INTRODUCTION:People with severe mental illness (SMIs) are at an increased risk of morbidity and reduced life expectancy. Obstructive sleep apnoea (OSA), a prevalent but underdiagnosed condition in SMIs, may precipitate more physical health complications. This meta-analysis aimed to estimate the prevalence of OSA and assess its risk in SMIs populations. METHODS:We conducted a systematic review and meta-analysis on studies reporting either diagnosis or high risk of OSA in bipolar disorder (BD), schizophrenia (SCZ), and major depressive disorder (MDD). Databases were searched through January 2026. Pooled prevalence of OSA was calculated through a single-group meta-analysis, while odds ratios (ORs) comparing SMIs and control groups were estimated by a two-group meta-analysis. RESULTS:A total of 47 articles were included in the meta-analysis. The pooled prevalence of OSA in SMIs was 41.2%, largely influenced by clinical and sleep-referral settings, with a 38.3% prevalence in SCZ, 38.2% in MDD and 35.6% in BD. Compared to healthy controls (HCs) without psychiatric diagnosis, participants with SMIs had significantly higher odds of being diagnosed with OSA (OR = 6.96; 95% CI = 2.48, 19.51; k = 2; p-value < 0.001). High risk of OSA was present in 46.7% of SMI individuals. BD participants showed significantly higher excessive daytime sleepiness compared to HCs (SMD = 0.63; 95% CI = 0.28, 0.98; k = 2; p-value < 0.001). CONCLUSION:People with SMIs have a high prevalence of OSA and are at an increased risk of OSA compared to the general population. These findings highlight the considerable burden of OSA in SMIs and support the need for systematic assessment within psychiatric care settings.

The VALFASS study evaluated the SPF-10, a new 10-item patient-reported outcome measure developed with direct patient involvement to assess self-perceived functioning in schizophrenia. Covering autonomy, relationships, occupation, independence, and everyday capabilities, the SPF-10 was designed to address limitations of existing instruments, including limited patient input, reduced feasibility for routine use, and incomplete capture of the patient perspective. This cross-sectional, multicenter study included 155 participants: 44 recently exacerbated patients with schizophrenia, 55 clinically stable patients, and 56 healthy controls. The SPF-10 showed excellent feasibility, with a 100% item response rate and a median completion time of 5 min. Exploratory factor analysis supported a two-dimensional structure, Personal and Social Relationships and Self-Care and Capabilities, explaining 57.7% of the variance. The total SPF-10 score discriminated well between patients and controls (AUC = 0.888) and between patients with moderate-to-severe functional impairment and those with mild or no impairment (AUC = 0.851). A cut-off score of ≤32 yielded 80.8% sensitivity, 84.4% specificity, and 82.6% overall correct classification. Correlations with clinician-rated functioning measures were moderate (PSP r = 0.559; GAF r = 0.521), supporting its complementary value, and internal consistency was good in both patients and controls (Cronbach's α = 0.868 and 0.838, respectively). Overall, the SPF-10 showed adequate psychometric performance and high clinical applicability. Its brief format, patient-centered development, and ability to capture aspects of functioning not fully reflected by clinician-rated instruments support its potential value as a complementary tool for person-centered assessment and care planning in schizophrenia.

