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The EU-GEI Project was funded by grant agreement Health-F2-2010-241909 from the European Community’s Seventh Framework program. The Brazilian study was funded by grant 2012-0417-0 from the São Paulo Research Foundation, D'Andrea, Giuseppe; Lal, Jatin; Tosato, Sarah;Gayer-Anderson, Charlotte;Jongsma, Hannah E.;Stilo, Simona A.; van der Ven, Els;Quattrone, Diego;Velthorst, Eva;Berardi, Domenico;Rossi Menezes, Paulo; Arango, Celso; Parellada, Mara; Lasalvia, Antonio; La Cascia, Caterina; Ferraro, Laura; La Barbera, Daniele; Sideli, Lucia; Bobes, Julio; Bernardo, Miguel; Sanjuan, Julio; Santos, Jose Luis; Arrojo, Manuel; Marta Del-Ben, Cristina; Tripoli, Giada; Llorca, Pierre-Michel; de Haan, Lieuwe; Selten, Jean-Paul; Tortelli, Andrea; Szoke, Andrei; Muratori, Roberto; Rutten, Bart P.; van Os, Jim; Jones, Peter B.; Kirkbride, James B.; Murray, Robin M.; di Forti, Marta; Tarricone, Ilaria; Morgan, Craig

AbtractStudies conducted in psychotic disorders have shown that DNA-methylation (DNAm) is sensitive to the impact of Childhood Adversity (CA). However, whether it mediates the association between CA and psychosis is yet to be explored. Epigenome wide association studies (EWAS) using the Illumina Infinium-Methylation EPIC array in peripheral blood tissue from 366 First-episode of psychosis and 517 healthy controls was performed. Adversity scores were created for abuse, neglect and composite adversity with the Childhood Trauma Questionnaire (CTQ). Regressions examining (I) CTQ scores with psychosis; (II) with DNAm EWAS level and (III) between DNAm and caseness, adjusted for a variety of confounders were conducted. Divide-Aggregate Composite-null Test for the composite null-hypothesis of no mediation effect was conducted. Enrichment analyses were conducted with missMethyl package and the KEGG database. Our results show that CA was associated with psychosis (Composite: OR = 1.68; p = p < 0.001; neglect: OR = 2.27; p =

Schizophrenia (SZ), Bipolar Disorder (BD) and Depression (D) run in families. This susceptibility is partly due to hundreds or thousands of common genetic variants, each conferring a fractional risk. The cumulative effects of the associated variants can be summarised as a polygenic risk score (PRS). Using data from the EUGEI case-control study, we aimed to test whether PRSs for three major psychiatric disorders (SZ, BD, D) and for intelligent quotient (IQ) as a neurodevelopmental proxy, can discriminate affective psychosis (AP) from schizophrenia-spectrum disorder (SSD). Participants (573 cases, 1005 controls) of european ancestry from 17 sites as part of the EUGEI study were successfully genotyped following standard quality control procedures. Using standardised PRS for SZ, BD, D, and IQ built from the latest available summary statistics, we performed simple or multinomial logistic regression models adjusted for 10 principal components for the different clinical comparisons. In case-control comparisons PRS-SZ, PRS-BD and PRS-D distributed differentially across psychotic subcategories. In case-case comparison, both PRS-SZ (OR=0.7, 95 %CI 0.53-0.92) and PRS-D (OR=1.29, 95%CI 1.05-1.6) differentiated global AP from SSD; and within AP categories, only PRS-SZ differentiated BD from psychotic depression (OR=2.38, 95%CI 1.32-4.29). Combining PRS for severe psychiatric disorders in prediction models for psychosis phenotypes can increase discriminative ability and improve our understanding of these phenotypes. Our results point towards potential usefulness of PRSs for diagnostic prediction in specific populations such as high-risk or early psychosis phases.

