Obesity is a well-established risk factor for major depressive disorder (MDD), yet the risk is not uniform, highlighting the need for precise risk stratification. This study aimed to develop a metabolomics-based prediction model to identify high-risk metabolic phenotypes among obese participants and to elucidate the causal metabolic pathways involved.

Forty-one-thousand-four-hundred-fifty-nine obese participants were followed for a median of 14.4 years. We integrated multiple machine learning (ML) algorithms to develop predictive models for 3-, 5-, and 9-year MDD risk, with a temporal validation within the same biobank. Furthermore, we investigated the potential causal relationships within the obesity-metabolite-MDD using mediation Mendelian randomization (MR).

During follow-up, 3,642 incident MDD cases were documented. The optimized LightGBM model demonstrated superior predictive performance, achieving AUCs of 0.844 (95% CI: 0.773–0.914), 0.824 (95% CI: 0.771–0.875), and 0.834 (95% CI: 0.796–0.871) for 3-, 5-, and 9-year intervals, respectively, significantly outperforming existing clinical models. Temporal validation confirmed the model’s robustness (AUCs: 0.738–0.776). MR analysis confirmed that key metabolites causally mediate the pathway from obesity to MDD (mediation proportions: −11.5% and −35.3%, all PME < 0.05).

These findings challenge the notion of a uniform obesity–MDD association, demonstrating that metabolomic signatures can effectively stratify MDD risk. We present a validated ML framework for the early identification of high-risk individuals with obesity, offering a precision medicine approach to guide targeted metabolic and psychiatric interventions.

Neurodevelopmental disorder traits are associated with a range of psychosocial difficulties, yet the longitudinal processes linking these traits to mental health remain insufficiently explored. This study examined developmental associations among autism spectrum disorder (ASD) traits, attention-deficit/hyperactivity disorder (ADHD) traits, social maladjustment, and mental health from childhood through adolescence.

Longitudinal data were drawn from 9,619 students across 11 grade cohorts in mainstream classrooms. Cross-lagged structural equation modeling was used to estimate independent longitudinal associations among ASD traits, ADHD traits, social maladjustment, and mental health, while controlling for confounding factors. ASD and ADHD traits were modeled simultaneously to clarify their unique developmental patterns.

ASD traits were consistently associated with later internalizing problems and peer difficulties. ADHD traits were associated with later internalizing and externalizing problems, as well as academic challenges and strained teacher–parent relationships. These associations differed by trait type, suggesting distinct developmental pathways. Several bidirectional associations also emerged: poorer mental health was associated with subsequent social maladjustment, which was subsequently linked to persistent developmental difficulties.

The findings indicate that social maladjustment is involved in the longitudinal associations between developmental disorder traits and mental health and may shape developmental trajectories. These results highlight the need for comprehensive support approaches that consider peer relationships, learning environments, and family–school relationships.

Adverse health behaviors, such as physical inactivity and smoking, constitute a potential pathway connecting loneliness to poor mental and physical health. No prior study has investigated the dynamic interplay between loneliness and a broad range of health behaviors across the first half of life.

We used data from a Norwegian population-based cohort study (n = 3,072) spanning 28 years from adolescence to midlife. Applying a propensity score-based causal inference approach, we examined bidirectional prospective associations between loneliness and health behaviors, comprising alcohol use, body mass index (BMI), smoking, and physical exercise.

Loneliness in adolescence was associated with lowered physical exercise (mean difference: −14.13 minutes/week, 95% CI: −26.54 to −1.72), and loneliness during young adulthood was linked to increased BMI (0.37 points, 0.12–0.63). In the reverse direction, moderate alcohol use (−0.07 SD, −0.13 to −0.01 and − 0.19 SD, −0.33 to −0.05), smoking (−0.12 SD, −0.23 to −0.01), and moderate physical exercise (−0.16 SD, −0.26 to −0.07 and − 0.07 SD, −0.14 to −0.01) during adolescence and emerging adulthood were linked to reduced loneliness. All other associations were consistent with a null effect.

Our results provide limited support for the causal effects of loneliness on health behaviors across the first half of life. By contrast, findings in the reverse direction suggest that health behaviors in young people – whether health-promoting or risky – are socially embedded and may facilitate socializing. To tackle youth loneliness, public health policies should promote equitable access to health-promoting behaviors.

