BMJ Mental Health

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.

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.

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.

BackgroundMajor depressive disorder (MDD), a leading cause of disability worldwide, exhibits substantial heterogeneity in treatment outcomes. Patients who do not respond to standard antidepressant therapy account for the majority of MDDs disease burden. Risk factors have been implicated in treatment response, including genes impacting on how antidepressants are metabolised. Yet, despite its clinical importance, risk factors for treatment-resistant depression (TRD) remain unexplored in low- and middle-income countries (LMIC). We used data from the DIVERGE study on MDD to investigate the risk factors of TRD in Pakistan. MethodsDIVERGE is a genetic epidemiological study that recruited adult MDD patients ([&ge;]18 years) between Sep 27,2021 to Jun 30, 2025, from psychiatric care facilities across Pakistan. Detailed phenotypic information was collected by trained interviewers and blood samples taken. Infinium Global Diversity Array with Enhanced PGx-8 from Illumina was used for genotyping followed by DRAGEN calling to infer metaboliser phenotypes for Cytochrome P450 (CYP) enzyme genes. We defined TRD as minimal to no improvement after [&ge;]12 weeks of adherent antidepressant therapy. We conducted multi-level logistic regression to test the association of demographic, clinical and pharmacogenetic variables with TRD. FindingsAmong 3,677 eligible patients, polypharmacy was rampant; 86% were prescribed another psychotropic drug along with an antidepressant. Psychological therapies were uncommon (6%) while 49% of patients had previously visited to a religious leader/faith healer in relation to their mental health problems. TRD was experienced by 34% (95%CI: 32-36%) patients. The TRD group was characterised by more psychotic symptoms and suicidal behaviour (OR=1.39, 95%CI=1.04-1.84, p=0.02; OR=1.03, 95%CI=1.01-1.05, p=0.005). Social support (OR=0.55, 95%CI=0.44-0.69, p=1.4x10-7) and parents being first cousins (OR=0.81, 95%CI=0.69-0.96, p=0.01) were associated with lower odds of TRD. In 1,085 patients with CYP enzyme data, poor (OR=1.85, 95%CI=1.11-3.07, p=0.01) and ultra-rapid (OR=3.11, 95%CI=1.59-6.12, p=0.0009) metabolizers for CYP2C19 had increased risk of TRD compared with normal metabolisers. InterpretationThere was an excessive use of polypharmacy in the treatment of depression while psychological therapies were uncommon highlighting the need for more evidence-based practice. This first large study of MDD from Pakistan uncovered the importance of culture-specific forms of social support in preventing TRD, highlighting opportunities for interventions in low-income settings. Pharmacogenetic markers can be leveraged to predict TRD.

ImportanceSemaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), is a highly effective medication to treat type 2 diabetes and obesity. However, concerns about potential suicidality persist, creating clinical uncertainty about its neuropsychiatric safety. ObjectiveTo assess risks of suicidality after initiating semaglutide compared to initiating SGLT2i and by duration of continuous semaglutide treatment. DesignActive-comparator, new-user target trial emulation to estimate inverse probability-weighted marginal cause-specific hazard ratios (HRs). For duration-of-treatment analyses, we used clone-censor-weight methods to estimate exposure-adjusted effects. SettingVeterans Health Administration. ParticipantsU.S. Veterans with type 2 diabetes receiving care from March 1, 2018 to September 1, 2025. ExposureInitiation of semaglutide vs SGLT2i; duration of semaglutide use ([&le;]6, 7-12, >12 months). OutcomesIncident suicidal ideation; suicide attempt or death; and a composite outcome. ResultsA total of 102,361 Veterans met inclusion criteria, including 11,478 new initiators of semaglutide and 90,883 new initiators of an SGLT2i. After overlap weighting, baseline characteristics were well balanced between treatment groups (mean [SD] age, 60.1 [11.7] years; BMI, 37.8 [6.8] kg/m2; hemoglobin A1c, 7.0% [1.4]; 85.5% male; 61.9% non-Hispanic White). During a median follow-up of 2.2 years, 9077 incident suicidal ideation events and 696 suicide attempts or deaths occurred. The incidence rate of suicidal ideation was 56.3 and 37.7 per 1000 person-years among semaglutide initiators and SGLT2i initiators, respectively (hazard ratio [HR], 0.99; 95% CI, 0.93-1.06; P = 0.86). For suicide attempts or deaths, the incidence rates were 4.30 and 2.64 per 1000 person-years, respectively (HR, 1.05; 95% CI, 0.84-1.31; P = .86). In adherence-adjusted analyses, sustained semaglutide treatment for more than 12 months, compared with 6 or fewer months, was associated with a 74% lower risk of suicide attempts or deaths (HR, 0.27; 95% CI, 0.14-0.54; P<.001). ConclusionAmong U.S. Veterans with type 2 diabetes, initiators of semaglutide were not observed to have an increased risk of suicidality compared with initiators of SGLT2i. Those with longer semaglutide treatment (beyond 12 months) had decreased risk of suicide attempt or death, suggesting longer term treatment is safe and may protect against for those outcomes.

