Cross-disorder research and replication of neuroimaging findings remains scarce. Social dysfunction is an early manifestation across diverse neuropsychiatric disorders that may relate to altered default mode network (DMN) integrity. This study aimed to replicate previous findings linking social dysfunction with diminished resting-state DMN functional connectivity and altered task-based DMN functional activation in response to emotional faces across schizophrenia (SZ), Alzheimer’s disease (AD), and healthy controls (HC), and to extend these findings to major depressive disorder (MDD). Resting-state fMRI and task-based fMRI data on implicit facial emotional processing were acquired in an overlapping cohort (resting-state fMRI: N=167; SZ=32, MDD=44, AD=29, HC=62. Task-based fMRI: N=152; SZ=30, MDD=42, AD=26, HC=54). Additionally, mega-analyses (N=317 for resting-state fMRI; N=291 for task-based fMRI) of the current and a prior independent sample were conducted. Social dysfunction was indexed with the Social Functioning Scale (SFS) and the De Jong-Gierveld Loneliness (LON) scale. The association between higher mean SFS+LON social dysfunction scores and diminished DMN connectivity within the dorsomedial prefrontal cortex across SZ/AD/HC participants was replicated, and extended to MDD patients. Similar observations within the dorsomedial and rostromedial prefrontal cortex were found in the mega-analysis. Associations between social dysfunction and DMN activation in response to sad and happy faces were not replicated or found in the mega-analysis. To conclude, diminished dorsomedial prefrontal cortex DMN connectivity emerged as a transdiagnostic neurobiological marker for social dysfunction, suggesting a potential treatment target for precision medicine approaches. DMN functional responses to emotional faces may not be a sensitive biomarker for social dysfunction.

Previous studies have evaluated the role of the microRNA-137 (miRNA137) regulatory pathway in schizophrenia by using in silico or in vitro predicted target genes. These approaches do not capture the dynamic spatiotemporal nature of the miRNA137 regulatory pathway or tend to overestimate direct miRNA binding sites. To provide a more accurate representation of the miRNA137 pathway during human brain development, we evaluated the biological functionality of direct ex vivo miRNA137 targets previously documented in the early prenatal and adult brain. We studied the role of differential expression and genetic predisposing variation to schizophrenia and related disorders within these miRNA137 targets by gene set enrichment analyses (GSEA) and gene-set based polygenic score predictions in an independent schizophrenia case-control cohort. All results were compared to those from in silico or in vitro predicted targets. Only direct miRNA137 targets at prenatal and adult human brain displayed significant enrichments in synaptic and neuronal functions and captured the transcriptomic and genetic predisposing variation to schizophrenia. Furthermore, while adult target genes showed a more consistent enrichment in predisposing variation to schizophrenia and bipolar disorder in case/control polygenic models, prenatal target genes predicted negative symptomatology in schizophrenia patients. Our results suggest that using direct, temporally specific miRNA137 targets significantly improved the detection of biological mechanisms underlying its relationship with psychosis, clarified the association between schizophrenia and related conditions, and suggested association with specific symptomatology domains at different developmental stages of the disorder.

Schizophrenia (SZ) is increasingly framed as a disorder of large-scale brain networks emerging from atypical early neurodevelopment, yet how network architecture relates to cortical folding abnormalities remains unclear. Here, we introduce a sulcal morphological-centred network framework that integrates normative modelling of sulcal width with diffusion-derived structural connectivity and transcriptomic data in a large multisite cohort (n = 5,392; 377 SZ). Individuals with SZ showed widespread sulcal widening, affecting 30 of 40 sulci and most pronounced in frontal, temporal and occipital regions. Critically, sulci with higher degree centrality, reflecting greater embedding within the structural connectome, exhibited disproportionately greater widening in SZ (p spin = 0.02), indicating that network hubs of cortical folding are preferentially affected. Transcriptomic integration using partial least squares regression identified a single component explaining 56.5% of SZ-related sulcal widening variance (p perm = 0.041), implicating genes enriched for synaptic signalling and energy metabolism with adult cortical expression bias and genetic enrichment for cross-disorder psychiatric risk. In contrast, oppositely weighted genes showed prenatal expression bias and enrichment for rare disruptive variants in autism spectrum disorder. Together, these findings link aberrant sulcal morphology in SZ to the brain's network topology and molecular architecture, positioning cortical folding as a network-embedded phenotype in SZ.

