Psychological Medicine

BackgroundPsilocybin is a classic psychedelic that acutely alters brain functional connectivity. These changes are linked to therapeutic doses and subjective effects, with some evidence that changes persist beyond acute drug administration. However, the effects of lower doses on sustained connectivity changes remain unclear. MethodsTen healthy volunteers received three psilocybin doses (between 5 and 20 mg) in a randomized and blinded order, with at least one week between doses. Resting-state functional magnetic resonance imaging was completed at baseline and one week after a single dose. Functional connectivity changes were analyzed in relation to dose and altered conscious states at both the level of individual brain region connections (edges) and resting-state networks. ResultsDose-dependent changes in 77 edges (76 increases, 1 decrease, of 1275 possible) were observed, but none survived multiple-comparison correction. At the network level, we observed one dose-dependent between-network increase (of 21 possible), and one dose-dependent within-network increase (of seven possible); the latter surviving correction. Alterations in conscious state were positively associated with widespread connectivity changes (dose-adjusted), with many network-level associations surviving correction. These directional patterns showed that lower doses and smaller conscious state alterations were linked to decreased connectivity, whereas higher doses and greater conscious state alterations were linked to increased connectivity. ConclusionsDose level and acute subjective effects were positively associated with multiple functional connectivity changes one week after a low-to-moderate psilocybin dose. Further research is warranted to characterize these sustained effects and their therapeutic relevance to inform studies adopting similar dosing regimens in clinical cohorts. Trial RegistrationAustralian New Zealand Clinical Trials Registry: ACTRN12621000560897 Date registered: 12 May 2021 URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=381526&isReview=true

BackgroundDepression is associated with social dysfunction, but the mechanisms linking affective symptoms to disrupted close relationships remain poorly understood. One possibility is that depression alters how people experience rewards shared with close others and how they interpret partners actions. It remains unclear whether neural sensitivity to shared reward predicts social valuation during more complex interactions such as reciprocated trust. MethodsIn this preregistered fMRI study, participants completed a reward-sharing task and a Trust Game with a close friend, a stranger, and a computer. We measured striatal shared reward sensitivity (SRS; friend > computer) and tested whether it related to subsequent investment behavior and brain responses to trust reciprocation. Depressive symptoms and perceived closeness were assessed via self-report. ResultsIn a final sample of n = 123, participants reporting more depressive symptoms invested more in their friend than in the computer. Striatal SRS predicted temporoparietal junction responses to reciprocated trust, but this association depended jointly on social closeness and depression -- with depression reversing the expected pattern among individuals reporting closer relationships. Striatal SRS was also inversely associated with connectivity between the default mode network and cerebellum during reciprocity. ConclusionsThese findings suggest that closeness calibrates the striatal SRS link to regional activity and network-level responses during social exchange, while depression alters how striatal SRS relates to regional activity, potentially disrupting how individuals interpret and respond to close others.

Major depressive disorder (MDD) is a highly prevalent psychiatric disorder with changes in motivation to work for rewards being a core symptom. Transcutaneous vagus nerve stimulation (tVNS) has emerged as a promising therapy but its effects on the core features of MDD, such as changes in motivation, remained relatively unexplored. In this randomised, single-blind, cross-over, controlled trial, we used a grip strength effort task to investigate how tVNS impacted choices to exert different levels of physical effort for varying monetary rewards in MDD patients (n=53) and a non-depressed control group (n=45). Compared to sham stimulation, tVNS enhanced the efficiency with which participants with severe depressive symptoms allocated physical effort for rewards (reward-effort efficiency). These effects were not seen in participants with less severe symptoms. Specifically, we found that the effect of tVNS on reward-effort efficiency was driven by reduced unnecessary effort, i.e., a reduction in choices to exert additional effort when this was not required to gain a larger reward. These findings suggest a potential motivational mechanism by which tVNS exerts its therapeutic effects in MDD. Determining whether the effects of tVNS are linked to broader changes in executive functioning, such as improvements in cognitive flexibility in MDD, should be a key aim for future work.

BackgroundDepression is a mood disorder frequently associated with episodic memory impairment. However, it remains unclear whether functional brain activity differs between depressed and non-depressed individuals during encoding or retrieval of autobiographical or non-autobiographical memories. Clarifying these differences is important for refining theoretical models of memory impairment in depression and, potentially, for developing targeted interventions. MethodsWe conducted three coordinate-based meta-analyses examining encoding and retrieval of autobiographical and non-autobiographical memory in control participants and individuals with current, remitted, or subthreshold depression, or those at risk for depression. Studies were identified via database searches and analysed using Seed-based d Mapping. ResultsWe included coordinates from 21 fMRI studies. During encoding, depression was associated with reduced activity in the thalamus, the caudate, the salience network, the frontoparietal executive control network, and motor-related areas (ten studies, N = 506). During non-autobiographical retrieval, depression was associated with higher activity in the right inferior frontal gyrus (six studies, N = 332). During autobiographical retrieval, depression was associated with reduced activity in the right insula and fusiform gyrus, alongside increased activity in the left anterior cingulate cortex and the left middle frontal gyrus (ten studies, N = 423). Between-study heterogeneity was low and no evidence for publication bias was found. DiscussionOur results indicate that depression may be associated with impaired salience integration during encoding and autobiographical retrieval. In contrast, during non-autobiographical retrieval, increased frontal activity suggests a more vigilant or self-monitoring retrieval mode. Functional brain activity changes in depression therefore appear stage- and content-specific.

