Importance Childhood trauma is associated with increased risk for bipolar disorder, but the biological mechanisms of this association remain incompletely defined. Gray matter differences observed after trauma exposure overlap with those reported in bipolar disorder, suggesting that the association of childhood trauma with bipolar disorder might be mediated through brain morphology. Objective To determine whether cortical thickness, cortical surface, or subcortical volume mediate the association of childhood trauma with bipolar disorder. Design, Setting, and Participants This case-control study conducted a cross-sectional analysis of individuals with bipolar disorder and healthy controls from 19 international cohorts (Enhancing NeuroImaging Genetics Through Meta-Analyses [ENIGMA] Bipolar Disorder Working Group) from January 2010 to December 2022. Data were analyzed from January 2025 to January 2026. Exposures The primary exposure was the severity of total childhood trauma assessed with the Childhood Trauma Questionnaire, with secondary analyses of 5 subscales (emotional neglect and abuse, physical neglect and abuse, and sexual abuse). Main Outcomes and Measures The primary outcome was bipolar disorder diagnosis (case vs control). The primary measure was the mediation effects of childhood trauma on diagnosis via gray matter (75 bilateral-averaged cortical thickness, surface, and subcortical volume measures). The mediation pathway from severity of childhood trauma to bipolar disorder through brain morphology was specified a priori. High-dimensional mediation analysis, with leave-one-site-out cross-validation and permutation testing for significance (false discovery rate [FDR]), was conducted. Results The final sample included 2221 healthy controls (mean [SD] age, 35.6 [13.2] years; 1274 female [57%]) and 1031 participants with bipolar disorder (mean [SD] age, 38.6 [13.7] years; 579 female [56%]). Severity of childhood trauma was directly associated with higher likelihood of having a bipolar disorder diagnosis (median coefficient, 0.841; 95% CI, 0.834-0.851; range, 0.776-0.893; FDR P < .001). Less than 1% of the association between childhood trauma and bipolar disorder was mediated by brain morphology. Statistically significant mediators were hippocampal volume (median coefficient, 0.004; 95% CI, 0.002-0.005; range, 0-0.008; FDR P < .001), medial orbitofrontal gray matter thickness (median coefficient, 0.002; 95% CI, 0.002-0.003; range, 0-0.004; FDR P < .001), and superior frontal gyrus gray matter thickness (median coefficient, 0.002; 95% CI, 0.002-0.003; range, 0-0.005; FDR P < .001). Conclusions and Relevance This study found that severity of childhood trauma exposure was associated with bipolar disorder diagnosis in part through a smaller hippocampus, thinner cortex in the medial orbitofrontal gyrus, and thinner cortex in the superior frontal gyrus. The identification of this mechanistic pathway improves understanding of the disorder, could help to identify those at risk, and enable the development of new interventions.

There is a need for greater recognition of clinical psychopharmacology endpoints, including instances where specific psychotropic medications may become unnecessary, redundant, contradictory, or otherwise inappropriate and therefore merit deprescribing. To address circumstances warranting psychotropic medication deprescribing. The American Society of Clinical Psychopharmacology convened a panel of 45 international psychopharmacology experts who developed and completed a multiround Delphi survey and conducted a focused literature review between January and May of 2025, in order to identify areas of consensus or disagreement on key aspects of the deprescribing of psychotropic medications. These included collaborative risk-benefit assessments with patients; pharmacokinetic and pharmacodynamic factors; pharmacogenomics; distinguishing redundant or conflictual from complementary mechanisms of action; managing adverse effects; assuring medication adherence; drug tolerance or tachyphylaxis; medication misuse; and the psychological context and ramifications of deprescribing. Consensus was achieved on 44 of 50 final Delphi statements (88%). Panelists unanimously agreed that components of a pharmacotherapy regimen should undergo periodic review to ensure that treatments target relevant symptoms and have favorable risk-benefit ratios. Key points of consensus were that deprescribing: (1) should not occur without first assessing medication adherence; (2) merits consideration if less than partial therapeutic response is apparent, or if treatment goals have been reached and relapse prevention is not a long-term objective; (3) involves psychological ramifications that warrant attention; (4) should be followed by close clinical monitoring; and (5) risk-benefit decisions should ideally involve active patient participation within a shared decision-making model. Through this Consensus Statement, the Task Force identified circumstances in which the selective elimination of certain psychotropic medications may be clinically indicated. Empirical trials are needed to assess the implementation of deprescribing protocols and gauge their safe, effective, and acceptable outcomes.

