Epidemiology and Psychiatric Sciences

BackgroundBrain disorders are leading contributors to increasing disability and spending worldwide. In 2022 the Swiss Brain Health Plan (SBHP) was launched to promote brain health and prevent brain disorders. To guide the implementation of the SBHP, we performed a detailed analysis of the health and economic burden of brain disorders in Switzerland. MethodsWe analyzed Global Burden of Disease 2023 disability-adjusted life years (DALYs) and Institute for Health Metrics and Evaluation (IHME) cause-specific health-care spending estimates for Switzerland. DALYs were quantified for 1990 - 2023. Spending was analyzed for 2000 - 2019 across six types of care. We examined age and sex patterns, spending distribution, and international comparisons with six other countries (Germany, France, Denmark, Norway, Italy, Singapore). To assess short- and longer-term association between burden and spending estimates, we fitted panel regression models with disorder and year fixed effects under one-year and five-year lag specifications. FindingsBoth disease burden and spending were highly concentrated in a small number of conditions in Switzerland. In 2023, ten brain disorders accounted for 82{middle dot}9% of Switzerlands total DALY burden. In 2019, ten brain disorders accounted for 86{middle dot}0% of all direct brain-health spending, with dementia alone comprising 29{middle dot}5% of total expenditures. Among seven analyzed comparator countries, Switzerland had the highest per-capita brain-health spending and the highest spending per DALY. In fixed-effects panel models that accounted for spending persistence, lagged DALYs were not statistically associated with subsequent spending. Suicide prevention and addiction showed significant lower-than-expected health-sector spending (self-harm: {beta} = -0{middle dot}23; drug use disorders: {beta} = -0{middle dot}08 to -0{middle dot}18 across lag models). InterpretationBrain disorders generate a large burden in Switzerland. Within the IHME estimates, the burden-spending relationship over time appears limited. The implementation of the SBHP will refer to the current data and call for a burden-informed financing to guide strategic cross-sectorial allocation and prevention investments. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe drew on evidence from the Global Burden of Disease (GBD) 2023 estimates on neurological and mental health conditions, and on cause-specific health-care spending data from the Institute for Health Metrics and Evaluation for Switzerland and selected high-income countries. These sources show that brain disorders are major contributors to disability and premature mortality, and that Switzerland is among the worlds highest spenders per capita on health care. Prior work has described the costs of individual brain disorders and drivers of health expenditure growth; however, it has often treated burden and spending as partly separate domains, leaving the country-level link between cause-specific disability-adjusted life-years (DALYs) and cause-specific spending, over time and in either direction, poorly characterized. Added value of this studyTo our knowledge, this is the first study in a single country to systematically link cause-specific DALYs and cause-specific direct health-care spending for brain disorders and to examine their longitudinal and bi-directional associations. Using harmonized GBD 2023 estimates and IHME 2019 cause-specific health spending data, we quantify the health and economic burden of 23 brain disorders in Switzerland across age, sex, care setting, and time, and benchmark patterns against six other high-income countries. By applying panel regression models with disorder and year fixed effects, we assess whether modeled spending shows any association with prior modeled burden once spending persistence is accounted for, and identify conditions with higher or lower spending relative to burden. Implications of all the available evidenceSwitzerland bears a major burden of brain disorders and devotes substantial resources to their care, yet within the modeled estimates, spending does not consistently correspond to burden over time. Disorders with long-standing multisectoral programs tended to show lower spending-to-burden ratios, suggesting that coordinated action beyond the health sector may reduce downstream health-sector demand. For Switzerland and similar health systems, these findings support national brain-health strategies that strengthen life-course prevention and early intervention, and that integrate financing with burden data to inform priority setting and periodic reassessment of resource allocation.

