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Treatment resistance (TR) in patients with first-episode psychosis (FEP) is a major cause of disability and functional impairment, yet mechanisms underlying this severe disorder are poorly understood. As one view is that TR has neurodevelopmental roots, we investigated whether its emergence relates to disruptions in synchronized cortical maturation quantified using gyrification-based connectomes. Seventy patients with FEP evaluated at their first presentation to psychiatric services were followed up using clinical records for 4 years; of these, 17 (24.3%) met the definition of TR and 53 (75.7%) remained non-TR at 4 years. Structural MRI images were obtained within 5 weeks from first exposure to antipsychotics. Local gyrification indices were computed for 148 contiguous cortical regions using FreeSurfer; each subject’s contribution to group-based structural covariance was quantified using a jack-knife procedure, providing a single deviation matrix for each subject. The latter was used to derive topological properties that were compared between TR and non-TR patients using a Functional Data Analysis approach. Compared to the non-TR patients, TR patients showed a significant reduction in small-worldness (Hedges’s g = 2.09, P < .001) and a reduced clustering coefficient (Hedges’s g = 1.07, P < .001) with increased length (Hedges’s g = −2.17, P < .001), indicating a disruption in the organizing principles of cortical folding. The positive symptom burden was higher in patients with more pronounced small-worldness (r = .41, P = .001) across the entire sample. The trajectory of synchronized cortical development inferred from baseline MRI-based structural covariance highlights the possibility of identifying patients at high-risk of TR prospectively, based on individualized gyrification-based connectomes.

ObjectiveStressful life events have been implicated in the onset of psychotic disorders, but there are few robust studies. We sought to examine the nature and magnitude of associations between adult life events and difficulties and first-episode psychoses, particularly focusing on contextual characteristics, including threat, intrusiveness, and independence.MethodThis study forms part of the Childhood Adversity and Psychosis Study (CAPsy), an epidemiological case-control study in London, United Kingdom. Data on life events and difficulties (problems lasting 4 wk or more) during 1 year prior to onset (cases) or interview (controls) were assessed using the semi-structured Life Events and Difficulties Schedule (LEDS). Data were available on 253 individuals with a first episode of psychosis and 301 population-based controls.ResultsWe found strong evidence that odds of exposure to threatening and intrusive events in the 1 year prior to onset were substantially higher among cases compared with controls, independent of age, gender, ethnicity, and social class (ORs > 3). This was consistent across diagnostic categories. We found further evidence that the effect of threatening events and difficulties was cumulative (1 event odds ratio [OR] 2.69 [95% confidence interval (CI) 1.51–4.79]; 2 events OR 4.87 [95% CI 2.34–10.16]; ≥3 events OR 5.27 [95% CI 1.83–15.19]; 1 difficulty OR 3.02 [95% CI 1.79–5.09]; 2 difficulties OR 9.71 [95% CI 4.20–22.40]; ≥3 difficulties OR 12.84 [95% CI 3.18–51.85]).ConclusionsThreatening and intrusive life events and difficulties are common in the year pre-onset among individuals with a first episode of psychosis. Such experiences may contribute to the development of psychotic disorders.

