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Background: Cannabis use and familial vulnerability to psychosis have been associated with social cognition deficits. This study examined the potential relationship between cannabis use and cognitive biases underlying social cognition and functioning in patients with first episode psychosis (FEP), their siblings, and controls., Methods: We analyzed a sample of 543 participants with FEP, 203 siblings, and 1168 controls from the EU-GEI study using a correlational design. We used logistic regression analyses to examine the influence of clinical group, lifetime cannabis use frequency, and potency of cannabis use on cognitive biases, accounting for demographic and cognitive variables., Results: FEP patients showed increased odds of facial recognition processing (FRP) deficits (OR = 1.642, CI 1.123-2.402) relative to controls but not of speech illusions (SI) or jumping to conclusions (JTC) bias, with no statistically significant differences relative to siblings. Daily and occasional lifetime cannabis use were associated with decreased odds of SI (OR = 0.605, CI 0.368-0.997 and OR = 0.646, CI 0.457-0.913 respectively) and JTC bias (OR = 0.625, CI 0.422-0.925 and OR = 0.602, CI 0.460-0.787 respectively) compared with lifetime abstinence, but not with FRP deficits, in the whole sample. Within the cannabis user group, low-potency cannabis use was associated with increased odds of SI (OR = 1.829, CI 1.297-2.578, FRP deficits (OR = 1.393, CI 1.031-1.882, and JTC (OR = 1.661, CI 1.271-2.171) relative to high-potency cannabis use, with comparable effects in the three clinical groups., Conclusions: Our findings suggest increased odds of cognitive biases in FEP patients who have never used cannabis and in low-potency users. Future studies should elucidate this association and its potential implications.

Background: Urbanicity is a well-established risk factor for psychosis. Our recent multi-national study found an association between urbanicity and clinical psychosis in Northern Europe but not in Southern Europe. In this study, we hypothesized that the effect of current urbanicity on variation of schizotypy would be greater in North-western Europe countries than in Southern Europe ones., Methods: We recruited 1080 individuals representative of the populations aged 18-64 of 14 different sites within 5 countries, classified as either North-western Europe (England, France, and The Netherlands) with Southern Europe (Spain and Italy). Our main outcome was schizotypy, assessed through the Structured Interview for Schizotypy-Revised. Our main exposure was current urbanicity, operationalized as local population density. A priori confounders were age, sex, ethnic minority status, childhood maltreatment, and social capital. Schizotypy variation was assessed using multi-level regression analysis. To test the differential effect of urbanicity between North-western and Southern European, we added an interaction term between population density and region of recruitment., Results: Population density was associated with schizotypy (β = 0.248,95%CI = 0.122-0.375;p < 0.001). The addition of the interaction term improved the model fit (likelihood test ratio:χ 2  = 6.85; p = 0.009). The effect of urbanicity on schizotypy was substantially stronger in North-western Europe (β = 0.620,95%CI = 0.362-0.877;p < 0.001) compared with Southern Europe (β = 0.190,95%CI = 0.083-0.297;p = 0.001)., Conclusions: The association between urbanicity and both subclinical schizotypy and clinical psychosis, rather than being universal, is context-specific. Considering that urbanization is a rapid and global process, further research is needed to disentangle the specific factors underlying this relationship., (© 2024 The Author(s). Acta Psychiatrica Scandinavica published by John Wiley & Sons Ltd.)

Social isolation has been linked to a range of psychiatric issues, but the behavioral component that drives it is not well understood. Here, a genome-wide associations study (GWAS) was carried out to identify genetic variants that contribute specifically to social isolation behavior (SIB) in up to 449,609 participants from the UK Biobank. 17 loci were identified at genome-wide significance, contributing to a 4% SNP-based heritability estimate. Using the SIB GWAS, polygenic risk scores (PRS) were derived in ALSPAC, an independent, developmental cohort, and used to test for association with self-reported friendship scores, comprising items related to friendship quality and quantity, at age 12 and 18 to determine whether genetic predisposition manifests during childhood development. At age 18, friendship scores were associated with the SIB PRS, demonstrating that the genetic factors can predict related social traits in late adolescence. Linkage disequilibrium (LD) score correlation using the SIB GWAS demonstrated genetic correlations with autism spectrum disorder (ASD), schizophrenia, major depressive disorder (MDD), educational attainment, extraversion, and loneliness. However, no evidence of causality was found using a conservative Mendelian randomization approach between SIB and any of the traits in either direction. Genomic Structural Equation Modeling (SEM) revealed a common factor contributing to SIB, neuroticism, loneliness, MDD, and ASD, weakly correlated with a second common factor that contributes to psychiatric and psychotic traits. Our results show that SIB contributes a small heritable component, which is associated genetically with other social traits such as friendship as well as psychiatric disorders., (© 2024. Crown.)

Childhood adversity is associated with various clinical dimensions in psychosis; however, how genetic vulnerability shapes the adversity-associated psychopathological signature is yet to be studied. We studied data of 583 First Episode Psychosis (FEP) cases from the EU-GEI FEP case-control study, including Polygenic risk scores for major depressive disorder (MDD-PRS), bipolar disorder (BD-PRS) and schizophrenia (SZ-PRS); childhood adversity measured with the total score of the Childhood Trauma Questionnaire (CTQ); and positive, negative, depressive and manic psychopathological domains from a factor model of transdiagnostic dimensions. Genes and environment interactions were explored as a departure from a multiplicative effect of PRSs and total CTQ on each dimension. Analyses were adjusted for age, sex, 10 PCA, site of recruitment and for medication. A childhood adversity and PRS multiplicative interaction was observed between A) the CTQ and MDD-PRS on the predominance of positive (β = 0.42, 95% CI = [0.155, 0.682], p = 0.004); and depressive (β = 0.33, 95% CI = [0.071, 0.591], p = 0.013) dimensions; B) between the CTQ and BD-PRS on the positive dimension (β = 0.45, 95% CI = [0.106, 0.798], p = 0.010), and C) with the CTQ and SZ-PRS on the positive dimension (β = -0.34, 95% CI = [-0.660, -0.015], p = 0.040). Bonferroni corrected p-value of significance was set at 0.0125. In conclusion, despite being underpowered, this study suggests that genetic liability for MDD and BD may have a moderating effect on the sensibility of childhood adversity on depressive and positive psychotic dimensions. This supports the hypothesis of an affective pathway to psychosis in those exposed to childhood adversity., (© 2024. The Author(s).)