Bipolar disorder's (BD) clinical heterogeneity has an unresolved genetic basis. We meta-analyzed genome-wide association studies (GWAS) of 16 BD subphenotypes in 226,032 individuals from 57 cohorts (38,022 cases); 10 advanced to multivariate and multi-trait analyses. Four factors (compulsive, psychotic, dysregulated, internalizing) explained 82.8% of shared genetic variance. BD1 and BD2 loaded on distinct factors despite a high genetic correlation; 87.0% of common-factor loci were significant in neither subtype. Unipolar mania aligned with psychosis over internalizing, and was distinguishable from BD1, and rapid cycling showed heritable cross-domain liability. We identified 356 risk loci, 158 novel, including the first univariate-GWAS associations for psychosis, unipolar mania, rapid cycling and schizoaffective disorder-and 249 credible genes (89 high-confidence), 12 with approved-drug or clinical-phase annotations. Cell-type association showed a midbrain dopaminergic-GABAergic gradient along the psychotic factor. BD's genetic architecture appears hierarchical-a general liability resolving into dimensions of course and comorbidity, beyond subtypes.

BACKGROUND:Bipolar disorder (BD) is a major mood disorder influenced by both genetic and environmental factors. While DNA methylation from peripheral tissues can reflect both genetic and environmental influences and reveal insights into disease biology, it remains understudied in BD. DNA methylation signatures may complement polygenic scores (PGS) and hold potential as biomarkers. Here, we conducted the largest epigenome-wide association study (EWAS) of BD to date and evaluated the predictive value of polymethylation scores (PMS) in classifying case-control status. METHODS:DNA methylation from peripheral blood of 1729 cases and 1747 controls, comprising twelve cohorts, was obtained. We performed meta-analyses for the total sample, male-only, and female-only analyses. Differentially methylated regions (DMRs) were identified using the comb-p method. Polymethylation scores for BD (BD-PMS) were tested for association with BD, and in combination with PGS. FINDINGS:We identified 47 differentially methylated CpG positions (DMPs) in the total and four in the female-only analysis. Ninety, fourteen and six DMRs were identified in the total sample, female-only, and male-only analyses, respectively. Genes annotated to the top DMPs were enriched for immune activation and phosphorylation pathways. DMRs were annotated to genes relevant to neurotransmission, including GABBR1 and CACNA2D4. BD-PMS explained 2% of the variance in BD case-control status, and improved the variance explained from 7.9 to 8.5% when combined with PGS. For bipolar I disorder, BD-PMS explained 4.9% of the variance, and improved the variance explained by PGS from 15.9 to 18.5%. Association of BD with PMS for schizophrenia and major depression suggests pleiotropic epigenetic effects. INTERPRETATION:DNA methylation signatures of BD are detectable in blood using adequately powered data and may reveal novel BD biology that is not captured by genetic studies. PMS from large cohorts have the potential to facilitate the development of prediction tools to aid clinical decision-making. FUNDING:This investigation was primarily funded by the Research Council of Norway (RCN #250299, #273446, #223273) and the University of Bergen. A complete list of funding organisations is provided in the Acknowledgements.

