American Journal of Psychiatry

Hoarding disorder (HD) affects approximately 2-3% of adults and is associated with substantial functional disability and limited access to evidence-based care. The aim of the current analysis was to examine the naturalistic effectiveness of therapist-delivered video cognitive-behavioral therapy (CBT) for HD in a large real-world sample, and to characterize individual-level treatment response, time-to-response, and moderators of outcome. This retrospective, observational analysis examined clinical data from 305 adults diagnosed with HD who received therapist-delivered video CBT through an online specialty therapy platform between September 2021 and February 2026. Hoarding symptom severity was assessed using the Hoarding Rating Scale-Self Report (HRS-SR). Linear mixed models examined symptom change from baseline to three timepoints: session 10, session 20, and each patient's final session. HRS-SR scores decreased from M = 22.4 (SD = 7.6) at baseline to M = 16.4 (SD = 8.2) at final session (Hedges' g = 0.81, 95% CI: 0.68-0.94). By the final session, median percent improvement was 25.0% [IQR: 3.0-46.7%]. A total of 39.3% of patients achieved [≥]35% HRS-SR reduction, 27.4% of patients who began above the clinical threshold achieved remission, 36.4% demonstrated reliable improvement, and 22.9% of eligible patients achieved clinically significant change. Among patients who achieved and maintained [≥]35% reduction through their final session (n = 120), median time to first response was session 9, with 54.2% responding within 10 sessions. Analyses of secondary outcomes showed significant improvements in clutter severity, depressive and anxiety symptoms, stress, quality of life, and functional disability (Hedges' g = 0.21-0.47). Greater baseline severity, more sessions, and longer treatment duration significantly moderated outcomes; prior OCD treatment history did not. Findings suggest that therapist-delivered video CBT for HD, delivered remotely in a real-world setting, produces outcomes consistent with controlled trials and may be a clinically effective and scalable approach for a condition historically underserved by mental health systems.

Objective. Persistent, distressing psychotic-like experiences (PLEs) are associated with neurobiological alterations and increased psychosis risk. We combined individual-level neuroimaging measures with effect sizes from large neuroimaging studies to create a summary score ('Psychosis Neuroscore') reflecting neuroanatomic liability for psychosis, and examined its ability to predict PLE trajectories in young adolescents. Method. Using latent growth mixture models, we estimated PLE trajectories from four annual visits of the Adolescent Brain Cognitive Development Study (N=9584, ages 9-10 at baseline). Using baseline T1-weighted and diffusion-weighted imaging data, we calculated Psychosis Neuroscores, as well as Neuroscores for two psychiatric disorders with late adolescent/adult onset (Major Depressive Disorder, Bipolar Disorder). We compared Psychosis Neuroscores to i) other psychiatric Neuroscores, ii) modifiable risk factors, and iii) established risk factors in predicting trajectory membership. Results. We identified four trajectories of distressing PLEs: Persistent Elevated (N=1,968, 21%), Gradual Decreasing (N=3,424, 36%), Rapid Decreasing (N=1,593, 17%) and Low/No Distress (N=2,599, 27%). Adolescents with Persistent Elevated PLEs had significantly higher Multimodal (combined T1 and diffusion-weighted) and T1-weighted Psychosis Neuroscores than all other trajectories (Odds Ratios [ORs] 1.27-1.34,pFDR<.01). Bipolar Disorder Neuroscores showed a similar pattern (ORs 1.16-1.23,pFDR<.01). Psychosis Neuroscores showed comparable associations with established risk factors in predicting trajectory membership, but smaller associations than modifiable risk factors, including screen time, physical activity, and sleep disturbances. Conclusion. Psychosis Neuroscores differentiate youth with persistent PLEs from those with decreasing, remitting or low PLEs, demonstrating their potential utility for early risk stratification. Integration with established risk factors may enhance psychosis risk prediction in youth.