BackgroundLoneliness is a psychosocial stressor associated with elevated risk of severe mental illness (SMI), including major depressive disorder (MDD), schizophrenia (SCZ), and bipolar disorder (BD). Loneliness is theorized to become biologically embedded via inflammation-related mechanisms, yet its causal relationship with SMI and the role of inflammatory signaling remain unclear. AimsTo investigate whether loneliness causally influences SMI risk and whether inflammatory cytokines mediate this relationship. MethodWe applied univariable Mendelian randomization (MR) to estimate the causal effect of loneliness on SMI and multivariable MR (MVMR) to assess mediation by inflammatory signaling. We integrated genome-wide association study (GWAS) summary statistics for loneliness and SMI with genetic instruments for inflammatory cytokines. MVMR models estimated the direct effect of loneliness after accounting for inflammatory signaling using eQTL and pQTLs for interleukin-1 receptor antagonist (IL-1RA), interleukin-6 (IL-6), IL-6 receptor (IL-6R), tumor necrosis factor alpha (TNF-), and TNF receptors (TNF-R1/2). Bidirectional MR examined potential reverse causal pathways between inflammation, SMI, and loneliness. ResultsMR provided evidence consistent with a causal effect of loneliness on SCZ and MDD. Results were also consistent with inflammatory cytokine pathways for IL-1RA, IL-6R, and TNF-R1, partially mediating the loneliness-SCZ and loneliness-MDD causal effect. No significant effects were identified for BD in UVMR or MVMR models. Bidirectional MR suggested evidence of reverse causation between SCZ and loneliness. ConclusionsThe findings support a causal risk-increasing effect of loneliness on SCZ and MDD, partially mediated by systemic inflammatory signaling, implicating pathways as a plausible mechanistic link between psychosocial stress and mental illness risk and highlighting potential opportunities for prevention and targeted intervention through inflammation and social pathways.

BackgroundMindfulness-based interventions (MBIs) have been increasingly adopted in educational settings to support cognitive development in youth. Executive function (EF)--encompassing inhibitory control, working memory, and cognitive flexibility--is a plausible target of MBI given its reliance on attention regulation. However, prior reviews have yielded mixed conclusions, partly due to inconsistent construct definitions and the pooling of heterogeneous outcome measures. ObjectivesTo (1) estimate the pooled effect of MBI on EF in youth aged 3-18 years using only construct-validated, direct EF measures, (2) examine potential moderators including age group, EF domain, and risk of bias, and (3) test dose-response relationships via meta-regression on intervention duration. MethodsWe searched PubMed, PsycINFO, CINAHL, Scopus, and Web of Science from inception to March 2026, supplemented by reference-list searches from two existing systematic reviews and a scoping review. Only English-language publications were eligible. Eligible studies were randomised controlled trials (RCTs) or quasi-RCTs of MBI (excluding yoga-only interventions) in typically developing youth, with at least one direct behavioural or computerised EF outcome. Risk of bias was assessed using Cochrane RoB 2. Hedges g was computed for each study, and pooled using a DerSimonian-Laird random-effects model. Subgroup analyses by age group, EF domain, and risk of bias were conducted, alongside leave-one-out sensitivity analyses, Eggers regression test, trim-and-fill, and Knapp-Hartung-adjusted meta-regression on intervention duration. Evidence certainty was rated using GRADE. ResultsThirteen RCTs (nine school-age, four preschool; total N = 1,560) met inclusion criteria. The pooled effect was g = 0.365 (95% CI 0.264 to 0.465; p < .00001), with negligible heterogeneity (I2 = 0.0%; Q = 6.76, p = .87). Effects were consistent across age groups (school-age g = 0.389; preschool g = 0.318) and EF domains (inhibitory control, working memory, cognitive flexibility; pbetween = .60). Meta-regression on intervention duration (4-20 weeks) was non-significant (p = .79). The effect was robust in leave-one-out analyses, in the low risk-of-bias subgroup (g = 0.361; k = 8), and after trim-and-fill adjustment (g = 0.354). The 95% prediction interval (0.252 to 0.477) was entirely positive. GRADE certainty was rated MODERATE, downgraded once for risk of bias. ConclusionsMBIs appear to produce a small, statistically significant improvement in EF in youth aged 3-18 years, with moderate certainty of evidence per the GRADE framework. The effect is consistent across preschool and school-age samples and across EF domains, with no significant dose-response relationship within the 4-20 week range studied. Emerging mediation evidence suggests that EF improvement may serve as an important pathway through which MBI supports emotion regulation, though this requires replication. Further large-scale, pre-registered RCTs with active control conditions and longitudinal follow-up are warranted.