Eating disorders (EDs) are increasingly recognised among neurodivergent and transgender and gender diverse (TGD) individuals, yet most assessment and treatment models remain grounded in cisnormative and neuronormative assumptions and frameworks. Sensory processing, spanning interoception and exteroception, has been proposed as a potential factor that may help explain observed associations between neurodivergent traits, gender incongruence, and EDs. Empirical evidence, however, remains limited. This study examined whether sensory processing characteristics accounted for variance in observed associations between neurodivergent traits (with a focus on Autism and attention deficit/hyperactivity disorder, ADHD), gender incongruence, and ED symptoms in an adult community sample. Participants (N = 195) completed an online Qualtrics survey involving validated self-report measures of exteroception, interoceptive sensibility, gender congruence, and ED symptoms (for example, Eating Disorder Examination Questionnaire Short, EDE-QS and Nine Item Avoidant or Restrictive Food Intake Disorder Screener, NIAS). Correlation, regression, and effects analyses were used to explore associations among self-reported neurodivergent traits, gender incongruence, sensory processing, and ED symptoms. Gender incongruence and Autistic traits showed positive associations with restrictive and avoidant ED symptoms. ADHD traits showed positive associations with a broader range of ED symptoms, including restrictive, avoidant, and binge eating presentations. Gender incongruence also showed positive associations with sensory processing differences across both exteroceptive and interoceptive domains: namely, elevated visual and auditory sensitivity and reduced body trust. Furthermore, interoceptive sensibility, particularly lower body trust, showed significant statistical relations with ADHD motor traits and EDE-QS scores. Interoceptive sensibility also showed significant statistical relations in models including gender incongruence and EDE-QS scores. Exteroceptive hypersensitivity showed a partial statistical relation in models examining gender incongruence and NIAS scores. To the authors’ knowledge, this study provides the first lived experience-led empirical intersectional investigation linking interoception and exteroception with neurodivergent traits, gender incongruence, and ED symptoms. Results highlight the relevance of intersectional, sensory-informed, and identity-affirming perspectives for future research and the ongoing development of ED assessment and care. We invited adults to complete an anonymous online survey about eating disorder symptoms, how comfortable they felt with their gender, their sensory experiences, and traits linked with Autism or ADHD. A total of 195 people took part between July and September 2025. People who felt less comfortable or less congruent with their physical characteristics in relation to their gender identity reported more eating disorder symptoms. How people make sense of internal bodily cues and trust their bodies (interoceptive sensibility) helped explain these links. Lower trust in bodily signals and lower noticing of internal sensations were associated with more eating problems. Heightened exteroception, particularly sensitivity to sights and sounds, was also linked with gender incongruence and eating disorder symptoms. Autistic traits were mostly related to avoidant or restrictive eating. ADHD traits were related to a wider set of disordered eating behaviours, including restricting and binge eating. These findings suggest that more investigations into the role of sensory processing in disordered eating in the context of neurodivergence and gender diversity might help tailor treatment in order to better meet the support needs of gender diverse and neurodivergent individuals.

There is a lack of consensus in the field about the indefinite use of psychostimulants for adult ADHD and the circumstances under which their deprescribing warrants consideration. To address this gap in knowledge, the American Society of Clinical Psychopharmacology (ASCP) convened a Task Force on the deprescribing of psychotropic medications, including stimulant medications for adult ADHD, which entailed a focused literature review and 2-round Delphi survey querying 45 international psychopharmacology experts on factors related to deprescribing. Consensus (≥75% agreement, defined by endorsements of “strongly agree” or “moderately agree”) was reached on 10 of 11 (91%) Delphi statements. Survey responses plus literature review suggest that stimulant deprescribing may be appropriate when 1) the diagnosis of ADHD is deemed incorrect upon reevaluation unless another stimulant-responsive condition is evident; 2) cognitive complaints have other more likely etiologies for which stimulant medications are inappropriate; 3) cognitive benefits are absent; 4) stimulant medications exacerbate medical or other psychiatric comorbidities; 5) adverse effects, if present, are non-remediable; 6) stimulant medications are misused; and 7) untreated comorbid non-cannabis substance use disorders are present. Panelists just fell short of consensus in perceiving regular use of cannabis as an insufficient reason to deprescribe stimulant medications in adult ADHD patients. In sum, clinical circumstances and rationales can be identified that support decisions to deprescribe stimulant medications for adult ADHD. Deliberate stimulant misuse or abuse, comorbid medical or psychiatric contraindications, and diagnostic inaccuracy pose strong reasons to consider deprescribing stimulants, potentially in favor of alternative pharmacotherapies and psychotherapies for adult ADHD.