Tourette syndrome (TS) is a neurodevelopmental disorder characterized by symptoms that emerge in childhood and often improve or even disappear in adulthood, providing a model for understanding how altered brain development shapes neural structure and function. We investigate brain structural alterations in TS and Chronic Tic Disorders (TS/CTD) across development, presenting the largest structural neuroimaging analysis for TS/CTD to date (1,803 individuals from the ENIGMA-TS Working Group), and integrating with large-scale genomewide association studies. Nonlinear age effects were observed in cortical thickness across development and in thalamic volume in children, indicating altered trajectories of brain maturation . Pediatric and adult TS/CTD showed distinct structural patterns, with widespread alterations in childhood and more focal changes in adulthood. Children also showed the most prominent effects highlighting the involvement of orbitofrontal cortex and putamen, alongside additional regions such as frontal and paralimbic areas. Genetic pleiotropy analyses identified overlap between TS/CTD-associated genetic effects on brain structure and neuroanatomical differences. Cross-disorder comparisons revealed correlations with ADHD and OCD and age-related patterns. These findings demonstrate altered neurodevelopmental trajectories in TS/CTD and implicate systems underlying inhibitory control and urge regulation.

Problematic Sexual Behaviour (PSB) is defined as difficult to control recurrent sexual behaviours that continue despite adverse consequences, leading to social and functional impairment. There is debate whether PSB is a disorder of compulsion or addiction; PSB often co-occurs with neuropsychiatric disorders, but further elucidation regarding underlying biology is required. A deficiency in reward neurotransmitter systems (reward deficiency syndrome: RDS) may underlie a shared vulnerability to addiction. We conducted the first case-control genome wide association study (GWAS) of PSB in patients (n=448), and comparison participants with (n=196) and without PSB (n=1488). We used polygenic risk scores (PRS) to test genetic overlap with related psychiatric, behavioural and personality phenotypes. Three models were used: 1) All-PSB (patient + comparison) vs. controls, 2) Patient-PSB vs controls, and 3) RDS (yes/no). Results suggested genetic overlap of PSB with psychiatric conditions, with PRS for major depression, substance use, and others predicting PSB status. PRS for related behavioural phenotypes (e.g., externalizing, age at first sex, number of lifetime sexual partners) and personality traits also predicted PSB. The patient model showed stronger associations than the All-PSB model, and RDS had both shared and distinct genetics with PSB. As expected with the sample size, only suggestive hits were observed with single variant and gene-based tests. PSB may share genetic mechanisms with various conditions. Further research in larger cohorts is needed to better understand the underlying genetics and environmental factors involved, and to improve diagnostic classification, intervention and treatment prospects.

Suicidality phenotypes, including suicidal ideation (SI), non-fatal suicide attempt (SA), and suicide death (SD), are heritable and exhibit both shared and phenotype-specific genetic influences. Using genomic structural equation modelling, we estimated the shared genetic architecture across GWAS of SI (176,147 cases, 1,010,300 controls), SA (53,919 cases, 1,063,988 controls), and SD (7,584 cases, 652,070 controls) and conducted a multivariate GWAS of a latent suicidality factor capturing their shared liability. This analysis identified 36 genome-wide significant loci, including seven not previously reported in any suicidality GWAS. Follow-up analyses identified residual genetic variance specific to each phenotype, including three SD-specific genomic risk loci. Conditioning suicidality phenotypes on genetic liability to psychiatric disorders revealed significant residual genetic variance across SI, SA, SD, and the suicidality common factor. Together, these results suggest that suicidality reflects both shared genetic liability and phenotype-specific contributions.

Background: Schizophrenia, bipolar disorder, and depression share substantial genetic liability. However, the molecular mechanisms underlying this shared architecture remain poorly characterized. In particular, the role of circulating proteins as potential mediators and therapeutic targets is not well understood. Methods: Based on large-scale genome-wide association studies, we constructed a latent psychiatric common factor using genomic structural equation modeling. We then performed proteome-wide Mendelian randomization to estimate the associations between circulating proteins and this shared liability, based on four independent proteomic cohorts. Protein-psychiatric common factor associations were prioritized through comprehensive sensitivity analyses and colocalization. We additionally performed tissue- and single-cell expression enrichment analyses and a systematic druggability assessment. Results: We identified 36 circulating proteins with evidence of association with the psychiatric common factor that withstood multiple sensitivity analyses. Several proteins showed distinct tissue-specific expression patterns, with enrichment in brain, immune, or liver tissues, highlighting convergent neuroimmune and systemic pathways. For instance, genetically predicted higher levels of MAPK3, FES, MRE11A, HS6ST3, OLFM1, BTN3A1, BTN3A2 and BTN3A3 were associated with increased psychiatric risk, whereas higher levels of CD40, ITIH3, and ITIH4 were associated with decreased risk. Druggability assessment identified CD40, MAPK3, FES, MRE11A and BTN3A1 as established or potential therapeutic targets. Conclusions: By integrating genetic, proteomic, and transcriptomic data, this study identifies circulating proteins that associated with the shared genetic effects on three major psychiatric disorders. These findings provide biologically grounded candidates for therapeutic targeting and offer insights into shared disease mechanisms.