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.

BackgroundThe mechanisms underpinning associations between sleep and psychiatric conditions are poorly understood, partly due to challenges with longitudinal sleep studies outside the laboratory. Children and young people with rare genetic conditions caused by micro-deletions or -duplications (Copy Number Variants or CNVs) have increased risk of disrupted sleep and poorer neurodevelopmental (ND) outcomes. The Sleep Detectives study aims to investigate this by tracking behavioural and neurophysiological signatures of sleep health in young people with ND risk or ND-CNVs. To optimally achieve this, we have worked with families with ND-CNVs and charity partners to co-design our tools, methods, study protocol, and materials. MethodWe established a Lived Experience Advisory Group (LEAP) with nine parents and 13 children and young people with ND-CNVs, alongside representatives of UK charities Max Appeal and Unique. Together, the research team and LEAP co-designed two in-person family workshops in which we collected feedback on the acceptability of sleep monitoring devices, the design of bespoke cognitive tasks, and overall study protocol. Informal interviews and surveys were conducted with LEAP members and researchers, to enable the team to reflect and learn from their Patient/Public Involvement (PPI) experiences. ResultsKey outputs included pre-workshop invitation and briefing materials and insights that iteratively refined the main study design, including the need for flexibility to increase accessibility, selection of sleep devices, customisation of cognitive tasks, and choice of language in documents. The PPI process was highly valued by LEAP members, workshop attendees, and the research team. One investigator described the PPI work as "reinvigorating my love of research by helping me focus on science that matters". Participating families also established peer support networks. ConclusionsInvolving families affected by ND-CNVs in co-designing the Sleep Detectives study maximised opportunities for acceptability, accessibility and scalability. The research team gained inspiration and deeper understanding of the impact of ND-CNVs on families. Families gained awareness about research, established connections with each other and peer support, and were enthusiastic about future research involvement. This experience empowered families to engage more deeply with the research process and helped the PPI work to be more impactful and inclusive. Plain English summaryChildren and young people with rare genetic conditions caused by small deletion or duplication of genetic material are more likely to experience sleep difficulties such as insomnia, restless sleep, and tiredness. They also show an increased likelihood of neurodevelopmental conditions such as learning disability and autism, and mental health issues such as anxiety. The Sleep Detectives team wanted to explore how these genetic conditions affect childrens sleep, cognition and psychiatric health. To make sure that the project design was well suited to the children and young people that would be invited to participate, the team worked closely with families to design the study. Parents and caregivers of affected children and young people were invited to join a Lived Experience Advisory Panel (LEAP), together with charity representatives and Sleep Detective researchers, to co-design two hands-on workshops, and advise on study design. Children and young people and parents/caregivers attending the workshops tried out and provided feedback on tools and devices that the research team were developing. They also advised on the arrangements and support families might need whilst taking part, and on the study protocol. This collaborative approach helped ensure the study design was optimally suited for the recruitment and participation of children and young people and their families. This report documents our public involvement work for the Sleep Detectives study, illustrating the difference the partnership between researchers and families has made to the project, and the wider benefits for all concerned.