Introduction: Engagement with mental health services (MHCS) during the first episode of psychosis (FEP) is critical for symptom control, quality of life, and relapse prevention. However, disengagement rates remain high in Uganda with severe consequences for patients and caregivers. This study protocol describes a mixed-methods investigation which aims to examine the relationship between patients and caregivers lived experiences and mental health service engagement during first-episode psychosis. Methods and Analysis. The mixed-methods study will recruit 82 patients with first-episode psychosis and their primary caregivers from Butabika National Referral Mental Hospital in Kampala, Uganda. Inclusion criteria are ages 18-60, less than 12 weeks on antipsychotic medications, living in the greater Kampala Metropolitan Area, with a consenting caregiver. Caregivers must be an adult (> 18years) providing full-time care for at least 6 months prior. Patients with substance use disorders will be excluded. Qualitative data on the lived experiences of patients and caregivers will be collected using the draw-write-and-tell method, while quantitative data on service engagement and associated factors will be collected using semi-structured questionnaires. The data will be analysed using Stata version 18, and participants will be reimbursed for their time. Ethics and Dissemination. Ethical clearance has been obtained from the School of Medicine Research and Ethics Committee (SOMREC) Ref: Mak-SOMREC-2024-1002 and institutional approval from Butabiika National Referral Mental Hospital. All participants will provide informed consent prior to participation. Data will be de-identified and securely stored, with results disseminated through peer-reviewed academic publications, conferences and community stakeholder workshops.

BackgroundEarly Intervention for Psychosis Services (EIPS) enhance outcomes for individuals experiencing their first episode of psychosis (FEP). However, in low-resource settings, there is limited knowledge about i) the pathways patients take to access EIPS, ii) the proportion and factors associated with acceptance of referral to EIPS, and iii) if different pathways to EIPS services affect clinical outcomes. Ugandas first EIPS, the Specialised Treatment Early in Psychosis Service at Makerere University Hospital (STEP_MaKH), presents a unique opportunity to explore these important questions. AimsWe aimed to examine the pathways to EIPS, the factors associated with referral to specialised psychosis care and the impact of initial treatment-seeking behaviour on long-term symptom remission and quality of life. MethodsWe conducted a multiple-method study. Pathways to care were assessed retrospectively using the WHO Encounter Form among adults with FEP eligible for referral to STEP_MaKH. Among those who completed referral and enrolled in STEP_MaKH. Symptom severity and quality of life were followed prospectively for 12 months. Modified Poisson regression identified predictors of referral completion. Kaplan-Meier methods and Cox proportional hazards models examined time to symptom remission and time to achieving a good quality of life. ResultsOf the 187 adults with first-episode psychosis eligible for referral to STEP_MaKH, Native/religious healers (n = 86) were the predominant first point of contact. Only 56 (29.9%) accepted referral to STEP_MaKH. Participants referred from Mulago National Referral Hospital more likely to enrol than those referred from Butabika (RR = 4.7; 95% CI: 2.90-7.87). Longer delays from first treatment contact were associated with reduced likelihood of reaching STEP_MaKH (RR = 0.99 per month; p = 0.041). After enrolment, symptoms improved rapidly with 60% achieving PANSS remission by Month 1, and fewer than 10% remained non-remitted by Months 2-3. In adjusted Cox models, participants initially seen by mental health workers achieved remission more quickly than those initially seen by non-medical personnel (HR = 1.48; 95% CI: 1.05-2.10). Older age was associated with slower remission (HR = 0.94; p = 0.023). Quality of life improved over the follow-up period, with earlier attainment of good quality of life among those initially managed by mental health workers. ConclusionsPathways to care for FEP in Uganda are complex and culturally mediated, with substantial attrition before specialised early psychosis care is reached. Referral completion is strongly shaped by referral site and by delays in the care pathway. Once in specialised care, clinical outcomes improve rapidly, and initial contact with mental health workers is associated with faster symptom remission and earlier gains in quality of life. Strengthening referral systems, reducing pathway delays, and developing collaborative detection-and-referral links with community and frontline providers are key priorities for optimising early psychosis outcomes in low-resource settings.

BackgroundAnorexia nervosa (AN) is a severe psychiatric disorder associated with profound malnutrition, multisystem medical complications, and one of the highest mortality rates among mental illnesses. Despite decades of research into its biological and neurocognitive mechanisms, effective pharmacological treatments remain limited. While systematic reviews synthesize results from published studies, clinical trial registries offer a complementary perspective by capturing ongoing research efforts, discontinued studies, and emerging therapeutic strategies that may not yet be reflected in the published literature. ObjectiveThis study aimed to characterize the landscape of clinical research in AN by systematically analyzing studies registered on ClinicalTrials.gov. MethodsWe conducted a structured analysis of studies registered on ClinicalTrials.gov related to AN. Trial characteristics, including study design, intervention type, phase classification, geographic distribution, and recruitment status, were extracted and analyzed using an automated text-based classification pipeline. ResultsNearly 400 studies investigating AN were identified over the past 25 years. Approximately 71% were classified as interventional studies; however, a large proportion were not associated with conventional clinical trial phases, suggesting that many registered trials correspond to mechanistic or exploratory investigations rather than therapeutic development programs. The geographic distribution of studies revealed a strong predominance of North America and Western Europe. A substantial proportion of trials were terminated or discontinued, highlighting the significant challenges associated with conducting interventional studies in this population. Observational studies generally included larger sample sizes than interventional trials. ConclusionsRegistry-based analyses provide valuable insights into the evolving landscape of clinical research in AN. Despite considerable scientific activity, important gaps remain between mechanistic knowledge and the development of therapeutic interventions. Understanding these gaps may help inform future translational research strategies aimed at improving treatment options for this severe disorder.