This study compared Spain's responsiveness in healthcare and the non-healthcare systems to population mental health (MH) needs with that of all other European Union (EU) countries and the United Kingdom (UK) using data from the 2023 Headway Initiative. Regarding responsiveness in healthcare, Spain scored 3.4 (out of 10), ranking 17th, whereas in the nonhealthcare system Spain scored 4.5, ranking 25th. Spain's responsiveness to population MH needs remains comparatively lower than that of most European countries. Improved governance and integration of services, digitalisation, research and prevention should guide future MH policies in Spain, for which increased MH expenditure will be required.

Cortical brain morphology in early-onset psychosis (EOP; age of onset < 19 years) is poorly understood, partly due to recruitment constraints linked to its low incidence. We pooled T1-weighted magnetic resonance imaging (MRI) data from 387 adolescents with EOP (mean age=16.1±1.5; 49.6% female) and 338 healthy controls (CTR; mean age=15.8±1.9, 54.4% female) from nine research sites worldwide. Using harmonized processing protocols with FreeSurfer, we extracted cortical brain metrics from 34 bilateral regions. Univariate regression analysis revealed widespread lower bilateral cortical thickness (left/right hemisphere: d=-0.36/-0.31), surface area (left/right: d=-0.42/-0.41), cortical volume (left/right: d=-0.58/-0.56), and Local Gyrification Index (LGI; left/right: d=-0.39/-0.52) in EOP relative to CTR. Subgroup analyses showed broader and more pronounced case-control differences in early-onset schizophrenia for area, volume, and LGI. We found no associations with antipsychotic medication use, illness duration, age of onset, or positive symptoms. Negative symptoms were related to smaller left lingual volumes (partial r=-0.21; p FDR =0.014) and antidepressant users had smaller area (d=-0.43; p FDR =0.034) and volume (d=-0.50; p FDR =0.003) of the right rostral anterior cingulate compared to non-users. Cortical alterations in EOP showed a similar pattern to those observed in prior studies on adults with schizophrenia (SCZ; r=0.62) and bipolar disorders (BD; r=0.61). However, surface area alterations were overall 1.5 times greater for EOP than adult SCZ and 4.6 times greater than adult BD. In the largest study of its kind, we observed an extensive pattern of cortical alterations in adolescents with psychotic disorders, highlighting the potential impact of aberrant neurodevelopment on cortical morphology in this clinical group.

It is estimated that, globally, the mean point prevalence of diagnosable mental disorders in children and adolescents is higher than 11%, and around half of cases of major mental disorders have their onset before the age of 18. Mental disorders with onset in childhood or adolescence have an enormous impact on the developing brain, body and personal identity, as well as on the short- and long-term social, educational and functional capacity of individuals. Child and adolescent psychiatry - as a discipline, profession, academic field, and network of clinical services - is still relatively young, with its formal evolution beginning in the 20th century. Therefore, it is not surprising that there are currently many challenges, but also opportunities and expected future developments, in this area. In this paper, we identify and address the core challenges, possible solutions, opportunities, and future directions of child and adolescent psychiatry. In the first part of the paper, challenges and possible solutions are discussed regarding diagnostic issues, stigma, access to care, shortage of mental health professionals, evidence-based treatments, treatment adherence, parental participation/engagement, integration with schools, digital influences and cyberbullying, and war/forced displacement. In the second part, opportunities and developments are addressed that relate to early identification and intervention, resilience, interdisciplinary collaborations, integration with primary care, community-based approaches, use of digital technologies, precision child and adolescent psychiatry, artificial intelligence and related ethical issues, and cultural diversity and competences. Despite the significance and impact of mental disorders in children and adolescents, clinical delivery and research on these conditions remain underfunded and underprioritized, even in high-income countries, with clinical services and prevention/early intervention research receiving minimal investment. Addressing mental health in children and young people requires multi-level strategies beyond individual treatment, including tackling structural and socioeconomic barriers and creating opportunities for strengthening resilience and well-being. A well-trained workforce, adequate policies, and increased public awareness are crucial. Overall, the current gaps demand urgent action and global funding rebalancing to more adequately meet the critical needs of children and young people challenged by mental illness.