Stimulant use disorder (StimUD) is a significant public health problem, but genetic studies have been limited by small sample sizes. We conducted genome-wide association studies (GWAS) of StimUD in the Million Veteran Program (MVP) and All of Us (AOU), followed by meta-analysis with FinnGen and 10 additional datasets, for a total of 709,369 individuals (Ncases=33,977, Ncontrols=675,392) in four broad ancestry groups: European (EUR) (Ncases=22,564, Ncontrols=624,672), African (AFR) (Ncases=7,574, Ncontrols=34,189), Admixed American (AMR) (Ncases=3,657, Ncontrols=15,698), and East Asian (EAS) (Ncases=182, Ncontrols=833). Population-specific SNP heritability was 6.1% in EUR and 2.4% in AFR. We discovered a total of 19 genome-wide-significant loci, six in EUR, including DRD2*rs5794864, P=7.32E-10, one in AFR, five in a multi-ancestry meta-analysis, including CHRNA5*rs55781567, P=3.27E-9, two in a male-only meta-analysis, including FTO*rs8057044, P=9.50E10-9, and five in a meta-analysis of sex-stratified results. In a hold-out AOU subsample (NEUR=18,841, NAFR=12,263, NAMR=9,739), ancestry-specific polygenic risk scores were significantly associated with StimUD in EUR (OR=3.28, 95% confidence interval (CI)=2.89-3.71) and AMR (OR=2.01, 95% CI=1.71-2.37). Transcriptome-wide association studies, fine-mapping, and colocalization analyses prioritized additional genes (e.g., GPX1, BSN). Genetic correlation, Mendelian randomization, and causal mixture analyses revealed relationships with other substance use and use disorder phenotypes, including cannabis use disorder (rg=0.94, P=5.43E-237) and opioid use disorder (rg=1.01, P=4.40E-107), and other psychiatric traits, including anxiety, depression, neuroticism, and attention-deficit/hyperactivity disorder. This is the first well-powered GWAS of StimUD, and it offers significant insights into disease biology.

Forensic patients often have complex and costly healthcare needs, even following discharge from secure care. However, little is known about their health and justice outcomes after community reintegration. To address this gap in the literature, we conducted a systematic review and meta-analysis to estimate the incidence of key post-discharge outcomes among community-discharged forensic patients, including any reoffending, violent reoffending, reconvictions, readmissions, all-cause mortality, and suicide. We systematically searched PsycINFO, Embase, CINAHL, Medline, PubMed, and ProQuest Dissertations from database inception to May 2025 (PROSPERO CRD42024529265). Random-effect meta-analyses were used to generate pooled incidence estimates, with heterogeneity quantified using prediction intervals. A total of 49 studies met inclusion criteria (total patient n = 18,871) and contributed to the meta-analyses. The pooled incidence rate per 100,000 person-years was: any reoffending 3,889 (95% CI 2,055, 7,359; 95% PI 290, 52,136); violent reoffending 1,851 (95% CI 1,229, 2,789; 95% PI 201, 17,068); reconvictions 3,291 (95% CI 2,591, 4,179; 95% PI 950, 11,394); readmissions 7,945 (95% CI 5,507, 11,463; 95% PI 1,225, 51,548); all-cause mortality 1,789 (95% CI 1,341, 2,388; 95% PI 673, 4,756); and suicide 407 (95% CI 319, 519; 95% PI 225, 735). Overall, the reoffending rate for forensic patients discharged to the community was lower than that reported for other cohorts of people charged with general and violent offences. However, despite typically receiving long admission periods, discharged forensic patients continue to experience high rates of readmission, all-cause mortality, and suicide relative to other psychiatric patient groups in the community. Together, our findings highlight a need for enhanced post-discharge suicide support for forensic patients living in the community to better facilitate successful, long-term reintegration.