Abstract Background: Mental health services are shifting towards person-centred care based on collaboration and shared decision making. Yet evidence indicates that these approaches may not be consistently embedded in the assessment and management of risk or safety. Methods: We conducted a cross-sectional online survey to examine perceived barriers and enablers to shared decision-making in risk assessment and management with people living with severe mental illness. Questionnaire development and data analysis were guided by the Theoretical Domains Framework, a psychological framework used to identify and understand factors influencing behaviour change. Items were rated on a 5 point Likert scale. In total, 243 service users and mental health professionals completed the survey. Results: Most service users reported that risk or safety had been discussed with them, but only half felt involved in the risk assessment or management process. Two thirds reported not receiving a copy of their risk assessment or management plan. Service users strongly agreed that communication with professionals about risk and safety requires improvement, and that risk is a difficult and emotive topic to discuss. Professionals reported high motivation to involve service users but identified time constraints and service user related factors as key barriers. Principal component analysis identified four components: (1) motivation; (2) social influences and memory/decision making; (3) beliefs about consequences; and (4) team, environment and training factors. More experienced professionals reported fewer negative beliefs about consequences, such as concerns about causing distress or disengagement. Conclusion: Findings highlight the need for clearer communication, organisational support and targeted training to enhance shared decision-making in risk assessment and management practices.

Background: AI powered cognitive behavioral therapy CBT chatbots represent a scalable approach to addressing the global mental health treatment gap However causal evidence on their population level effectiveness in low and middle income countries LMICs remains limited and patient perspectives on acceptability and engagement are critical determinants of sustained use Brazils Estrategia de Saude da Familia ESF deployed an AI powered CBT chatbot Saude Mental Digital SMD to registered patients aged 18 and older at participating primary care units with eligibility determined by a composite vulnerability score exceeding a predetermined threshold Objective: To estimate the causal effect of AI powered CBT chatbot access on anxiety and depressive symptoms among primary care patients in Minas Gerais Brazil leveraging the eligibility score threshold as an exogenous source of variation Methods: We conducted a fuzzy regression discontinuity design fuzzy RDD study using linked administrative and clinical data from 312 ESF primary care units across Minas Gerais N 43287 patients January 2022 December 2024 The running variable was the composite vulnerability score with a threshold of 60 points determining chatbot eligibility The primary outcome was the 12 week change in the Patient Health Questionnaire Anxiety and Depression Scale PHQ ADS composite score Two stage least squares 2SLS estimation was used with local polynomial regression and triangular kernel weighting Bandwidth selection followed the Calonico Cattaneo Titiunik CCT optimal procedure Results: The fuzzy RDD estimated a local average treatment effect LATE of 473 points 95 CI 691 to 255 p 0001 on the PHQ ADS composite score at the eligibility threshold indicating clinically meaningful symptom reduction among compliers First stage estimates confirmed a strong 312 percentage point jump in chatbot uptake at the threshold F statistic 1274 Subgroup analyses revealed larger treatment effects among patients in rural municipalities 618 95 CI 902 to 334 those with lower educational attainment 582 95 CI 844 to 320 and women 537 95 CI 761 to 313 McCrary density tests confirmed no evidence of running variable manipulation p 067 Results were robust across alternative bandwidths polynomial orders and kernel specifications Conclusions: AI powered CBT chatbot access causally reduces anxiety and depressive symptoms among primary care patients near the eligibility threshold in Brazil with particularly pronounced benefits for rural less educated and female populations These findings provide quasi experimental evidence supporting the scalable deployment of AI powered CBT tools within public primary care systems in LMICs while underscoring the importance of incorporating patient perspectives on acceptability to maximize engagement and sustained therapeutic benefit