Background Complementary and Alternative Medicine (CAM) contributes significantly to the utilization of healthcare services in mental health care in sub-Saharan Africa. However, there is limited evidence on the utilization of CAM in the particular setting of post-conflict northern Uganda. This study sought to establish the prevalence, forms, and socio-demographic determinants of CAM use among patients attending the Mental Health Unit at Gulu Regional Referral Hospital (GRRH). Methods This is a cross-sectional study conducted in a hospital setting from June to August 2025. Convenience sampling was employed to recruit 407 participants. A structured questionnaire was employed for data collection. Data analysis was done using STATA software version 18.0. Descriptive statistics were calculated, and bivariate analysis with Prevalence Ratios (PR) with 95% confidence intervals was employed to determine factors that are significantly associated with the use of CAM. Results The lifetime prevalence of CAM use was 63.4% (258/407), with 41.3% (168/407) using CAM currently. The most frequent CAM practices used were herbal medicine (50.4%), spiritual practices (33.7%), and traditional medicine (19.8%). For current users, spiritual practices were most frequent (88.7%). The reasons for using CAM were recommendations from others (84.8%) and cultural or religious beliefs (63.4%). Predictors of CAM use were primary education (PR = 1.36, p = 0.017), living in an urban area (PR = 1.23, p = 0.007), separated (PR = 1.39, p = 0.050), and having a mental health disorder for six or more months (PR range = 1.55-1.72). Catholics (PR = 0.72, p = 0.0007) and Protestants (PR = 0.76, p = 0.011) were less likely to use CAM than Born Again Christians. Conclusion The level of CAM use among patients accessing mental health services in GRRH of northern Uganda is significantly high, while the reporting of CAM use to healthcare providers is remarkably low. This is a challenge that requires urgent attention. Recommendations include integrating the use of CAM into medical practice, developing national policy guidelines on CAM, working in collaboration with traditional/spiritual healers, and conducting public education campaigns.

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.

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 Little is known about the provision of diagnoses to young people with mental health disorders. We investigated diagnosis provision by NHS mental health services, focusing on 17-year-olds in South London between 2009-2024, and compared with estimated disorder prevalence. Methods To examine diagnosis provision in the population, we extracted diagnosis data from records of the NHS mental healthcare provider serving South London, using the Maudsley Biomedical Research Centre Clinical Record Interactive Search application; we then compared these data with the corresponding population size, obtained from the Office for National Statistics. To assess diagnosis provision in those with mental health disorders, we compared diagnosis data with the number of young people estimated to have met criteria for a disorder, derived from epidemiological interview data collected in the Environmental Risk (E-Risk) Longitudinal Twin Study and weighted according to characteristics of 17-year-old South Londoners. To assess diagnosis provision in those with mental health disorders within health services, we compared diagnosis data with the number estimated to have met criteria for a disorder and used any health service for their mental health, again derived from weighted E-Risk Study data. Findings Of 17-year-olds from South London in 2009-2024, 4.0% (n=8,958/223,404) had a diagnosis in mental health records during the previous year. This diagnosis provision covered <1 in 16 of those estimated to have had a mental health disorder, and <1 in 4 of those estimated to have also used health services. Diagnosis provision was lower in girls than boys and in young people with Black/Asian/Mixed/Other ethnicity than those with White ethnicity, in those estimated to have had a mental health disorder and used health services. Interpretation These findings demonstrate gaps and biases in mental health diagnosis provision for young people, including within health services, and reveal the imperative need to strengthen young people's mental healthcare.