BACKGROUND:Bipolar disorder (BD) is associated with clinical and biological markers of premature aging. In this largest study of brain age in BD to date, with 2919 participants, we compared brain-predicted age difference (brain-PAD) in individuals with BD and healthy comparison (HC) participants. Brain-PAD is a machine learning-estimated metric that quantifies the difference between an individual's predicted brain age and their chronological age, a potential clinical bio-signature of premature brain aging. Within individuals with BD, we also examined how medication and clinical characteristics were related to brain-PAD. METHODS:Age was predicted from 77 MRI measures of regional subcortical and lateral ventricle volumes, cortical thickness, and surface area for 1342 BD and 1577 HC adult participants, aged 18-75 yrs. old (μ = 37.2; SD = 12.3), from the curated ENIGMA Bipolar Disorder working group (ENIGMA-BD) and leveraging an ENIGMA machine learning model previously trained and validated using independent samples. Chronological age was subtracted from predicted age to produce an individual-level estimate known as brain-PAD. Linear mixed models (adjusting for sex and age as fixed effects and site as a random effect) were used to examine group differences and clinical associations. RESULTS:BD was associated with higher brain-PAD, compared to HC, primarily among older patients, as demonstrated by a significant age by diagnosis interaction (+0.05 [SE: 0.02] years). Individuals with BD on antiepileptic (AED) medications only (+3.20 [SE: 0.78] years) or on both AED and second-generation antipsychotics (SGA) (+3.74 [SE: 0.89] years) demonstrated greater brain-PAD compared to individuals who were not on any of the examined medications. Those taking lithium, whether alone or with AED and SGA independently, showed no difference in brain-PAD compared to individuals not taking any of the examined medications. However, individuals who were taking lithium showed lower brain-PAD compared to those on AED (-4.48 [SE: 0.84] years) or AED and SGA (-5.01 [SE:0.92] years). Individuals with a BD I subtype diagnosis had a higher brain-PAD (+1.50 [SE:0.55] years) compared to those with BDII or subtypes that are not otherwise specified (NOS). CONCLUSIONS:Results from this study suggest compounding effects of BD diagnosis and older age on brain-PAD, an ML-derived summary metric of structural alterations. Within BD, brain-PAD was differentially related to medication use, consistent with prior findings from ENIGMA-BD. Notably, AED use was generally related to more advanced brain age. Lithium use, alone or in combination with other medications, was not associated with advanced brain age, suggesting a possible neuroprotective effect of lithium. Brain-PAD as an ML-derived summary metric of structural alterations of the brain may provide clinical utility in assessing long-term holistic brain health to monitor the effectiveness of lifestyle modifications or treatments over time. LIMITATIONS:The cross-sectional nature of the study design and the limited granularity of the clinical data limit interpretation. Longitudinal studies with detailed chronicity data, medications and clinical measures overtime will improve brain-PAD modeling in BD.

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.

Childhood maltreatment (CM) has been consistently associated with increased risk and poorer outcomes in bipolar disorder (BD). However, the behavioural and cognitive mechanisms linking CM and suicidality remain poorly understood, limiting the development of targeted preventive interventions. We estimated a regularised partial correlation network to explore the interplay between CM subtypes (emotional, physical, or sexual abuse; emotional and physical neglect), cognitive domains (attention/processing speed, executive function/working memory, socio-emotional cognition, decision-making), impulsivity traits (attentional, motor, non-planning), and suicidal behaviours (ideation, planning, attempts) in 249 euthymic individuals with BD (mean age = 46.14, SD = 8.60; 59.84% female; 71.89% BD type I). CM was assessed using the Childhood Trauma Questionnaire (CTQ), cognition with a comprehensive neuropsychological battery, impulsivity with the Barratt Impulsiveness Scale (BIS-11), and suicidality with the Columbia Suicide Severity Rating Scale (C-SSRS) and structured interview. Age, sex, and social desirability (CTQ minimisation/denial subscale) were included as covariates. CM was associated with both cognitive functioning (poorer executive function and working memory, attention/processing speed, and socio-emotional cognition) and suicidality (suicidal ideation and, to a lesser extent, suicide attempts). Emotional abuse was linked to suicidal ideation (strongest association among CM subtypes; r = 0.27, p <0.001) and showed the highest centrality within the network (strength z = 1.76; expected influence z = 1.95). All CM subtypes were associated with impulsivity traits. Motor impulsivity emerged as a behavioural bridge between CM and suicidality (bridge expected influence z = 0.21), whereas higher socio-emotional cognition, particularly the ability to manage emotions, was associated with fewer suicide attempts. These findings highlight specific cognitive and behavioural mechanisms linking CM and suicidality in BD. Emotional abuse and socio-emotional cognition represent promising targets for trauma-informed and personalised interventions.

