Background: Diminished Expression (DE) and Amotivation/Apathy (AA) are widely recognized as two main factors of negative symptoms. This study aimed to 1) examine the longitudinal stability of the DE-AA structure and its variation throughout a 5-year follow-up in people with first-episode psychosis (FEP), and 2) investigate whether DE and AA have distinct predictive value compared with the unitary construct of negative symptoms. Study Design: 227 participants from the EUropean Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) and Genetics and Psychosis (GAP) studies were included at FEP and were followed up 5 years later. One-factor (global negative symptoms), uncorrelated two-factor (DE-AA), and correlated two-factor structures were modelled using confirmatory factor analysis. Regression analyses were applied to examine the associations between these factors and negative symptom trajectories, functioning, and quality-of-life outcomes. Study Results: The correlated two-factor model composed of DE and AA best fitted the data and exhibited 5-year stability. The regression model adjusted for AA accounted for more variance (59.2%) than global negative symptoms (52.8%) in explaining the enduring course of negative symptoms. Baseline AA was the only negative symptom factor that significantly predicted individuals' functional outcome at follow-up (B=-1.76, p=0.037). All negative symptom dimensions negatively predicted employment status, whereas lower educational attainment was primarily related to AA severity at baseline. Conclusions: Our findings support the validity and longitudinal stability of the two-dimensional (DE-AA) approach to negative symptoms in individuals with FEP. AA in particular exhibited distinctive predictive value, underscoring its potential clinical utility for early identification and the development of targeted interventions. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The study was supported by the Biomedical Research Centre of the South London and Maudsley Trust, the Psychiatry Research Trust, and Medical Research Council to Dr Diego Quattrone (grant number MR/W030608/1) and the MRC fellowship to Dr Marta Di Forti (grant number MR/M008436/1). YL was supported by the King's-China Scholarship Council scholarship programme (K-CSC; grant number 202208060331) ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee of Biomedical Research Centre of the South London and Maudsley Trust gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors

Objective: Psychotic disorders are heterogeneous in their clinical presentation and outcome. While early research focused on poor prognoses in schizophrenia, recent longitudinal studies tracking first-episode psychosis (FEP) have identified more favourable outcome trajectories. This study investigates the stability and predictive value of metacognitive and social cognitive impairments-Jumping to Conclusions (JTC) bias and Facial Emotion Recognition (FER) deficits-as intermediate phenotypes of psychosis over a 5-year follow-up period. Method: A total of 134 FEP patients and 105 population-based controls from the GAP and EU-GEI follow-up study in London were reassessed after an average of 4.8 years. JTC was measured using the 60:40 Beads task, while FER was assessed through the Degraded Facial Affect Recognition (DFAR) task Clinical, functional, and social outcomes-including hospital admissions, symptom severity, and employment status-were evaluated. Mixed models and regression modeling examined the stability of these cognitive traits and their association with long-term outcomes. Results: JTC and FER impairments remain stable over time, supporting their classification as intermediate phenotypes. However, neither JTC nor FER was associated with clinical outcomes (hospitalization rates, symptom severity) or social functioning (employment, independent living, relationships). A weak correlation was found between global FER impairment and negative symptoms at follow-up, but no associations emerged with real-world functional measures. Additionally, while patients demonstrated greater impairments than controls, the differences were more quantitative than qualitative, aligning with the psychosis continuum hypothesis. Conclusions: These findings demonstrate that JTC and FER are stable in people with psychosis and controls. Therefore, they may serve as important treatment targets for early intervention in psychosis. Future research should integrate the potential role of environmental factors as well as genetic influence to deepen our understanding of cognitive impairments in psychotic disorders.