Background A symptom dimension approach may best examine the heterogeneous expression of psychosis. However, whether and how premorbid predisposition and cognitive factors explain phenotypes variation is still debated. This study aimed to test the predictive value of combined cognition and premorbid adjustment on transdiagnostic symptom dimensions in a large sample of people suffering from the first episode of psychosis (FEP). Methods FEP patients were part of the EUGEI study. Psychopathology was rated using the OPerational CRITeria system. Multidimensional item response modelling estimate a bifactor model of psychosis by Mplus, composed of a general factor and five specific symptom dimensions. WAIS-brief version measured IQ, and Premorbid Adjustment Scale estimated premorbid social (SF) and academic adjustment (AF). We set a multivariate analysis of the covariance having symptom-dimensions as the output and SF, AF, and IQ as the main predictors, adjusted by age, gender, country, and ethnicity. Since lifetime frequency of cannabis use related to both premorbid and cognitive characteristics, and symptom dimensions, it was added as an independent predictor, collected by the Cannabis Experience Questionnaire. Sensitivity analyses were run with IQ subtests. Results The sample included 785 FEP patients [61.2% (N=481) males; Mean age=33.8 (12.3)]. IQ [Pillai=0.019, F(6, 765)=2.52; p=0.020] and SF [Pillai=0.032, F(6, 765)=4.26; p Positive symptoms were slightly predicted by a lower IQ (B=-0.005, 95% C.I. -0.01, 0.0, p=0.038) and sensitivity analysis revealed the role of a worse processing speed (B=-0.04, 95% C.I. -0.07, -0.01, p=0.003) and working memory (B=-0.02, 95% C.I. -0.05, -0.04, p=0.013) abilities in this relationship. Negative symptoms were higher in subjects with a worse SF (B=-0.12, 95% C.I. -0.18, -0.06, p Discussion The opposed relationship between premorbid sociability and an IQ, particularly its “hold” perceptual-reasoning sub-test – linked to an early coherent self-construction – with manic and negative symptoms, suggests divergent neurodevelopmental trajectories among patients endorsing these different phenotypes. On the other hand, the specific predictive value for positive symptoms of lower processing speed and working memory – well-recognised cognitive markers in psychosis – implies an encoding problem. Worse premorbid sociability but not low general cognition predicted depressive symptoms, thus suggesting a difference between mood downregulation and flat affect, often unrecognised. The cannabis-effect on positive symptoms was expected; this analysis suggests its possible interaction with cognitive characteristics, which deserves further attention.

Background Studies have shown that cannabis can increase the risk of psychosis from 1.7 to 3.9 times. Both frequency and potency seem to contribute to differences in the incidence of psychosis across Europe. Despite this evidence, sceptics argue that that the association between cannabis use and psychotic disorders could be explained by: (a) subjects who start experiencing psychosis use cannabis as a form of self-medication; (b) the co-morbid effect of other psychotogenic drugs (e.g., amphetamines); or (c) there is a common genetic vulnerability between cannabis use and psychosis. Thus, we aim to analyse: 1) reported reasons to start using cannabis, 2) if these predict differences in patterns of use (frequency and potency), 3) the association of both reasons to start and pattern of use with PRS for Schizophrenia, as it can explain whether patients with a higher genetic burden also start smoking cannabis after experiencing a higher psychological discomfort. Methods Using data from the multicentric EUGEI First-Episode Psychosis (FEP) case-control study we examined differences in reasons to start using cannabis between cases and controls. Data were obtained from the Cannabis Experiences Questionnaire modified version. Logistic regression models were used to test if reason to start predicted different patterns of use. Finally, we used regression to test if Polygenic risk scores for schizophrenia (SZ PRS) explained variance in reasons to start. Results Up to 85% of controls compared to 68% of FEP started using cannabis because either friends or family were using it. Instead, 18% of cases started using cannabis to feel better compared 5% of controls, reporting the 13.4% of cases and 10.3% of controls having start due to “other reasons”. Regression models showed that being a case was positively associated with starting use in order to feel better (RRR 4.67, z=7.58, p Discussion These preliminary findings show that a higher proportion of patients with psychosis than controls start using cannabis as a way to make them feel better, although they are a minority. Furthermore, both cases and controls that started smoking “to feel better” presented higher chances to start smoking more frequently. Lastly, PRS did not predict the reasons to start smoking cannabis.