Background:Large-scale T1-weighted MRI studies have established grey-matter abnormalities in bipolar disorder (BD), with our group contributing to consensus findings. However, structural connectivity, particularly within emotion- and reward-related circuits, remains poorly understood. Diffusion-weighted MRI (dMRI) enables investigation of white-matter pathways, yet prior work is constrained by small samples, methodological heterogeneity, and unclear medication effects. We conducted the largest dMRI network analysis in BD, relating symptom burden and polypharmacy to tractography-derived connectivity and graph-theoretic metrics. Methods:Cross-sectional structural and diffusion MRI scans from 449 individuals with BD (35.7±12.6 years) and 510 controls (33.3±12.6 years), aged 18-65, were analyzed across 16 ENIGMA-BD sites. Standardized segmentation/parcellation and constrained spherical deconvolution tractography generated individual structural connectivity matrices. Graph-theoretic metrics of global and subnetwork organization were related to symptom severity and medications. Results:BD showed widespread network alterations (lower density and efficiency, longer path length, and higher betweenness centrality), altered microstructural organization in a limbic-basal ganglia circuit, and abnormal streamline counts in a default-mode/salience/fronto-limbic-basal ganglia network. Longer illness duration, later onset, and psychosis history were associated with greater abnormalities in network architecture, whereas more manic episodes were associated with greater fronto-limbic connectivity. Antidepressant (particularly SSRI), anticonvulsant, and antipsychotic use related to poorer global and fronto-limbic connectivity; no clear lithium effects emerged. Conclusions:As the largest structural connectivity study in BD, we reveal widespread disruption in reward and emotion-regulation networks influenced by illness severity and medication use. Results show that multisite harmonization is feasible and highlight ENIGMA-BD as a scalable framework for identifying reproducible neurobiological markers.

Importance:Childhood trauma is associated with increased risk for bipolar disorder, but the biological mechanisms of this association remain incompletely defined. Gray matter differences observed after trauma exposure overlap with those reported in bipolar disorder, suggesting that the association of childhood trauma with bipolar disorder might be mediated through brain morphology. Objective:To determine whether cortical thickness, cortical surface, or subcortical volume mediate the association of childhood trauma with bipolar disorder. Design, Setting, and Participants:This case-control study conducted a cross-sectional analysis of individuals with bipolar disorder and healthy controls from 19 international cohorts (Enhancing NeuroImaging Genetics Through Meta-Analyses [ENIGMA] Bipolar Disorder Working Group) from January 2010 to December 2022. Data were analyzed from January 2025 to January 2026. Exposures:The primary exposure was the severity of total childhood trauma assessed with the Childhood Trauma Questionnaire, with secondary analyses of 5 subscales (emotional neglect and abuse, physical neglect and abuse, and sexual abuse). Main Outcomes and Measures:The primary outcome was bipolar disorder diagnosis (case vs control). The primary measure was the mediation effects of childhood trauma on diagnosis via gray matter (75 bilateral-averaged cortical thickness, surface, and subcortical volume measures). The mediation pathway from severity of childhood trauma to bipolar disorder through brain morphology was specified a priori. High-dimensional mediation analysis, with leave-one-site-out cross-validation and permutation testing for significance (false discovery rate [FDR]), was conducted. Results:The final sample included 2221 healthy controls (mean [SD] age, 35.6 [13.2] years; 1274 female [57%]) and 1031 participants with bipolar disorder (mean [SD] age, 38.6 [13.7] years; 579 female [56%]). Severity of childhood trauma was directly associated with higher likelihood of having a bipolar disorder diagnosis (median coefficient, 0.841; 95% CI, 0.834-0.851; range, 0.776-0.893; FDR P < .001). Less than 1% of the association between childhood trauma and bipolar disorder was mediated by brain morphology. Statistically significant mediators were hippocampal volume (median coefficient, 0.004; 95% CI, 0.002-0.005; range, 0-0.008; FDR P < .001), medial orbitofrontal gray matter thickness (median coefficient, 0.002; 95% CI, 0.002-0.003; range, 0-0.004; FDR P < .001), and superior frontal gyrus gray matter thickness (median coefficient, 0.002; 95% CI, 0.002-0.003; range, 0-0.005; FDR P < .001). Conclusions and Relevance:This study found that severity of childhood trauma exposure was associated with bipolar disorder diagnosis in part through a smaller hippocampus, thinner cortex in the medial orbitofrontal gyrus, and thinner cortex in the superior frontal gyrus. The identification of this mechanistic pathway improves understanding of the disorder, could help to identify those at risk, and enable the development of new interventions.