Introduction Evidence suggests that childhood maltreatment affects cognitive performance in both patients with psychosis and community controls. However, the interplay between childhood maltreatment, post-traumatic stress symptoms (PTSS), and intelligence has not been investigated. This study investigated the relationship between childhood maltreatment, subclinical PTSS, and intelligence among patients with first-episode psychosis (FEP) and community controls.Methods Patients with FEP (N = 602) and controls (N = 853) from the EU-GEI study were assessed for childhood maltreatment, PTSS, and intelligence quotient (IQ).Results PTSS were associated with lower IQ among community controls but not among patients with FEP. In the FEP group, an interaction (p = 0.044) between PTSS and childhood maltreatment on IQ was found, such that the association between PTSS and lower IQ was only present among those exposed to childhood maltreatment. No interaction was evident in controls (p = 0.826).Conclusions The findings suggest the relevance of cognitive rehabilitation for FEP patients with childhood maltreatment and PTSS.

Objectives: To establish whether the risk of psychotic disorders in cannabis users changes with time following cannabis cessation using data from the European Network of National Networks studying Gene-Environment Interactions in Schizophrenia (EU-GEI) case-control study. Methods: The EU-GEI case-control study collected data from first episode psychosis patients and population controls across sites in Europe and Brazil between May 2010 and April 2015. Adjusted logistic regressions were applied to examine whether the odd of psychosis case status changed: (1) with time following cannabis cessation and (2) across different cannabis use groups. Results: Psychosis risk declined following cessation of cannabis use (beta = -0.002; 95% CI -0.004 to 0.000; P = 0.067). When accounting for duration of use, this effect remained (beta = -0.003; 95% CI -0.005 to -0.001; P = 0.013). However, in models adjusting for frequency and potency of use the result was not significant. Analysis of different cannabis use groups indicated that ex-users who stopped 1 to 4 weeks previously had the highest risk for psychotic disorder compared to never users (OR = 6.89; 95% CI 3.91-12.14; P < 0.001); risk declined for those who stopped 5 to 12 weeks previously (OR = 2.70; 95% CI 1.73-4.21; P < 0.001) and 13 to 36 weeks previously (OR = 1.53; 95% CI 1.00-2.33; P = 0.050). Ex-users who stopped 37 to 96 weeks (OR = 1.01; 95% CI 0.66-1.57; P = 0.949), 97 to 180 weeks (OR = 0.73; 95% CI 0.45-1.19; P = 0.204), and 181 weeks previously or more (OR = 1.18; 95% CI 0.76-1.83; P = 0.456) had similar psychosis risk to those who had never-used cannabis. Conclusion: Risk of psychotic disorder appears to decline with time following cannabis cessation, receding to that of those who have never used cannabis after 37 weeks or more of abstinence. Although, preliminary results suggest that frequent users of high potency types of cannabis might maintain an elevated risk compared to never users even when abstaining for longer than 181 weeks.

Background Multiple genetic and environmental risk factors play a role in the development of both schizophrenia-spectrum disorders and affective psychoses. How they act in combination is yet to be clarified.Methods We analyzed 573 first episode psychosis cases and 1005 controls, of European ancestry. Firstly, we tested whether the association of polygenic risk scores for schizophrenia, bipolar disorder, and depression (PRS-SZ, PRS-BD, and PRS-D) with schizophrenia-spectrum disorder and affective psychosis differed when participants were stratified by exposure to specific environmental factors. Secondly, regression models including each PRS and polyenvironmental measures, including migration, paternal age, childhood adversity and frequent cannabis use, were run to test potential polygenic by polyenvironment interactions.Results In schizophrenia-spectrum disorder vs controls comparison, PRS-SZ was the strongest genetic predictor, having a nominally larger effect in nonexposed to strong environmental factors such as frequent cannabis use (unexposed vs exposed OR 2.43 and 1.35, respectively) and childhood adversity (3.04 vs 1.74). In affective psychosis vs controls, the relative contribution of PRS-D appeared to be stronger in those exposed to environmental risk. No evidence of interaction was found between any PRS with polyenvironmental score.Conclusions Our study supports an independent role of genetic liability and polyenvironmental risk for psychosis, consistent with the liability threshold model. Whereas schizophrenia-spectrum disorders seem to be mostly associated with polygenic risk for schizophrenia, having an additive effect with well-replicated environmental factors, affective psychosis seems to be a product of cumulative environmental insults alongside a higher genetic liability for affective disorders.