Background: Previous evidence suggests that higher body size is associated with bipolar disorders, however, whether this association is causal remains uncertain. Interpretation is further complicated by heterogeneity across age, variation in clinical presentation, and potentially distinct underlying aetiologies. Aims: To determine whether body size exerts heterogenous causal effects on bipolar disorder subtypes and symptom profiles. Methods: By leveraging genetic instruments that differentiate effects at different life stages, summary-level univariable and multivariable Mendelian randomisation (MR) analyses were used to estimate how age-specific body size relates to adult psychiatric and symptomatic bipolar features; major depressive disorder (MDD), depressive symptom scores, subthreshold mania symptoms, bipolar disorder, bipolar type I and bipolar type II. Genetic instruments derived from genome-wide association studies (GWASs) for adult body mass index (BMI) (n= 681,275), childhood body size (n= 453,169) and mid-to-later life body size (n= 453,169) served as proxies for prepubertal and adult BMI measures. Results: In univariable MR, higher genetically proxied adult BMI increased the odds of MDD (odds ratio (OR) = 1.13, 95% CI 1.09-1.16), subthreshold mania (OR = 1.09, 95% CI 1.0-1.19)), and depressive scores (Beta = 0.07, 95% CI 0.05-0.09). There was little evidence that childhood body size had an effect on any outcome. Robust evidence suggested bipolar disorder and MDD increased adult BMI in our reverse univariable analyses. Using multivariable MR, robust evidence indicated that increased adult body size after accounting for childhood body size increased the odds of MDD, subthreshold mania and depressive scores. Conclusions: Body size may exert different causal effects on bipolar disorder depending on age and symptoms, with detrimental effects occurring during adulthood. Weaker evidence suggested varying effects across bipolar subtypes. Triangulation of findings and higher powered GWASs to detect symptom-specific genetic variants are required to explore whether body size contributes to distinct aetiologies across bipolar patients, informing the identification of novel and personalised treatment targets.

Background Chronic pain and depression are leading causes of disability and frequently co-occur. Depression presents with diverse symptoms, but despite this variability, the prevalence of individual depressive symptoms in chronic pain and the genetic and causal associations linking these traits remain poorly characterised. Methods Using data from 142,688 age- and sex-matched UK Biobank participants, we compared depressive symptom severity levels and item-level Patient Health Questionnaire-9 (PHQ-9) prevalences, spanning affective, cognitive and somatic domains, between participants with and without chronic pain. Using genome-wide association study (GWAS) summary statistics of multisite chronic pain (MCP), major depressive disorder (MDD), and individual symptoms of depression, genetic correlations and bidirectional causal effects between MCP and depressive phenotypes (MDD and individual symptoms) were estimated via linkage disequilibrium score regression (LDSC) and two-sample Mendelian randomisation (MR), respectively. Results Depression (at every severity level) was more common in the chronic pain group compared to controls, with the largest between-group difference for severe symptoms (7.50-fold increase). All individual depressive symptoms were at least 2.79 times as prevalent in chronic pain. Additionally, chronic pain had a significant and positive genetic correlation with MDD (rg = 0.59) and all depressive symptoms (rg = [0.24, 0.55]). MR supported a bidirectional causal association between MCP and MDD (MCP[-&gt;]MDD: OR = 1.85, pFDR < 0.001, MDD[-&gt;]MCP: {beta} = 0.17, pFDR < 0.001). At the symptom level, MR indicated bidirectional effects between MCP and anhedonia (MCP[-&gt;]anhedonia: OR = 1.60, pFDR < 0.001, anhedonia[-&gt;]MCP: {beta} = 0.08, pFDR = 0.005), and unidirectional effects of MCP on appetite/weight gain (OR = 1.90, pFDR = 0.022) and appetite/weight loss (OR = 1.63, pFDR = 0.005), concentration problems (OR = 1.63, pFDR = 0.044), and suicidal thoughts (OR = 1.46, pFDR = 0.021). Additionally, genetic liability to concentration problems was associated with a lower risk of MCP ({beta} = -0.04, pFDR = 0.022). Conclusion Chronic pain is associated with a marked depressive burden spanning all symptom domains. Shared genetic architecture and symptom-specific causal pathways, particularly involving anhedonia, highlight potential targets for improved treatment of comorbid chronic pain and depression.