Nonsuicidal self-injury (NSSI) in adolescents with depressive disorder is characterized by recurrent impulsivity and is a predictor of future suicidal behavior, necessitating effective and feasible interventions. Mindfulness-based cognitive therapy for adolescents (MBCT-A), a first-line treatment for depression, was evaluated in this trial for its efficacy in reducing NSSI in this population.

In this randomized, single-blind, controlled trial, 94 hospitalized adolescents diagnosed with depressive disorder and engaging in NSSI were allocated to either MBCT-A plus treatment-as-usual (TAU) or TAU alone. The primary outcome was the severity of NSSI, measured by the Adolescent Self-Harm Scale (ASHS) at baseline, post treatment (4 weeks), and at 1-month follow-up. Secondary outcomes encompassed symptoms of anxiety, depression, emotion regulation, risk behaviors, life satisfaction, resilience, rumination, coping styles, and mindfulness. Both intention-to-treat (ITT) and per-protocol (PP) analyses were conducted.

Both ITT and PP analyses revealed significant between-group differences in NSSI severity at 4 weeks. Compared to the control group, the MBCT-A group showed significant improvements in mindfulness awareness, nonreactivity, emotional awareness, depressive symptoms, emotion regulation, and rumination (all P < 0.05). At the 1-month follow-up, the intervention group maintained a significant reduction in NSSI severity (interaction effect: F = 9.454, P < 0.001).

MBCT-A is effective in reducing NSSI behavior and improving mindfulness, emotion regulation, and depressive symptoms among adolescents with depressive disorder and NSSI. These findings support the clinical application of MBCT-A for this high-risk population.

The United Kingdom legalized medical cannabis in 2018, yet little is known about people using cannabis medically with and without a prescription. This study aimed to estimate: 1) the percentage of people reporting using cannabis medically with and without a prescription; 2) the sources; 3) products used; and 4) associations between frequent product use and medical cannabis status.

Data were from national repeat cross-sectional surveys conducted in 2023 and 2024. UK participants were aged 16–65 who used cannabis in the past 12 months (n = 4,414). Multivariable regression analyses estimated associations between outcomes and medical cannabis status.

Overall, 12.9% of respondents reported receiving a medical cannabis prescription, 35.9% reported medical use without a prescription, and 51.2% reported no medical use. Cannabis was sourced through diverse routes; only 10.9% of people with prescriptions obtained all their cannabis from a prescription. Respondents with a prescription had a higher probability of reporting frequent use of drops, capsules, vape oils, edibles, drinks, solid concentrates, hash/kief, and topicals (aRRs = range between 1.82 and 3.51)) and a higher probability of screening positive for high-risk use (aRR = 3.09; 2.51–3.79) than respondents who did not use medically.

People with medical cannabis prescriptions show a higher probability of frequent use of processed products and of meeting a threshold for high-risk use. Healthcare encounters during medical cannabis prescribing should discuss risks related to products, potency, and adverse effects such as cannabis use disorder.

Compared with heterosexual persons, non-heterosexual persons have worse mental health. Sexual Minority Stress Theory (SMST) explains the disparity as resulting from stigma and discrimination. To the extent that heterosexual genetic relatives reared with non-heterosexual persons also have worse mental health, SMST is falsified. We conducted a systematic meta-analysis of studies containing family-genetic comparison data to interrogate the empirical support for SMST.

We systematically identified 17 empirical studies in which twins or non-twin siblings reported on both their sexual orientation and their mental health. Subsequently, we conducted a multilevel meta-analysis, focusing on the degree to which any sexual orientation disparity in mental health diminished with genetic relatedness.

Most of the mental health disparities between non-heterosexual and heterosexual persons were eliminated after controlling for family-genetic factors.

The mental health disparity between non-heterosexual and heterosexual persons is reduced by up to two-thirds once familial background factors are accounted for by comparing monozygotic twins discordant for sexual orientation. This suggests that shared familial causes, and not minority stress, are the most important causes of mental health disparities in non-heterosexual persons.

Major depressive disorder and generalized anxiety disorder frequently co-occur, leading to heterogeneous presentations that complicate diagnosis and treatment. While diagnostic categories often obscure symptom variability, network approaches offer a powerful way to examine how symptoms relate to one another within and across conditions. By identifying symptom clusters, these methods can provide insights into potential mechanisms of comorbidity and symptom maintenance and may ultimately help guide more personalized treatment.