Randomized controlled trials (RCTs) guide treatment decisions in youth with mental health disorders, yet concerns remain about their generalizability. Here we conducted a Preferred Reporting Items for Systematic Reviews and Meta-Analyses-compliant systematic review and meta-analysis (CRD42024629137) to assess the inclusivity and representativeness of RCTs on pharmacological and nutraceutical interventions in children and adolescents with Diagnostic and Statistical Manual of Mental Disorders and/or International Classification of Diseases-defined mental disorders. Random-effects meta-analyses were conducted by disorder, and temporal trends were assessed. Primary outcomes were the representativeness of RCTs with respect to sex (pooled proportion of female participants) and race/ethnicity (distribution of racial and ethnic groups); secondary outcomes included the exclusion of key clinical populations (for example, autistic individuals, those with intellectual disability and those with suicide risk). A total of 397 RCTs (46,989 participants; mean age 10.2 ± 3.1 years) were included, mostly targeting attention deficit hyperactivity disorder (34.5%) or autism spectrum disorder (29.7%). Female participants represented 28.3%. Only 53.7% of RCTs reported racial data; 75.0% were white, 10.1% Black, 6.2% Hispanic and 2.0% Asian. Autistic individuals and those with learning disabilities were excluded in 56.5% and 44.3% of trials, respectively; 76.0% of depression RCTs excluded participants at suicide risk. There is a persistent mismatch between the youth most affected by mental health disorders and those included in RCTs. Some vulnerable populations including people of colour, women and special populations seem to be under-represented, requiring more inclusive practice to support equitable and effective care. This systematic review and meta-analysis of 397 randomized controlled trials identifies an under-representation of women, people of colour and vulnerable youth populations in mental health research, highlighting the need for more inclusive methodologies in clinical trials.

Schizophrenia (SCZ) frequently co-occurs with substance use disorders (SUDs), yet the genetic basis of this comorbidity remains unclear. Using the latest European-ancestry genome-wide association studies (GWAS) for SCZ, cannabis use disorder (CanUD), opioid use disorder (OUD), problematic alcohol use (PAU), tobacco use disorder (TUD), and a general addiction factor (AF), together with two SCZ and one SUD case-control samples with individual-level genotype data, we applied multiple complementary genomic approaches to characterize their shared genetic architecture. Significant positive genome-wide genetic correlations were observed across all SCZ-SUD pairs. Local genetic correlation analyses identified multiple genomic regions contributing to this shared architecture, with both positive and negative correlations, and evidence of genomic regions shared across multiple SCZ-SUD pairs. Polygenic overlap analyses indicated substantial sharing (25-50%) of trait-associated variants between SCZ and SUDs. Genomic structural equation modelling supported a common latent factor underlying SCZ and all SUDs, accounting for approximately 23% of SCZ variance. Cross-trait polygenic risk score (PRS) analyses showed bidirectional associations between SCZ and SUD genetic liability. Mendelian randomization analyses provided evidence for a bidirectional causal relationship between SCZ and CanUD. Horizontal pleiotropy analyses identified numerous loci with concordant and discordant effects across traits, including loci shared among multiple SCZ-SUD pairs. Gene mapping and enrichment analyses indicated pathways related to neuroplasticity, synaptic transmission, immune system, metabolism and proteolysis, including both shared and SCZ-SUD specific biological processes. Overall, these findings suggest that part of SCZ liability reflects genetic susceptibility to SUDs with potential implications for patient stratification and clinical management.