The European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) Project was funded by grant agreement Health-F2-2010-241909 (Project EU-GEI) from the European Community’s Seventh Framework programme., Tarricone, I., D'Andrea, G., Jongsma, H.E., Tosato, S., Gayer-Anderson, C., Stilo, S.A., Suprani, F., Iyegbe, C., Van Der Ven, E., Quattrone, D., Di Forti, M., Velthorst, E., Rossi Menezes, P., Arango, C., Parellada, M., Lasalvia, A., La Cascia, C., Ferraro, L., Bobes, J., Bernardo, M., Sanjuán, I., Santos, J.L., Arrojo, M., Del-Ben, C.M., Tripoli, G., Llorca, P.-M., De Haan, L., Selten, J.-P., Tortelli, A., Szöke, A., Muratori, R., Rutten, B.P., Van Os, J., Jones, P.B., Kirkbride, J.B., Berardi, D., Murray, R.M., Morgan, C.

There has been much recent debate concerning the relative clinical utility of symptom dimensions versus conventional diagnostic categories in patients with psychosis. We investigated whether symptom dimensions rated at presentation for first-episode psychosis (FEP) better predicted time to first remission than categorical diagnosis over a four-year follow-up. The sample comprised 193 FEP patients aged 18-65. years who presented to psychiatric services in South London, UK, between 2006 and 2010. Psychopathology was assessed at baseline with the Positive and Negative Syndrome Scale and five symptom dimensions were derived using Wallwork/Fortgang's model; baseline diagnoses were grouped using DSM-IV codes. Time to start of first remission was ascertained from clinical records. The Bayesian Information Criterion (BIC) was used to find the best fitting accelerated failure time model of dimensions, diagnoses and time to first remission. Sixty percent of patients remitted over the four years following first presentation to psychiatric services, and the average time to start of first remission was 18.3. weeks (SD = 26.0, median = 8). The positive (BIC = 166.26), excited (BIC = 167.30) and disorganised/concrete (BIC = 168.77) symptom dimensions, and a diagnosis of schizophrenia (BIC = 166.91) predicted time to first remission. However, a combination of the DSM-IV diagnosis of schizophrenia with all five symptom dimensions led to the best fitting model (BIC = 164.35). Combining categorical diagnosis with symptom dimension scores in FEP patients improved the accuracy of predicting time to first remission. Thus our data suggest that the decision to consign symptom dimensions to an annexe in DSM-5 should be reconsidered at the earliest opportunity.

The GAP multidisciplinary study carried out in South London, recruited 410 first episode of psychosis patients and 370 controls; the aim was to elucidate the multiple genetic and environmental factors influencing the onset and outcome of psychosis. The study demonstrated the risk increasing effect of adversity in childhood (especially parental loss, abuse, and bullying) on onset of psychosis especially positive symptoms. Adverse life events more proximal to onset, being from an ethnic minority, and cannabis use also played important roles; indeed, one quarter of new cases of psychosis could be attributed to use of high potency cannabis. The “jumping to conclusions” bias appeared to mediate the effect of lower IQ on vulnerability to psychosis. We confirmed that environmental factors operate on the background of polygenic risk, and that genetic and environment act together to push individuals over the threshold for manifesting the clinical disorder. The study demonstrated how biological pathways involved in the stress response (HPA axis and immune system) provide important mechanisms linking social risk factors to the development of psychotic symptoms. Further evidence implicating an immune/inflammatory component to psychosis came from our finding of complement dysregulation in FEP. Patients also showed an upregulation of the antimicrobial alpha-defensins, as well as differences in expression patterns of genes involved in NF-κB signaling and Cytokine Production. Being of African origin not only increased risk of onset but also of a more difficult course of illness. The malign effect of childhood adversity predicted a poorer outcome as did continued use of high potency cannabis.

Purpose of Review We review recent developments on risk factors in schizophrenia. Recent Findings The way we think about schizophrenia today is profoundly different from the way this illness was seen in the twentieth century. We now know that the etiology of schizophrenia is multifactorial and reflects an interaction between genetic vulnerability and environmental contributors. Environmental risk factors such as pregnancy and birth complications, childhood trauma, migration, social isolation, urbanicity, and substance abuse, alone and in combination, acting at a number of levels over time, influence the individual’s likelihood to develop the disorder. Summary Environmental risk factors together with the identification of a polygenic risk score for schizophrenia, research on gene–environment interaction and environment–environment interaction have hugely increased our knowledge of the disorder.