Background Escalating mental health service demands have created a need to better identify young people most likely to require continued support from mental health services at the transition between childhood and adulthood. Anxiety is the most common adolescent mental health condition, yet its clinical significance and prognosis are not well understood. We aimed to examine the risk of young adult-onset psychiatric disorders in individuals with an adolescent anxiety disorder, and identify stratifiers of risk of subsequent psychiatric disorders in this group. Methods Individuals from the Norwegian Mother, Father, and Child Cohort Study (MoBa) with linked health records and aged 18 or over as of the 31st December 2023 were included. Those diagnosed with any ICD-10 anxiety disorder when aged 10-17 years were defined as having an adolescent anxiety disorder (n=2107, controls n=47,582). Polygenic scores (PGS) for psychiatric and neurodevelopmental conditions were calculated using LDpred2. Anxiety, comorbidities, and parental psychiatric history were defined through linked ICD-10 diagnoses. Sex was defined through linked records. Individuals were defined as having a young adult-onset psychiatric disorder if they first received any new psychiatric diagnosis aged 18-24. Results Adolescent anxiety diagnosis was associated with increased risk of all adult-onset psychiatric disorders (HR= 2.33-8.65). Post-traumatic stress disorder PGS, parental history of severe mental illness, and female sex were associated with increased risk of transition to a young adult-onset psychiatric disorder in people with an adolescent anxiety disorder. Conclusions Adolescent anxiety greatly increases the risk of a psychiatric disorder during the transition to adult life. Clinicians should consider female sex and parental psychiatric history when prioritising young people with anxiety for adult mental health service support. Future research needs to further consider whether polygenic scores would aid risk stratification in clinical practice.

ObjectiveTo charactertise emergency department (ED) use among young people with bipolar disorder (BD) and compare patterns to those observed in anxiety, depressive, and psychotic disorders. Design, setting and participantsData linkage study using administrative ED presentation records (January 2020 to October 2020) and a transdiagnostic youth mental health cohort of 2243 individuals aged 12-30 years in New South Wales, Australia. Main outcome measuresED presentation patterns (any presentation, frequency, and rates) and reasons for presentation (mental health-related and non-mental health-related). ResultsOf the 354 young people with BD, 309 (87.3%) presented to an ED at least once. ED presentation rates were higher for BD than for anxiety (incidence rate ratio [IRR]=1.82, p<.001) and depressive disorders (IRR=1.32, p<.001), but similar to psychotic disorders (IRR=0.91, p=.379). Differences were primarily driven by mental health-related presentations. Recurrent mental health presentations were associated with illness progression (clinical stage and functional impairment) rather than diagnosis. However, the likelihood of mental health-related presentations remained higher in BD compared with anxiety and depressive disorders after adjustment. ConclusionsYoung people with BD have high rates of ED use, comparable to those with psychotic disorders. Although mental health-related presentations are more common in BD than in anxiety and depressive disorders, recurrence is largely explained by markers of illness progression. These findings highlight the need for community-based services that provide continuous and coordinated care for young people with complex mental health needs.

Task-sharing approaches have shown promise in low-resource settings, yet few culturally adapted interventions have been systematically evaluated for forcibly displaced populations. Since 2016, over 1.7 million Venezuelans have migrated to Peru, facing significant barriers to healthcare and elevated risks of anxiety, depression, and post-traumatic stress disorder (PTSD). This protocol describes COMPASS (Cognitive-behavioral Open-source Mental-health Program Adapted for migrants, Sustainably delivered by lay providers and Supported by evidence). COMPASS is a transdiagnostic, open-source cognitive behavioral therapy program co-designed with forcibly displaced populations. This protocol describes the procedures for an ongoing randomized pilot trial with n = 90 forcibly displaced Venezuelan people (Clinicaltrials.gov: NCT06635486). COMPASS guides, or lay providers, trained through an intensive apprenticeship model, will deliver 6-12 weekly remote sessions. Primary outcomes include changes in anxiety, depression, and PTSD symptoms, assessed with validated Spanish-language measures. Secondary outcomes include feasibility (recruitment, retention, fidelity) and acceptability (therapist and participant ratings). Exploratory outcomes will examine integration, migration experiences, and demographic moderators of intervention effectiveness. Analyses will follow the intention-to-treat principle, using descriptive statistics and regression models to evaluate symptom trajectories across baseline, post-intervention, and 3- and 6-month follow-ups. This study represents the first effectiveness evaluation of an open-source, lay-delivered CBT program tailored for forcibly displaced people in Peru. Findings will inform feasibility, acceptability, and preliminary effectiveness of COMPASS, with potential to expand scalable, culturally relevant mental health services for forcibly displaced populations in resource-constrained settings worldwide.