Background: Alcohol use disorder (AUD) is associated with altered gene expression across diverse cell types in reward-related brain regions, including the ventral tegmental area (VTA), which is rich in dopaminergic neurons. The VTA plays a central role in reward processing, learning, and memory; however, cell type-specific gene expression changes within the VTA remain uncharacterized. Methods: We applied single-nucleus RNA sequencing (snRNA-seq) to profile transcriptomic alterations associated with AUD in the VTA. Postmortem VTA samples from four individuals of European ancestry [two with AUD (one male, one female) and two matched controls (one male, one female)] were analyzed using the 10X Genomics Chromium Fixed RNA Profiling protocol. Differentially expressed genes (DEGs) were identified using Seurat, and enriched KEGG pathways was assessed by gene set enrichment analysis. Results: Nuclei were classified into six major cell types: astrocytes, endothelial cells, mature neurons, microglia, oligodendrocytes, and oligodendrocyte precursor cells (OPCs). At thresholds of P < 0.05 and |fold change| > 2.0, we identified 547 DEGs in astrocytes, 727 DEGs in endothelial cells, 715 DEGs in mature neurons, 421 DEGs in microglia, 263 DEGs in oligodendrocytes, and 432 DEGs in OPCs. DEGs across VTA cell types were enriched for pathways related to mitochondrial function, neurodegeneration, and synaptic signaling. Notably, DEGs in mature neurons were enriched for addiction-related pathways. Further subdivision of mature neurons into dopaminergic, GABAergic, glutamatergic, and unclassified subtypes revealed 526, 930, 896, and 569 DEGs, respectively. Neuronal DEGs indicate a convergence on mitochondrial/oxidative phosphorylation and neurodegeneration-related pathways across subtypes, whereas addiction- and synapse-related pathways show dopaminergic neuron-specific enrichment. Conclusions: This study provides the first cell type-resolved transcriptomic profiling of the human VTA, revealing AUD-associated gene expression alterations across neuronal, glial, and endothelial cells. The observed cell type-specific changes in synaptic plasticity and addiction-related genes offer new insights into molecular mechanisms underlying AUD pathophysiology.

Genomic insights into psychiatric disorders remain heavily skewed toward European populations. In European-ancestry studies, educational attainment is typically negatively genetically correlated with major depression but paradoxically positively correlated with schizophrenia, raising the question of whether these relationships generalize across ancestries. We investigated whether this cross-trait architecture extends to East Asian ancestry (EAS). Using EAS GWAS summary statistics for major depressive disorder (MDD), schizophrenia (SZ), and educational attainment (EDU), we applied multi-trait (MTAG) and pleiotropy-informed (PLEIO) analyses to characterize shared genetic architecture across these traits. Across MTAG and PLEIO analyses, we identified 32 unique genome-wide significant loci (p < 5 x 10-8), including seven novel loci revealed in depression analysis that overlapped schizophrenia-associated signals, consistent with shared cross-trait architecture. Results reinforce a convergent risk architecture for affective and psychotic disorders in this population. Fine-mapping analyses prioritized variants mapping to candidate genes, including serine/threonine kinase VRK2, nominating targets for future follow-up. Cross-trait analyses supported a positive genetic relationship between EDU and MDD (rg = 0.308, p = 9.63 x 10-17) in East Asian data, contrasting to the negative correlation typically observed in European ancestry. These findings suggest that the genetic relationship between educational attainment and psychiatric risk may not be fully transferable across ancestries. In an independent cohort of individuals at ultra-high risk for psychosis, MTAG-derived polygenic risk scores improved case-control discrimination relative to single-trait GWAS-based scores. These results underscore the importance of ancestry-specific genomic frameworks for interpreting cross-trait psychiatric architecture and improving polygenic prediction.