Importance: Psychotic disorders contribute significantly to the global disease burden, yet the latest international incidence study of psychotic disorders was conducted in the 1980s. Objectives: To estimate the incidence of psychotic disorders using comparable methods across 17 catchment areas in 6 countries and to examine the variance between catchment areas by putative environmental risk factors. Design, Setting, and Participants: An international multisite incidence study (the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions) was conducted from May 1, 2010, to April 1, 2015, among 2774 individuals from England (2 catchment areas), France (3 catchment areas), Italy (3 catchment areas), the Netherlands (2 catchment areas), Spain (6 catchment areas), and Brazil (1 catchment area) with a first episode of nonorganic psychotic disorders (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10] codes F20-F33) confirmed by the Operational Criteria Checklist. Denominator populations were estimated using official national statistics. Exposures: Age, sex, and racial/ethnic minority status were treated as a priori confounders. Latitude, population density, percentage unemployment, owner-occupied housing, and single-person households were treated as catchment area-level exposures. Main Outcomes and Measures: Incidence of nonorganic psychotic disorders (ICD-10 codes F20-F33), nonaffective psychoses (ICD-10 codes F20-F29), and affective psychoses (ICD-10 codes F30-F33) confirmed by the Operational Criteria Checklist. Results: A total of 2774 patients (1196 women and 1578 men; median age, 30.5 years [interquartile range, 23.0-41.0 years]) with incident cases of psychotic disorders were identified during 12.9 million person-years at risk (crude incidence, 21.4 per 100 000 person-years; 95% CI, 19.4-23.4 per 100 000 person-years). A total of 2183 patients (78.7%) had nonaffective psychotic disorders. After direct standardization for age, sex, and racial/ethnic minority status, an 8-fold variation was seen in the incidence of all psychotic disorders, from 6.0 (95% CI, 3.5-8.6) per 100 000 person-years in Santiago, Spain, to 46.1 (95% CI, 37.3-55.0) per 100 000 person-years in Paris, France. Rates were elevated in racial/ethnic minority groups (incidence rate ratio, 1.6; 95% CI, 1.5-1.7), were highest for men 18 to 24 years of age, and were lower in catchment areas with more owner-occupied homes (incidence rate ratio, 0.8; 95% CI, 0.7-0.8). Similar patterns were observed for nonaffective psychoses; a lower incidence of affective psychoses was associated with higher area-level unemployment (incidence rate ratio, 0.3; 95% CI, 0.2-0.5). Conclusions and Relevance: This study confirmed marked heterogeneity in risk for psychotic disorders by person and place, including higher rates in younger men, racial/ethnic minorities, and areas characterized by a lower percentage of owner-occupied houses., The European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) Project is funded by grant agreement HEALTH-F2-2010-241909 (Project EU-GEI) from the European Community’s Seventh Framework Programme. The Brazilian study was funded by grant 2012/0417-0 from the São Paulo Research Foundation. Dr Kirkbride is funded by the Wellcome Trust and grant 101272/Z/13/Z from the Royal Society. Ms Jongsma and Dr Jones are funded by the National Institute of Health Research Collaboration of Leadership in Applied Health Research and Care East of England.

BackgroundJumping to conclusions (JTC), which is the proneness to require less information before forming beliefs or making a decision, has been related to formation and maintenance of delusions. Using data from the National Institute of Health Research Biomedical Research Centre Genetics and Psychosis (GAP) case–control study of first-episode psychosis (FEP), we set out to test whether the presence of JTC would predict poor clinical outcome at 4 years.MethodsOne-hundred and twenty-three FEP patients were assessed with the Positive and Negative Syndrome Scale (PANSS), Global Assessment of Functioning (GAF) and the probabilistic reasoning ‘Beads’ Task at the time of recruitment. The sample was split into two groups based on the presence of JTC bias. Follow-up data over an average of 4 years were obtained concerning clinical course and outcomes (remission, intervention of police, use of involuntary treatment – the Mental Health Act (MHA) – and inpatient days).ResultsFEP who presented JTC at baseline were more likely during the follow-up period to be detained under the MHA [adjusted OR 15.62, 95% confidence interval (CI) 2.92–83.54,p= 0.001], require intervention by the police (adjusted OR 14.95, 95% CI 2.68–83.34,p= 0.002) and have longer admissions (adjusted IRR = 5.03, 95% CI 1.91–13.24,p= 0.001). These associations were not accounted for by socio-demographic variables, IQ and symptom dimensions.ConclusionsJTC in FEP is associated with poorer outcome as indicated and defined by more compulsion police intervention and longer periods of admission. 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 programmes.