The material detailed in this paper was first presented at the Festschrift for Professor Gordon Parker in September 2025. One of Gordon's main areas of research has been bipolar disorder. This paper first addresses general aspects of Gordon's approach to research, before focussing on themes within his bipolar disorder research portfolio, in particular phenomenology, bipolar II disorder, the distinction between borderline personality disorder and bipolar II disorder, and treatments for bipolar II disorder, particularly lamotrigine.

MRI studies in bipolar disorder (BD) have yielded inconsistent findings, partly due to the varied use of psychotropic medications. This study utilised a mega-analysis approach, accounting for concurrent medication status (syndrome-based and Neuroscience-based Nomenclature (NbN) classifications), in order to assess the association of medication status with subcortical brain volumes in BD. Data from 2,664 BD patients and 4,065 controls (CN) were pooled from 34 research groups as part of the ENIGMA Bipolar Disorder Working Group. Standardized ENIGMA protocols were used to measure subcortical brain volumes. Linear-mixed-effects regression evaluated the association between psychotropic medications and subcortical volumes, and moderation analyses explored interactions. Medication-free patients (n = 410) showed mild ventricular enlargement (d = 0.07) and increased putamen volume (d = 0.06) compared to CN. Patients taking psychotropic medications exhibited smaller subcortical volumes (d = -0.06 to -0.11) and larger ventricles (d = 0.11 to 0.19). Use of antiepileptic and antipsychotic medications was associated with smaller hippocampal and thalamic volumes (d = -0.07 to -0.14), while NbN classification indicated that the categories of ‘valproate’ and ‘dopamine and other monoamine receptor antagonists’ are key variables when considering volume differences between BD and CN. Concurrent lithium use weakened the negative association between antiepileptic use and hippocampal volume (β = 0.19, q = 0.038) in patients. Medication status is associated with altered subcortical brain volumes in BD. The NbN classification provides a useful framework for future studies, emphasizing the need for comprehensive longitudinal research to further unravel complex clinical-pharmacological-neurobiological interactions in BD.

Exteroception, the processing of environmental sensory information, may be relevant to eating disorder (ED) symptoms, but limited research has examined its associations across specific ED symptom dimensions. This study primarily examined whether self-reported exteroceptive sensibility was associated with dietary restraint, eating concern, weight concern, shape concern, avoidant/restrictive eating symptoms, binge-eating symptoms, and orthorexia-related symptoms. Secondary analyses investigated sociodemographic differences in self-reported exteroceptive sensibility and whether sociodemographic variables moderated associations between self-reported exteroceptive sensibility and ED symptom dimensions. A non-clinical community sample of 221 Australian adults completed self-report measures of ED symptoms and exteroceptive sensibility. Spearman correlations assessed associations between exteroceptive sensibility and ED symptom dimensions. Group comparisons assessed sociodemographic differences in exteroceptive sensibility, and regression-based moderation models examined whether sociodemographic variables (e.g. sex assigned at birth, gender identity, and age) moderated associations between exteroceptive sensibility and ED symptom dimensions. Self-reported exteroceptive sensibility was positively associated with dietary restraint, eating concern, weight concern, shape concern, avoidant/restrictive eating symptoms, and binge-eating symptoms. Associations with orthorexia-related symptoms were weaker and did not remain statistically significant after Holm–Bonferroni correction. Associations were strongest for avoidant/restrictive eating symptoms. Exteroceptive sensibility differed across several sociodemographic variables, but moderation analyses provided limited evidence that these variables altered associations between exteroceptive sensibility and ED symptom dimensions. Self-reported exteroceptive sensibility was positively associated with multiple ED symptom dimensions, with the strongest associations observed for avoidant/restrictive eating symptoms. Findings support consideration of sensory experiences in ED assessment and care. Level of evidence: Level III, cross-sectional analytic study.