ImportanceBlood neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) are entering clinical use in neurology as markers of neuroaxonal and astrocytic injury, but their utility in psychiatry is unclear. ObjectiveTo determine whether psychiatric diagnoses are associated with altered plasma NfL and GFAP levels. Design, Setting, and ParticipantsThis population-based study examined plasma NfL and GFAP among 47,495 participants from the UK Biobank (54.0% female; 93.5% White; mean [SD] age 56.8 [8.2] years) who provided blood samples and sociodemographic and clinical data between 2006 and 2010. Normative modeling was applied to assess associations between 7 lifetime psychiatric diagnostic categories and deviations from expected NfL and GFAP levels, while accounting for neurological diagnoses, cardiometabolic burden, and substance use. Data were analyzed between July 2025 and March 2026. Main Outcomes and MeasuresDeviations in plasma NfL and GFAP levels from normative predictions. ResultsRelative to the reference population, plasma NfL levels were higher among individuals with bipolar disorder (d=0.20; 95% CI, 0.03-0.37; p=0.03), recurrent depressive disorder (d=0.23; 95% CI, 0.07-0.38; p=0.009), and depressive episodes (d=0.06; 95% CI, 0.02-0.10; p=0.01), lower among individuals with anxiety disorders (d=-0.07; 95% CI, -0.12 to -0.02; p=0.008), but did not differ in schizophrenia spectrum, stress-related, or other psychiatric disorders. Plasma GFAP levels were not elevated in any psychiatric disorders. Variability in NfL levels was greater among individuals with schizophrenia spectrum disorders (variance ratio [VR]=1.30; p=0.005), depressive episodes (VR=1.06; p=0.006), and anxiety disorders (VR=1.08; p=0.005). Variability in GFAP levels was increased only in anxiety disorders (VR=1.08; p=0.01). Plasma NfL levels exceeding percentile-based normative thresholds were more common among individuals with schizophrenia spectrum disorders, bipolar disorder, recurrent depressive disorder, and depressive episodes. Neurological diagnoses, cardiometabolic burden, and substance use were associated with plasma NfL and GFAP levels. Conclusions and RelevanceThis study provides population-level evidence of plasma NfL elevation in bipolar and depressive disorders and increased variability in schizophrenia spectrum, bipolar and depressive disorders, supporting its potential as a biomarker in psychiatry and informing its ongoing neurological applications. Plasma GFAP levels, in contrast, were largely unaltered across psychiatric disorders. Key PointsO_ST_ABSQuestionC_ST_ABSAre plasma neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) levels altered in psychiatric disorders? FindingsIn this cohort study including 47,495 individuals, normative modeling revealed that plasma NfL levels were elevated in bipolar and depressive disorders, whereas plasma GFAP levels were not elevated in any psychiatric disorder. Plasma NfL levels also showed higher variability in schizophrenia spectrum, bipolar, and depressive disorders. MeaningPlasma NfL shows distinct alterations in schizophrenia spectrum and affective disorders, supporting its further investigation as a biomarker in clinical psychiatry and highlighting the need to consider psychiatric comorbidity in neurological applications.