Background. There is growing evidence to suggest a clinically significant overlap between autism spectrum conditions and psychotic disorders. Preliminary evidence suggest that autism diagnoses and autistic traits are associated with poorer outcomes following a first episode of psychosis. Methods. This study used data from the Cambridgeshire and Peterborough National Health Service Foundation Trust (CPFT) Research Database to examine clinical outcomes in autistic and non-autistic people following a first episode of psychosis. We describe patterns of community and inpatient service use, using descriptive statistics , Cox regression, binomial logistic regression, and negative binomial regression. Results. Data from 282 autistic and 7127 non-autistic people with psychosis were analysed. Autism was associated with greater community service use (use of mental health emergency lines, mental health detentions by police), as well as greater likelihood of psychiatric hospital admission (adjusted hazard ratio 1.34, 95% confidence interval 1.05 -1.7, p<0.05) and longer inpatient stays (median 111 versus 48 days, p<0.0001). Learning disability played a significant role in the utilisation of community and inpatient services, with lower rates of community service use but longer inpatient admissions. Conclusions. This study indicates a differing pattern of service use between autistic and non-autistic people following psychosis that warrants further research into how best to support autistic people with psychosis.

Background: Observational studies have consistently reported associations between social media use (SMU) and poorer mental health outcomes; however, such designs cannot establish causality. This study synthesised evidence from randomized experiments to estimate the effects of restricting SMU on mental health outcomes. Methods: A systematic search was conducted across MEDLINE, Embase, PsycINFO, and Cochrane CENTRAL to identify experimental trials evaluating interventions that constrained SMU for at least 24 hours and included an unconstrained control condition. Multilevel random-effects meta-analyses were used to synthesise effect estimates. Prespecified meta-regressions explored study-level moderators, and population-level impact fractions were estimated relative to global SMU prevalence. Results: From 7,784 screened records, 37 reports representing 35 distinct studies were included (pooled N = 7,160). Most interventions lasted one to three weeks and targeted college-aged youth. Pooled estimates favoured SMU constraints across outcomes, with magnitude and precision varying by domain. Confidence intervals were entirely above zero, consistent with a beneficial response for depressive symptoms (g = 0.22; 95% CI, 0.12 to 0.32), perceived stress (g = 0.15; 95% CI, 0.01 to 0.29), anxiety symptoms (g = 0.19; 95% CI, 0.05 to 0.34), fear of missing out/nomophobia (g = 0.14; 95% CI, 0.04 to 0.24), and well-being (g = 0.36; 95% CI, 0.10 to 0.63). Heterogeneity was substantial for several outcomes (I2 > 75%). In bivariate meta-regressions, higher baseline SMU was associated with larger effects for anxiety symptoms ({beta} = 0.13; 95% CI, 0.03 to 0.22), and longer interventions were associated with larger effects for depressive symptoms ({beta} = 0.16; 95% CI, 0.02 to 0.30). Inferences revealed that a short-term reduction in SMU globally could plausibly mitigate 17.5% and 15.4% of depressive and anxiety symptom cases, respectively. Conclusions: Experimental design-based evidence supports the causal case for an effect of SMU on mental health, with constraints producing improvements across multiple outcomes and no evidence of harm. Population-level inferences suggest that even individually modest effects may translate into meaningful public health benefits given the high prevalence of SMU exposure. These findings suggest that reducing SMU may represent a low-intensity, low-cost, scalable strategy to support mental health and improve well-being.