The relationship between reduced social connectedness and mental health outcomes is increasingly acknowledged. Yet, relatively little is known about how two crucial subjective aspects of social disconnectedness - loneliness and social relationship dissatisfaction (SRD) - are related to clinical and functional recovery. This cohort study aimed to investigate the associations of loneliness and SRD with various mental health outcomes among 15,512 outpatients from a Dutch mental health service. Demographics and data on loneliness, SRD, symptomatic distress, suicidal ideation, and role functioning, as well as treatment duration, and mortality, were collected. The study analyzed the associations between these factors overall and by diagnostic group, gender, and age, using cross-sectional and longitudinal regression, while controlling for relevant covariates. Findings revealed significant, independent, associations between loneliness, SRD, symptomatic distress, and role functioning across different diagnostic groups. Particularly strong associations were noted in bipolar and psychosis-related disorders. Gender did not significantly influence the strength of associations. In older patients, lower levels of loneliness and SRD were observed, but the impact on clinical and functional outcomes was consistent across ages. Higher loneliness and SRD were associated with longer treatment durations, regardless of age, gender or diagnosis. This study indicates the wide-reaching effects of perceived social disconnectedness on recovery and emphasizes interventions targeting loneliness and SRD to enhance outcomes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background and Hypothesis: Recent findings suggest the incidence of first-episode psychotic disorders (FEP) varies according to setting-level deprivation and cannabis use, but these factors have not been investigated together. We hypothesized deprivation would be more strongly associated with variation in FEP incidence than the prevalence of daily or high-potency cannabis use between settings., Study Design: We used incidence data in people aged 18-64 years from 14 settings of the EU-GEI study. We estimated the prevalence of daily and high-potency cannabis use in controls as a proxy for usage in the population at-risk; multiple imputations by chained equations and poststratification weighting handled missing data and control representativeness, respectively. We modeled FEP incidence in random intercepts negative binomial regression models to investigate associations with the prevalence of cannabis use in controls, unemployment, and owner-occupancy in each setting, controlling for population density, age, sex, and migrant/ethnic group., Study Results: Lower owner-occupancy was independently associated with increased FEP (adjusted incidence rate ratio [aIRR]: 0.76, 95% CI: 0.61-0.95) and non-affective psychosis incidence (aIRR: 0.68, 95% CI: 0.55-0.83), after multivariable adjustment. Prevalence of daily cannabis use in controls was associated with the incidence of affective psychoses (aIRR: 1.53, 95% CI: 1.02-2.31). We found no association between FEP incidence and unemployment or high-potency cannabis use prevalence. Sensitivity analyses supported these findings., Conclusions: Lower setting-level owner-occupancy and increased prevalence of daily cannabis use in controls independently contributed to setting-level variance in the incidence of different psychotic disorders. Public health interventions that reduce exposure to these harmful environmental factors could lower the population-level burden of psychotic disorders., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Purpose: While severely distressing events are known to affect mental health adversely, some survivors develop only short-lived or no psychiatric symptoms in the aftermath of a disaster. In the WTC Health Program General Responder Cohort (WTCHP GRC) we examined whether social support was protective against the development of depression or anxiety symptoms after the 9/11 WTC attacks and explored in a subsample whether trait resilience moderated this relationship., Methods: We analyzed data from 14,033 traditional and 13,478 non-traditional responders who attended at least three periodic health monitoring visits between 2002 and 2019. Linear mixed-effects models were used to examine depression (Patient Health Questionnaire-9; PHQ-9) and anxiety (Generalized Anxiety Disorder screener; GAD-7) scores. In a subsample of 812 participants, we also assessed if the association between social support and symptoms was moderated by an individual's trait resilience level (Connor-Davidson Resilience Scale, CD-RISC)., Results: For both traditional and non-traditional responders, perceived social support around 9/11 was associated with lower levels of depressive (β = - 0.24, S.E. = 0.017, z = - 14.29, p < 0.001) and anxiety symptoms (β = - 0.17, S. E. = 0.016, z = - 10.48, p < 0.001). Trait resilience scores were higher in responders with at least one source of social support during the aftermath of 9/11 compared to those without (mean 71.56, SD 21.58 vs mean 76.64, SD 17.06; β = 5.08, S.E. = 0.36, p < 0.001). Trait resilience moderated the association between social support and depressive (p < 0.001) and anxiety trajectories (p < 0.001) for traditional responders., Conclusion: Our findings suggest that perceived social support around a severely distressing event may have long-term protective effects on symptoms of depression and anxiety., (© 2023. The Author(s).)

Background: Incidence of first-episode psychosis (FEP) varies substantially across geographic regions. Phenotypes of subclinical psychosis (SP), such as psychotic-like experiences (PLEs) and schizotypy, present several similarities with psychosis. We aimed to examine whether SP measures varied across different sites and whether this variation was comparable with FEP incidence within the same areas. We further examined contribution of environmental and genetic factors to SP., Methods: We used data from 1497 controls recruited in 16 different sites across 6 countries. Factor scores for several psychopathological dimensions of schizotypy and PLEs were obtained using multidimensional item response theory models. Variation of these scores was assessed using multi-level regression analysis to estimate individual and between-sites variance adjusting for age, sex, education, migrant, employment and relational status, childhood adversity, and cannabis use. In the final model we added local FEP incidence as a second-level variable. Association with genetic liability was examined separately., Results: Schizotypy showed a large between-sites variation with up to 15% of variance attributable to site-level characteristics. Adding local FEP incidence to the model considerably reduced the between-sites unexplained schizotypy variance. PLEs did not show as much variation. Overall, SP was associated with younger age, migrant, unmarried, unemployed and less educated individuals, cannabis use, and childhood adversity. Both phenotypes were associated with genetic liability to schizophrenia., Conclusions: Schizotypy showed substantial between-sites variation, being more represented in areas where FEP incidence is higher. This supports the hypothesis that shared contextual factors shape the between-sites variation of psychosis across the spectrum.

Background: Psychotic experiences (PEs) and social isolation (SI) seem related during early stages of psychosis, but the temporal dynamics between the two are not clear. Literature so far suggests a self-perpetuating cycle wherein momentary increases in PEs lead to social withdrawal, which, subsequently, triggers PEs at a next point in time, especially when SI is associated with increased distress. The current study investigated the daily-life temporal associations between SI and PEs, as well as the role of SI-related and general affective distress in individuals at clinical high risk (CHR) for psychosis., Methods: We used experience sampling methodology in a sample of 137 CHR participants. We analyzed the association between SI, PEs, and distress using time-lagged linear mixed-effects models., Results: SI did not predict next-moment fluctuations in PEs, or vice versa . Furthermore, although SI-related distress was not predictive of subsequent PEs, general affective distress during SI was a robust predictor of next-moment PEs., Conclusions: Our results suggest that SI and PEs are not directly related on a moment-to-moment level, but a negative emotional state when alone does contribute to the risk of PEs. These findings highlight the role of affective wellbeing during early-stage psychosis development.

Racial disparities in prescriptions of anti-psychotics have been highlighted before. However, (i) the evidence on other medications, including anti-depressant or mood stabilizing medications is lacking, and (ii) the role of potentially confounding factors and (iii) specificity of such disparities to schizophrenia (SCZ), are still unknown. We used electronic health records (EHRs) from 224,212 adults to estimate the odds ratios of receiving a prescription for different nervous system medications among patients with SCZ of different race/ethnicity, and analogous linear models to investigate differences in prescribed medication doses. To verify specificity of the observed patterns to SCZ, we conducted analogous analyses in depression and bipolar disorder (BD) patients. We found that Black/African American (AA) and Hispanic patients with SCZ were more likely to be prescribed haloperidol (Black/AA: OR = 1.52 (1.33-1.74); Hispanic: OR = 1.32 (1.12-1.55)) or risperidone (Black/AA: OR = 1.27 (1.11-1.45); Hispanic: OR = 1.40 (1.19-1.64)), but less likely to be prescribed clozapine (Black/AA: OR = 0.40 (0.33-0.49); Hispanic: OR = 0.45 (0.35-0.58)), compared to white patients. There were no race/ethnicity-related differences in the prescribed medication doses. These patterns were not specific to SCZ: Asian, Hispanic and Black/AA patients with BD or depression were more likely to be prescribed anti-psychotics, but less likely to be prescribed antidepressants or mood-stabilizers. In conclusion, we found racial/ethnic disparities in the medications prescribed to patients with SCZ and other psychiatric conditions. We discuss the potential implications for the quality of care for patients of diverse races/ethnicities., (© 2024. The Author(s).)