Background There has been much debate about whether research into psychosis should be conducted using symptom dimensions as opposed to diagnostic categories. Indeed, dimensions, like categories, may be practical but arbitrary tools for research and clinical practice; hence, they should not be based on psychometric data only. The aim of this study was to externally validate empirically derived symptom dimensions using combined genetic and environmental data. Specifically, we examined the hypothesis that the continuous multivariate distribution of psychosis is a function of cannabis use and genetic liability to schizophrenia, as summarised by polygenic risk score (SZ-PRS). Methods As part of the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) study, we analysed a large multinational sample of First Episode Psychosis patients (FEP) and population controls, with available genotype and psychopathology information. Using item response modelling in Mplus, we estimated a bifactor model of psychotic symptoms in FEP, and of psychotic experiences in controls. Using PRSice, we built SZ-PRS by weighting individuals’ risk variants by the log(odds ratio), where the odds ratio was extracted from the latest summary statistics of Psychiatric Genomic Consortium mega-analyses on schizophrenia. Finally, we used linear regression to test the combined associations of the positive symptom/experience dimensions with SZ-PRS and daily/current cannabis use, separately in FEP and controls, after covarying for 10 ancestry principal components, sex, age, and primary diagnosis. Results The continuous distribution of psychosis was represented by two bi-factor models composed of 1) in FEP, one general psychosis factor and five specific dimensions; 2) in controls, one general psychosis factor and three specific dimensions. Linear regression modelling showed that in 617 FEP, both daily cannabis use (B=0.31; 95%CI 0.11 to 0.52; p=0.002) and SZ-PRS (B=0.22; 95%CI 0.04 to 0.39; p=0.014) were independently associated with the dimension of positive symptoms. Similar results were found in 979 population controls, with a positive association of both current use of cannabis (B=0.26, 95%CI 0.06 to 0.46; p=0.011) and SZ-PRS (B=0.13, 95%CI 0.02 to 0.25; p=0.022) with the dimension of psychotic experiences. Discussion We found two factors associated with the latent dimensional structure of psychosis. SZ risk variants and cannabis use independently map onto specific dimensions of positive symptoms, contributing to variation across the psychosis continuum. Our study supports the theory that psychotic experiences in the general population are biologically similar to clinical psychotic symptoms.

Background The importance of inherited factors in the development of affective psychosis, which includes bipolar disorder and major depression disorder, is widely accepted, but the fact that monozygotic twin concordance is substantially less than 100% suggests that environmental factors (ERF) are likely to play an important role as well. While the link between a variety of ERF and schizophrenia-spectrum disorder is well established, less is known about how these ERF impact in affective psychosis. In the current study we aim to analyse the role of environmental risk factors in the expression of affective disorder compared with schizophrenia-spectrum disorder, and its interaction with the genetic risk by using polygenic risk score (PRS). Methods DNA was obtained from most participants (73.6% of 1130 cases and 78.5% of 1499 controls) among 16 European cities as part of the EUGEI case-control study. PRS for SZ, BD and MDD were built using the latest available data from the Psychiatric Genomic Consortium (PGC). Multinomial logistic regression models were used to test whether the association of genetic load (by PRSs) with different diagnostic categories based on DSMIV from OPCRIT items were greater if there was also evidence of ERF (urbanicity, migration, cannabis use and childhood trauma) through the inclusion of interaction terms between the different PRSs and the ERF. Analyses were conducted for each environmental factor separately and for a combined poly-environmental risk score based on Maudsley Environmental Score (MPES) will be calculated. Results Being 1st generation migrant was not associated with any of the diagnostic categories, nor independently nor in interaction with PRSs. Living in urban environment increases the risk of SSD (RRR=1.68, 95% CI 1.06 – 2.67), but without interacting with any genetic measure. Regarding cannabis use, having ever used cannabis is independently significantly associated with SSD (RRR=2.26, 95% CI 1.69 – 3.02) and BD (RRR=5.3, 95% CI 2.69 – 10.46), showing as well in the latter group an interaction with PRS MDD (RRR=2.3, 95% CI 1.18 – 4.49). Although daily use of cannabis strongly predicted risk of SSD and BD, having use more than once a week only increased risk for SSD. Neither having used cannabis more than once a week or daily interacted with any of the PRSs. Having been exposed to any childhood trauma was independently significantly associated with all three diagnostic groups, but did not show any significant interaction with PRSs. Lastly, despite MPES increased risk for SSD and BD, it didn’t interact significantly with any PRSs. Discussion These results suggest that despite evidence of both PRSs on one hand and urbanicity, cannabis and childhood trauma overall increase risk of belonging to any psychotic diagnostic category separately, we only found some suggestion of potential interaction between genetic vulnerability to MDD and cannabis use associated with BD. Nonetheless, due to most of the interactions showing the expected trend, analyses examining interactions between PRSs and ERF with the different diagnostic groups with bigger samples are warranted.