ImportancePrenatal exposure to gestational diabetes mellitus (GDM) has been associated with adverse metabolic, neurodevelopmental, and psychiatric outcomes in offspring. However, whether GDM-exposed youth exhibit heterogeneous neuroanatomical patterns remains unclear. ObjectiveTo identify distinct cortical thickness subtypes among GDM-exposed youth and examine their associations with anthropometric, neurocognitive, psychiatric/behavioral and neuroimaging measures both cross-sectionally and longitudinally. Design, Setting, and ParticipantsThis cohort study used the Adolescent Brain Cognitive Development (ABCD)(R)data, a multisite longitudinal population study. Subtype and Stage Inference (SuStaIn), an unsupervised machine learning framework, was applied to cross-sectional structural MRI data to identify cortical thickness patterns in 573 GDM-exposed youth and 2854 healthy controls. Posthoc longitudinal analyses included 1,853 observations from a subset of GDM-exposed youth with 1-, 2-, and 4-year follow-up visits to examine subtype differences in developmental trajectories over time. Exposure(s)Prenatal exposure to GDM. Main Outcome(s) and Measure(s)The primary outcomes included identification of cortical thickness subtypes and their inferred regional ordering patterns. Secondary outcomes included subtype-specific anthropometric, neurocognitive, psychiatric/behavioral and neuroimaging measures. ResultsThe GDM-exposed sample had a mean age of 119.02 {+/-} 7.34 months and was 47.5% female. Two cortical thickness subtypes were identified. Between subtypes, Subtype 1 (63.2%) was characterized by earlier inferred insula involvement and was associated with greater height (d = 0.36, pFDR < 0.001) and weight (d = 0.26, pFDR = 0.007), whereas Subtype 2 exhibited earlier inferred frontal involvement and nominally higher Attention-Deficit/Hyperactivity Disorder (ADHD) prevalence (d = 0.08, p = 0.036), steeper longitudinal cortical thinning across all six cortical regions of interest ({beta} range: -0.05 to -0.13, all pFDR < 0.05), and a smaller decline in Obsessive-Compulsive Disorder (OCD) prevalence over time ({beta} = -1.02, pFDR = 0.049). Conclusions and RelevanceGDM exposure was associated with two distinct offspring cortical thickness subtypes, each showing different inferred regional ordering patterns and clinical associations. One subtype showed an insula-cingulate-predominant pattern associated with anthropometric measures, whereas the other showed a frontal-predominant pattern associated with nominally higher psychiatric measures and faster cortical thinning over time.

Adolescence is a critical developmental window for the emergence of substance use and psychosis-spectrum symptoms, yet early risk for these outcomes remains poorly understood. Using longitudinal data from the Adolescent Brain Cognitive Development (ABCD) Study (n=10,134), we tested whether demographic, clinical, and structural and functional neuroimaging measures assessed in childhood (mean baseline age=9.96 years) predict later adolescent substance use, psychotic-like experiences, and/or their co-occurrence. Multivariate machine learning models reliably predicted later emergence of psychotic-like experiences (AUROC=0.780) and their co-occurrence with substance use (AUROC= 0.828), as well as substance use on its own (AUROC=0.626). Distinct patterns of functional brain connectivity, task-related brain activation, demographic, and clinical factors differentiated each outcome. Findings suggest that partially dissociable developmental risk profiles are detectable as early as childhood, and results underscore the importance of explicitly modeling comorbidity when interrogating risk factors for mental health outcomes.

Background Evidence on factors associated with cannabis for medical purposes (CMP) authorizations among Veterans Affairs Canada (VAC) clients remains limited and inconsistent, particularly concerning mental health and posttraumatic stress disorder (PTSD), a leading indication for use. We investigated demographic, clinical and service characteristics associated with VAC authorizations for CMP reimbursement. Method We linked VAC administrative CMP program data with responses from the 2019 Life After Services Studies cross-sectional survey of Regular Force veterans released between 1998 and 2018. Multivariable logistic regressions examined associations between CMP reimbursement (yes/no) and demographic, clinical and well-being factors, with analyses stratified by PTSD status. Results Among 1,289 respondents (weighted n=33,131), 18.4% were authorized for CMP reimbursement. Younger age (<40 vs. [&ge;]60 years: OR 4.78, 95% CI: 2.24-10.21), unemployment with inability to work vs. employed (OR 3.10, 95% CI: 1.78-5.40), land service vs. air (OR 2.07, 95% CI: 1.22-3.50), PTSD (OR 2.81, 95% CI: 1.69-4.66), anxiety (OR 2.32, 95% CI: 1.45-3.70), and severe pain vs. no pain (OR 3.61, 95% CI: 1.97-6.60) were independently associated with authorization. Unemployment and severe pain were consistent correlates across PTSD strata. Among those without PTSD, younger age, multiple physical conditions, and frequent mental health visits were significant; among those with PTSD, shorter service, witnessing destruction, and suicidal ideation were additional factors. Conclusions CMP authorization patterns among Canadian veterans reflect the intersection of mental health, pain, and functional impairment, with variation by PTSD status. These findings underscore the need for longitudinal research on CMP mechanisms, effectiveness and safety.