Background: Schizophrenia (SZ) and autism spectrum disorders (ASD) are characterized by difficulties in theory of mind (ToM). We examined group differences in performance on a ToM-related test and associations with an estimated IQ., Methods: Participants [ N = 1227, SZ ( n = 563), ASD ( n = 159), and controls ( n = 505), 32.2% female] completed the Reading the Mind in the Eyes Test (RMET) and assessments of cognitive ability. Associations between IQ and group on RMET were investigated with regression analyses., Results: SZ ( d = 0.73, p < 0.001) and ASD ( d = 0.37, p < 0.001) performed significantly worse on the RMET than controls. SZ performed significantly worse than ASD ( d = 0.32, p = 0.002). Adding IQ to the model, SZ ( d = 0.60, p < 0.001) and ASD ( d = 0.44, p < 0.001) continued to perform significantly worse than controls, but no longer differed from each other ( d = 0.13, p = 0.30). Small significant negative correlations between symptom severity and RMET performance were found in SZ (PANSS positive: r = -0.10, negative: r = -0.11, both p < 0.05). A small non-significant negative correlation was found for Autism Diagnostic Observation Schedule scores and RMET in ASD ( r = -0.08, p = 0.34)., Conclusions: SZ and ASD are characterized by impairments in RMET. IQ contributed significantly to RMET performance and accounted for group differences in RMET between SZ and ASD. This suggests that non-social cognitive ability needs to be included in comparative studies of the two disorders.

Background: Social cognitive impairment is a recognized feature of psychotic disorders. However, potential age-related differences in social cognitive impairment have rarely been studied., Study Design: Data came from 905 individuals with a psychotic disorder, 966 unaffected siblings, and 544 never-psychotic controls aged 18-55 who participated in the Genetic Risk and Outcome of Psychosis (GROUP) study. Multilevel linear models were fitted to study group main effects and the interaction between group and age on emotion perception and processing (EPP; degraded facial affect recognition) and theory of mind (ToM; hinting task) performance. Age-related differences in the association between socio-demographic and clinical factors, and EPP and ToM were also explored., Study Results: Across groups, EPP performance was associated with age (β = -0.02, z = -7.60, 95% CI: -0.02, -0.01, P < .001), with older participants performing worse than younger ones. A significant group-by-age interaction on ToM (X2(2) = 13.15, P = .001) indicated that older patients performed better than younger ones, while no age-related difference in performance was apparent among siblings and controls. In patients, the association between negative symptoms and ToM was stronger for younger than older patients (z = 2.16, P = .03)., Conclusions: The findings point to different age-related performance patterns on tests of 2 key social cognitive domains. ToM performance was better in older individuals, although this effect was only observed for patients. EPP was less accurate in older compared with younger individuals. These findings have implications with respect to when social cognitive training should be offered to patients., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Childhood adversity and cannabis use are considered independent risk factors for psychosis, but whether different patterns of cannabis use may be acting as mediator between adversity and psychotic disorders has not yet been explored. The aim of this study is to examine whether cannabis use mediates the relationship between childhood adversity and psychosis., Methods: Data were utilised on 881 first-episode psychosis patients and 1231 controls from the European network of national schizophrenia networks studying Gene-Environment Interactions (EU-GEI) study. Detailed history of cannabis use was collected with the Cannabis Experience Questionnaire. The Childhood Experience of Care and Abuse Questionnaire was used to assess exposure to household discord, sexual, physical or emotional abuse and bullying in two periods: early (0-11 years), and late (12-17 years). A path decomposition method was used to analyse whether the association between childhood adversity and psychosis was mediated by (1) lifetime cannabis use, (2) cannabis potency and (3) frequency of use., Results: The association between household discord and psychosis was partially mediated by lifetime use of cannabis (indirect effect coef. 0.078, s.e. 0.022, 17%), its potency (indirect effect coef. 0.059, s.e. 0.018, 14%) and by frequency (indirect effect coef. 0.117, s.e. 0.038, 29%). Similar findings were obtained when analyses were restricted to early exposure to household discord., Conclusions: Harmful patterns of cannabis use mediated the association between specific childhood adversities, like household discord, with later psychosis. Children exposed to particularly challenging environments in their household could benefit from psychosocial interventions aimed at preventing cannabis misuse.

Background: The 22q11.2 deletion (22q11Del) is among the strongest known genetic risk factors for psychosis. Stress, a known risk factor for psychosis in the general population, has seldom been studied in 22q11Del. We investigated how lifetime stressors related to symptomatic outcomes in patients with 22q11Del. We also explored this association in individuals with 22q11.2 duplications (22q11Dup), which may be potentially protective against psychosis., Method: One hundred individuals (46 with 22q11Del, 30 with 22q11Dup, and 24 healthy controls; M age = 17.30 years±10.15) were included. Logistic models were used to examine cross-sectional associations between lifetime acute and chronic stressors (severity and count) and the presence (score ⩾3) of positive, negative, and general symptoms, assessed via the Structured Interview for Psychosis-risk Syndromes (SIPS)., Results: The 22q11Dup group reported the greatest number and severity of acute lifetime stressors, but did not differ from 22q11Del in chronic stressor count or severity. Lifetime chronic and acute stressors were uniquely associated with positive symptoms in 22q11Del (chronic count: odds ratio [OR] = 2.35, p = 0.02; chronic severity: OR = 1.88, p = 0.03; acute count: OR = 1.78, p = 0.03), but not with negative or general symptoms ( p s > 0.05)., Conclusion: Findings suggest that stress may play a role in psychotic symptoms in 22q1Del, while the 22q11Dup CNV appears protective against psychotic symptoms despite higher rates of stressors. Interventions that mitigate effects of stressors in 22qDel may reduce the odds of psychosis in this group. Prospective longitudinal research is needed to replicate these findings.

In many individuals with a diagnosis of schizophrenia social functioning is impaired across the lifespan. Social cognition has emerged as one of the possible factors that may contribute to these challenges. Neuroimaging research can give further insights into the underlying mechanisms of social (cognitive) difficulties. This review summarises the evidence on the associations between social cognition in the domains of theory of mind and emotion perception and processing, and individuals' social functioning and social skills, as well as associated neural mechanisms. Eighteen behavioural studies were conducted since the last major review and meta-analysis in the field (inclusion between 7/2017 and 1/2022). No major review has investigated the link between the neural mechanisms of social cognition and their association with social functioning in schizophrenia. Fourteen relevant studies were included (from 1/2000 to 1/2022). The findings of the behavioural studies showed that associations with social outcomes were slightly stronger for theory of mind than for emotion perception and processing. Moreover, performance in both social cognitive domains was more strongly associated with performance on social skill measures than questionnaire-based assessment of social functioning in the community. Studies on the underlying neural substrate of these associations presented mixed findings. In general, higher activation in various regions of the social brain was associated with better social functioning. The available evidence suggests some shared regions that might underlie the social cognition-social outcome link between different domains. However, due to the heterogeneity in approaches and findings, the current knowledge base will need to be expanded before firm conclusions can be drawn., (© 2023. Springer Nature Limited.)