BackgroundThe severity of positive psychotic symptoms largely defines emerging psychosis syndromes. However, depressive and negative symptoms are strongly psychologically and biologically interlinked. A transdiagnostic exploration of symptom severity across early illness syndromes could enhance the understanding of shared common factors and future trajectories of mental illness. We aimed to identify subgroups based on the severity of positive, negative, and depressive symptoms and assess relationships with: 1) premorbid functioning, 2) longitudinal illness course, 3) genetic risk, and 4) brain volume differences. MethodsWe analysed 749 participants from a multisite, naturalistic, longitudinal (18 months) cohort study of: clinical high risk for psychosis (n=147), recent onset psychosis (n=161), and healthy controls (n=286), and recent onset depression (n=155). Participants were stratified into subgroups based on severity of baseline positive, negative, and depression symptoms. Baseline and longitudinal differences between groups for clinical, functioning, and polygenic risk scores (schizophrenia, depression, cross-disorder) were assessed with ANOVAs and linear mixed models. Voxel-based morphometry was used to examine whole-brain grey matter volume differences. Discovery findings were replicated in a held-out sample (n=610). ResultsParticipants were stratified into no (n=241), mild (n=50), moderate (n=182), and severe symptom (n=254) subgroups. The mean (SD) age was 25.3 (6.0) and 344 (47.3%) were male. Symptom severity was associated with poorer premorbid functioning and illness trajectory, greater genetic risk, and lower brain volume. Findings were not confounded by the original study groups or symptoms and were largely replicated. Conclusions and relevanceTransdiagnostic symptom severity is linked to shared aetiologies, prognoses, and biological markers across diagnoses and illness stages. Such commonalities could guide therapeutic selection and future research aiming to detect unique contributions to specific psychopathologies.

Importance: Conventional repetitive transcranial magnetic stimulation (rTMS) can be ineffective in individuals who have previously failed brain stimulation, ketamine and/or multiple lines of therapies. Modern accelerated rTMS protocols using image-guided targets have not been systematically investigated in these individuals. The goal of this study was to assess the feasibility and efficacy of personalized, connectivity-guided, accelerated intermittent theta-burst stimulation (iTBS) in patients with treatment-resistant depression (TRD) of varying refractoriness. Objective: To assess whether connectivity-guided, accelerated iTBS produces significant reductions in depression severity, and to what extent this benefit extends to ultra treatment-resistant depression (UTRD). Design: This was an open-label feasibility trial of connectivity-guided, accelerated iTBS in patients with TRD. Two distinct groups of participants were recruited from a neurosurgical-psychiatry clinic with UTRD and an interventional psychiatry clinic with TRD. Patients were stratified into a priori treatment-resistance subgroups. Patients received five days of open-label treatment. Outcome measures were collected immediately prior to and after treatment, as well as at 4- and 12-weeks post-treatment. Setting: This trial (NCT05813093) was conducted between November 2023 and July 2025 at Sunnybrook Health Sciences Centre in Toronto, Ontario, Canada. Participants: Patients with major depressive disorder. A total of 96 participants were screened, with 73 meeting eligibility criteria (UTRD=30, TRD=43). One withdrew due to inability to tolerate the baseline MRI, and the other withdrew voluntarily prior to treatment. Intervention: Participants underwent a neuronavigated accelerated iTBS (600 pulses) protocol using personalized left dorsolateral prefrontal cortex (dlPFC) targets derived from functional magnetic resonance imaging (fMRI), comprising eight daily treatments, repeated over five days. Main Outcomes: Primary outcomes were i) change in Hamilton Depression Rating Scale (HAM-D17) from baseline to the end of the fifth day of treatment, and ii) the difference in change in HAM-D17 between UTRD and TRD subgroups. Results: Connectivity-guided fMRI targeting yielded personalized targets clustered around the anterolateral dlPFC. Accelerated iTBS elicited rapid antidepressant effects ({Delta}HAM-D17 -9.01 [SD 6.06], t = -12.45, p < 0.001) regardless of treatment-resistance group ({Delta}HAM-D17 -9.64 [SD 5.94] vs -8.10 [SD 6.12], t = -1.05, p = 0.299), which were sustained up to 12 weeks after treatment. Overall response and remission rates at the end of treatment were 40.8% and 16.9%. Self-report scales revealed broad symptomatic relief outside of core depressive symptoms. Conclusions & Relevance: This study demonstrated that fMRI connectivity-guided, accelerated iTBS induces sustained antidepressant effects and broader psychiatric benefits in patients across the spectrum of TRD. In a cohort unlikely to respond to most antidepressant therapies, connectivity-guided, accelerated iTBS offers a safe, well-tolerated option that can achieve benefit, or when ineffective, allow patients to expeditiously proceed with subsequent therapies than conventional rTMS. Trial Registration: This clinical trial was registered at clinicaltrials.gov with NCT05813093.