Little is known about the impact of different forms of childhood adversity on outcomes in first-episode psychosis (FEP) patients beyond the first year of treatment. We investigated associations between different types of childhood adversity and outcomes of FEP patients over the 5 years following their first contact with mental health services for psychosis. 237 FEP cases aged 18-65 years were followed on average for 5 years after first presentation to psychiatric services in South London, UK. Childhood adversity prior to 17 years of age was assessed at baseline using the Childhood Experience of Care and Abuse Questionnaire (CECA.Q). The results showed that exposure to at least one type of childhood adversity was significantly associated with a lower likelihood of achieving symptomatic remission, longer inpatient stays, and compulsory admission over the 5-year follow-up. There was no evidence though of a dose-response effect. Some specificity was evident. Childhood parental separation was associated with significantly greater likelihood of non-compliance with antipsychotic medications, compulsory admission, and substance dependence. Institutional care was significantly associated with longer total length of inpatient stays; and parental death was significantly associated with compulsory admissions. Clinicians should screen FEP patients for childhood adversity and tailor interventions accordingly to improve outcomes.

BackgroundRisk prediction algorithms have long been used in health research and practice (e.g. prediction of cardiovascular disease and diabetes). However, similar tools have not been developed for mental health. For example, for psychotic disorders, attempts to sum environmental risk are rare, unsystematic and dictated by available data. In light of this, we sought to develop a valid, easy to use measure of the aggregate environmental risk score (ERS) for psychotic disorders.MethodsWe reviewed the literature to identify well-replicated and validated environmental risk factors for psychosis that combine a significant effect and large-enough prevalence. Pooled estimates of relative risks were taken from the largest available meta-analyses. We devised a method of scoring the level of exposure to each risk factor to estimate ERS. Relative risks were rounded as, due to the heterogeneity of the original studies, risk effects are imprecisely measured.ResultsSix risk factors (ethnic minority status, urbanicity, high paternal age, obstetric complications, cannabis use and childhood adversity) were used to generate the ERS. A distribution for different levels of risk based on simulated data showed that most of the population would be at low/moderate risk with a small minority at increased environmental risk for psychosis.ConclusionsThis is the first systematic approach to develop an aggregate measure of environmental risk for psychoses in asymptomatic individuals. This can be used as a continuous measure of liability to disease; mostly relevant to areas where the original studies took place. Its predictive ability will improve with the collection of additional, population-specific data.

Aim Several studies have suggested that lifetime cannabis consumption and childhood abuse synergistically contribute to the risk for psychotic disorders. This study aimed to extend existing findings regarding an additive interaction between childhood abuse and lifetime cannabis use by investigating the moderating role of type and frequency of cannabis use. Methods Up to 231 individuals presenting for the first time to mental health services with psychotic disorders and 214 unaffected population controls from South London, United Kingdom, were recruited as part of the Genetics and Psychosis study. Information about history of cannabis use was collected using the Cannabis Experiences Questionnaire. Childhood physical and sexual abuse was assessed using the Childhood Experience of Care and Abuse Questionnaire. Results Neither lifetime cannabis use nor reported exposure to childhood abuse was associated with psychotic disorder when the other environmental variable was taken into account. Although the combination of the two risk factors raised the odds for psychosis by nearly three times (adjusted OR = 2.94, 95% CI: 1.44–6.02, P = 0.003), no evidence of interaction was found (adjusted OR = 1.46, 95% CI: −0.54 to 3.46, P = 0.152). Furthermore, the association of high-potency cannabis and daily consumption with psychosis was at least partially independent of the effect of childhood abuse. Conclusions The heavy use of high-potency cannabis increases the risk of psychosis but, in addition, smoking of traditional resin (hash) and less than daily cannabis use may increase the risk for psychosis when combined with exposure to severe childhood abuse.