This study investigated if the association between childhood maltreatment and cognition among psychosis patients and community controls was partially accounted for by genetic liability for psychosis. Patients with first-episode psychosis (N = 755) and unaffected controls (N = 1219) from the EU-GEI study were assessed for childhood maltreatment, intelligence quotient (IQ), family history of psychosis (FH), and polygenic risk score for schizophrenia (SZ-PRS). Controlling for FH and SZ-PRS did not attenuate the association between childhood maltreatment and IQ in cases or controls. Findings suggest that these expressions of genetic liability cannot account for the lower levels of cognition found among adults maltreated in childhood., (© 2023. The Author(s).)

Background: Child maltreatment (CM) and migrant status are independently associated with psychosis. We examined prevalence of CM by migrant status and tested whether migrant status moderated the association between CM and first-episode psychosis (FEP). We further explored whether differences in CM exposure contributed to variations in the incidence rates of FEP by migrant status., Methods: We included FEP patients aged 18-64 years in 14 European sites and recruited controls representative of the local populations. Migrant status was operationalized according to generation (first/further) and region of origin (Western/non-Western countries). The reference population was composed by individuals of host country's ethnicity. CM was assessed with Childhood Trauma Questionnaire. Prevalence ratios of CM were estimated using Poisson regression. We examined the moderation effect of migrant status on the odds of FEP by CM fitting adjusted logistic regressions with interaction terms. Finally, we calculated the population attributable fractions (PAFs) for CM by migrant status., Results: We examined 849 FEP cases and 1142 controls. CM prevalence was higher among migrants, their descendants and migrants of non-Western heritage. Migrant status, classified by generation (likelihood test ratio:χ 2 = 11.3, p = 0.004) or by region of origin (likelihood test ratio:χ 2 = 11.4, p = 0.003), attenuated the association between CM and FEP. PAFs for CM were higher among all migrant groups compared with the reference populations., Conclusions: The higher exposure to CM, despite a smaller effect on the odds of FEP, accounted for a greater proportion of incident FEP cases among migrants. Policies aimed at reducing CM should consider the increased vulnerability of specific subpopulations.

Background: Use of illegal stimulants is associated with an increased risk of psychotic disorder. However, the impact of stimulant use on odds of first-episode psychosis (FEP) remains unclear. Here, we aimed to describe the patterns of stimulant use and examine their impact on odds of FEP., Methods: We included patients with FEP aged 18-64 years who attended psychiatric services at 17 sites across 5 European countries and Brazil, and recruited controls representative of each local population (FEP = 1130; controls = 1497). Patterns of stimulant use were described. We computed fully adjusted logistic regression models (controlling for age, sex, ethnicity, cannabis use, and education level) to estimate their association with odds of FEP. Assuming causality, we calculated the population-attributable fractions for stimulant use associated with the odds for FEP., Findings: Prevalence of lifetime and recent stimulant use in the FEP sample were 14.50% and 7.88% and in controls 10.80% and 3.8%, respectively. Recent and lifetime stimulant use was associated with increased odds of FEP compared with abstainers [fully adjusted odds ratio 1.74,95% confidence interval (CI) 1.20-2.54, P = .004 and 1.62, 95% CI 1.25-2.09, P < .001, respectively]. According to PAFs, a substantial number of FEP cases (3.35% [95% CI 1.31-4.78] for recent use and 7.61% [95% CI 3.68-10.54] for lifetime use) could have been prevented if stimulants were no longer available and the odds of FEP and PAFs for lifetime and recent stimulant use varied across countries., Interpretation: Illegal stimulant use has a significant and clinically relevant influence on FEP incidence, with varying impacts across countries., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

It has been suggested that autistic traits are associated with less frequent alcohol use in adolescence. Our study seeks to examine the relationship between autistic traits and alcohol use in a large adolescent population. Leveraging data from the IMAGEN cohort, including 2045 14-year-old adolescents that were followed-up to age 18, we selected items on social preference/skills and rigidity from different questionnaires. We used linear regression models to (1) test the effect of the sum scores on the prevalence of alcohol use (AUDIT-C) over time, (2) explore the relationship between autistic traits and alcohol use patterns, and (3) explore the specific effect of each autistic trait on alcohol use. Higher scores on the selected items were associated with trajectories of less alcohol use from the ages between 14 and 18 (b = - 0.030; CI 95% = - 0.042, - 0.017; p < 0.001). Among adolescents who used alcohol, those who reported more autistic traits were also drinking less per occasion than their peers and were less likely to engage in binge drinking. We found significant associations between alcohol use and social preference (p < 0.001), nervousness for new situations (p = 0.001), and detail orientation (p < 0.001). Autistic traits (social impairment, detail orientation, and anxiety) may buffer against alcohol use in adolescence., (© 2022. The Author(s).)

Background: 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 EUropean Network of national schizophrenia networks studying Gene-Environment Interactions (EU-GEI) first episode 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)., Methods: Participants (842 cases, 1284 controls) from 16 European EU-GEI sites were successfully genotyped following standard quality control procedures. The sample was stratified based on genomic ancestry and analyses were done only on the subsample representing the European population (573 cases, 1005 controls). Using 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., Results: In case-control comparisons PRS-SZ, PRS-BD and PRS-D distributed differentially across psychotic subcategories. In case-case comparisons, both PRS-SZ [odds ratio (OR) = 0.7, 95% confidence interval (CI) 0.54-0.92] and PRS-D (OR = 1.31, 95% CI 1.06-1.61) differentiated AP from SSD; and within AP categories, only PRS-SZ differentiated BD from psychotic depression (OR = 2.14, 95% CI 1.23-3.74)., Conclusions: 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 the potential usefulness of PRSs in specific populations such as high-risk or early psychosis phases.

Abtract: Studies 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 = <0.001; abuse: OR = 2.16; p < 0.001; neglect: OR = 2.27; p = <0.001). None of the CpG sites significantly mediated the adversity-psychosis association after Bonferroni correction (p < 8.1 × 10 -8 ). However, 28, 34 and 29 differentially methylated probes associated with 21, 27, 20 genes passed a less stringent discovery threshold (p < 5 × 10 -5 ) for composite, abuse and neglect respectively, with a lack of overlap between abuse and neglect. These included genes previously associated to psychosis in EWAS studies, such as PANK1, SPEG TBKBP1, TSNARE1 or H2R. Downstream gene ontology analyses did not reveal any biological pathways that survived false discovery rate correction. Although at a non-significant level, DNAm changes in genes previously associated with schizophrenia in EWAS studies may mediate the CA-psychosis association. These results and associated involved processes such as mitochondrial or histaminergic disfunction, immunity or neural signalling requires replication in well powered samples. The lack of overlap between mediating genes associated with abuse and neglect suggests differential biological trajectories linking CA subtypes and psychosis., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: A history of childhood adversity is associated with psychotic disorder, with an increase in risk according to the number of exposures. However, it is not known why only some exposed individuals go on to develop psychosis. One possibility is pre-existing polygenic vulnerability. Here, we investigated, in the largest sample of first-episode psychosis (FEP) cases to date, whether childhood adversity and high polygenic risk scores for schizophrenia (SZ-PRS) combine synergistically to increase the risk of psychosis, over and above the effect of each alone., Methods: We assigned a schizophrenia-polygenic risk score (SZ-PRS), calculated from the Psychiatric Genomics Consortium (PGC2), to all participants in a sample of 384 FEP patients and 690 controls from the case-control component of the EU-GEI study. Only participants of European ancestry were included in the study. A history of childhood adversity was collected using the Childhood Trauma Questionnaire (CTQ). Synergistic effects were estimated using the interaction contrast ratio (ICR) [odds ratio (OR) exposure and PRS - OR exposure - OR PRS + 1] with adjustment for potential confounders., Results: There was some evidence that the combined effect of childhood adversities and polygenic risk was greater than the sum of each alone, as indicated by an ICR greater than zero [i.e. ICR 1.28, 95% confidence interval (CI) -1.29 to 3.85]. Examining subtypes of childhood adversities, the strongest synergetic effect was observed for physical abuse (ICR 6.25, 95% CI -6.25 to 20.88)., Conclusions: Our findings suggest possible synergistic effects of genetic liability and childhood adversity experiences in the onset of FEP, but larger samples are needed to increase precision of estimates.

