BMJ Mental Health

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.

Objectives To explore caregiver and clinicians perspectives on implementing mental health conversations and supports for caregivers of children with chronic conditions in paediatric outpatient clinics. Specifically, views were sought on (a) screening approaches and measures (phase 1) and (b) how feedback and support could be provided to caregivers experiencing mental health difficulties (phase 2). Methods Caregivers and clinicians from two outpatient clinics (neuromuscular and diabetes) at a tertiary paediatric hospital in Melbourne, Australia participated in online focus groups in July and August 2024. Caregivers were recruited from outpatient clinics and clinicians were recruited via email. Both groups were combined for phase 1 before separating into breakout rooms for phase 2. Two authors conducted reflexive thematic analysis of transcripts using NVivo. Results Sixteen participants (caregivers n = 8; and clinicians n = 8) took part in in two semi-structured focus groups. Analysis generated two overarching domains, each comprising multiple themes. Domain 1, Addressing caregiver mental health, captured themes of overwhelm and invisibility, diverse caregiving roles, and the need for time and resources to support wellbeing conversations. Domain 2, Housing the mental health conversation, encompassed themes of screening preferences, caregiver agency in confidentiality, delivery of feedback, and access to tailored supports. Conclusions Caregivers and clinicians support routine caregiver mental health discussions in paediatric outpatient settings. Caregivers favour screening at diagnosis and key transitions, with clear, and actionable feedback delivered away from the child. Questions about record-keeping warrant further exploration, as do the perspectives of fathers.

Background: Adults with severe mental health conditions (often referred to as severe mental illness, SMI) experience 15 to 20 year mortality gap relative to the general population, with lung cancer a significant contributor. National cancer policy targets earlier diagnosis but does not explicitly address how pathways function for this group. Aims: This study aimed to describe lung cancer risk, prevalence, screening eligibility, referral activity and diagnostic pathway performance for adults with SMI in South East London (SEL), and to examine where along the pathway inequalities arise. Methods: Co-designed with experts with lived experience and voluntary sector, this exploratory mixed-methods service evaluation combined quantitative analysis of routinely collected data from the Quality Outcomes Framework (QOF), SMI Register and Cancer Waiting Times Record (April 2023-March 2024) with semi-structured qualitative interviews (n=11 clinical staff) and focus groups (n=6 adults with lived experience of SMI). Quantitative and qualitative data were analysed using descriptive statistics and framework-based thematic analysis respectively, and findings were integrated using a joint display approach, organised by the Consolidated Framework for Implementation Research (CFIR). Results: Lung cancer prevalence was approximately double among adults with SMI (0.17% vs 0.09% in the general population). Despite Urgent Suspected Cancer (USC) referral rates being more than twice as high in the SMI population (63 vs 28 per 100,000), fewer cancers were detected via planned general practice (GP) routes (11% vs 20%), the 28-day Faster Diagnosis Standard was not met for any SMI patient diagnosed with lung cancer during the study period; overall FDS performance was 76% in the SMI population compared with 84% in the general population; and appointment non-attendance was more than double that in the general population (6% vs 3%). Qualitative findings identified individual, service and system-level mechanisms, including stigma, diagnostic overshadowing, fragmented coordination, and rigid pathway protocols, that compound disadvantage across lung cancer pathway stages. Conclusions: Inequality in lung cancer outcomes for adults with SMI accumulates across the pathway rather than arising at a single point of failure. Addressing this requires proportionate adaptations within existing cancer pathways, alongside routine reporting of cancer outcomes stratified by SMI population. Keywords: severe mental health conditions, lung cancer, health inequalities, cancer screening, diagnostic pathway, mixed methods