The rising prevalence and legalisation of cannabis worldwide have underscored the need for a comprehensive understanding of its biological impact, particularly on mental health. Epigenetic mechanisms, specifically DNA methylation, have gained increasing recognition as vital factors in the interplay between risk factors and mental health. This study aimed to explore the effects of current cannabis use and high-potency cannabis on DNA methylation in two independent cohorts of individuals experiencing first-episode psychosis (FEP) compared to control subjects. The combined sample consisted of 682 participants (188 current cannabis users and 494 never users). DNA methylation profiles were generated on blood-derived DNA samples using the Illumina DNA methylation array platform. A meta-analysis across cohorts identified one CpG site (cg11669285) in the CAVIN1 gene that showed differential methylation with current cannabis use, surpassing the array-wide significance threshold, and independent of the tobacco-related epigenetic signature. Furthermore, a CpG site localised in the MCU gene (cg11669285) achieved array-wide significance in an analysis of the effect of high-potency (THC = > 10%) current cannabis use. Pathway and regional analyses identified cannabis-related epigenetic variation proximal to genes linked to immune and mitochondrial function, both of which are known to be influenced by cannabinoids. Interestingly, a model including an interaction term between cannabis use and FEP status identified two sites that were significantly associated with current cannabis use with a nominally significant interaction suggesting that FEP status might moderate how cannabis use affects DNA methylation. Overall, these findings contribute to our understanding of the epigenetic impact of current cannabis use and highlight potential molecular pathways affected by cannabis exposure.

BACKGROUND:The association between cannabis and psychosis is established, but the role of underlying genetics is unclear. We used data from the EU-GEI case-control study and UK Biobank to examine the independent and combined effect of heavy cannabis use and schizophrenia polygenic risk score (PRS) on risk for psychosis. METHODS:Genome-wide association study summary statistics from the Psychiatric Genomics Consortium and the Genomic Psychiatry Cohort were used to calculate schizophrenia and cannabis use disorder (CUD) PRS for 1098 participants from the EU-GEI study and 143600 from the UK Biobank. Both datasets had information on cannabis use. RESULTS:In both samples, schizophrenia PRS and cannabis use independently increased risk of psychosis. Schizophrenia PRS was not associated with patterns of cannabis use in the EU-GEI cases or controls or UK Biobank cases. It was associated with lifetime and daily cannabis use among UK Biobank participants without psychosis, but the effect was substantially reduced when CUD PRS was included in the model. In the EU-GEI sample, regular users of high-potency cannabis had the highest odds of being a case independently of schizophrenia PRS (OR daily use high-potency cannabis adjusted for PRS = 5.09, 95% CI 3.08-8.43, p = 3.21 × 10-10). We found no evidence of interaction between schizophrenia PRS and patterns of cannabis use. CONCLUSIONS:Regular use of high-potency cannabis remains a strong predictor of psychotic disorder independently of schizophrenia PRS, which does not seem to be associated with heavy cannabis use. These are important findings at a time of increasing use and potency of cannabis worldwide.

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. 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.

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.

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.