Background: The role of loneliness and social exclusion in the development of paranoia is largely unexplored. Negative affect may mediate potential associations between these factors. We investigated the temporal relationships of daily-life loneliness, felt social exclusion, negative affect, and paranoia across the psychosis continuum., Method: Seventy-five participants, including 29 individuals with a diagnosis of non-affective psychosis, 20 first-degree relatives, and 26 controls used an Experience Sampling Method (ESM) app to capture the fluctuations in loneliness, feelings of social exclusion, paranoia, and negative affect across a 1-week period. Data were analysed with multilevel regression analyses., Results: In all groups, loneliness and feelings of social exclusion were independent predictors of paranoia over time (b = 0.05, p  < .001 and b = 0.04, p  < .05, respectively). Negative affect predicted paranoia (b = 0.17, p  < .001) and partially mediated the associations between loneliness, social exclusion, and paranoia. It also predicted loneliness (b = 0.15, p  < .0001), but not social exclusion (b = 0.04, p  = .21) over time. Paranoia predicted social exclusion over time, with more pronounced effects in controls (b = 0.43) than patients (b = 0.19; relatives: b = 0.17); but not loneliness (b = 0.08, p  = .16)., Conclusion: Paranoia and negative affect worsen in all groups following feelings of loneliness and social exclusion. This highlights the importance of a sense of belonging and being included for mental well-being. Loneliness, feeling socially excluded, and negative affect were independent predictors of paranoid thinking, suggesting they represent useful targets in its treatment., Competing Interests: None., (© 2023 The Author(s).)

Background and Hypothesis: It is argued that availability of diagnostic models will facilitate a more rapid identification of individuals who are at a higher risk of first episode psychosis (FEP). Therefore, we developed, evaluated, and validated a diagnostic risk estimation model to classify individual with FEP and controls across six countries., Study Design: We used data from a large multi-center study encompassing 2627 phenotypically well-defined participants (aged 18-64 years) recruited from six countries spanning 17 research sites, as part of the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions study. To build the diagnostic model and identify which of important factors for estimating an individual risk of FEP, we applied a binary logistic model with regularization by the least absolute shrinkage and selection operator. The model was validated employing the internal-external cross-validation approach. The model performance was assessed with the area under the receiver operating characteristic curve (AUROC), calibration, sensitivity, and specificity., Study Results: Having included preselected 22 predictor variables, the model was able to discriminate adults with FEP and controls with high accuracy across all six countries (ranges AUROC  = 0.84-0.86). Specificity (range = 73.9-78.0%) and sensitivity (range = 75.6-79.3%) were equally good, cumulatively indicating an excellent model accuracy; though, calibration slope for the diagnostic model showed a presence of some overfitting when applied specifically to participants from France, the UK, and The Netherlands., Conclusions: The new FEP model achieved a good discrimination and good calibration across six countries with different ethnic contributions supporting its robustness and good generalizability., Competing Interests: R.M.M. has received honoraria from Janssen, Sunovian, Lundbeck and Otsuka. M.B. has been a consultant for, received grant/research support and honoraria from, and been on the speakers/advisory board of ABBiotics, Adamed, Angelini, Casen Recordati, Janssen-Cilag, Menarini, Rovi and Takeda. Other authors declare that they have no conflict of interest. All other authors declare no conflict of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of the University of Maryland's school of medicine, Maryland Psychiatric Research Center.)

Cluster studies identified a subgroup of patients with psychosis whose premorbid adjustment deteriorates before the onset, which may reflect variation in genetic influence. However, other studies reported a complex relationship between distinctive patterns of cannabis use and cognitive and premorbid impairment that is worthy of consideration. We examined whether: (1) premorbid social functioning (PSF) and premorbid academic functioning (PAF) in childhood and adolescence and current intellectual quotient (IQ) define different clusters in 802 first-episode of psychosis (FEP) patients; resulting clusters vary in (2) polygenic risk scores (PRSs) for schizophrenia (SCZ&#95;PRS), bipolar disorder (BD&#95;PRS), major depression (MD&#95;PRS), and IQ (IQ&#95;PRS), and (3) patterns of cannabis use, compared to 1,263 population-based controls. Four transdiagnostic clusters emerged (BIC = 2268.5): (1) high-cognitive-functioning (n = 205), with the highest IQ (Mean = 106.1, 95% CI: 104.3, 107.9) and PAF, but low PSF. (2) Low-cognitive-functioning (n = 223), with the lowest IQ (Mean = 73.9, 95% CI: 72.2, 75.7) and PAF, but normal PSF. (3) Intermediate (n = 224) (Mean&#95;IQ = 80.8, 95% CI: 79.1, 82.5) with low-improving PAF and PSF. 4) Deteriorating (n = 150) (Mean&#95;IQ = 80.6, 95% CI: 78.5, 82.7), with normal-deteriorating PAF and PSF. The PRSs explained 7.9% of between-group membership. FEP had higher SCZ&#95;PRS than controls [F(4,1319) = 20.4, P < .001]. Among the clusters, the deteriorating group had lower SCZ&#95;PRS and was likelier to have used high-potency cannabis daily. Patients with FEP clustered according to their premorbid and cognitive abilities. Pronounced premorbid deterioration was not typical of most FEP, including those more strongly predisposed to schizophrenia, but appeared in a cluster with a history of high-potency cannabis use., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Background: Ethnic minorities in the Netherlands face an excess psychosis risk, and understanding of causality remains limited. Linguistic disadvantage and other indicators of societal exclusion might play a role, and offer potential targets for public health interventions., Aim: To establish the contribution of linguistic disadvantage, indicators of social distance and perceived discrimination to the increased risk of psychoses in migrants and ethnic minorities., Methods: We used the Dutch data from an international case-control study into psychotic disorders (the EU-GEI study). A first episode of psychosis was our outcome variable, and we used well-defined data on established confounders (e.g. age and sex) and indicators of ethnicity, social distance, linguistic disadvantage and perceived discrimination as our predictor variables., Results: Ethnic minorities face an increased psychosis risk. This appears to be the case for both first- and second- generation migrants and so-called &lsquo;Western&rsquo; and non-Western migrants. Though confounders and social distance appear to contribute, linguistic disadvantage appears to play a role in the excess psychosis risk in first-generation migrants., Conclusion: Reducing the social consequences of linguistic disadvantage or social distance might be a starting point for concrete public health interventions aimed at preventing the increased psychosis risk faced by first-generation migrants.