Cultural engagement is associated longitudinally with better mental health and reduced depression incidence, but evidence has largely relied on self-reported symptoms and diagnoses, leaving uncertainty about clinically recorded disorders, and residual confounding remains a concern. Here, we examined whether cultural engagement (including going to cinemas, museums, galleries, exhibitions, theatre, concerts, or opera) predicts hospital-treated mental disorders in 8,274 adults aged 50 years or older from the English Longitudinal Study of Ageing. Participant records were linked to ICD-10 diagnoses in Hospital Episode Statistics and mortality records with follow-up of up to 20 years. In fully adjusted Cox models accounting for sociodemographic, lifestyle, and social factors and multiple testing, frequent cultural engagement was associated with lower risk of any mental disorders (HR 0.71, 95% CI 0.62-0.82, FDR adjusted P value<0.001), dementia (0.71, 0.56-0.89, FDR adjusted P value=0.010), substance misuse (0.75, 0.59-0.95,FDR adjusted P value=0.040), and mood disorders (0.73, 0.56-0.95, FDR adjusted P value=0.044), but not neurotic disorders. Associations persisted after excluding early incident cases and adjusting for baseline depressive symptoms and cognition, and showed robustness to unmeasured confounders. To further probe causality, eye disease, ear disease, and traumatic brain injury, which share similar socio-demographic profiles to mental disorders, were prespecified as negative control outcomes. Cultural engagement was not associated with any negative control outcomes. These findings provide triangulated statistical data to suggest that cultural engagement is associated with reduced risk of several clinically recorded mental disorders and support further testing of cultural engagement as a population mental health strategy.

Objectives People with mental health conditions experience increased rates of diagnostic errors and delays in acute treatment. While causes such as diagnostic overshadowing (misattribution of physical symptoms to mental health conditions) are well documented, less attention has been paid to the organisational and structural conditions that shape diagnostic work. This study examines how physical illness is diagnosed in patients with mental health conditions in emergency departments (EDs), with a focus on the structural conditions that enable or constrain safe diagnostic practice. Method We conducted a multi-site ethnography across three purposively selected EDs in England between April 2023 and April 2024, varying in size, population demographics, and local service configuration. Data were collected through 284 hours of non-participant observation and 20 semi-structured interviews with ED staff. Results Our analysis identified four recurring structural gaps that shaped the conditions under which physical health diagnosis took place for patients with mental health conditions: a design gap, whereby targets and physical layouts constrained diagnostic reasoning; a preparedness gap, reflecting the lack of structural support to allow staff to act on their existing knowledge and skills; a coordination gap, reflecting fragmented ownership and the challenges of joint assessment across mental and physical healthcare teams; and an expectation gap, whereby unmet need elsewhere in the system increased demand for ED services that were beyond its formal scope. These gaps made diagnostic errors and delay more likely for patients with mental health conditions seeking physical healthcare in the ED. Conclusions As new dedicated mental health EDs are introduced in England, there is an opportunity to avoid reproducing these structural gaps in new settings. Our study suggests that improving physical healthcare for patients with mental health conditions requires changes to how EDs are designed, resourced and supported, and how they connect with the wider health and care system. Keywords: mental health, diagnostic inequality, emergency departments

Background. Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and irritable bowel syndrome (IBS) frequently co-occur following infection, yet shared genetic architecture at the locus level has not been systematically characterised. Aims. To estimate global and local genetic correlations between ME/CFS (including infection-onset subgroup), IBS, major depressive disorder (MDD) and loneliness/isolation, and characterise ME/CFS cell-type heritability enrichment. Method. GWAS summary statistics: DecodeME (15,579 ME/CFS; 9,738 infection-onset), FinnGen R9 (9,296 IBS), PGC MDD Wave 2 (45,396) and UK Biobank loneliness (N=455,364). LDSC for global correlations; LAVA for local correlations across 2,495 loci; MAGMA for cell-type enrichment (Descartes Human atlas); coloc.abf for colocalisation. Results. All pairwise global correlations were significant after Bonferroni correction, including ME/CFS-all-MDD (rg=0.598, 95% CI 0.46-0.74) and ME/CFS-all-IBS (rg=0.573, 0.39-0.75). Of 4,232 local tests, 16 reached FDR<0.05; two lonelinessxMDD loci were Bonferroni-significant. ME/CFS-MDD showed three FDR-significant local correlations, but all were boundary-estimated and non-Bonferroni-significant. A borderline infection-onset ME/CFS-IBS signal occurred at chr12q24.22 ({rho}=1.000, FDR=0.046), but colocalisation did not support a shared causal variant (PP.H4=0.007). ME/CFS heritability was enriched in inhibitory neurons (P=1.210x-7) and enteric nervous system neurons (FDR=0.004), with no FDR-significant peripheral immune cell-type enrichment in the atlas used. Conclusions. High global ME/CFS-MDD correlation was accompanied by limited, boundary-estimated, non-Bonferroni-robust local sharing; the data do not support reducing ME/CFS to depression at the genetic-architecture level. Neural enrichment, including enteric nervous system neurons, supports involvement of neural components in ME/CFS susceptibility without excluding immune mechanisms. A borderline ME/CFS-IBS signal at a NOS1-containing region generated hypotheses requiring replication.