Wellbeing is commonly defined as the combination of feeling good and functioning well and typically conceptualized as two related but distinct components. Hedonic wellbeing emphasizes pleasure, happiness, and life satisfaction, while eudaimonic wellbeing focuses on meaning, personal growth, flourishing, and the realization of ones potential. The Mental Health Continuum-Short Form was developed as a comprehensive measure of wellbeing and includes three subscales assessing emotional, social, and psychological wellbeing. Although the Mental Health Continuum total score is often interpreted as an indicator of overall wellbeing, the underlying genetic structure of its three subscales and its genetic overlap with other commonly used wellbeing measures remains unclear. Using data from 5,212 individuals from the Netherlands Twin Register (72% female, mean age 36.4), we fitted multivariate twin models to examine the genetic architecture of the Mental Health Continuum and its associations with other wellbeing measures (quality of life, life satisfaction, subjective happiness, and flourishing). Results indicate that, at the genetic level, the Mental Health Continuum is best explained by its three distinct subscales rather than by a latent factor. When considering the Mental Health Continuum together with the other wellbeing measures, we found moderate to high genetic correlations (r = 0.52 - 0.83), indicating substantial overlap in the genetics underlying the wellbeing constructs. However, we did not find evidence for a single common genetic factor underlying all constructs. These findings highlight the multidimensional structure of wellbeing, but the moderate to high genetic correlations across measures suggest that it is important to align the level of measurement (phenotypic vs genetic) with the research question.

BackgroundEarly-life adversity (ELA) is a risk factor for enduring pain in youth and is associated with alterations in brain morphology and function. However, it remains unclear whether ELA-related neurobiological changes contribute to the development of enduring pain in early adolescence. MethodsUsing data from the Adolescent Brain Cognitive Development (ABCD) Study, we examined multimodal magnetic resonance imaging (MRI) markers in children assessed at baseline (ages 9-11 years) and at 2-year follow-up (ages 11-13 years). ELA exposure was defined at baseline to maximise temporal separation between early adversity and later enduring pain. Participants with enduring pain at follow-up (n = 322) were compared to matched pain-free controls (n = 644). Structural MRI, diffusion MRI (fractional anisotropy, mean diffusivity), and resting-state functional connectivity data were analysed. Linear models tested main effects of enduring pain, ELA, and their interaction on brain metrics, controlling for relevant covariates. ResultsELA exposure was associated with smaller caudate and nucleus accumbens volumes, and reduced surface area of the left rostral middle frontal gyrus. No significant effects of enduring pain or ELA-by-enduring pain interaction were observed across grey matter, white matter, or functional connectivity measures. ConclusionsELA was associated with alterations in fronto-striatal regions in late childhood, but these changes were not linked to enduring pain in early adolescence. These findings suggest that ELA-related neurobiological alterations may represent early markers of vulnerability rather than concurrent correlates of enduring pain. Longitudinal follow-up is needed to determine whether these alterations contribute to later chronic pain risk.

Polygenic risk scores (PRS) have shown increasing utility for risk stratification across complex diseases, but for psychiatric disorders such as bipolar disorder (BD), current PRS explain only a fraction of disorder liability (~1-9%), with predictive performance further diminished in non-European populations and real-world clinical cohorts. To explore the potential of integrating social and environmental risk factors alongside genetic liability to improve risk prediction, we evaluated the relationship between a PRS for BD (PRSBD) and six social risk measures - perceived stress, discrimination in medical settings, neighborhood social cohesion, perceived neighborhood disorder, cost-related medication nonadherence, and adverse childhood experiences - to BD case status in 115,275 participants (7,000 cases; 108,275 controls) from the All of Us Research Program. PRSBD was associated with BD case status across ancestry groups, though liability-scale variance explained was attenuated relative to what has been reported for curated research cohorts (R2 = 1.86% in European, 0.60% in African, 1.65% in Latino/Admixed American ancestries). Each social risk factor tested exhibited a larger effect size than PRSBD, with perceived stress (OR = 2.05 per SD) and adverse childhood experiences (OR = 2.68 for [&ge;]4 ACEs) demonstrating the strongest associations. Individuals in the lowest genetic risk decile with high social burden exhibited BD prevalence comparable to or exceeding those in the highest genetic risk decile with low social burden. These findings demonstrate the substantial explanatory power of social risk factors and support the development of integrated genetic-social risk frameworks for more accurate and equitable psychiatric risk prediction.