Background: Psychosis rates are higher among some migrant groups. We hypothesized that psychosis in migrants is associated with cumulative social disadvantage during different phases of migration., Methods: We used data from the EUropean Network of National Schizophrenia Networks studying Gene-Environment Interactions (EU-GEI) case-control study. We defined a set of three indicators of social disadvantage for each phase: pre-migration, migration and post-migration. We examined whether social disadvantage in the pre- and post-migration phases, migration adversities, and mismatch between achievements and expectations differed between first-generation migrants with first-episode psychosis and healthy first-generation migrants, and tested whether this accounted for differences in odds of psychosis in multivariable logistic regression models., Results: In total, 249 cases and 219 controls were assessed. Pre-migration (OR 1.61, 95% CI 1.06-2.44, p = 0.027) and post-migration social disadvantages (OR 1.89, 95% CI 1.02-3.51, p = 0.044), along with expectations/achievements mismatch (OR 1.14, 95% CI 1.03-1.26, p = 0.014) were all significantly associated with psychosis. Migration adversities (OR 1.18, 95% CI 0.672-2.06, p = 0.568) were not significantly related to the outcome. Finally, we found a dose-response effect between the number of adversities across all phases and odds of psychosis (⩾6: OR 14.09, 95% CI 2.06-96.47, p = 0.007)., Conclusions: The cumulative effect of social disadvantages before, during and after migration was associated with increased odds of psychosis in migrants, independently of ethnicity or length of stay in the country of arrival. Public health initiatives that address the social disadvantages that many migrants face during the whole migration process and post-migration psychological support may reduce the excess of psychosis in migrants.

Background and Hypothesis: Facial Emotion Recognition is a key domain of social cognition associated with psychotic disorders as a candidate intermediate phenotype. In this study, we set out to investigate global and specific facial emotion recognition deficits in first-episode psychosis, and whether polygenic liability to psychotic disorders is associated with facial emotion recognition., Study Design: 828 First Episode Psychosis (FEP) patients and 1308 population-based controls completed assessments of the Degraded Facial Affect Recognition Task (DFAR) and a subsample of 524 FEP and 899 controls provided blood or saliva samples from which we extracted DNA, performed genotyping and computed polygenic risk scores for schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MD)., Study Results: A worse ability to globally recognize facial emotion expressions was found in patients compared with controls [B= -1.5 (0.6), 95% CI -2.7 to -0.3], with evidence for stronger effects on negative emotions (fear [B = -3.3 (1.1), 95% CI -5.3 to -1.2] and anger [B = -2.3 (1.1), 95% CI -4.6 to -0.1]) than on happiness [B = 0.3 (0.7), 95% CI -1 to 1.7]. Pooling all participants, and controlling for confounds including case/control status, facial anger recognition was associated significantly with Schizophrenia Polygenic Risk Score (SZ PRS) [B = -3.5 (1.7), 95% CI -6.9 to -0.2]., Conclusions: Psychosis is associated with impaired recognition of fear and anger, and higher SZ PRS is associated with worse facial anger recognition. Our findings provide evidence that facial emotion recognition of anger might play a role as an intermediate phenotype for psychosis., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Background and Hypothesis: Evidence suggests that childhood maltreatment (ie, childhood abuse and childhood neglect) affects educational attainment and cognition. However, the association between childhood maltreatment and Intelligence Quotient (IQ) seems stronger among controls compared to people with psychosis. We hypothesised that: the association between childhood maltreatment and poor cognition would be stronger among community controls than among people with first-episode of psychosis (FEP); compared to abuse, neglect would show stronger associations with educational attainment and cognition; the association between childhood maltreatment and IQ would be partially accounted for by other risk factors; and the association between childhood maltreatment, educational attainment, and IQ would be stronger among patients with affective psychoses compared to those with nonaffective psychoses., Study Design: 829 patients with FEP and 1283 community controls from 16 EU-GEI sites were assessed for child maltreatment, education attainment, and IQ., Study Results: In both the FEP and control group, childhood maltreatment was associated with lower educational attainment. The association between childhood maltreatment and lower IQ was robust to adjustment for confounders only among controls. Whereas childhood neglect was consistently associated with lower attainment and IQ in both groups, childhood abuse was associated with IQ only in controls. Among both patients with affective and nonaffective psychoses, negative associations between childhood maltreatment and educational attainment were observed, but the crude association with IQ was only evident in affective psychoses., Conclusions: Our findings underscore the role of childhood maltreatment in shaping academic outcomes and cognition of people with FEP as well as controls., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: In Europe, the incidence of psychotic disorder is high in certain migrant and minority ethnic groups (hence: 'minorities'). However, it is unknown how the incidence pattern for these groups varies within this continent. Our objective was to compare, across sites in France, Italy, Spain, the UK and the Netherlands, the incidence rates for minorities and the incidence rate ratios (IRRs, minorities v. the local reference population)., Methods: The European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) study was conducted between 2010 and 2015. We analyzed data on incident cases of non-organic psychosis (International Classification of Diseases, 10th edition, codes F20-F33) from 13 sites., Results: The standardized incidence rates for minorities, combined into one category, varied from 12.2 in Valencia to 82.5 per 100 000 in Paris. These rates were generally high at sites with high rates for the reference population, and low at sites with low rates for the reference population. IRRs for minorities (combined into one category) varied from 0.70 (95% CI 0.32-1.53) in Valencia to 2.47 (95% CI 1.66-3.69) in Paris (test for interaction: p = 0.031). At most sites, IRRs were higher for persons from non-Western countries than for those from Western countries, with the highest IRRs for individuals from sub-Saharan Africa (adjusted IRR = 3.23, 95% CI 2.66-3.93)., Conclusions: Incidence rates vary by region of origin, region of destination and their combination. This suggests that they are strongly influenced by the social context.

Emerging research on psychological adjustment during the COVID-19 outbreak has suggested that young people may be particularly vulnerable to increases in negative affect during the pandemic. However, the association between alcohol use in youth and change in negative affect during this unprecedented time is not clear. Using an online survey, this study obtained scores on negative affect ( before and during the COVID-19 pandemic), pandemic-related stress, change in drinking frequency, and traits including resilience, impulsivity and anhedonia, from a sample of drinkers and non-drinkers, up to the age of 21. Young drinkers experienced a greater increase in negative affect during the pandemic compared to non-drinkers, and this differential rise in negative affect was mediated by the pandemic-related stress of social isolation. Young drinkers also experienced a decrease in alcohol use during the pandemic, but this was not associated with a change in negative affect. Interestingly, young drinkers with greater resilience and lower anhedonia reported less increase in negative affect during the COVID-19 pandemic. Taken together, these results show that the greater increase in negative affect that young drinkers experienced during the COVID-19 pandemic, compared to their non-drinking counterparts, was mediated by pandemic-related social isolation. Moreover, greater resilience and lower anhedonia may have served as protective factors for mitigating the social isolation-induced worsening of negative affect in young drinkers during the pandemic. These findings may inform future studies investigating potential indicators of maladaptive affective responses to public health crises in vulnerable adolescent populations.