Purpose Suicide rates continue to increase in many nations despite awareness and prevention campaigns. While economic factors, substance abuse and availability of means have been associated with suicide rates, much of the population-level variability remains unexplained. To assess the association between national-level flourishing index scores, flourishing subdomains and age-standardised suicide mortality rates. Methods This study used national-level, cross-sectional data from Global Flourishing Study (GFS) and the Global Burden of Disease (GBD) Study (2021). Generalised linear models were used to assess the relationships between the exposures and outcomes. The exposures included the flourishing index and flourishing domain scores (happiness/life satisfaction, mental/physical health, meaning/purpose, character/virtue, close social relationships, and financial/material stability). The primary outcome was suicide mortality (GBD 2021). Results There were 202,838 participants included in the GFS from 22 countries nations that differed widely by socioeconomic status, cultural background, and religious tradition. In the main age-adjusted analysis, national flourishing index scores were inversely associated with the GBD estimates of suicide mortality (B=-5.2; 95%CI[-8.9, -1.4]). The two flourishing domains associated with suicide mortality were meaning/purpose (B=-4.6; 95%CI[-7.3, -1.8]) and close social relationships (B=-4.8; 95%CI[-8, -1.6]), with little evidence of associations found with the other four domains. Conclusion Measures of flourishing may be more closely associated with suicide mortality than previously used measures of wellbeing. Flourishing, particularly in domains of meaning/purpose and close social relationships, should be considered in further research of causal factors and in national frameworks for suicide prevention.

ABSTRACT Alternative-splicing events (ASE) increase transcriptomic variability and play key roles in biological functions. The contribution of ASE to bipolar disorder (BD) remains largely unexplored. We performed a Transcriptome-Wide Alternative-Splicing Analysis (TWASA) to identify ASEs and genes potentially involved in BD. The study comprised 635 individuals: a discovery sample (DS) of 31 individuals from eight multiplex BD families (16 BD cases; 15 unaffected relatives), and a replication sample (RS) of 604 subjects (372 BD cases; 232 controls). Sequencing was conducted on RNA from lymphoblastoid cell lines (DS) and whole blood (RS). TWASA was performed using VAST-TOOLS (VT), rMATS (RM), and MAJIQ/MOCCASIN (MCC). Gene-set association analyses of genes containing ASEs were performed across six psychiatric disorders. Novel ASE (nASE) were investigated in the DS using FRASER. Limited gene overlap was observed across TWASA tools. MCC identified 2,031 complex ASEs involving 1,508 genes, showing the strongest genetic association with BD across psychiatric phenotypes. Prioritization of MCC-identified ASE genes yielded 441 candidates, including DOCK2 as top candidate from the DS. Replication was obtained for 98 genes, five with an identical ASE, and four ( RBM26 , QKI , ANKRD36 , and TATDN2 ) showing a concordant percentage-spliced-in direction with the DS. Finally, 578 nASE were identified in the DS, with no evidence of familial segregation or differences in ASE types. This first TWASA in BD reveals tool-specific variability, complex ASE for genes specifically associated with BD, and novel candidate genes for BD. Alternative transcript isoform abundance may represent a mechanism contributing to BD pathophysiology.

Background Anxiety disorders and treatment-resistant major depressive disorder (TRD) are often comorbid. Studies suggest ketamine has anxiolytic and antidepressant properties. Aims To investigate if subcutaneous racemic ketamine, delivered twice weekly for 4 weeks, reduces anxiety in people with TRD. Method The Ketamine for Adult Depression Study was a multisite 4-week randomised, double-blind, active (midazolam)-controlled trial. The study initially used fixed low dose ketamine (0.5 mg/kg, cohort 1), before protocol revision to flexible, response-guided dosing (0.5–0.9 mg/kg, cohort 2). This secondary analysis assessed anxiety using the Hamilton Anxiety (HAM-A) scale (primary measure) and ‘inner tension’ item 3 of the Montgomery–Åsberg Depression Rating Scale (MADRS), at baseline, 4 weeks (end treatment) and 4 weeks after treatment end. Analyses of change in anxiety between ketamine and midazolam groups included all participants who received at least one treatment (n = 174), with a mixed effects repeated measures model used to assess the primary anxiety measure. The trial was registered at www.anzctr.org.au (ACTRN12616001096448). Results In cohort 1 (n = 68) the reduction in HAM-A score was not statistically significant: −1.4 (95% CI [−8.6, 3.2], P = 0.37), whereas a significant reduction was seen for cohort 2 (n = 106) of −4.0 (95% CI [−10.6, −1.9], P = 0.0058), favouring ketamine over midazolam. These effects were mediated by total MADRS and were not maintained at 4 weeks after treatment end. MADRS item 3 was also significantly reduced in cohort 2 (P = 0.026) but not cohort 1 (P = 0.96). Conclusion Ketamine reduces anxiety in people with TRD when administered subcutaneously in adequate doses.