OBJECTIVE:Although conduct problems (CPs) are continuously distributed, little is known about how dimensional measures of CPs map onto brain structure. Therefore a large sample was used to comprehensively assess associations between dimensionally measured CPs and brain structure. METHOD:T1-weighted structural brain magnetic resonance imaging scans from 14,160 youths (5-21 years old, 46.2% female) across 18 international case-control, community-based, and population-based cohorts were preprocessed using ENIGMA-standardized protocols. Regression models examined associations between CPs and cortical thickness, surface area, and subcortical volumes, adjusting for age, sex, and intracranial volume. Moderation by sex, age, and callous-unemotional traits was also investigated. RESULTS:Widespread but small (β = -0.02 to -0.07) negative associations were observed between CPs and surface area (total surface area, 23/34 regions), cortical thickness (average thickness, 15/34 regions), and amygdalar and hippocampal volumes. Sex was a key moderator, with many surface area associations limited to boys and some thickness associations limited to girls. Some associations were stronger in younger children and at lower levels of callous-unemotional traits. The impact of adjusting for IQ and other psychopathology varied by outcome (eg, most surface area findings survived IQ adjustment, whereas cortical thickness associations did not). CONCLUSION:CPs were associated with subtle, yet widespread, alterations in brain structure. Findings overlapped with differences observed in categorically measured conduct disorder, but novel associations with cortical thickness were identified. This provides further evidence that neuroanatomical differences are not limited to youth with clinically elevated CPs. Our findings have potential implications for neurocognitive models of CPs as they extend beyond the regions highlighted in these models. STUDY REGISTRATION INFORMATION:Investigating dimensional relationships between conduct problems and brain structure: an ENIGMA mega-analysis; https://osf.io/nzj3r/.

Introduction:Insight in psychosis has been associated with psychosis remission, treatment compliance and better functioning, but also with depression, increased suicide risk and worse subjective wellbeing. This insight paradox has not been sufficiently studied. Methods:Participants (N = 443) came from the first-episode psychosis OPTiMiSE trial. Insight was assessed with the clinician-rated Positive and Negative Syndrome Scale for Schizophrenia (PANSS)-G12 item. We investigated the cross-sectional associations of insight with clinical measures at baseline and at 4 weeks and the effect of insight change over the 4-week follow-up on outcomes at that point, whilst adjusting for baseline insight and other potential confounders. Results:At baseline and at week 4 better insight was cross-sectionally associated with higher rates of psychosis remission, lower illness severity and better psychosocial functioning (p < .001). At baseline, but not at week 4, better insight was cross-sectionally linked with more severe depressive symptomatology (p = .001), higher suicidality levels (p = .033) and worse subjective wellbeing (p = .022). Insight improvement was associated with higher rates of psychosis remission (p < .001), lower illness severity (p < .001) and better functioning (p = .014) at 4 weeks. Better baseline insight, but not insight change, was related to more severe depression (p < .001) and worse subjective wellbeing (p = .001) at 4 weeks. Conclusions:Insight was cross-sectionally associated with positive and negative clinical measures at baseline, but the latter was not replicated at 4 weeks. Improvement in insight over 4 weeks was not linked with any adverse outcome, offering reassurance to those making efforts to enhance insight early in treatment.