Esketamine nasal spray (NS) is an established treatment for patients with treatment resistant depression (TRD). To further optimise real-world outcomes, consensus is needed regarding strategies to enhance patient outcomes and decision-making factors for pivotal timepoints in esketamine NS treatment. This modified Delphi panel (3 rounds) established expert consensus (≥80% agreement) from 30 European psychiatrists experienced in management of patients with TRD receiving esketamine NS. During the acute phase (4-12 weeks), modest/subjective reductions in core symptoms important to both patients and physicians supported esketamine NS continuation, especially with long disease course/resistance to multiple therapies. Consensus was reached that such a modest improvement during the acute phase should justify esketamine NS continuation (and supplementation of other treatment modalities with esketamine NS). Esketamine NS dose/frequency maximisation (84 mg weekly) was advocated for, to enhance acute phase outcomes, alongside strategies reflective of individual clinical characteristics. Monitoring in the continuation phase (6-9 months) should prioritise residual/fluctuating symptoms, changes in symptom severity, functional recovery status and comorbidity management/emergence. Should residual symptoms persist, dose/frequency escalation, among other all-phase options, were supported. Prolonging maintenance phase treatment (≥12 months) depended on the degree of clinical worsening when tapering, the risks/consequences of relapse, chronicity of the last depressive episode, residual symptoms and recurrence history. Across all phases, recommended treatment plans included integration of psychotherapy, optimisation of concomitant antidepressants/augmentation strategies, comorbidity management and strengthening support networks. Overall, the consensus advocated for an approach reflective of TRD complexities, prioritising meaningful outcomes for individual patients.

Posttraumatic stress disorder (PTSD) is a chronic and disabling condition and identifying beneficial therapies is timely and important. We aimed to estimate the efficacy of 3,4-methylenedioxymethamphetamine-assisted therapy (MDMA-AT) compared with control on clinical and functional outcomes in PTSD. A PRISMA-compliant search (PROSPEROCRD42022353261) up to August 14, 2025, covered nine databases and manual searches to identify randomised controlled trials (RCTs). Methodological quality was assessed using the Cochrane Risk of Bias tool (RoB2), and the certainty of the evidence for each outcome was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. Of 1035 records identified, 14 studies met inclusion criteria for qualitative synthesis; eight trials provided sufficient data for quantitative synthesis (k = 24). Random-effects meta-analyses indicated that MDMA-AT was associated with reductions in PTSD symptom severity (n = 298, k = 9, SMD = -1.19, 95 % CI [-1.95, -0.42]; I² = 68.8 %, τ2 = 1.02), dissociative symptoms (n = 148, k = 5, SMD = -0.37, 95 % CI [-0.70, -0.04]; I² = 0.0 %, τ2 = 0), and may improve functioning (n = 227, k = 4, SMD = -0.83, 95 % CI [-1.47, -0.19]; I² = 61.2 %, τ2 = 0.27). No clear evidence of benefit was observed for depressive symptoms. Most studies showed a high risk of bias in the measurement of the outcome, and some concerns due to deviations from the intended intervention; the overall certainty of the evidence was very low. The number of trials remains limited, with considerable heterogeneity in certain outcomes, small sample sizes, and the absence of active controls in most studies, which likely compromised blinding integrity. Current findings suggest that MDMA-AT may warrant further investigation as a potential treatment for PTSD; however, larger, higher-quality RCTs with active controls and long-term follow-up are needed to determine its efficacy.

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.

A large within-person discrepancy between fluid and crystallised cognition may represent a sensitive cross-sectional proxy for an atypical cognitive trajectory. However, this proxy has not been widely studied in bipolar disorder (BD), and replication data regarding the prevalence and predictors of large discrepancy profiles in BD are therefore lacking. Using a shared analytic pipeline, we analysed cross-sectional cognitive data from 16 independent BD cohorts across 10 countries (n= 3339). Fluid-crystallised discrepancy profiles (FCDPs) were defined as the within-cohort standardised difference between fluid and crystallised cognition. A large (&gt;0.5SD difference) FCDP was taken as a proxy for an atypical cognitive trajectory. We estimated the prevalence of large FCDPs in each cohort and examined sociodemographic and clinical predictors using regression, then compared, synthesised, and meta-analysed the results. In two cohorts with prospective data, we calculated FCDPs in follow up data as well as longitudinal short-term (~1-2 years) fluid cognitive change scores. The pooled prevalence of large FCDPs was 34%, with similar proportions across cohorts despite differences in age, illness duration and clinical features. Clinical course variables showed little or no association with large FCDPs. In the prospective cohorts, large FCDPs were highly stable over ~2 years but largely unrelated to short-term longitudinal cognitive change. Nonetheless, ~20% of participants showed short-term decline, suggesting heterogeneity in how longer-term cognitive deviations and immediate change relate within BD. The pattern of results suggest that a sizeable subgroup of BD shows a meaningful discrepancy between fluid and crystallised cognition that is not readily explained by aging or illness chronicity indicators. The pattern is consistent with either a long-standing neurodevelopmental vulnerability or an early-onset decrement in fluid cognition that then remains relatively stable over time. However, another BD subgroup may still exhibit genuinely progressive cognitive deterioration that is not well captured by the discrepancy-based trajectory proxy.