Background. Something in discourse with a person experiencing psychosis often "feels off" before formal assessment is completed, yet this disturbance has not been quantified at the level of ongoing dyadic conversation. Prior work has largely treated patient speech in isolation, limiting our capacity to measure how communicative disruption emerges within clinical exchange. Methods. We applied a three-level decomposition of conversational alignment in 109 patients with psychotic disorders (26 female) and 60 healthy controls (22 female) at baseline and 12 months (n = 115). Register divergence (dAUCnorm) captured lexical distance between interviewer and patient; embedding-based synchrony (rembed) measured semantic trajectory coupling; within-speaker coherence was computed separately for each speaker. We used linear mixed-effects models adjusted for timepoint and participant clustering. Results. Patients showed significantly greater lexical-semantic divergence from the interviewer (d = 0.48, p < .001) and reduced embedding-based synchrony (d = -0.59, p < .001), both effects replicating at each time point. Critically, the interviewer's within-speaker coherence was reduced during conversations with patients (d = -0.33, p = .016), indicating that the disruption extends beyond the patient to the interaction itself. Register divergence tracked impoverished thinking and synchrony tracked disorganized thinking (both FDR-corrected q = .038). Group differences were persistent at 12 months, indicating a partially stable profile. Conclusions. Conversational alignment in psychosis reveals a dyadic failure of semantic coordination that destabilizes the interviewing clinician's coherence even when patient narrative continuity is preserved. These transcript-derived alignment metrics offer a scalable approach to quantifying interpersonal communicative function from routine clinical encounters.

Background: The biological mechanisms linking generalized anxiety disorder (GAD) and COVID-19 remain poorly understood, despite substantial evidence of their comorbidity. To address this gap, we examined genetic and epigenetic factors underlying their co-occurrence. Methods: In a multi-ancestry sample of 893 participants, we conducted genome-wide and epigenome-wide analyses of GAD and COVID-19 severity. Integrating large-scale genome-wide datasets and information regarding methylation quantitative trait loci, complementary analytic approaches were used to identify regional methylation patterns, assess genetically regulated DNA methylation in blood and brain tissue, and evaluate causal loci shared between GAD and COVID-19. Results: GAD was associated with epigenome-wide significant variation in loci involved in chromatin regulation and synaptic signaling. Conversely, COVID-19-related epigenetic signals were enriched in immune-inflammatory and host-response pathways. Mild COVID-19 was epigenetically related to endothelial-inflammatory signals, while severe COVID-19 was linked to epigenetic changes implicated in myeloid and thrombo-inflammatory pathways. Epigenetic signals shared between GAD and COVID-19 implicated processes related to stress adaptation and tissue homeostasis. Genetically informed analyses identified 60 shared loci, including MAPT, ZFP57, and FBXL18, indicating pleiotropy between GAD and COVID-19 in genetically regulated DNA methylation variation. Brain-specific analyses further highlighted convergence in additional loci (i.e., MICB and HLA-DPB1), suggesting neuroimmune mechanisms underlying GAD-COVID-19 shared methylation patterns. Conclusions: These findings support that GAD and COVID-19 share epigenetic and genetic architecture involving pathways related to vascular integrity, immune function, and cellular adaptation, highlighting a potential neuroimmune basis for their co-occurrence.