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.

Evidence indicates that migrant and ethnic minority groups have an elevated risk of psychosis in a number of countries. Social disadvantage is one of the hypotheses put forward to explain these findings. The aim of this study is to investigate main effects, association and synergism between social disadvantage and migration on odds of psychotic experiences. We collected information on social disadvantage and migration from 332 patients and from 301 controls recruited from the local population in South London. Two indicators of social disadvantage in childhood and six indicators of social disadvantage in adulthood were analyzed. We found evidence that the odds of reporting psychotic experience were higher in those who experienced social disadvantage in childhood (OR= 2.88, 95% CI 2.03-4.06), social disadvantage in adulthood (OR= 9.06, 95% CI 5.21–15.74) and migration (OR = 1.46, 95% CI 1.05–2.02). When both social disadvantage and migration were considered together, the association with psychosis was slightly higher for social disadvantage in childhood and migration (OR 3.46, 95% CI 2.12–5.62) and social disadvantage in adulthood and migration (OR 9.10, 95% CI 4.63-17.86). Migrant cases were not more likely than non-migrant cases to report social disadvantage (p = 0.71) and no evidence of an additive interaction between migration and social disadvantage was found (ICR 0.32 95% CI -4.04–4.69). Preliminary results support the hypothesis that the association between social disadvantage and psychosis is independent of migration status.Disclosure of interestThe authors have not supplied their declaration of competing interest.

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 Early cannabis use has consistently been associated with an increased risk for the later development of psychosis. Studies suggest that Conduct Disorder (CD) is more common amongst young people who later go on to develop psychosis. CD has been associated with greater and earlier cannabis use in general population samples. Based on this evidence, we hypothesised that among patients experiencing their first episode of psychosis, the presence of CD symptoms prior to age 15 would be associated with cannabis use. Method 102 patients experiencing a first episode of psychosis were interviewed to assess CD symptoms prior to age 15 and use of cannabis and other substances. Results The number of CD symptoms was significantly associated with lifetime cannabis use (odds ratio = 5.41 (1.76–16.57), p = 0.03) and with first use of cannabis before age 14 (odds ratio = 1.46 (1.12–1.92), p = 0.006), after controlling for stimulant/hallucinogen use and level of education. Conclusions Among patients experiencing a first episode of psychosis, CD symptoms were significantly associated with use of cannabis and with use by age 14. Among individuals vulnerable for psychosis, CD symptoms may independently increase the likelihood of cannabis use which in turn increases the risk of psychosis.

Major advances have been made in our understanding of the epidemiology of schizophrenia. We now know that the disorder is more common and severe in young men, and that the incidence varies geographically and temporally. Risk factors have been elucidated; biological risks include a family history of the disorder, advanced paternal age, obstetric complications, and abuse of drugs such as stimulants and cannabis. In addition, recent research has also identified social risk factors such as being born and brought up in a city, migration, and certain types of childhood adversity such as physical abuse and bullying, as well as social isolation and adverse events in adult life. Current research is focussing on the significance of minor psychotic symptoms in the general population, gene-environmental interaction, and how risk factors impact on pathogenesis; perhaps all risk factors ultimately impact on striatal dopamine as the final common pathway.

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 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.

BackgroundMany studies have reported that cannabis use increases the risk of a first episode of psychosis (FEP). However, only a few studies have investigated the nature of cannabis-related experiences in FEP patients, and none has examined whether these experiences are similar in FEP and general populations. The aim of this study was to explore differences in self-reported cannabis experiences between FEP and non-psychotic populations.MethodA total of 252 subjects, who met International Classification of Diseases (ICD)-10 criteria for FEP, and 217 controls who reported cannabis use were selected from the Genetics and Psychosis (GAP) study. The Medical Research Council Social Schedule and the Cannabis Experience Questionnaire were used to collect sociodemographic data and cannabis use information, respectively.ResultsBoth ‘bad’ and ‘enjoyable’ experiences were more commonly reported by FEP subjects than controls. Principal components factor analysis identified four components which explained 62.3% of the variance. Linear regression analysis on the whole sample showed that the type of cannabis used and beliefs about the effect of cannabis on health all contributed to determining the intensity and frequency of experiences. Linear regression analysis on FEP subjects showed that the duration of cannabis use and amount of money spent on cannabis were strongly related to the intensity and frequency of enjoyable experiences in this population.ConclusionsThese results suggest a higher sensitivity to cannabis effects among people who have suffered their first psychotic episode; this hypersensitivity results in them reporting both more ‘bad’ and ‘enjoyable’ experiences. The greater enjoyment experienced may provide an explanation of why FEP patients are more likely to use cannabis and to continue to use it despite experiencing an exacerbation of their psychotic symptoms.