Background: In the UK, over 36 million contacts are made annually by people living with dementia (PLWD) to either primary or secondary community mental health services. As dementia progresses, PLWD may experience increased distress and resort to 999 calls for an ambulance, which may in turn result in conveyance to Accident & Emergency (A&E). Nearly 1 million A&E attendances are made by PLWD. This trend is set to rise sharply as the prevalence rates of dementia increase over time and as the condition progresses, with associated healthcare costs impacting overall care delivery. This may lead to reduced resource allocation for dementia emergency services, negatively affecting the experiences of both providers and service users. Aim(s): To explore ways to improve access and quality of care to emergency crisis care for PLWD from the perspective of healthcare staff providing this type of support. Methods: This qualitative study explored (1) the experiences, resources, and needs of healthcare professionals in emergency and community settings to support access for PLWD, and (2) the mechanisms influencing dementia crisis response. The COREQ Checklist was used to improve transparency, credibility, and reproducibility. Inter-rater reliability was calculated. PPIE contributors co-developed recommendations for healthcare professionals, and study findings informed a comic-based dissemination resource shared with third-sector organisations to support community awareness and engagement. Results: Fifteen interviews were held with emergency services staff. Inter-rater reliability was substantial between two raters (k = 0.62). Four overarching themes, with associated subthemes, were identified relating to crisis care delivery, barriers to effective response, and strategies employed to address these challenges. Additional themes captured decision-making processes at key points in the care pathway, including initial crisis response, during intervention, and at discharge from emergency and community services. Decision-making was characterised by the need to balance patient safety with autonomy in determining care in the best interests of PLWD and their informal carers. Discussion: This exploratory study reveals frontline staff perspectives on challenges and actionable strategies for dementia crisis care. Findings support targeted service improvements, cross-sector collaboration, and co-produced resources to enhance outcomes for PLWD and their informal carers.

Objective. Persistent, distressing psychotic-like experiences (PLEs) are associated with neurobiological alterations and increased psychosis risk. We combined individual-level neuroimaging measures with effect sizes from large neuroimaging studies to create a summary score ('Psychosis Neuroscore') reflecting neuroanatomic liability for psychosis, and examined its ability to predict PLE trajectories in young adolescents. Method. Using latent growth mixture models, we estimated PLE trajectories from four annual visits of the Adolescent Brain Cognitive Development Study (N=9584, ages 9-10 at baseline). Using baseline T1-weighted and diffusion-weighted imaging data, we calculated Psychosis Neuroscores, as well as Neuroscores for two psychiatric disorders with late adolescent/adult onset (Major Depressive Disorder, Bipolar Disorder). We compared Psychosis Neuroscores to i) other psychiatric Neuroscores, ii) modifiable risk factors, and iii) established risk factors in predicting trajectory membership. Results. We identified four trajectories of distressing PLEs: Persistent Elevated (N=1,968, 21%), Gradual Decreasing (N=3,424, 36%), Rapid Decreasing (N=1,593, 17%) and Low/No Distress (N=2,599, 27%). Adolescents with Persistent Elevated PLEs had significantly higher Multimodal (combined T1 and diffusion-weighted) and T1-weighted Psychosis Neuroscores than all other trajectories (Odds Ratios [ORs] 1.27-1.34,pFDR<.01). Bipolar Disorder Neuroscores showed a similar pattern (ORs 1.16-1.23,pFDR<.01). Psychosis Neuroscores showed comparable associations with established risk factors in predicting trajectory membership, but smaller associations than modifiable risk factors, including screen time, physical activity, and sleep disturbances. Conclusion. Psychosis Neuroscores differentiate youth with persistent PLEs from those with decreasing, remitting or low PLEs, demonstrating their potential utility for early risk stratification. Integration with established risk factors may enhance psychosis risk prediction in youth.