Antidepressants are widely prescribed for major depressive disorder, yet only one-third of patients achieve remission after initial treatment. Previous genome-wide association studies (GWAS) of clinically assessed antidepressant response combined multiple antidepressant classes, potentially obscuring class-specific effects. This study focused on selective serotonin reuptake inhibitors (SSRIs), often first-line due to better tolerability. Data from 15 cohorts across four ancestries were integrated: European (N = 3887; 11 studies), East Asian (N = 1068; 4), African (N = 277; 1), and Admixed American (N = 250; 1). GWAS of non-remission and percentage improvement were conducted within cohorts, followed by ancestry-specific meta-analyses and trans-ancestry meta-regression. Single nucleotide polymorphism (SNP)-based heritability was estimated in European samples. Polygenic scores were used for leave-one-out prediction and to assess shared genetic architecture with psychiatric traits. Gene-level and gene-set enrichment analyses were also performed. No genome-wide significant variants were identified for either outcome in any ancestry-specific or trans-ancestry analyses. However, trans-ancestry meta-regression yielded eight independent loci with suggestive associations (p < 1 x 10-5) for non-remission and 17 for percentage improvement. Gene-set analyses revealed nominal enrichment of the serotonergic synapse pathway for non-remission. SNP-based heritability estimates were not significantly different from zero for either outcome. Better SSRI response was nominally associated with lower genetic predisposition to major depressive disorder, post-traumatic stress disorder, and schizophrenia. This study represents the largest trans-ancestry GWAS of SSRI response, highlighting emerging biological signals. Limited power emphasises the need for larger and ancestrally diverse cohorts to better characterise the genetic architecture of antidepressant response.

Background: Prenatal substance exposure (PSE) occurs when an individual is exposed to substances in utero. PSEs may have lasting effects on mental health. We tested whether PSEs show threshold, cumulative, or individual substance associations with childhood psychiatric diagnoses. Methods: Clinical variables (demographics, ICD-9/10 diagnoses, PSE history) were extracted from electronic health records from the University of Minnesota Adoption Medicine Clinic. PSEs were identified from caregiver and child-protective-services narratives and/or toxicology (cord tissue/blood, meconium). For each ICD-9/10 diagnostic category, we fit logistic regression models comparing (1) exposure thresholds (0, 1, 2, 3, 4+ exposures), (2) a cumulative exposure count, and (3) individual substances to estimate marginal odds ratios (ORs) with 95% Confidence Intervals (CIs). Results: Psychiatric diagnoses increased with the number of PSEs. Relative to no exposure, odds of an Anxiety Disorder rose from OR 1.47 (95% CI 1.16-1.87) with one exposure to OR 2.03 (1.64-2.52) with >=4 exposures. Higher cumulative exposure scores were associated with Anxiety Disorders (OR 1.28, 1.18-1.38), Behavioral and Emotional Disorders (OR 1.42, 1.31-1.54), Substance Use Disorders (OR 1.52, 1.29-1.79), and Mood Disorders (OR 1.16, 1.04-1.30). Alcohol, tobacco, and marijuana exposures were associated with increased odds of at least one psychiatric diagnosis, and each substance showed at least one significant diagnostic cluster when modeled independently. Conclusion: Increasing numbers of PSEs were associated with higher odds of psychiatric diagnoses, with patterns varying by substance and outcome. These findings motivate research on exposure timing and combinations to support earlier identification and intervention for at-risk children.

Background Escalating mental health service demands have created a need to better identify young people most likely to require continued support from mental health services at the transition between childhood and adulthood. Anxiety is the most common adolescent mental health condition, yet its clinical significance and prognosis are not well understood. We aimed to examine the risk of young adult-onset psychiatric disorders in individuals with an adolescent anxiety disorder, and identify stratifiers of risk of subsequent psychiatric disorders in this group. Methods Individuals from the Norwegian Mother, Father, and Child Cohort Study (MoBa) with linked health records and aged 18 or over as of the 31st December 2023 were included. Those diagnosed with any ICD-10 anxiety disorder when aged 10-17 years were defined as having an adolescent anxiety disorder (n=2107, controls n=47,582). Polygenic scores (PGS) for psychiatric and neurodevelopmental conditions were calculated using LDpred2. Anxiety, comorbidities, and parental psychiatric history were defined through linked ICD-10 diagnoses. Sex was defined through linked records. Individuals were defined as having a young adult-onset psychiatric disorder if they first received any new psychiatric diagnosis aged 18-24. Results Adolescent anxiety diagnosis was associated with increased risk of all adult-onset psychiatric disorders (HR= 2.33-8.65). Post-traumatic stress disorder PGS, parental history of severe mental illness, and female sex were associated with increased risk of transition to a young adult-onset psychiatric disorder in people with an adolescent anxiety disorder. Conclusions Adolescent anxiety greatly increases the risk of a psychiatric disorder during the transition to adult life. Clinicians should consider female sex and parental psychiatric history when prioritising young people with anxiety for adult mental health service support. Future research needs to further consider whether polygenic scores would aid risk stratification in clinical practice.