BackgroundNegative symptoms are core features of schizophrenia that relate strongly to functional impairment, yet interventions targeting these symptoms remain largely ineffective. Emerging theoretical work highlights how environmental factors may shape and maintain negative symptoms. Although racial disparities in schizophrenia diagnosis among Black Americans are well documented and linked to racial stress and psychosis, the impact of racial stress on negative symptoms has not been examined. This study provides an initial test of a novel theory proposing that racial stress - here measured by racial discrimination - influences negative symptom severity through exacerbation of negative cognitions about the self, particularly defeatist performance beliefs (DPB). Study DesignParticipants diagnosed with schizophrenia-spectrum disorder (SSD) (N = 208; 80 Black, 128 White) completed the Positive and Negative Syndrome Scale (PANSS), the Defeatist Beliefs Scale, and self-report measures of subjective racial and ethnic discrimination (Racial and Ethnic Minority Scale and General Ethnic Discrimination Scale). Relationships among variables were tested using linear regression and mediation analysis. Study ResultsBlack participants exhibited significantly greater total and experiential negative symptoms than White participants with no group difference in DPB. Racial discrimination explained 46% of the relationship between race and negative symptoms. Among Black participants, higher DPB were associated with greater negative symptom severity. Discrimination was positively related to both DPB and negative symptoms. DPB partially mediated the relationship between discrimination and negative symptoms. ConclusionsFindings suggest that racial stress contributes to negative symptom severity via defeatist beliefs among Black individuals, highlighting potential targets for culturally informed interventions.

Previous research links Adverse Childhood Experiences (ACEs) with problem gambling, but most studies rely on retrospective reporting and focus narrowly on maltreatment, overlooking adversities such as parental mental health issues. Using data on 3794 young adults in the Avon Longitudinal Study of Parents and Children, we examined longitudinal associations between 10 prospectively measured ACEs (individually and cumulatively), and moderate-risk/problem gambling (Problem Gambling Severity Index >=3) at ages 17, 20 and 24, adjusted for socioeconomic and other background factors. Population attributable fractions (PAFs) estimated proportions of cases potentially attributable to ACEs. Most ACEs were associated with higher odds of moderate-risk/problem gambling across ages (24/30 estimates) after adjustment, though effect sizes were generally small (median adjusted odds ratio [aOR] 1.31, interquartile range 1.24-1.59), and confidence intervals (CIs) wide. Sexual abuse showed the strongest association (aORs 2.4-4.2, CIs 0.5-10.5), while bullying and parental conviction were associated at ages 17 and 20 only, parental separation age 24 only. Evidence for a dose-response relationship was weak. PAFs suggested ACEs accounted for up to 12% of moderate-risk/problem gambling cases. These findings highlight potential impacts of ACEs on later gambling behaviour, but imprecise estimates suggest findings should be interpreted cautiously and strengthened through larger datasets and meta-analyses.

Introduction People with bipolar disorder (BD) and concurrent opioid use disorder (OUD) experience more severe clinical outcomes, including higher mortality, treatment complexity, and worse psychiatric symptoms, yet they are underserved due to a lack of tailored clinical guidelines and limited supporting research on competing treatment options. While pharmacological treatments for BD are well-established, their use varies widely across settings, and their effectiveness in individuals with co-occurring OUD is unclear. We propose parallel population-based studies to emulate randomized controlled trials to assess the comparative effectiveness of pharmacological treatment options for BD among people with OUD in British Columbia and Ontario, Canada, 2010-2023. Methods and analysis We propose emulating a series of parallel target trials using linked population-level health administrative data for all individuals aged 18 years or older diagnosed with both BD and OUD and who initiated treatments for BD between 1 January 2010 and 31 December 2023. All analyses will be conducted in parallel in British Columbia and Ontario. We propose a series of four successive target trial emulations, comparing (i) lithium versus non-antipsychotic mood stabilizers such as divalproex, lamotrigine, and valproic acid; (ii) lithium versus 2nd generation antipsychotics with mood stabilizing properties such as risperidone, olanzapine, aripiprazole, and quetiapine; (iii) lithium versus combination treatments such as lithium and divalproex, lithium and olanzapine, lithium and aripiprazole, lithium and quetiapine, divalproex and olanzapine, and olanzapine and quetiapine; (iv) lithium and valproate (LATVAL) versus lithium and olanzapine, lithium and aripiprazole, lithium and quetiapine, divalproex and olanzapine, and olanzapine and quetiapine. Incident user and prevalent new user analyses are planned for proposed target trials (i)-(iv), pending sufficient data. Stratified analyses will be conducted for BD-I, manic and depressive phases of BD illness. We propose an initiator analysis (intention-to-treat, conditional on medication dispensation) to determine the effectiveness of the treatments and per-protocol analyses to determine the efficacy of the treatments after dealing with treatment switching and recommended dose adjustment. The outcomes will include psychiatric acute-care visits (hospitalizations and emergency department visits), BD treatment discontinuation and all-cause mortality. Subgroup and sensitivity analyses, including cohort and study timeline restrictions, eligibility criteria modifications, and outcome reclassifications, are proposed to assess the robustness of our results. Executing analyses in parallel across settings using a co-developed protocol will allow us to evaluate the replicability of findings. Ethics and dissemination The protocol, cohort creation, and analysis plan have been classified and approved as a quality improvement initiative by the Providence Health Care Research Ethics Board and the Simon Fraser University Office of Research Ethics. Results will be disseminated to local advocacy groups, clinical groups and decision-makers, national and international clinical guideline developers, presented at international conferences, and published in peer-reviewed journals.