We examined patients (N = 33,675) seeking treatment for anxiety or depression through a message-based psychotherapy platform. Participants completed standardized measures of anxiety (GAD-7) and depression (PHQ-9) at baseline. We estimated a Gaussian Graphical Model of anxiety and depressive symptoms and identified overlapping symptom clusters using a modified Walktrap algorithm. We assigned patients to clusters based on presenting symptoms. In a subsample (n = 10,718), we examined the relationship between baseline cluster probabilities and three outcome trajectories over 12 weeks of treatment.

We found four baseline symptom clusters relating to Affective Dysregulation, Worries, Neurovegetative symptoms, and Hyperarousal. Affective Dysregulation and Neurovegetative clusters were associated with poorer outcomes, whereas Worries and Hyperarousal were associated with recovery over partial improvement; Hyperarousal also differentiated recovery from non-response.

Symptom clusters derived from standard screening measures were associated with differential treatment trajectories. Targeting these symptom configurations may be particularly effective at disrupting multiple symptom pathways. Future research should examine whether personalized treatment strategies that consider symptom clusters based on simple screening in practice settings yield greater clinical improvement than traditional diagnostic categories.

Fluctuations in ovarian hormones are associated with changes in mood and emotional well-being. However, the neural mechanisms linking endocrine states and affective regulation remain poorly understood. We aimed to investigate how endogenous estradiol and progesterone modulate brain representations underlying emotion–action control in healthy young women.

A total of 116 naturally cycling women performed an approach–avoidance task with emotional facial expressions during functional magnetic resonance imaging. Multivoxel pattern analyses were used to examine the neural encoding of emotion–action contingencies, i.e., classifying task conditions from multivariate activation patterns. We then tested whether salivary concentrations of estradiol and progesterone were associated with classification accuracy in various brain regions.

Participants responded more slowly and less accurately when approaching angry faces or avoiding happy ones, reflecting control over automatic emotional tendencies. Multivoxel decoding revealed that task conditions could be reliably distinguished from activation patterns in the lateral frontal pole (FPl), striatum, central insula, dorsal and ventral cerebellum, primary visual cortex, and periaqueductal gray. Importantly, higher progesterone levels were correlated with reduced classification accuracy in the FPl (r=-.26, p=.006) and striatum (r=-.26, p=.007), and lower FPl decodability was linked to poorer mood during the preceding week (r=-.25, p=.011). Moreover, decoding accuracy in the FPl fully mediated the indirect association between progesterone and worse mood (R2=7.1%).

These findings suggest that progesterone-related alterations in frontostriatal affective representations may contribute to mood variation.

Recent increases in common mental disorder prevalence could partly reflect greater persistence of existing disorders. We examined 3-year persistence for anxiety, mood, and substance use disorders, defined as meeting diagnostic criteria at baseline and again during 3-year follow-up. We compared persistence rates with those observed 12 years earlier and investigated (changes in) determinants of persistence.

Data were from the third Netherlands Mental Health Survey and Incidence Study (NEMESIS-3), a population-based study (N = 6,194; 18–75 years; interviewed 2019–2022 and 2023–2024). A slightly modified Composite International Diagnostic Interview 3.0 assessed DSM-5 and DSM-IV diagnoses. Persistence was described from two perspectives: narrow (presence of a mental disorder of the same diagnostic category during follow-up) and broad (presence of any anxiety, mood, and/or substance use disorder during follow-up). Twelve-year trends were examined by comparing DSM-IV persistence in NEMESIS-3 with NEMESIS-2 (N = 6,646; interviewed 2007–2009 and 2010–2012) among adults aged 18–64 years.

In NEMESIS-3, 3-year narrow persistence was 41.6% for anxiety, 48.0% for mood, and 40.3% for substance use disorders. Broad persistence was higher: 57.1%, 63.2%, and 55.1%, respectively. Persistence increased in 12 years across all disorder groups: broad persistence for any mental disorder was 42.7% in NEMESIS-2 and 57.9% in NEMESIS-3. Higher broad persistence was significantly associated with younger age, living in a city, childhood trauma, and near-daily drug use in multivariable analyses. These associations were stable over time.

Three-year persistence of common mental disorders is substantial and has increased compared with 12 years earlier, suggesting growing challenges for treatment and long-term care.

Virtual reality (VR) has been widely used in outpatient psychiatric services and has demonstrated benefits across several clinical diagnoses, but its use and effects in inpatient settings remain to be explored. This systematic review aimed to examine the use of VR during psychiatric hospitalization, including types of VR applications, barriers and facilitators of implementation, and effects on various outcomes.

