7, p = 0.01) and TNF-α (d = 1.6, p