OBJECTIVE:To quantify the prevalence of cannabis use (CU) and cannabis use disorders (CUD) in Early-Onset Psychosis (EOP; <18 years) and examine their correlates, clinical and functional impact. METHOD:This PRISMA-compliant systematic review and meta-analysis (CRD420251070701) searched six databases until 1/7/2025, for studies evaluating CU/CUD in EOP. Data were extracted by independent researchers, and quality assessment was conducted using the Newcastle-Ottawa Scale. Heterogeneity, publication bias, subgroup and meta-regression analyses were performed. A narrative synthesis was conducted. RESULTS:Forty studies (N=3,473; age=16.2±1.6 years; male=59%) were included. In EOP, pooled prevalence was for current CU 32.8% (95%CI=18.5-51.2), for lifetime CU 40.2% (95%CI=31.3-49.7), and for lifetime CUD 36.6% (95%CI=18.2-59.9). In meta-regression analyses, current CU was associated with male sex (β=0.012, p=0.021) and hospitalization rates (β=0.006, p=0.021), but with less severe negative symptoms (β=-0.191, p=0.001) and lower proportion of schizophrenia diagnosis (β=-0.026, p=0.049). Lifetime CU was associated with cocaine use (β=0.101, p=0.003) and again less severe negative symptoms (β=-0.173, p=0.030). Our narrative synthesis indicated that CU commonly preceded psychosis onset, and was linked to negative outcomes (e.g. longer duration of untreated psychosis and higher hospitalization rates) in EOP. Study quality was mostly fair (67.5%); GRADE certainty ranged from low to moderate. CONCLUSION:CU and CUD are common in EOP and relate to clinical presentation. Screening and integrated substance use care should be embedded in primary care and clinical settings. Further longitudinal studies and randomized clinical trials to evaluate the efficacy of interventions to reduce CU and CUD are needed.

Neuropaediatric Rare Diseases (NRDs) impose a profound and multidimensional burden on patients, families, and healthcare systems. Persistently low clinical trial success rates reflect an unmet methodological need as much as a therapeutic one. A fundamental bottleneck is the absence of fit-for-purpose clinical outcome assessments. In fact, instruments validated for non-rare or adult populations fail to capture clinically meaningful change in heterogeneous, small, and developmentally complex NRD populations. Building directly on a systematic catalogue of methodological challenges in NRD outcome research published by our group (Acosta et al., 2025), this paper presents a structured set of actionable outcome strategies proposed by a large multidisciplinary expert group convened under the auspices of the European College of Neuropsychopharmacology (ECNP) and the International Society for CNS Clinical Trials and Methodology (ISCTM). Using a structured, iterative expert-opinion approach, each identified challenge served as a prompt for developing one or more candidate strategies, each mapped one-to-one to its corresponding barrier. Strategies are presented across four thematic domains: (1) innovative methodologies to enhance ecological validity and reduce rater context effects; (2) novel or adapted outcomes and endpoints that preserve clinical meaningfulness under conditions of high heterogeneity and limited sample sizes; (3) the purposeful use of natural history resources; and (4) approaches to support comparability and synthesis across programmes. Additional considerations address caregiver expectancy bias and recruitment, stakeholder alignment, maturational confounding, and preclinical-clinical connectivity. Collectively, these strategies constitute a practical, challenge-mapped “living” toolbox for clinical scientists designing NRD trials. Each strategy is already in use or validated in analogous rare-disease contexts. Realising their potential at scale requires institutional programmes, pre-competitive co-validation platforms, systematic stakeholder co-design, and early engagement with regulatory agencies as scientific partners in endpoint development.

Social isolation and loneliness are associated with schizophrenia, yet their distinct genetic contributions and developmental pathways across the psychosis spectrum remain poorly understood. Using data from the EU-GEI study (2045 patients and 2456 healthy controls), we examined whether genetic liability to loneliness and social isolation increases psychosis risk through a two-step strategy: first testing whether polygenic scores (PGS) for loneliness and four isolation-related traits (derived from UK Biobank GWAS) were associated with first-episode psychosis (FEP), schizophrenia-spectrum disorders (SSD), symptom dimensions, and retrospectively reported loneliness and social isolation during childhood and adolescence; and second testing whether these developmental experiences mediated the relationship between genetic liability and psychosis. Genetic liability to loneliness (LNL-PGS) was associated with increased psychosis risk in the combined sample and specifically with FEP, independent of schizophrenia and depression genetic risk, with stronger effects in males. In contrast, a PGS indexing frequency of family and friends’ visits (VISITS-PGS), as a proxy for objective isolation, was associated with SSD diagnosis—particularly in females—and greater negative symptom severity. At the developmental level, LNL-PGS predicted prolonged loneliness during adolescence (ages 12–16) among patients, especially males, while VISITS-PGS only predicted lower sociability in childhood in healthy controls. Mediation analyses revealed that adolescent loneliness partially mediated the association between LNL-PGS and psychosis risk, accounting for 21% of the total effect and up to 27% in males. Together, these findings support partially distinct genetic and developmental mechanisms—with sex-specific contributions—linking perceived loneliness and objective social isolation to psychosis risk, and highlighting adolescent loneliness as a potential target for early preventive interventions.