Background: Rett Syndrome (RTT) is a severe neurodevelopmental disorder affecting approximately 1 in 10,000 live female births worldwide. The Rett Syndrome Behaviour Questionnaire (RSBQ), remains one of the most widely used standardized behavioral assessment tools for RTT. However, the RSBQ was originally validated only in British English, limiting its applicability for Spanish-speaking caregivers and clinical centers across Latin America and Spain. Objective: The primary aim of this study was to develop and validate the comprehension of the Spanish translation of the RSBQ to ensure cultural and linguistic equivalence, enhance data reliability, and facilitate earlier, more accurate clinical assessments among Spanish-speaking RTT populations. Methods: Surveys were administered in two phases to Spanish-speaking caregivers between November 2023 and September 2025. Phase I consisted of 12 guided survey administrations with participants being able to ask clarifying questions and offer linguistic modifications of RSBQ questions. Phase II consisted of independent online administration of the refined Spanish RSBQ and a retest at least 7 days later. Participants were recruited through direct outreach and supported virtually during questionnaire completion. Results: Following data cleaning and quality control, a total of 51 caregivers successfully completed both surveys. The Spanish RSBQ demonstrated high caregiver comprehension and strong engagement across multiple Latin American countries, including Argentina, Mexico, and Peru. Responses were highly correlated between test and retest timepoints, and no question showed biased response distributions. A slight effect of response interval on test-retest correlation was observed, potentially indicating the impact of natural disease progression confounding retest evaluation for long (>80 day) intervals; however this effect did not impact the overall linguistic validation results as analysis of only <21 day test-retest responders confirmed the findings. Conclusions: This linguistic validation study represents the first formal step toward the clinical validation of the Spanish RSBQ, enabling broader inclusion of Spanish-speaking populations in RTT research. The collaborative, bilingual data collection strategy proved both feasible and effective, paving the way for multinational trials and expanding therapeutic accessibility through localized, patient-centered innovation.

Progress in pharmacological treatment development for neurodevelopmental disorders is hindered by a misalignment between targeted mechanisms, outcome measures, and trial designs. This study was initiated as a post-trial access pathway for bumetanide and later expanded with treatment-naive participants. Within this framework, we implemented a parent-cocreated sensory outcome measure set (PROMset) in an unmasked, multiple-baseline single-case experimental design with randomized baseline periods of 2-12 weeks, followed by 6 months of bumetanide treatment (up to 1.5 mg twice daily). Participants (7-19 years) had atypical sensory reactivity and a diagnosis of ASD, ADHD, epilepsy, or TSC. The primary outcome was a PROMset comprising seven PROMIS item banks assessing anxiety, depressive symptoms, sleep disturbance, fatigue, sleep-related impairment, cognitive function, and peer relationships. Secondary outcomes included SSP, SRS-2, RBS-R, and ABC. Of 113 enrolled participants (mean age 13.2 [SD 2.7], 64% male), 102 completed the trial and 95 had analyzable PROMsets. At baseline, PROMset scores showed substantial impairment across domains (mean deviation =9.0 T-score points, p<.001) and correlated with sensory reactivity (SSP; r=-0.40, p<.001). Individual-level analyses showed improvement in 24-41% of participants per PROM domain, most frequently in anxiety and depressive symptoms (41% and 38%; mean across-case Cohen's d=-1). Overall, 83% improved on at least one domain. Group-level analyses showed improvement across all secondary outcomes (p<.001), with superiority over historic placebo for RBS-R and SSP. Integrating PROMsets with individualized trial designs can reveal clinically meaningful changes, supporting a more sensitive and patient-centered framework for treatment evaluation in heterogeneous populations.

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.

ObjectiveThere is little longitudinal research investigating links between violence exposure and mental disorders among children in low- and middle-income countries (LMICs), despite high rates of violence. We examined cross-sectional and longitudinal violence-mental health associations among children in a large South African birth cohort, the Drakenstein Child Health Study, including direct clinical interviews capturing childrens mental disorders. MethodIn this birth cohort (N=974), we assessed lifetime violence exposure and four subtypes (witnessed community, community victimization, witnessed domestic, domestic victimization) at ages 4.5 and 8-years via caregiver reports. At 8-years, caregivers completed the Child Behaviour Checklist; and psychiatric disorders were assessed using the Mini-International Neuropsychiatric Interview for Children and Adolescents, a self-report measure. We tested for associations using linear/logistic regressions, adjusted for confounders. ResultsMost children (91%) had experienced violence by 8-years. Cross-sectionally, total violence exposure was associated with total (B =0.49 [95% CI 0.32, 0.66]), internalizing (0.32 [0.17, 0.47]), and externalizing problems (0.46 [0.31, 0.61]), and with increased odds of disorder at 8 years (aOR=1.09 [1.05, 1.13]). Longitudinally, total violence exposure up to 4.5-years was associated with total (B=0.27 [0.03, 0.52]), internalizing (0.24 [0.04. 0.44]), and externalizing scores (0.23 [0.008, 0.45]) at 8-years, but not with increased risk of psychiatric disorders. The strongest and most consistent associations were observed for domestic versus community violence subtypes. ConclusionOur strong cross-sectional but weaker longitudinal findings suggest that recent violence exposures may be more critical than early exposures for childrens mental health. Longitudinal exploration of other violence-affected LMIC populations is urgently needed.