Background FEP patients who use cannabis experience more frequent intoxication experiences compared to controls. It is not clear whether this is consequent to patients being more vulnerable to the effects of cannabis use or to their heavier pattern of use. We aimed to determine whether extent of use predicted psychotic-like and euphoric intoxication experiences in FEP patients and controls and whether this differs between groups. Methods We analysed data on lifetime cannabis using patients (n=655) and controls (n=654) across 15 sites from six countries in the EU-GEI study (2010–2015). We used multiple regression to model predictors of cannabis-induced experiences and Factorial ANOVA to determine if there was an interaction between caseness and extent of use. Results Both psychotic-like and euphoric experiences were more frequent in cases vs controls (p

Background The Clinical Record Interactive Search (CRIS) database provides anonymised data from the full electronic health records of all patients at the South London and Maudsley NHS Foundation Trust, a large provider of secondary mental health care. We have previously shown how the large volumes of available CRIS data pertaining to outcomes can be mined and integrated with patient data collected by historical research interview. The applications of this futuristic translational research model are yet to be fully explored. The aim of this study is to determine whether transcriptomic profiles at the onset of psychosis can discern the likely trajectory symptoms over the subsequent 5 years of illness. Methods The study sample consists of 200 first-episode psychosis cases (ICD-10 codes: F20-F29 or F30-F33) aged 18–65 years who presented to SLAM (South London and Maudsley NHS Trust) mental health services between the 1st of January 2010 and the 1st of January 2015. Patients were subsequently recruited to the GAP study. Patients were followed-up electronically for 5 years post recruitment using the CRIS research platform. RNA samples were collected at the baseline timepoint via PAXgene blood tubes and interrogates, using the Illumina HumanHT-12.v4 beadchip array. Samples were run at the National Institute for Health Research’s (NIHR) Biomedical Research Centre for Mental Health (BRC-MH) at the Institute of Psychiatry, Psychology and Neuroscience. A total of 4756 probes passed a stringent quality control across the 200 samples. Results CRIS data pertaining to the GAP cohort was interrogated for information on clinical symptoms over a 5-year period using text-mining and natural language processing apps that represent over 70 different dictionary definitions of psychotic and affective symptoms. Confirmatory factor analysis was used to reduce this to a much smaller set of orthogonal symptom dimensions which were then the subject of a genetic interrogation using gene expression data. The analysis was conducted using a statistical learning framework which combines Elastic net penalised regression methodology with K-fold cross-validation (via the GLMnet package in R). This identified gene transcripts that were predictive of longer term symptom trajectories in half of the available sample. The veracity of the model was further validated using the second withheld portion of the sample. Discussion The results of this discovery phase may provide a rationale for subsequent multi-modal investigations whose aims will be to further enrich the biomarker signature and to also understand the molecular mechanisms that sustain them.

Background Children who later develop Schizophrenia on average are more likely to present with lower IQ; this has been considered evidence for the neurodevelopmental theory of schizophrenia. Though, recent studies have shown that first episode psychosis patients with a history of cannabis use have significantly higher premorbid and current IQ compared to those who never used it. This suggests that abnormal early neurodevelopment does not explain the aetiology of all cases of Schizophrenia, leaving space to environmental hazards. The present study aims to: investigate differences in IQ, as a marker of neurodevelopment, and in exposure to environmental risk factors in a large sample first episode psychosis patients recruited across five different European countries, in comparison with their respective control groups. Methods We analysed data on IQ, socio-demographics and cannabis use from FEP=705 (51.1 % males) and healthy controls=1.034 (48.9 % males), as part of the European network of national schizophrenia networks studying European Gene-Environment-Interaction (EUGEI) study. Patients met ICD-10 criteria for psychosis, ascertained by using OPCRIT (McGuffin et al., 1991). The CEQmv(Di Forti et al., 2009) further modified for the EUGEI study, was used to collect data on cannabis use. We used ANOVAs where IQ was used as the outcome variable and case/control status and Country were respectively entered as independent predictors, along with other predictors. Results Case-control status (F (1,1.484)=133.1, p