Introduction: Disturbed sleep is a common feature of psychotic disorders that is also present in the clinical high risk (CHR) state. Evidence suggests a potential role of sleep disturbance in symptom progression, yet the interrelationship between sleep and CHR symptoms remains to be determined. To address this knowledge gap, we examined the association between disturbed sleep and CHR symptoms over time., Methods: Data were obtained from the North American Prodrome Longitudinal Study (NAPLS)-3 consortium, including 688 CHR individuals and 94 controls (mean age 18.25, 46% female) for whom sleep was tracked prospectively for 8 months. We used Cox regression analyses to investigate whether sleep disturbances predicted conversion to psychosis up to >2 years later. With regressions and cross-lagged panel models, we analyzed longitudinal and bidirectional associations between sleep (the Pittsburgh Sleep Quality Index in conjunction with additional sleep items) and CHR symptoms. We also investigated the independent contribution of individual sleep characteristics on CHR symptom domains separately and explored whether cognitive impairments, stress, depression, and psychotropic medication affected the associations., Results: Disturbed sleep at baseline did not predict conversion to psychosis. However, sleep disturbance was strongly correlated with heightened CHR symptoms over time. Depression accounted for half of the association between sleep and symptoms. Importantly, sleep was a significant predictor of CHR symptoms but not vice versa, although bidirectional effect sizes were similar., Discussion: The critical role of sleep disturbance in CHR symptom changes suggests that sleep may be a promising intervention target to moderate outcome in the CHR state., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Negative symptoms occur in individuals at ultrahigh risk (UHR) for psychosis. Although there is evidence that observer ratings of negative symptoms are associated with level of functioning, the predictive value of subjective experience in daily life for individuals at UHR has not been studied yet., Objective: This study therefore aims to investigate the predictive value of momentary manifestations of negative symptoms for clinical outcomes in individuals at UHR., Methods: Experience sampling methodology was used to measure momentary manifestations of negative symptoms (blunted affective experience, lack of social drive, anhedonia, and social anhedonia) in the daily lives of 79 individuals at UHR. Clinical outcomes (level of functioning, illness severity, UHR status, and transition status) were assessed at baseline and at 1- and 2-year follow-ups., Results: Lack of social drive, operationalized as greater experienced pleasantness of being alone, was associated with poorer functioning at the 2-year follow-up (b=-4.62, P=.01). Higher levels of anhedonia were associated with poorer functioning at the 1-year follow-up (b=5.61, P=.02). Higher levels of social anhedonia were associated with poorer functioning (eg, disability subscale: b=6.36, P=.006) and greater illness severity (b=-0.38, P=.045) at the 1-year follow-up. In exploratory analyses, there was evidence that individuals with greater variability of positive affect (used as a measure of blunted affective experience) experienced a shorter time to remission from UHR status at follow-up (hazard ratio=4.93, P=.005)., Conclusions: Targeting negative symptoms in individuals at UHR may help to predict clinical outcomes and may be a promising target for interventions in the early stages of psychosis., (©Isabell Paetzold, Karlijn S F M Hermans, Anita Schick, Barnaby Nelson, Eva Velthorst, Frederike Schirmbeck, EU-GEI High Risk Study, Jim van Os, Craig Morgan, Mark van der Gaag, Lieuwe de Haan, Lucia Valmaggia, Philip McGuire, Matthew Kempton, Inez Myin-Germeys, Ulrich Reininghaus. Originally published in JMIR Mental Health (https://mental.jmir.org), 19.11.2021.)

The influence of psychosocial stressors on psychosis risk has usually been studied in isolation and after the onset of the disorder, potentially ignoring important confounding relationships or the fact that some stressors that may be the consequence of the disorder rather than preexisting. The study of subclinical psychosis could help to address some of these issues. In this study, we investigated whether there was (i) an association between dimensions of subclinical psychosis and several psychosocial stressors including: childhood trauma, self-reported discrimination experiences, low social capital, and stressful life experiences, and (ii) any evidence of environment-environment (ExE) interactions between these factors. Data were drawn from the EUGEI study, in which healthy controls (N = 1497) and siblings of subjects with a psychotic disorder (N = 265) were included in six countries. The association between psychosocial stressors and subclinical psychosis dimensions (positive, negative and depressive dimension as measured by the Community Assessment of Psychic Experiences (CAPE) scale) and possible ExE interactions were assessed using linear regression models. After adjusting for sex, age, ethnicity, country, and control/sibling status, childhood trauma (β for positive dimension: 0.13, negative: 0.49, depressive: 0.26) and stressful life events (positive: 0.08, negative: 0.16, depressive: 0.17) were associated with the three dimensions. Lower social capital was associated with the negative and depression dimensions (negative: 0.26, depressive: 0.13), and self-reported discrimination experiences with the positive dimension (0.06). Our findings are in favor of independent, cumulative and non-specific influences of social adversities in subclinical psychosis in non-clinical populations, without arguments for E × E interactions., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Premorbid functioning and cognitive measures may reflect gradients of developmental impairment across diagnostic categories in psychosis. In this study, we sought to examine the associations of current cognition and premorbid adjustment with symptom dimensions in a large first episode psychosis (FEP) sample. We used data from the international EU-GEI study. Bifactor modelling of the Operational Criteria in Studies of Psychotic Illness (OPCRIT) ratings provided general and specific symptom dimension scores. Premorbid Adjustment Scale estimated premorbid social (PSF) and academic adjustment (PAF), and WAIS-brief version measured IQ. A MANCOVA model examined the relationship between symptom dimensions and PSF, PAF, and IQ, having age, sex, country, self-ascribed ethnicity and frequency of cannabis use as confounders. In 785 patients, better PSF was associated with fewer negative (B = -0.12, 95% C.I. -0.18, -0.06, p < 0.001) and depressive (B = -0.09, 95% C.I. -0.15, -0.03, p = 0.032), and more manic (B = 0.07, 95% C.I. 0.01, 0.14, p = 0.023) symptoms. Patients with a lower IQ presented with slightly more negative and positive, and fewer manic, symptoms. Secondary analysis on IQ subdomains revealed associations between better perceptual reasoning and fewer negative (B = -0.09, 95% C.I. -0.17, -0.01, p = 0.023) and more manic (B = 0.10, 95% C.I. 0.02, 0.18, p = 0.014) symptoms. Fewer positive symptoms were associated with better processing speed (B = -0.12, 95% C.I. -0.02, -0.004, p = 0.003) and working memory (B = -0.10, 95% C.I. -0.18, -0.01, p = 0.024). These findings suggest that the negative and manic symptom dimensions may serve as clinical proxies of different neurodevelopmental predisposition in psychosis., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Diagnostic categories do not completely reflect the heterogeneous expression of psychosis. Using data from the EU-GEI study, we evaluated the impact of schizophrenia polygenic risk score (SZ-PRS) and patterns of cannabis use on the transdiagnostic expression of psychosis. We analysed first-episode psychosis patients (FEP) and controls, generating transdiagnostic dimensions of psychotic symptoms and experiences using item response bi-factor modelling. Linear regression was used to test the associations between these dimensions and SZ-PRS, as well as the combined effect of SZ-PRS and cannabis use on the dimensions of positive psychotic symptoms and experiences. We found associations between SZ-PRS and (1) both negative (B = 0.18; 95%CI 0.03-0.33) and positive (B = 0.19; 95%CI 0.03-0.35) symptom dimensions in 617 FEP patients, regardless of their categorical diagnosis; and (2) all the psychotic experience dimensions in 979 controls. We did not observe associations between SZ-PRS and the general and affective dimensions in FEP. Daily and current cannabis use were associated with the positive dimensions in FEP (B = 0.31; 95%CI 0.11-0.52) and in controls (B = 0.26; 95%CI 0.06-0.46), over and above SZ-PRS. We provide evidence that genetic liability to schizophrenia and cannabis use map onto transdiagnostic symptom dimensions, supporting the validity and utility of the dimensional representation of psychosis. In our sample, genetic liability to schizophrenia correlated with more severe psychosis presentation, and cannabis use conferred risk to positive symptomatology beyond the genetic risk. Our findings support the hypothesis that psychotic experiences in the general population have similar genetic substrates as clinical disorders., (© 2021. The Author(s).)