Background Hospital admissions for mental health (MH) and stress related presentations (SRP; symptoms without a clear medical cause which may be psychosomatic in nature) among children and young people (CYP) have risen over time. Rehospitalisation contributes to service costs, may indicate gaps in community based care, and can also disrupt education and social development. Methods This retrospective cohort study used NHS Hospital Episode Statistics to identify all CYP aged 10 to 25 with >1 MH/SRP related hospital admissions in England between 1 April 2014 and 31 March 2018, with follow up until 31 March 2019. Admissions were classified from ICD10 codes into internalising, externalising, personality, and eating disorders, psychosis, self-harm, substance use, postpartum, or potentially psychosomatic diagnostic groups. Outcomes included 30 day all cause readmission, 1 year all cause readmission, and 1 year MH/SRP-specific rehospitalisation. Time to rehospitalisation, and number of MH/SRP readmissions were also evaluated. Clinical and sociodemographic characteristics associated with rehospitalisation were assessed using regression models, time to rehospitalisation using Kaplan Meier analyses, and diagnostic transitions were visualised using Sankey diagrams. Results Of 492,061 CYP with hospital admission for MH/SRP, approximately one third were rehospitalised within one year. Females, older CYP and those from more deprived areas had higher odds of all cause readmission. The odds of MH/SRP rehospitalisation were highest among those aged 14 to 15 years. Co occurring chronic physical health conditions, personality and eating disorders were associated with higher odds, and shorter time, to readmission. Conclusions Rehospitalisation following MH/SRP admissions is common and socioeconomically patterned among CYP. Targeted discharge planning and continuity of care interventions are needed, particularly for high risk CYP admitted with eating and personality disorders.

Understanding depressive symptoms dynamics and their determinants is crucial for designing effective mental health support initiatives. This study compared two methods for describing youth depressive symptoms trajectories and investigated associations of early-life factors (maternal education, maternal perinatal depression, domestic violence, physical, emotional, or sexual abuse, bullying victimisation, psychiatric disorder) with trajectory features. Prospective data from 8,264 mostly White European participants (54% female), including self-reported Short Moods and Feelings Questionnaires on ten occasions between 10-25 years, were used. Trajectories were summarised using functional principal component analysis (FPCA) and P-splines linear mixed-effect (PLME) models. Estimated derivatives were used to obtain magnitude and age of peak symptoms and peak symptoms velocity. Both methods performed comparably, but PLME models tended to over-smooth trajectories. Peak symptoms and peak velocity were higher and occurred >1 year earlier in females than males. All early-life factors were associated with higher peak symptoms, and most associated with higher and earlier peak velocity. Abuse and bullying additionally associated with earlier age of peak symptoms. FPCA is a useful alternative for characterising depressive symptoms trajectories and informing time-sensitive preventative measures to reduce impact of depression before symptoms reach their peak. Early-life stressors may accelerate timeline and intensity of symptoms escalation during adolescence. Lay summaryUnderstanding development of depressive symptoms and factors shaping them is crucial for designing effective mental health support initiatives. This study used data from over 8,000 young people regularly followed up from before birth to compare two cutting-edge methods for describing depressive symptoms trajectories and examined how known risk factors for adulthood depression relate to the severity and rate of change of depressive symptoms in adolescence. We found that both methods performed well and that the peaks in depressive symptoms and their rate of change were, on average, higher and occurred over a year earlier in females than males. Our findings additionally suggest that early-life stressors (e.g., abuse, bullying) may accelerate the development of depression, highlighting the importance of early prevention.