IntroductionFamily Constellation Therapy (FCT) has been widely disseminated in clinical, public health, and judicial settings despite persistent concerns regarding its theoretical basis, safety, and the limited availability of rigorous randomised evidence supporting its clinical use. ObjectiveThe aim of this systematic review is to assess the effects of FCT across all clinical conditions, explicitly considering both benefits and harms; and summarise the characteristics of studies and intervention settings used in randomised controlled trials of FCT. MethodsFollowing a prospectively registered protocol (CRD420251136190), we conducted a systematic search of seven databases (PubMed, EMBASE, APA PsycInfo, CENTRAL, BVS, Web of Science, and CINAHL) and grey literature (ICTRP and ProQuest database) without language or date restrictions to identify published and unpublished randomised controlled trials of FCT. Study selection, data extraction, risk of bias (RoB 2), and certainty of evidence (GRADE) were performed in duplicate. Statistical analyses followed a prospectively registered analysis plan with prespecified criteria for data pooling and for handling analytical limitations. ResultsNo reliable evidence was found to support the use of FCT for any condition across both clinical and non-clinical samples. All trials included were judged to be at high risk of bias and all comparisons were rated as very low-certainty evidence. Concerns regarding potential adverse effects were identified, and the available data was insufficient to establish the effectiveness of the intervention, precluding any clinical recommendation. ConclusionClinicians, policymakers, and consumers should reconsider adopting FCT while reliable evidence is not available.

3,4-methylenedioxymethamphetamine (MDMA) has emerged as a potential treatment for post-traumatic stress disorder (PTSD), generating considerable enthusiasm in the field. However, rapidly changing evidence in a fast-moving field can be challenging to integrate. Here, we present a living systematic review and open-data meta-analytic resource on MDMA treatment for PTSD. In this initial release, six randomized controlled trials comprising 286 participants are included in the database. Our primary model uses inverse-variance random-effects meta-analysis of standardized mean differences on primary outcomes of PTSD. Compared to control conditions, MDMA showed a greater reduction in PTSD symptoms (Hedges' g = -0.71). Meta-regression on both the number of dosing sessions and cumulative dose showed that a higher number of dosing sessions and a higher cumulative dose was related to larger effects of MDMA. Treatment with MDMA as compared to placebo also resulted in higher response (risk ratio (RR) = 1.35) and remission (RR = 2.25) rates. Most studies included in the database had a low risk of bias according to Cochrane guidelines, though these fail to capture pertinent challenges in the field such as expectancy, functional unblinding, potential issues with study conduct, and safety. The current findings were assigned an overall low certainty rating using the GRADE approach. Together, this systematic review and meta-analysis suggests that MDMA-assisted therapy results in short-term decreases in PTSD symptoms across studies to date, though more trials are needed. This living systematic review, meta-analysis, database, and online dashboard (sypres.io) will continue to be updated as evidence emerges, providing a valuable, open, and transparent resource for researchers in a rapidly evolving field.