BackgroundThe relationship between childhood adversity (CA) and psychotic disorder is well documented. As the adequacy of the current categorical diagnosis of psychosis is being increasingly questioned, we explored independent associations between different types of CA and specific psychotic symptom dimensions in a well-characterized sample of first-episode psychosis (FEP) patients.MethodThis study involved 236 FEP cases aged 18–65 years who presented for the first time to psychiatric services in South London, UK. Psychopathology was assessed with the Positive and Negative Syndrome Scale and confirmatory factor analysis was used to evaluate the statistical fit of the Wallwork/Fortgang five-factor model of psychosis. CA prior to 17 years of age (physical abuse, sexual abuse, parental separation, parental death, and being taken into care) was retrospectively assessed using the Childhood Experience of Care and Abuse Questionnaire.ResultsChildhood sexual abuse [β= 0.96, 95% confidence interval (CI) 0.40–1.52], childhood physical abuse (β= 0.48, 95% CI 0.03–0.93) and parental separation (β= 0.60, 95% CI 0.10–1.11) showed significant associations with the positive dimension; while being taken into care was associated with the excited dimension (β= 0.36, 95% CI 0.08–0.65), independent of the other types of CA. No significant associations were found between parental death and any of the symptom dimensions.ConclusionsA degree of specificity was found in the relationships between different types of CA and psychosis symptom dimensions in adulthood, suggesting that distinct pathways may be involved in the CA–psychosis association. These potentially different routes to developing psychosis merit further empirical and theoretical exploration.

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.

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. Maastricht Univ, Med Ctr, Dept Psychiat & Neuropsychol, Sch Mental Hlth & Neurosci,South Limburg Mental H, NL-6200 MD Maastricht, Netherlands Kings Coll London, Inst Psychiat, Dept Psychosis Studies, London WC2R 2LS, England Mondriaan Mental Hlth Trust, Maastricht, Heerlen, Netherlands Univ Groningen, Univ Med Ctr Groningen, Rob Giel Clin Res, Univ Ctr Psychiat, Groningen, Netherlands Kings Coll London, Inst Psychiat, Dept Hlth Serv & Populat Res, London WC2R 2LS, England Kings Coll London, Inst Psychiat, Dept Psychol, London WC2R 2LS, England Cardiff Univ, MRC, Ctr Neuropsychiat Genet, Cardiff CF10 3AX, S Glam, Wales Cent Inst Mental Hlth, Dept Psychiat & Psychotherapy, Mannheim, Germany Dokuz Eylul Univ, Sch Med, Dept Psychiat, Konak, Turkey Istanbul Univ, Istanbul Fac Med, Dept Psychiat, Psychot Disorders Res Unit, Istanbul, Turkey Ankara Univ, Sch Med, Dept Psychiat, Cebeci Hosp, TR-06100 Ankara, Turkey Ankara Univ, Brain Res Ctr, TR-06100 Ankara, Turkey Yale Univ, Sch Med, Dept 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.

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.

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.