Background Jumping to conclusions (JTC) is a well-established reasoning and data gathering bias found in patients with psychosis even at illness onset (First Episode Psychosis, FEP). Preliminary work in this field focused primarily on the association with delusions, although jumping to conclusions has also been found in non-deluded schizophrenia patients after remission, and in individual with at risk mental state. Moreover, psychotic patients tend to show impairments in social cognition, struggling in identifying, processing and interpreting social clues. Deficits in facial emotion recognition (FER) – a key component of the construct – represent a well-replicated finding in schizophrenia. Furthermore, deficits in global facial affect recognition have been found in FEP with the same severity as at further stages, especially for anger recognition. The present study aims to measure JTC and FER bias in a sample of FEP recruited across 5 European countries, compared with healthy controls. Methods Data on JTC (Beads task 60:40), FER (Degraded Facial Recognition task – DFAR) and socio-demographics have been analysed in a sample of 643 FEP and 1019 population controls recruited as part as the EU-GEI study across UK, Netherlands, France, Spain, and Italy. IQ scores were used to exclude cases and controls with current IQ

Background Robust evidence has demonstrated that cannabis use increases the risk to develop psychotic disorders. However, a limited number of studies have investigated if and how cannabis use influences psychopathology profiles at first episode psychosis (FEP). Based on the evidence that dopamine dysfunction contributes to explain positive symptoms in psychosis, and that the main cannabis’ psychoactive component, Δ9-Tetrahydrocannabinol (THC), modulates the dopamine system, we hypothesise that: 1) positive symptoms at FEP are more common among psychotic patients who used cannabis compared with never users; 2) this association is a dose-response relationship. Methods We analyzed a sample of 1130 FEP patients as part of the EUGEI study, recruited across six countries. The MRC Socio-demographic Schedule was used to collect sociodemographic information. Psychopathology was assessed with the OPerational CRITeria (OPCRIT), and symptom items were analyzed using Mplus to estimate a multidimensional model of psychosis. The Cannabis Experience Questionnaire modified version (CEQmv) was administered to collect information on cannabis, and different patterns of use were computed based on frequency of consumption and type of cannabis, as a proxy of exposure to THC. Results The lifetime rate of cannabis use was 63%. Fifty-five percent of cannabis users consumed mostly high-potency cannabis, and 46% showed a daily frequency. Mixed-effects linear regression revealed that frequency of cannabis use was associated with the positive symptom dimension score. Daily users of high-potency cannabis presented with the strongest association (Β=0.19, 95%CI=0.02–0.38), even after gender, age, ethnicity, other drug use, and study site were controlled for. Discussion Our results show that patients with a history of daily use of high potency cannabis express more positive symptoms at psychosis onset, even after taking into account other substance use and relevant sociodemographic factors.

Background Psychotic disorders are characterized by large heterogeneity in clinical presentation, response to treatment and cognitive functioning. Indeed, there is evidence of the presence of cognitive subgroups of patients across affective and non-affective psychosis. However, very little is known about these subgroups in first episode psychosis (FEP) and whether they can be informative about course of illness, particularly response to treatment. The aim of this study is to investigate the number and the pattern of cognitive clusters in FEP, their external validity and association with treatment response at 12-week and 1-year follow up. Methods The sample was composed by a total of 212 participants including 105 FEP patients from the South London and Maudsley Foundation Trust and 107 Healthy Controls (HC). All participants underwent a comprehensive clinical and neurocognitive battery. Z-score [mean=0, and standard deviation (SD)=1] were created for the whole sample based on the neurocognitive performance of the HCs. Treatment response at 12-week and 1-year follow-up was used to explore potential utility of subtypes in predicting response to treatment. Hierarchical cluster analysis was carried out to determine the number of cognitive clusters in FEP patients. A series of analyses of variance were carried out to determine if FEP clusters differed among each other in relation to demographic and clinical characteristics, level of functioning and from the HC sample in term of cognitive performance. Logistic regression was used to explore whether cognitive clustering was predictive of treatment response at 12-week and 1-year FU. Results Four cognitive clusters emerged: one with near normal cognition (42.9% of the FEP patients) with a general cognitive score of z=-0.20, one with selected cognitive deficits (14.3%) in the domains of verbal memory, processing speed and executive functions (general cognitive score of z=-0.55); and two severe deficit clusters consisting in one cluster with severe deficits (33.3%; general score of z=-1.48) and the other with a deeply compromised cognitive ability (9.55%; general cognitive score of z=-2.34). There were no significant differences between clusters in terms of clinical features at baseline (including diagnosis, positive and negative symptoms, medication), apart from the level of functioning that was significantly lower in the severely compromised cluster compared to the near normal cognition cluster. It emerged that majority (about 68%) of the patients from the near normal cognition cluster were responsive to treatment, whilst the majority of the selective and severely impaired clusters did not respond to treatment at 12-week follow-up. There were no significant results with regard to treatment response at 1-year FU. Discussion Distinct patterns of cognitive impairments exist within FEP that might be characterized by different response to treatment. Clinical presentation at the onset of the illness is not useful in predicting response to treatment later on in the course of the illness, while cognitive functioning might be a more valid indicator. Cognitive stratification could represent a promising way forward to elucidate pathophysiology of psychosis and to provide tailored interventions.