Voxel-based meta-analyses—also known as coordinate-based meta-analyses (CBMAs)—are powerful tools for synthesizing evidence from neuroimaging studies in human neuroscience, including investigations of psychological functions and differences in brain disorders. To achieve their full potential in accurately assessing the evidence, CBMAs should adhere to established best-practicmpe guidelines, such as the “Ten Simple Rules” published in 2018. Yet, even when studies report following these recommendations, the degree to which individual items are applicable or fully addressed is often unclear. To better support the evaluation of methodological rigor—which the 10 rules already promote but are not always consistently applied—, the developers of the most used CBMA methods followed a Delphi-style iterative process to create a reporting checklist focused on the methodological quality of CBMAs (Qual-CBMA). Qual-CBMA comprises criteria (e.g., preregistration, systematic search, homogeneous study characteristics, etc.) that authors should verify and comment on explicitly in the checklist (and, when unmet, also in the manuscript). The checklist encourages rigor and transparency by prompting authors to identify potential methodological limitations and to discuss their relevance—or irrelevance—in the context of their specific study. The checklist is designed as an aid to make reporting clearer and more transparent, not as a tool for evaluating whether authors have done something incorrectly. In this context, a high-quality CBMA is not defined by meeting every criterion, but by clearly commenting on the criteria—and explaining when unmet criteria are appropriately not applicable given the study’s objectives. We encourage authors to submit the Qual-CBMA checklist, together with their accompanying comments, when publishing new CBMAs, thereby reinforcing transparency and rigorous methodology and advancing understanding in cognitive neuroscience and clinical conditions.

Predicting symptom change is a key goal of machine learning in mental health. However, models can seem more accurate than they are due to regression to the mean, a common statistical effect often overlooked in machine learning. Here we outline its implications and a simple framework for separating genuine prediction from statistical artefact.

INTRODUCTION:Psychotic depression (PD) is a severe form of depression that can occur in both major depressive disorder (MDD) and bipolar disorder (BD). Although relatively prevalent, the prognostic impact of psychotic symptoms in depression remains controversial. OBJECTIVE:To systematically review the available evidence comparing PD and non-psychotic depression (NPD) in terms of clinical course, functional outcomes, and treatment outcomes. METHODS:A systematic search of electronic databases (PubMed, Cochrane Library and Web of Science) following PRISMA guidelines was conducted from inception to 31st January 2025 to integrate current evidence about the impact of psychotic symptoms in both unipolar and bipolar depressed patients. This study was registered in PROSPERO (CRD42024563172). RESULTS:Fourty-one studies met inclusion criteria. Compared to NPD, PD was associated with greater clinical severity, longer hospitalizations, and higher inpatient treatment rates. Several studies showed lower remission rates and greater chronicity in PD. Relapse, readmission, or shorter time to recurrence were also more common in PD. Evidence indicated a higher risk of suicide and poorer functional outcomes in PD. Treatment patterns showed more frequent use of ECT and pharmacological combinations in PD, although no consistent drug-specific differences emerged. Overall, heterogeneity across designs and outcome measures was substantial. CONCLUSIONS:Despite heterogeneity, evidence across 41 studies indicates that PD is a higher-risk depressive subtype, characterized by greater service use, higher relapse liability, lower sustained remission, increased suicidality, and poorer functioning. These findings support the need for intensified assessment and management and highlight the importance of large, standardized prospective studies, especially in BD.