A number of studies have suggested that age of cannabis use (Arseneault 2002), type of cannabis used (high potency cannabis preparations such as skunk) and frequency (Di Forti 2009) might be more important than the use of cannabis per se in increasing risk of psychosis. We investigated the interaction between pattern of cannabis use and social adversity. We hypothesised that the combined effect of skunk/every day use of cannabis and the experience of social adversity in adulthood would increase the likelihood of a diagnosis of psychosis over and beyond the main effects of cannabis use and social adversity alone. Detailed data on patterns of cannabis use and socio-demographic information have been collected as part of the GAP study and the on-going EU-GEI study of first episode psychosis being conducted in London, UK. A sample of 406 cases and 407 controls was recruited. To assess interaction on an additive scale, Interaction Contrast Ratios [ICR] were calculated. The regression model indicated that, compared with controls, cases were around 16 times (OR 16.2, 95% CI 7.4-35.1) more likely to report both social adversity and skunk and/or everyday use of cannabis. A significant additive interaction was found between pattern of cannabis use and social adversity (ICR 9.82, 95% CI 0.80-18.83, p=0.03). In essence, this suggests there were some people who developed psychosis who would not have developed it if either social adversity or heavy pattern of cannabis use had been absent.

Introduction Studies have reported high rates of schizophrenia and other psychoses in the Black Caribbean population in the UK, between two and 14 times higher than for the White population (Sharpley et al., 2001; Cantor-Graae & Selten, 2005; Fearon et al. 2006). We sought to clarify whether social adversity may contribute to the higher risk of psychosis in the Black Caribbean population. Method To address this question we used preliminary data from the ongoing EU-GEI study of first episode psychosis being conducted in London, UK. Socio-demographic information and data on social adversity were collected from 227 cases presenting with a first episode of psychosis to the South London & Maudsley National Health Service (NHS) Foundation Trust and from 199 controls representative of the local population. Logistic regression and odds ratios were calculated using Stata 11. Results 67% (n=150) of cases, compared with 25% (n=49) of controls, reported two or more markers of social adversity at admission. Compared with White British, Black Caribbean patients were 3.7 times more likely to experience adversity (i.e., being unemployed, living alone and being single) in adulthood (OR 3.7; 95%CI 1.2-10.7 p≤ 0.001). Interestingly, the same pattern was not evident for the other ethnic minority groups (Asian, Black African, Non British White and other minority). Conclusion These initial findings suggest that social adversity may be contributing to the high rates of psychosis observed in the Black Caribbean population in the UK.

198 (45%) refused or could not be contacted, and 5 (1%) lacked capacity to consent. Again, there was no evidence of differences in age, gender and ethnicity by each of these outcomes. Information on course and outcome was obtained for over 80% of cases, with an average length of follow-up of 9.8 years (sd 2.4). In a preliminary indicative analyses of course type in an initial sub-sample of 251 (57%) of the 438 traced, 100 (40%) experienced an episodic course (i.e., no episode lasted more than 6 months), 97 (39%) experienced a continuous course (i.e., no period of remission lasting more than 6 months), and 54 (21%) experienced neither (i.e., at least one episode of 6+ months and at least one remission of 6+ months). Discussion: We have completed an extensive follow-up at 10 years of 553 cases with a first episode of psychosis. Initial analyses suggest there are no systematic biases in follow-up rates by age, gender and ethnicity. Preliminary analyses of course type, in line with previous research, suggest marked heterogeneity in clinical outcomes, with indications that a sizeable proportion experience one or more periods of remission of symptoms lasting at least 6 months.

Background: Epidemiological studies have reported that the risk of developing psychosis in cannabis users is dose related. Experimental research has shown that the active constituent of cannabis responsible for its psychotogenic effect is Delta-9-Tetrahydrocannabinol (THC). Recent evidence shows the potency (% TCH) of the cannabis seized in the UK is increasing. Previous studies have also suggested that age at first use of cannabis might moderate the degree of risk for developing a psychotic disorder. We predicted that first episode psychosis patients would be more likely to have started using cannabis in early adolescence, to use higher potency cannabis and to use it more frequently than controls. Methods: We collected information concerning socio-demographic and clinical characteristics, and cannabis use (age at first use, frequency, length of use, type of cannabis used) from 280 firstepisode psychosis (FEP) patients and 174 matched healthy volunteers in South London. Results: Therewasno significant difference in the life-timeprevalence of cannabis use or age at first use between cases and controls. Nevertheless, in the cases group age at first use was positively correlated with age of onset of psychosis: the earlier the age at first cannabis use, the earlier the onset of psychosis (z=0.49; p