BACKGROUND: The importance of inherited factors for affective psychosis, which includes bipolar disorder and major depression disorder, is widely accepted, but the fact that monozygotic twin concordance is substantially less than 100% suggests that environmental factors (ERF) are likely to play an important role as well. While the link between a variety of ERF and non-affective psychosis is well stablished, less is known about how these ERF impact in affective psychosis. In the current investigation we aim to examine the different distribution of environmental risk factors among affective psychosis, non-affective psychosis and controls. METHODS: Using data from the multicentric EUGEI case-control study of First-Episode Psychosis (FEP), we study the presence of different ERF classically associated with psychosis (urbanicity, migration, cannabis use and childhood trauma) among categorical diagnoses (non-affective psychosis, bipolar disorder and major depression) based on DSMIV from OPCRIT items, compared with controls. Descriptive comparisons between groups were made with Chi square or ANOVA tests accordingly. RESULTS: We found significant differences in all the studied ERF, with the highest exposure to rural environment in the non-affective psychosis group (62.7%, Chi2 35.4, p

BACKGROUND: While it is generally accepted that childhood adversity (CA), mainly in the form of abuse and neglect is associated with psychosis, less attention has been paid to the specific effects of different adversity types and symptoms in patients. Concretely, the association between specific adversity types and the main symptom dimensions in First Episode of Psychosis (FEP), considering the timing of exposure has never been studied. This is the aim of the current investigation. METHODS: 1130 FEP patients were recruited as part of the EUGEI multicentric case-control study. The Childhood Experience of Care and Abuse Questionnaire (CECA.Q) was used to investigate the experiences of abuse (sexual, physical and psychological), household discord, neglect, bullying, parental separation and parental death prior the age of 17. Each adversity was categorized according to the time of exposure as follows (Early: before 12 years of age; Late: from 12 through 17). Symptom dimensions (positive, negative, disorganised, manic and depressive) were built from the OPerational CRITeria (OPCRIT) using Mplus. Linear regression was used to examine associations between each type of CA and the continuous symptom dimension scores. Results were controlled for age, sex, ethnicity, site and years of education. RESULTS: Early-sexual abuse [B = 0.417, 95% confidence interval (CI) 0.059–0.775], Late-neglect (B = 0.473, 95% CI 0.072–0.874] and Late-parental death [B = 0.547, 95% CI 0.219–0.876] showed a significant association with the positive symptom dimension; Late-bullying (B = 0.249, 95% CI 0.056–0.443] was significantly associated with the depressive dimension and Early-neglect (B = 0.249, 95% CI 0.011–0.487] with the manic dimension. DISCUSSION: Our results provide evidence for some specificity effects between different adversities and the positive, depressive and manic dimensions in FEP. In addition, the time at which such adversities occur seems to play role in such associations. The exploration of psychological and biological underlying mechanisms explaining such links is warranted.

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.

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 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.

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.