Background and HypothesisClozapine is the only medication with proven efficacy for treatment-resistant schizophrenia, yet many patients experience delays of several years before initiation. Our aim was to develop and validate a dynamic prediction model for clozapine initiation among patients with schizophrenia trained solely on electronic health record (EHR) data from routine clinical practice. Study DesignEHR data from all adults ([&ge;] 18 years) with a schizophrenia (ICD10: F20) or schizoaffective disorder (ICD10: F25) diagnosis who had been in contact with the Psychiatric Services of the Central Denmark Region between 1 January 2013 and 1 June 2024 were retrieved. 179 structured predictors were engineered (covering, e.g.,diagnoses, medications, coercive measures) and 750 predictors derived from clinical notes. At every psychiatric hospital visit, we predicted if an incident clozapine prescription occured within the next 365 days. XGBoost and logistic regression models were trained on 85% of the data with 5-fold stratified cross-validation. Performance was evaluated on the remaining 15% of the data (held out) using the area under the receiver operating characteristic curve (AUROC). Study ResultsThe training/test set comprised of 194,234/35,527 hospital visits, distributed on 4928/878 unique patients. In the test set, the best XGBoost model achieved an AUROC of 0.81, sensitivity of 32%, positive predictive value of 23% at a 7.5% predicted positive rate. ConclusionsA dynamic prediction model based solely on EHR data predicts clozapine initiation with high discrimination. If implemented as a clinical decision support tool, this model may guide clinicians towards more timely initiation of clozapine treatment.

Objective: Autistic individuals may face elevated risk for PTSD, yet the degree to which this risk differs by sex remains unknown. We examined the association between autism and incident PTSD, characterized sex differences in risk, identified high-risk subgroups, and described post-diagnosis clinical trajectories. Method: We conducted a population-based matched cohort study using Swedish national registers. Individuals born 1990 through 2010 were followed from age 6 years through December 31, 2017. Autistic individuals (N=42,862) were matched 1:10 to controls (N=412,251) on sex and birth year. Cox proportional hazards regression estimated hazard ratios (HRs) for incident PTSD. Among those who developed PTSD, we compared care utilization, hospitalization rates, and persistence of care contacts. Results: During mean follow-up of 5.1 years, 401 autistic individuals (0.9%) and 903 controls (0.2%) developed PTSD (incidence rates: 18.3 vs 4.2 per 10,000 person-years). Autism was associated with 4.4-fold increased PTSD risk (HR=4.37; 95% CI, 3.93-4.86). Risk was higher among females (HR=4.79) than males (HR=3.39; P interaction=.006). Among autistic individuals, comorbid ADHD conferred additional risk (HR=1.38; 95% CI, 1.14-1.68). Ten-year cumulative incidence reached 6.0% among autistic females with ADHD. Autistic individuals with PTSD had higher care utilization (mean visits: 5.0 vs 3.9; P<.001), more psychiatric hospitalizations (27.9% vs 19.8%; P=.002), and more persistent courses (24.8% vs 12.3% with contacts in all 3 post-diagnosis years; P=.001). Conclusion: Autism is associated with substantially elevated PTSD risk, particularly among females with comorbid ADHD. When PTSD occurs, autistic individuals experience more severe and persistent clinical courses, supporting targeted screening and sustained follow-up.

The end-of-career stage of the police lifecycle represents a profound shift in identity and psychological stability, yet it remains historically neglected in research. This mixed-methods study investigated perspectives of UK police leavers and those approaching retirement (N = 325) regarding desired improvements to organisational support. Content analysis identified four themes: Holistic support and long-term welfare, Institutional culture and professional worth, Navigating the structural transition, and Individual and systemic perspectives. Findings suggest that the psychological contract between the officer and the organisation is often breached at the exit point, shifting from a relational bond to a transactional disposal. Middle-ranking officers and early leavers report the highest levels of institutional abandonment. To address these gaps, this paper makes recommendations for developing effective transitions. By implementing post-service welfare, and adopting structured resettlement models, police organisations can fulfil their duty of care and mend the psychological contract for those who have served.