BACKGROUND:Virtual reality-based cognitive remediation therapy (VR-CRT) offers an ecologically valid approach to enhance real-world cognitive functioning in mood disorders (MD) or schizophrenia spectrum disorders (SSD). This study investigated baseline cognitive, clinical, and neural predictors of VR-CRT response in MD and SSD. METHODS:Sixty-two MD and SSD participants were randomized to receive four-week VR-CRT or control with assessments at baseline, treatment completion (week 5), and follow-up (week 17). Univariate general linear models examined predictors of VR-CRT improvement on daily-life cognitive skills, assessed using the Cognition Assessment in Virtual Reality (CAVIR). Predictors included age, diagnosis, baseline cognition, IQ-cognition discrepancy, dorsal prefrontal cortex (dPFC) activation during a working memory task, functional connectivity within the dorsal attention (DAN) and salience (SAL) networks, subjective cognition, and technological acceptance. RESULTS:Higher IQ-cognition discrepancy at baseline (i.e., better cognitive performance than expected from premorbid IQ) predicted greater treatment efficacy at treatment completion (β = 0.17, p = 0.045) and follow-up (β = 0.21, p = 0.008), while baseline cognition was not associated with treatment response (ps ≥ 0.15). Higher baseline dPFC activity predicted more improvements at both times (β = 2.27 p = 0.03; β = 1.82; p = 0.048, respectively). Higher DAN-SAL connectivity predicted improvements at treatment completion (β = 2.81 p = 0.047), but not at follow-up (p = 0.38). Age, sex, diagnosis, subjective cognition, and technological acceptance were not associated with cognitive change. CONCLUSIONS:Better cognitive performance than expected based on IQ, possibly reflecting higher cognitive fitness, and greater task-related engagement of dPFC may enhance VR-CRT responsiveness. This profile may indicate greater readiness for change and propensity to translate cognitive strategies into daily life.

JNJ-42165279 is a potent, selective inhibitor of fatty acid amide hydrolase (FAAH), the enzyme responsible for degradation of the endocannabinoid N-arachidonoylethanolamide (anandamide), which plays a role in regulation of fear and anxiety responses. This double-blind, randomised, placebo-controlled, phase 2a study assessed the efficacy, safety and pharmacodynamics of adjunctive treatment with JNJ-42165279 in participants with major depressive disorder (MDD) with anxious distress and inadequate response to selective serotonin reuptake inhibitors (SSRI) or serotonergic/noradrenergic reuptake inhibitors (SNRI). Eligible participants (18-64 years; N = 153) were randomised (1:1) to receive JNJ-42165279 (25 mg) or placebo orally once daily and were maintained on their current SSRI/SNRI treatment. The primary endpoint was the change from baseline at week 6 in the 17-item Hamilton Depression Rating Scale (HDRS17). The study results did not show a significant treatment effect of adjunctive JNJ-42165279 on the primary endpoint versus placebo (least square mean difference [standard error]:-0.2 [1.04]; one-sided p=0.416) in the enriched intent-to-treat population. Findings for the key secondary efficacy endpoints also did not demonstrate an additional benefit of adjunctive JNJ-42165279 treatment over placebo. Treatment with JNJ-42165279 produced substantial increases in the mean concentrations of fatty acid amides in plasma, and the plasma JNJ-42165279 and anandamide levels were strongly correlated. The safety results were consistent with the known safety profile of JNJ-42165279. Overall, adjunctive treatment with JNJ-42165279 at the dose tested did not provide significant benefit in reducing depression/ anxiety symptoms versus placebo but showed no new safety signals in participants with MDD and anxious distress.

BACKGROUND:Obesity, which is common in bipolar disorder (BD), is associated with smaller hippocampal volumes. We do not know the role of weight/weight gain in relation to longitudinal hippocampal changes among individuals with BD. METHODS:In collaboration with the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis)-BD Working Group, we obtained T1-weighted magnetic resonance imaging and clinical data from 233 participants with BD and 701 healthy control participants (HCs) scanned twice, 2.84 ± 1.63 years apart on average. We estimated subcortical volumes using FreeSurfer longitudinal image processing stream and used linear mixed models to assess the bidirectional relationship between baseline body mass index (BMI) or BMI change and hippocampal volume or volume change. While the hippocampus was our a priori region of interest, we repeated these analyses in other subcortical regions. RESULTS:Baseline BMI predicted future hippocampal atrophy, but baseline brain structure did not predict future weight changes. BMI increased significantly over time (F1,1085 = 15.98, p < .001). Individuals with lower baseline BMI experienced greater weight gain (F1,922 = 105.12, p < .001). Greater weight gain was associated with greater hippocampal atrophy over time (F1,899 = 16.33, p = .001), more so in participants with BD than HCs (F1,898 = 6.91, p = .009). Consequently, lower baseline BMI predicted greater future hippocampal volume loss (F1,904 = 14.77, p < .001). These associations were not observed in other subcortical regions. CONCLUSIONS:Our findings suggest that weight gain is a modifiable risk factor for hippocampal atrophy, especially in individuals with lower BMI and those with BD. Prevention of weight gain in general, but especially in people with BD, could provide neuroprotective benefits.

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.