Objective: To compare the incidence of psychosis among migrants with the incidence among the native Dutch in Amsterdam, Gouda and Voorhout., Design: We identified patients with a first treated episode of psychosis (ICD-10 codes F20-F33) in 2010-2013 as part of the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) study. Information on the composition of the population made it possible to calculate incidence rates., Method: We analyzed the Incidence Rate Ratios (IRR) of psychosis among various ethnic groups compared to the native Dutch using a Poisson model., Results: The standardized rates in Amsterdam were 55.3/ 100,000 person-years (py) for migrants and 24.9/ 100,000py for native Dutch. In Gouda and Voorhout, these rates were 28.5 en 20.0/ 100,000py. We found increased rates among Moroccan males of the first (IRR=4.07 [95%-CI: 1.76-9.42]) and second generation (IRR=6.48 [3.30-12.68]) in Amsterdam. In Gouda and Voorhout, we found increased rates both among Moroccan males (IRR=3.37 [1.17-9.74]) of the first generation and Moroccan females of the second generation (IRR=7.10 [2.79-18.06]). High rates were also found in Amsterdam for male migrants from Eastern Europe (IRR=4.52 [2.24-9.11]), migrants from sub-Saharan Africa (IRR=3.15 [1.68-5.91]) and first-generation migrants, both males and females, from Surinam and the Netherlands Antilles. We found a decreased incidence for Western migrants., Conclusion: We found an increased incidence of psychosis among non-Western migrants and in Amsterdam also among Eastern-European migrants. The variation by region of origin and destination generation, and gender suggests that this risk is strongly influenced by the societal context.

Background: Ethnic minority groups in Western countries face an increased risk of psychotic disorders. Causes of this long-standing public health inequality remain poorly understood. We investigated whether social disadvantage, linguistic distance and discrimination contributed to these patterns., Methods: We used case-control data from the EUropean network of national schizophrenia networks studying Gene-Environment Interactions (EU-GEI) study, carried out in 16 centres in six countries. We recruited 1130 cases and 1497 population-based controls. Our main outcome measure was first-episode ICD-10 psychotic disorder (F20-F33), and exposures were ethnicity (white majority, black, mixed, Asian, North-African, white minority and other), generational status, social disadvantage, linguistic distance and discrimination. Age, sex, paternal age, cannabis use, childhood trauma and parental history of psychosis were included as a priori confounders. Exposures and confounders were added sequentially to multivariable logistic models, following multiple imputation for missing data., Results: Participants from any ethnic minority background had crude excess odds of psychosis [odds ratio (OR) 2.03, 95% confidence interval (CI) 1.69-2.43], which remained after adjustment for confounders (OR 1.61, 95% CI 1.31-1.98). This was progressively attenuated following further adjustment for social disadvantage (OR 1.52, 95% CI 1.22-1.89) and linguistic distance (OR 1.22, 95% CI 0.95-1.57), a pattern mirrored in several specific ethnic groups. Linguistic distance and social disadvantage had stronger effects for first- and later-generation groups, respectively., Conclusion: Social disadvantage and linguistic distance, two potential markers of sociocultural exclusion, were associated with increased odds of psychotic disorder, and adjusting for these led to equivocal risk between several ethnic minority groups and the white majority.

Background: Daily use of high-potency cannabis has been reported to carry a high risk for developing a psychotic disorder. However, the evidence is mixed on whether any pattern of cannabis use is associated with a particular symptomatology in first-episode psychosis (FEP) patients., Method: We analysed data from 901 FEP patients and 1235 controls recruited across six countries, as part of the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) study. We used item response modelling to estimate two bifactor models, which included general and specific dimensions of psychotic symptoms in patients and psychotic experiences in controls. The associations between these dimensions and cannabis use were evaluated using linear mixed-effects models analyses., Results: In patients, there was a linear relationship between the positive symptom dimension and the extent of lifetime exposure to cannabis, with daily users of high-potency cannabis having the highest score ( B = 0.35; 95% CI 0.14-0.56). Moreover, negative symptoms were more common among patients who never used cannabis compared with those with any pattern of use ( B = -0.22; 95% CI -0.37 to -0.07). In controls, psychotic experiences were associated with current use of cannabis but not with the extent of lifetime use. Neither patients nor controls presented differences in depressive dimension related to cannabis use., Conclusions: Our findings provide the first large-scale evidence that FEP patients with a history of daily use of high-potency cannabis present with more positive and less negative symptoms, compared with those who never used cannabis or used low-potency types.

Objective: It is unclear whether deviations in brain and behavioral development, which may underpin elevated substance use during adolescence, are predispositions for or consequences of substance use initiation. Here, we examine behavioral and neuroimaging indices at early and mid-adolescence in drug-naive youths to identify possible predisposing factors for substance use initiation and its possible consequences., Method: Among 304 drug-naive adolescents at baseline (age 14 years) from the IMAGEN dataset, 83 stayed drug-naive, 133 used alcohol on 1 to 9 occasions, 42 on 10 to 19 occasions, 27 on 20 to 39 occasions, and 19 on >40 occasions at follow-up (age 16 years). Baseline measures included brain activation during the Monetary Incentive Delay task. Data at both baseline and follow-up included measures of trait impulsivity and delay discounting., Results: From baseline to follow-up, impulsivity decreased in the 0 and 1- to 9-occasions groups (p < .004), did not change in the 10- to 19-occasions and 20- to 29-occasions groups (p > .294), and uncharacteristically increased in the >40-occasions group (p = .046). Furthermore, blunted medial orbitofrontal cortex activation during reward outcome at baseline significantly predicted higher alcohol use frequency at follow-up, above and beyond behavioral and clinical variables (p = .008)., Conclusion: These results suggest that the transition from no use to frequent drinking in early to mid-adolescence may disrupt normative developmental changes in behavioral control. In addition, blunted activity of the medial orbitofrontal cortex during reward outcome may underscore a predisposition toward the development of more severe alcohol use in adolescents. This distinction is clinically important, as it informs early intervention efforts in preventing the onset of substance use disorder in adolescents., (Copyright © 2020 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Perceived discrimination is associated with worse mental health. Few studies have assessed whether perceived discrimination (i) is associated with the risk of psychotic disorders and (ii) contributes to an increased risk among minority ethnic groups relative to the ethnic majority., Methods: We used data from the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions Work Package 2, a population-based case-control study of incident psychotic disorders in 17 catchment sites across six countries. We calculated odds ratios (OR) and 95% confidence intervals (95% CI) for the associations between perceived discrimination and psychosis using mixed-effects logistic regression models. We used stratified and mediation analyses to explore differences for minority ethnic groups., Results: Reporting any perceived experience of major discrimination (e.g. unfair treatment by police, not getting hired) was higher in cases than controls (41.8% v. 34.2%). Pervasive experiences of discrimination (≥3 types) were also higher in cases than controls (11.3% v. 5.5%). In fully adjusted models, the odds of psychosis were 1.20 (95% CI 0.91-1.59) for any discrimination and 1.79 (95% CI 1.19-1.59) for pervasive discrimination compared with no discrimination. In stratified analyses, the magnitude of association for pervasive experiences of discrimination appeared stronger for minority ethnic groups (OR = 1.73, 95% CI 1.12-2.68) than the ethnic majority (OR = 1.42, 95% CI 0.65-3.10). In exploratory mediation analysis, pervasive discrimination minimally explained excess risk among minority ethnic groups (5.1%)., Conclusions: Pervasive experiences of discrimination are associated with slightly increased odds of psychotic disorders and may minimally help explain excess risk for minority ethnic groups.