BACKGROUND AND HYPOTHESIS:Previous research in both clinical and non-clinical populations has suggested an association between intelligence quotient (IQ) and psychosis. The social defeat hypothesis posits that low status and repeated humiliation increase the risk of psychosis. The present study investigated the relationship between IQ and subclinical psychosis in the general population, while also examining the potential mediating and confounding roles of psychosocial stressors and core schemata. STUDY DESIGN:We analyzed data from 1497 healthy controls in the EU-GEI dataset, a multicenter study conducted across six countries. IQ and the positive dimension of subclinical psychosis (measured by the positive dimension of the Community Assessment of Psychic Experiences questionnaire) were analyzed using linear regression models adjusting for age, sex, childhood trauma, stressful life events, and core schemata (positive and negative schemata). Mediation analysis was conducted to explore indirect effects. STUDY RESULTS:IQ was associated with subclinical psychosis. The results remained statistically significant after adjustment for several confounders. In the mediation analysis, IQ had no total or direct effect, but a small negative indirect effect through negative-other schemata (ß = -0.040; 95% Confidence Interval: -0.55, -0.024), childhood trauma (ß = -0.029; 95% CI -0.042, -0.016), negative-self schemata (ß = -0.009; 95% CI -0.017, -0.001), and stressful life events (ß = -0.012; 95% CI -0.021, -0.003). CONCLUSION:These findings support the idea that cognitive vulnerability is associated with an increased risk of subclinical psychotic symptoms, with psychosocial stressors and core schemata possibly playing a mediating role, in line with the social defeat hypothesis.

Abstract Elucidating the neurobiological basis of neurodevelopmental and psychiatric conditions (NDPCs) remains challenging because brain alterations vary within diagnoses and overlap across them. Whether diverse alterations follow a systematic organization that may reflect shared vulnerabilities remains unknown. Here, we assembled 10,135 individuals with schizophrenia, autism, bipolar, obsessive-compulsive, generalized anxiety, and major depressive disorders, and 11,998 reference participants across six continents through the ENIGMA consortium. Using normative modeling, we quantified individual deviations in cortical thickness, surface area, and subcortical volumes relative to lifespan reference trajectories (5 to 80 years). We show that structural deviations converged along cortical axes reflecting connectome organization, maturation, and cytoarchitectonic diversity. These axes mirrored typical population variation, but their expression differed across diagnoses and partly scaled with symptom severity. Even rare and highly individualized extreme deviations followed this organization, concentrating in densely connected regions. Finally, brain structural deviations overlapped substantially across diagnoses, while differences between them increased toward the association cortex. Together, we provide large-scale evidence that structural deviations across NDPCs are systematically constrained by the brain’s intrinsic architecture. This shared organization provides a framework for reconciling individual variability with transdiagnostic similarities and motivates an integrative, systems-level understanding of mental health.