OBJECTIVES:To investigate pharmacological treatment patterns in individuals with bipolar disorder (BD) with and without comorbid substance use disorder (SUD) and anxiety disorder (AX), we leveraged the Global Bipolar Cohort to analyze cross-regional practices across North America, Europe, and the Pacific. METHODS:Fourteen cohorts contributed aggregate data on pharmacotherapy, demographics, diagnostic subtypes, and comorbidities. Proportional meta-analyses using generalized linear mixed models were conducted to examine prescription trends and identify clinical differences. RESULTS:The sample (N = 11,521) was 60% female and 84% Caucasian. Participants were categorized into four mutually exclusive groups based on comorbidity status: those with comorbid AX only, comorbid SUD only, both AX and SUD, or neither. The AX+SUD subgroup showed higher rates of attention-deficit/hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), rapid cycling, obesity, and unemployment, reflecting a more severe clinical profile. Regional variations were notable: North American cohorts reported higher prevalence of AX and SUD than European and Pacific cohorts. Antidepressants use for AX were more common in Europe and the Pacific, while North American prescribing patterns were more variable. Benzodiazepine use was high among individuals with SUD across all regions. Lithium and first-generation antipsychotic prescriptions varied, with higher rates observed in Europe. CONCLUSIONS:Findings underscore the heterogeneity of BD and the influence of comorbid AX and SUD on illness burden and treatment. Regional prescribing variations underscore the need for context-specific guidelines. Gaps in data on medication-assisted treatment for SUD point to areas for future research. These insights can support more individualized and effective care for complex BD presentations.

Background The Global Bipolar Cohort (GBC) was established to identify existing bipolar disorder (BD) cohorts worldwide and foster collaborations focused on descriptive and analytic outcomes relevant to BD. A distributed analytic framework has been implemented to engage multiple sites without the need for central data pooling. This report describes the GBC endeavor and global functional impairment patterns. Cross-cohort comparisons of functional correlates are limited by heterogeneous measures and data-sharing constraints. Large, culturally diverse comparisons are needed to distinguish broadly reproducible correlates from cohort-specific effects. Participating sites completed a 28-item descriptive survey covering diagnostic methods, cognition, genetics, treatment, functioning, and follow-up strategies. We implemented a harmonized local logistic regression model of dichotomized functional outcome and shared summary statistics only. Results We identified 69 cohorts across five continents. Thirty-seven cohorts contributed functional outcome analyses from 17,130 participants. Outcome measures included clinician-rated disability scales and social indicators such as employment and marital status. The proportion classified with poor functioning ranged from 16% to 77% (mean 50%). In 32 of 37 cohorts, the overall regression model significantly explained variance in functioning. Current depressive symptoms were the most robust and reproducible correlate of poor functional outcome: they were assessed in 29 cohorts, significant in 22 (75.8%), ranked among the top three correlates in 22, and were the top-ranked correlates in 19. Associations between depressive burden and poor functioning were observed across clinician-rated disability scales and work or social indicators, and across geographically diverse cohorts. Comorbid substance use disorder and medication-related variables were associated with poorer functioning in subsets of cohorts, whereas sex, ancestry, bipolar subtype, psychosis history, and premorbid IQ showed weak or inconsistent associations. Cognitive measures, available in a minority of regression models, showed modest and non-uniform effects. Conclusions Across heterogeneous international cohorts, current depressive symptom burden emerged as the most consistent correlate of poor functioning in bipolar disorder. These findings replicate earlier multisite work at a larger scale, show that protocol-based distributed analyses can identify reproducible clinical signals without sharing individual-level data, and support prioritizing detection and treatment of depressive symptoms when aiming to improve real-world functioning. Future work should expand longitudinal harmonization and representation of under-studied populations.