Aim: To determine whether the neural phenotype (whole-brain resting-state functional connectivity pattern) of attention deficit hyperactivity disorder associated with prenatal alcohol exposure (ADHD+PAE) differs from that in unexposed children with ADHD of probable familial origin (ADHD-PAE). Method: Resting-state functional MRI was acquired from 26 children with ADHD+PAE, 25 with ADHD-PAE, and 25 typically developing (TD) children, all aged 8-13 years. Mean connectivity matrices based on the Cole-Anticevic Brainwide Network Parcellation of the brain were compared between the groups. Results: Within the frontoparietal network (FPN), children with ADHD+PAE showed widespread lower group-mean connectivity than children with ADHD-PAE; effects were concentrated primarily in cerebellar-cerebral cortical and cerebral cortical-cerebral cortical connections. Children with ADHD-PAE showed widespread hyperconnectivity relative to TD children. Children with ADHD+PAE showed mixed hyper- and hypoconnectivity relative to TD. Interpretation: These results are consistent with other MRI findings indicating that ADHD+PAE is neurally distinct from ADHD-PAE; PAE may be associated with broadly reduced connectivity, especially across cerebellar-cerebral cortical systems.

Background. Nascent findings suggest that people with attention-deficit/hyperactivity disorder (ADHD) experience higher rates of mortality. To date, study samples have been insufficiently well-characterized to examine the mechanisms via which this neurodevelopmental condition elevates mortality risk. Methods. We used data from the 2007 and 2011 waves of the US National Health Interview Survey, a general population-based cohort study comprising 52097 adults (28675 women) aged 18 years or older at baseline. ADHD diagnosis and an array of demographic, socioeconomic, lifestyle, and co-morbidity (somatic and psychiatric) covariates were self-reported. Findings. At baseline, compared with unaffected individuals, participants with ADHD were more likely to be socioeconomically disadvantaged, smoke cigarettes, consume alcohol, and report symptoms of psychological distress. A median 7.75 years of mortality surveillance (range: 7.25-12.25) gave rise to 6597 deaths from all-causes. After adjustment for age, sex, ethnicity, and survey year, ADHD was associated with a markedly elevated risk of death (hazard ratio [95% confidence interval]: 1.58 [1.20-2.09]). Statistical adjustment for socioeconomic circumstances (11% attenuation), physical co-morbidities (15%), and lifestyle factors (17%) had only a modest impact on the ADHD-death gradient, with the greatest explanatory power apparent for symptoms of depression and anxiety (58%). The magnitude of the association of ADHD with mortality was commensurate to that for several well-established risk factors such as poverty (1.66 [1.55-1.78]), hypertension (1.41 [1.32-1.51]), and diabetes (1.71 [1.59-1.85]) but somewhat lower than cigarette smoking (2.51 [2.29-2.76]) after controlling for age, sex, ethnicity, and survey year. Associations between ADHD and cause-specific mortality from cardiovascular disease, cancer, and chronic respiratory disease were inconclusive. Interpretation. In the present study, the influence of ADHD on total mortality appears to be largely embodied via a series of malleable characteristics, particularly mental illness. If confirmed elsewhere, these results raise the possibility that risk factor modification via standard pharmacological and behavioral interventions could help reduce rates of premature mortality in this patient group. Funding. This paper received no direct funding. GDB is supported by the UK Medical Research Council (MR/P023444/1) and the US National Institute on Aging (1R56AG052519-01, 1R01AG052519-01A1).