The review was registered in PROSPERO (#CRD42023446524). Following PRISMA guidelines, databases (Ovid, SciVerse, Web of Science, Cochrane Library, ProQuest, and WorldCat) were searched from 1983 to 2025 using keywords related to VR and psychiatric disorders. Studies involving the use of VR with psychiatric inpatients (≥85%) were included. Descriptive statistics and narrative syntheses were used to summarize findings. Study quality was assessed with the Mixed Methods Appraisal Tool.

After full-text screening, 37 studies (N = 1,004) met inclusion criteria. VR was used for both assessment and intervention, with cognitive-behavioral therapy/exposure (35%) and assessment (24%) being the most frequently used. VR use in inpatient units appeared feasible, acceptable, and safe for inpatients and clinicians, though findings remain preliminary. Several facilitators (e.g. adequate staff training and supervision) and common barriers (e.g. technical difficulties and limited resources) were identified. The most consistent improvements were observed in clinical symptoms (e.g. anxiety) compared with psychosocial, cognitive, and physiological outcomes.

These findings suggest that inpatient settings represent a promising, yet understudied context for VR-based assessments and interventions. High-quality trials and systematic reporting of implementation are needed in future studies to inform research and clinical practice.

Psychosis, social anxiety, and autism are clinical constructs that share important phenotypic features, particularly social dysfunction. A critical determinant of social functioning is an individual’s ability to recognize when social cues, such as eye gaze, are meant for them. Emerging computational modeling data in psychosis suggest that altered gaze perception stems from deficits in evidence accumulation – the process of gathering and integrating information – when processing social cues. We investigated whether aberrant evidence accumulation during gaze perception is associated with social functioning or, as a secondary aim, with psychopathology in a transdiagnostic sample with varying levels of psychotic, socially anxious, or autistic characteristics.

We examined gaze perception in 111 individuals (aged 14–30) with varying levels of social dysfunction, psychosis proneness, social anxiety, and autistic traits. Drift diffusion models (DDM) characterized key processes driving perceptual judgements in a self-referential gaze perception task, including the efficiency of evidence accumulation. We tested whether evidence accumulation was associated with social functioning, social cognition, and these different psychopathology dimensions.

Impaired evidence accumulation during gaze perception showed strong associations with impaired social cognition and modest associations with diminished social functioning and elevated psychosis and social anxiety symptoms. Evidence accumulation was not associated with autism traits.

Evidence accumulation for social cues relates to social cognition – a key determinant of social functioning. It may also be relevant to real-world social functioning and multiple psychopathology dimensions, including psychosis and social anxiety. Therefore, evidence accumulation should be investigated as a mechanism supporting social difficulties and related psychopathology.

Depression and anxiety disorders and symptoms are among the leading causes of disability and global disease burden in young people. Scalable, unified interventions are required to address subthreshold emotional symptoms in adolescents as a preventive strategy. This study evaluated the effectiveness of a transdiagnostic treatment for adolescents with subthreshold emotional symptoms.

A multicenter, two-arm, randomized controlled trial was conducted. The Unified Protocol for Adolescents (UP-A) was compared with an active control consisting of protocolized progressive relaxation. A total of 676 adolescents (72.6% female; Mage = 13.77; SD = 1.39; range = 12–18 years) participated in the study. Primary outcomes were self-reported depressive and anxiety symptoms at postintervention, 6 months, and 12 months. The trial is registered with ClinicalTrials.gov (NCT05322642).

Three hundred seventy-eight participants were allocated to the UP-A group and 298 to the control group. Adherence was high in both conditions (≈78% attended >70% of sessions). Both interventions showed significant reductions in depressive and anxiety symptoms over time, with no significant between-group differences. At 12 months, the UP-A group showed marginally lower depressive symptoms and neuroticism. Significant treatment effects favoring the UP-A were observed for hyperactivity, conduct problems, and total mental health difficulties. Improvements were maintained across most outcomes at both follow-ups.

The comparable improvements observed across both conditions suggest that structured, group-based school interventions may help reduce emotional symptoms in adolescents with subthreshold presentations, rather than reflecting the superiority of a specific protocol. These findings support their potential for broad dissemination within stepped-care frameworks and for enhancing accessibility and real-world effectiveness of evidence-based treatments.