Background: The NHS Improving Access to Psychological Therapies (IAPT) programme, now rebranded as NHS Talking Therapies, faces persistent capacity constraints with average wait times exceeding 90 days for cognitive behavioral therapy (CBT) in many Clinical Commissioning Group areas. AI-powered CBT platforms have been introduced as a digital adjunct within stepped care, yet longitudinal evidence on anxiety symptom trajectories and their predictors in routine NHS settings remains limited. Objective: To model individual anxiety symptom trajectories among patients referred to an AI-powered CBT platform within NHS primary care, identify distinct trajectory classes, and examine patient-level and practice-level predictors of differential treatment response using multilevel growth curve modeling. Methods: A prospective cohort study was conducted using linked clinical and administrative data from 6,284 patients (aged 18-65) referred to the CalmLogic AI-CBT platform across 187 general practices in four NHS England Integrated Care Systems (ICSs) between April 2023 and September 2025. Patients completed GAD-7 assessments at baseline, 4 weeks, 8 weeks, 12 weeks, and 24 weeks. Three-level growth curve models (assessments nested within patients nested within practices) with random intercepts and random slopes were fitted. Growth mixture modeling (GMM) was subsequently applied to identify latent trajectory classes. Predictors were examined at Level 2 (patient demographics, baseline severity, comorbidities, digital literacy, engagement intensity) and Level 3 (practice deprivation index, list size, urban/rural classification, and IAPT wait time). Results: The unconditional growth model revealed a significant average linear decline in GAD-7 scores of -0.94 points per month (p < .001), with substantial between-patient variation in both intercepts (variance = 14.82, p < .001) and slopes (variance = 0.38, p < .001). Significant between-practice variation accounted for 8.7% of intercept variance (ICC = 0.087). Growth mixture modeling identified four distinct trajectory classes: Rapid Responders (28.4%, steep early decline stabilising by week 8); Gradual Improvers (34.1%, steady linear decline through 24 weeks); Partial Responders (22.8%, modest early improvement followed by a plateau at clinically significant levels); and Non-Responders (14.7%, minimal change or slight deterioration). Higher baseline severity, female gender, and greater module completion predicted membership in the Rapid Responder class. Practice-level IAPT wait times exceeding 90 days independently predicted faster improvement trajectories (coefficient = -0.31, p = .003), suggesting that AI-CBT has its greatest incremental value in capacity-constrained areas. Patients in the most deprived quintile showed slower trajectories (coefficient = 0.22, p = .011) despite equivalent engagement levels, indicating a deprivation-related treatment response gap. Conclusions: AI-powered CBT platforms integrated within NHS primary care produce significant anxiety symptom reduction on average, but treatment response is heterogeneous, with four distinct trajectory classes identified. The finding that longer IAPT wait times predict better AI-CBT outcomes supports the platform's positioning as a scalable bridge intervention for capacity-constrained services. The deprivation-related response gap warrants targeted support strategies for patients in the most disadvantaged communities.

Importance: Suicide is a leading cause of death in the United States with risk strongly influenced by Interpersonal trauma, contributing to treatment resistance and clinical complexity. Objective: To assess clinical and genetic factors in individuals who died from suicide, with and without interpersonal trauma exposure. Design: Individuals who died from suicide with and without trauma were compared in a retrospective case-case design. Prevalence of 19 broad clinical categories was assessed between groups. Results directed selection of 42 clinical subcategories, and 40 polygenic scores (PGS) for further assessment. Multivariable logistic regression models, adjusted for critical covariates and multiple tests, were formulated. Models were also stratified by age group (<26yo and >=26yo), sex, and age/sex. Setting: A population-based evaluation of comorbidity and polygenic scoring in two suicide death subgroups. Participants: A total of 8 738 Utah Suicide Mortality Research Study individuals (23.9% female, average age = 42.6 yo) who died from suicide were evaluated, divided into trauma (N = 1 091) and non-trauma exposed (N = 7 647) individuals. A subset of unrelated European genotyped individuals was also assessed in PGS analyses (Trauma N = 491; Non-trauma N = 3 233). Exposures: Trauma is here defined as interpersonal trauma exposure, including abuse, assault, and neglect from International Classification of Disease coding. Main Outcomes and Measures: Prevalence of comorbid clinical sub/categories and PGS enrichment in trauma versus non-trauma exposed suicide deaths. Results: Overall, trauma-exposed individuals died from suicide earlier (mean age of 38.1 yo versus 43.3 yo; P <0.0001) and were disproportionately female (38% versus 21%, OR = 3.3, CI = 2.9-3.8). Prevalence of asphyxiation and overdose methods, prior suicidality, psychiatric diagnoses, and substance use (OR range = 1.3-3.7) were elevated in trauma exposed individuals who died from suicide. Genetic PGS were also elevated in trauma-exposed individuals who died from suicide for depression, bipolar disorder, cannabis use, PTSD, insomnia, and schizophrenia (OR range = 1.1-1.4) with ADHD and opioid use showing uniquely elevated PGS in trauma exposed males (OR range = 1.2-1.4). Conclusions and Relevance: Results demonstrated multiple convergent lines of age- and sex-specific evidence differentiating trauma-exposed from non-trauma exposed suicide death. Such findings suggest unique biological backgrounds and may refine identification and treatment of this high-risk group.