AbstractBackgroundWhile cannabis use is a well-established risk factor for psychosis, little is known about any association between reasons for first using cannabis (RFUC) and later patterns of use and risk of psychosis.MethodsWe used data from 11 sites of the multicentre European Gene-Environment Interaction (EU-GEI) case–control study. 558 first-episode psychosis patients (FEPp) and 567 population controls who had used cannabis and reported their RFUC.We ran logistic regressions to examine whether RFUC were associated with first-episode psychosis (FEP) case–control status. Path analysis then examined the relationship between RFUC, subsequent patterns of cannabis use, and case–control status.ResultsControls (86.1%) and FEPp (75.63%) were most likely to report ‘because of friends’ as their most common RFUC. However, 20.1% of FEPp compared to 5.8% of controls reported: ‘to feel better’ as their RFUC (χ2 = 50.97; p < 0.001). RFUC ‘to feel better’ was associated with being a FEPp (OR 1.74; 95% CI 1.03–2.95) while RFUC ‘with friends’ was associated with being a control (OR 0.56; 95% CI 0.37–0.83). The path model indicated an association between RFUC ‘to feel better’ with heavy cannabis use and with FEPp-control status.ConclusionsBoth FEPp and controls usually started using cannabis with their friends, but more patients than controls had begun to use ‘to feel better’. People who reported their reason for first using cannabis to ‘feel better’ were more likely to progress to heavy use and develop a psychotic disorder than those reporting ‘because of friends’.

AbstractBackgroundTobacco is a highly prevalent substance of abuse in patients with psychosis. Previous studies have reported an association between tobacco use and schizophrenia. The aim of this study was to analyze the relationship between tobacco use and first-episode psychosis (FEP), age at onset of psychosis, and specific diagnosis of psychosis.MethodsThe sample consisted of 1105 FEP patients and 1355 controls from the European Network of National Schizophrenia Networks Studying Gene–Environment Interactions (EU-GEI) study. We assessed substance use with the Tobacco and Alcohol Questionnaire and performed a series of regression analyses using case-control status, age of onset of psychosis, and diagnosis as outcomes and tobacco use and frequency of tobacco use as predictors. Analyses were adjusted for sociodemographic characteristics, alcohol, and cannabis use.ResultsAfter controlling for cannabis use, FEP patients were 2.6 times more likely to use tobacco [p ⩽ 0.001; adjusted odds ratio (AOR) 2.6; 95% confidence interval (CI) [2.1–3.2]] and 1.7 times more likely to smoke 20 or more cigarettes a day (p = 0.003; AOR 1.7; 95% CI [1.2–2.4]) than controls. Tobacco use was associated with an earlier age at psychosis onset (β = −2.3; p ⩽ 0.001; 95% CI [−3.7 to −0.9]) and was 1.3 times more frequent in FEP patients with a diagnosis of schizophrenia than in other diagnoses of psychosis (AOR 1.3; 95% CI [1.0–1.8]); however, these results were no longer significant after controlling for cannabis use.ConclusionsTobacco and heavy-tobacco use are associated with increased odds of FEP. These findings further support the relevance of tobacco prevention in young populations.

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.

Abstract: BackgroundPsychosis rates are higher among some migrant groups. We hypothesized that psychosis in migrants is associated with cumulative social disadvantage during different phases of migration.MethodsWe used data from the EUropean Network of National Schizophrenia Networks studying Gene-Environment Interactions (EU-GEI) case-control study. We defined a set of 3 indicators of social disadvantage for each phase: pre-migration, migration, and post-migration.Results249 cases and 219 controls were assessed. Pre-migration (OR 1.61, 95%CI 1.06-2.44, p=0.027) and postmigration 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. We found a dose-response effect between number of adversities across all phases and odds of psychosis (≥6: OR 14.09, 95%CI 2.06-96-47, p=0.007).ConclusionsThe 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 be reduce the excess of psychosis in migrants.Disclosure of InterestNone Declared

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_PRS), bipolar disorder (BD_PRS), major depression (MD_PRS), and IQ (IQ_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_IQ = 80.8, 95% CI: 79.1, 82.5) with low-improving PAF and PSF. 4) Deteriorating (n = 150) (Mean_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_PRS than controls [F(4,1319) = 20.4, P < .001]. Among the clusters, the deteriorating group had lower SCZ_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.

Abstract 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.

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 (rangesAUROC = 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.