Most genetic variants associated with complex heritability phenotypes lie in non-coding regions and are thought to influence disease risk by regulating gene expression. However, most transcriptome-wide association approaches primarily model local (cis) genetic effects, leaving much of gene regulation unexplained. Here, we show that incorporating distal (trans) regulatory effects improves the prediction of gene expression and the identification of disease-associated genes. Using RNA sequencing data from six human post-mortem brain regions, we developed INGENE and MODULE, two models capturing the combined influence of candidate trans-acting variants within gene coexpression networks. Integrating these models with conventional cis-based predictors improved gene expression imputation (maximum likelihood estimation, α = 0.05) for 18,744 genes across regions. Applying this framework to Psychiatric Genomics Consortium wave 3 genotypes identified 766 genes associated with schizophrenia (PFDR < 0.01), including 641 not previously reported by transcriptome-wide analyses. These findings highlight the contribution of distal regulatory mechanisms and gene network interactions to schizophrenia risk.

In this study, we performed an integrative analysis of de novo tandem repeats (TRs) to unravel the missing heritability that may be hidden in 85,394 active cis-regulatory elements (cCREs) from ENCODE through target sequencing in a Spanish cohort of 200 ASD trios, using a robust bioinformatic pipeline. For the integrative analysis, we use data from 1,637 ASD simplex quad families from the Simons Simplex Collection (SSC). We then incorporated multiple layers of functional annotation, including predicted transcription factor (TF) binding sites, gene mapping based on physical proximity and expression correlation, pathogenicity scoring, single-cell RNA-seq data from human brain in ASD cases and controls and cortical organoid expression data. Together, our analyses identified multiple ASD-relevant candidate genes supported by convergent lines of evidence. Notably, ECHS1 emerged as a strong candidate, affected by several de novo TRs in both the Spanish cohort and the SSC. It was also identified as the most significantly associated gene through expression-based gene mapping (T-Gene) and showed consistent differential expression in excitatory neurons of the cerebral cortex at the single-cell level along with increased expression in late-stage cortical organoids. These findings remark the value of integrating genetic and transcriptomic information to improve the identification of potential risk genes for ASD, particularly within non-coding regions. Our approach also highlights the importance of identifying complex genetic variation, such as de novo TRs, that are typically missed in conventional exome or whole-genome analyses, and require specialized bioinformatic strategies for accurate detection and interpretation.

BACKGROUND:Prolonged childhood and adolescent loneliness (CAL) may mark an early socio-emotional vulnerability relevant to psychosis and interact with genetic liability. We examined whether CAL increases odds of first-episode psychosis (FEP), relates to diagnostic subtype and functioning, and interacts with polygenic risk scores (PGS) for schizophrenia (SCZ), bipolar disorder (BIP), and major depression (MDD). STUDY METHODS:We analyzed 2565 participants (1084 FEP, 1481 controls) from European Gene-Environment Interactions in Schizophrenia (EU-GEI) study. CAL was assessed retrospectively before age 12 (LNL12) and at 12-16 years (LNL12-16). Functioning was rated with a modified Global Assessment of Functioning (GAF). Genome-wide PGS for SCZ, BIP, and MDD were calculated using polygenic risk score-continuous shrinkage. Mixed-effects logistic and linear regression models tested associations of CAL with FEP, subtype, and functioning, including sex-stratified analyses. Additive gene-environment interaction was examined using dichotomized PGS and the Relative Excess Risk due to Interaction. STUDY RESULTS:Both LNL12 (OR = 2.90, 95% CI, 2.30-3.66) and LNL12-16 (OR = 2.34, 95% CI, 1.94-2.84) were associated with FEP, independent of premorbid social isolation. CAL increased FEP odds in both sexes. LNL12-16, but not LNL12, was associated with affective versus non-affective psychosis (OR = 1.37, 95% CI, 1.02-1.83), more clearly in females (OR = 1.79, 95% CI, 1.16-2.77). CAL was also associated with poorer functioning, with 3-4-point lower GAF Disability scores. Significant additive interactions were observed between LNL12-16 and SCZ-PGS, and between LNL12 and MDD-PGS, although the latter did not replicate in European-ancestry sensitivity analyses. CONCLUSIONS:Prolonged CAL is linked to higher risk of FEP, preferentially affective psychosis in females, poorer functioning, and developmental potentiation of polygenic liability.