Background: The incidence of antidepressant withdrawal reactions in longer-term users and the influence of dosage is insufficiently understood. Objectives: Informed by neuropharmacological models and user surveys, this study examined symptom change during tapering and if increases were specifically associated with reductions below 75% of the minimum effective dose. Design: This was a prospective longitudinal cohort study with seven assessments over six months. Methods: Altogether 32 Swiss adult primary care patients who were on antidepressants for at least six months and in stable remission were assessed at baseline (week 0) before they started tapering and after 2, 4, 6, 8, 16, and 26 weeks. Withdrawal symptoms were measured repeatedly using an adapted version of the Discontinuation-Emergent Signs and Symptoms Scale (DESS) and the main outcome was intra-individual symptom change during intervals. Antidepressant dose was standardized relative to the minimum effective dose in the treatment of depressive and anxiety disorders. Results: Across intervals, reductions below 75% of the minimum effective dose were associated with symptom increases, while reductions above that threshold or no reductions were associated with symptom decreases. After adjusting for potential confounders, the rate of clinically relevant symptom increases contingent on dose reductions below 75% of the minimum effective dose was 33%, as compared to 13% during intervals with no dose reductions (OR=3.2, 1.4 to 7.4). We thus estimated that 60% of the risk of clinically relevant symptom increases was attributable to pharmacological withdrawal effects. The adjusted incidence rates for clinically relevant and severe withdrawal reactions were 32% and 11%, respectively. Conclusions: Consistent with neuropharmacological research findings, we found that antidepressant withdrawal symptoms emerge mostly following reductions below 75% of the minimum effective dose, affecting about one-third of patients. Even small reductions may trigger clinically relevant withdrawal reactions in this lowest dose-range, stressing the need for personalized tapering plans.

IntroductionDespite evidence supporting child and adolescent cognitive behavioural therapy (CBT) globally, interventions remain largely unavailable within public systems. This gap requires implementation models integrating development, training, and scalability research within real-world settings and changes in management structures. Here we developed and implemented manualised psychotherapeutic protocols through a national capacity-building initiative in Greece. MethodsWe designed a structured implementation pathway conducted through the Child and Adolescent Mental Health Initiative (CAMHI), a public-private partnership involving clinical and academic institutions across Greece: (1) pre-implementation research through national reviews and national surveys of health professionals; (2) co-development and iterative pilot implementation of evidence-based interventions through supervised practice within the National Health System; and (3) dissemination research supporting scalability and institutionalisation within public structures. ResultsPre-implementation research identified gaps in the availability of clinical protocols in Greek services; a survey of 120 psychologists and psychiatrists indicated the need for psychotherapeutic training. Three evidence-based protocols were co-developed: CBT for anxiety (6-12 years), CBT for depression (12-17 years), and behavioural parent training (BPT) for disruptive behaviour (4-14 years). During a three-stage pilot, 45 clinicians delivered interventions to 140 cases (anxiety n=52; depression n=25; BPT n=63); 117 (83{middle dot}5%) completed treatment. Significant symptom reductions were observed for anxiety (d=-2{middle dot}92; RCADS-25), depression (d=-1{middle dot}79, RCADS-25), and disruptive behaviour (d=-2{middle dot}3, SNAP-IV), with 63%, 38% and 44% showing reliable improvement at the treatment endpoint. A train-the-trainer model is under implementation for national scale-up. Institutionalisation includes integration into child and adolescent psychiatry curricula. Sustainability safeguards were established through Law 5015/2023, with the Ministry of Health assuming operations by 2027. DiscussionPilot results demonstrate the feasibility of evidence-based psychotherapeutic interventions embedded within real-world child and adolescent services in Greece. Integrated implementation approaches provide a viable pathway for developing, refining, and scaling clinical manuals within public health provision.

Background: We previously examined the burden and predictors of sustained mental health care engagement in Ugandan first episode psychosis patients by retrospective chart review methods. However, the extensive requirements of chart reviews meant that we could only extract data from a random 10% sample of 1677 newly enrolled Ugandan first-episode psychosis patients at Butabika National Referral Mental Hospital in 2018. The Hekima Platform has been designed to transform handwritten files into datasets for analysis. Objectives: This study aims to: (1) utilize the Hekima Platform to transform paper-based clinical charts of all 1677 Ugandan psychosis patients enrolled at Butabika Hospital for the first time in 2018 into a standardized, anonymized longitudinal database and (2) re-examine predictors of sustained MHC engagement in this cohort. Methods: We will digitize and archive all patient charts. We will then use the Hekima Platform to extract handwritten clinical data into machine-readable text using user-trained machine learning and deep learning models and natural language processing (NLP) techniques to generate a structured, anonymized database. A minimum 10% random sample of extracted data will be manually validated using Cohen's kappa. For the analytical aim descriptive statistics bivariate analysis and multivariable logistic regression will model predictors of sustained engagement. Exploratory machine learning approaches are used as a complementary analytical strategy. Ethical approval has been obtained from the Uganda National Council for Science and Technology and Butabika Hospital's Research Ethics Committee. Expected outcomes: Patient clinical charts are a rich data source but there are extensive requirements to be able to use them for research. This study will generate the first AI-assisted standardized longitudinal database from handwritten psychiatric records in Uganda enabling well-powered analyses of predictors of MHC engagement. Findings will inform targeted interventions to improve retention in care and will offer a scalable model for mental health research in low- and middle-income countries.

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.

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.

Abstract Background Insomnia is a major public health problem affecting an estimated 852 million adults worldwide. Current pharmacological treatments, including benzodiazepines and Z-drugs, carry serious risks of dependency, cognitive impairment, and adverse events. These limitations have driven growing interest in complementary and alternative therapies, particularly herbal sedatives, which are perceived as natural and safer. However, evidence on their safety and efficacy remains insufficient and patchy. Objective: This review evaluated the effectiveness of lesser known herbal sedatives for insomnia. Methods The protocol was registered with PROSPERO (CRD420251101795). Eligibility was defined using the PICO framework: Population: adults aged [&ge;]18 years with insomnia; Interventions: Passiflora incarnata, Hawthorn, Melissa officinalis, Chamomile, Viola odorata, Nelumbo nucifera, Rhodiola rosea, and Eschscholtzia californica. Comparators: placebo or usual care; Primary and Secondary Outcomes: sleep quality (Pittsburgh Sleep Quality Index, Insomnia Severity Index, Epworth Sleepiness Scale), sleep duration, and sleep latency. Databases and registers were searched from January 2005 to July 2025. Randomized controlled trials, nonrandomized controlled trials, clinical trials, and observational studies were included. Five reviewers independently screened studies. Data extraction used a structured Excel spreadsheet. Risk of bias was assessed using RoB 2.0 for randomized trials and ROBINS-I V2 for nonrandomized studies. Random-effects meta-analyses (DerSimonian and Laird) were conducted in RevMan. Narrative synthesis followed SWiM guidelines. Results From 1,294 records, 32 studies met eligibility criteria. Meta-analysis of 23 RCTs demonstrated a statistically significant pooled effect favouring herbal sedatives (SMD -0.77, 95% CI -1.14 to -0.40, p=0.0001), with substantial heterogeneity (I square=92%). Subgroup analysis showed larger effects for chamomile (SMD -1.06) and Melissa officinalis (SMD -0.66). Most RCTs had high overall risk of bias; nonrandomized studies predominantly had critical risk of bias. Conclusions This systematic review provides preliminary evidence that several herbal sedatives, particularly chamomile and Melissa officinalis, may improve insomnia-related outcomes. However, methodological weaknesses, high risk of bias, and substantial heterogeneity limit evidence strength. Future research requires standardized extracts, large multicentre RCTs, and extended follow-up.

Background: While growing enthusiasm for the therapeutic potential of classic psychedelics has led to a rise in non-clinical use, attention to persisting adverse effects has emerged with delay. A subset of individuals reports persisting complications such as hallucinogen persisting perception disorder (HPPD), depersonalization/derealization disorder (DDD), anxiety and depression. Yet few medical services are equipped to address these complications. Aims: This qualitative study examines how societal, medical, and media discourses shape the experiences of individuals with persisting psychedelic-related complications, focusing on help-seeking trajectories. Methods: Thirteen semi-structured interviews with adults experiencing persisting psychedelic-related psychological symptoms (four women, nine men, age 19-49 years; HPPD (n = 10), DDD (n = 6), depression (n = 1), and anxiety (n = 1)) were conducted within a larger study on these complications. Data were analysed using reflexive thematic analysis. Reporting followed the COREQ guidelines. Results: Three interrelated themes emerged: (1) The dissonance between expectation and harm - idealised media and scientific portrayals of psychedelics shaped initial use and complicated recognition of adverse outcomes; (2) Stigma, silence, and self-blame - prohibitionist discourse and internalised shame significantly inhibited help-seeking; and (3) Between systemic absence and self-organised support - participants encountered clinical unpreparedness and epistemic dismissal, which often led them to rely on online peer communities and self-management strategies. Positive clinical encounters, characterised by professional expertise and nonjudgmental engagement, were experienced as helpful. Conclusions: Adequate clinical and conceptual frameworks for persisting psychedelic-related complications are lacking. An interdisciplinary, experience-informed approach integrating realistic risk communication, clinician training, and destigmatisation is required to support affected individuals.