Background Low-level systemic inflammation has been associated with late-life depressive symptoms. Whether individuals with higher inflammation derive preventive benefit from low-dose aspirin therapy is unknown. Methods We performed a post-hoc analysis of the ASPiring in Reducing Events in the Elderly (ASPREE) randomised, double-blind, placebo-controlled trial. Baseline C-reactive protein (hsCRP) was measured in plasma and depressive symptoms were assessed annually using the Center for Epidemiologic Studies Depression 10 Scale with elevated symptoms defined as CES-D-10 >= 8. Participants with elevated depressive symptoms at baseline were excluded. We fitted population-averaged logistic generalised estimating equation models adjusted for baseline sociodemographic and lifestyle covariates, including an hsCRP x treatment interaction to test effect modification by aspirin. Results Higher baseline hsCRP was associated with increased odds of elevated depressive symptoms during follow-up (OR 1.07 per SD increase in hsCRP, 95% CI 1.03-1.11). Low-dose aspirin allocation did not modify the hsCRP-depressive symptoms association (interaction OR 1.02, 95% CI 0.94-1.10). Findings were similar after additional adjustment for comorbidity and other covariates. Conclusions In community-dwelling older adults during the ASPREE randomised trial period, higher baseline hsCRP was modestly associated with elevated depressive symptoms. There was no evidence that low-dose aspirin was associated with reduced risk of depressive symptoms among participants with higher baseline inflammation.

Background: People affected by dementia experience intersecting care inequalities. We explored relationships between ethnicity and health and social care resource use among people with dementia in an ethnically diverse urban region. Methods: We conducted a retrospective observational cohort study using Discover-NOW, including patients with dementia between 1.4.2015 and 1.4.2025. We calculated ethnic density as the percentage of the Middle Layer Super Output Area (SOA) population self-identifying with the same ethnic group. Regression models, clustered by Local SOA, tested whether ethnic density moderated relationships between ethnicity and primary care, outpatient, inpatient, emergency and social care service use, controlling for sociodemographic characteristics, deprivation, comorbidities and time of diagnosis. Findings: We included 30,704 people with dementia. People from Black and Mixed ethnic groups used more primary care, and those from Asian ethnic groups less primary and secondary care, than White ethnic groups. Rates of local authority social care packages were similar across ethnic groups. High ethnic density predicted fewer GP consultations in Black ethnic groups, but more in South Asian groups. Interpretation: Among Black ethnic groups, primary care use was relatively high, especially in areas of low ethnic density, perhaps reflecting greater needs among communities at risk of racism and isolation. The trend towards increased primary care use among South Asian people in areas of higher ethnic density may reflect communities mitigating help-seeking hesitancy related to cultural and language barriers. Greater care integration could reduce care inequalities among minority ethnic communities who may experience fewer barriers to social relative to health care.

Importance: As new treatments increase quality and length of life in people with multiple sclerosis (MS), effective prevention and management of common comorbidities, including Diabetes Mellitus (DM), is increasingly important. Objective: To compare incidence of DM and its associations with hospitalisation and mortality in adults with MS and matched controls. Design: Using English primary care data from the Clinical Practice Research Datalink (CPRD), linked to Hospital Episode Statistics and national mortality records, we matched adults with MS diagnosed between 2000 and 2023, with up to ten controls without MS by age, sex, and practice. We excluded individuals with preexisting DM, defined using diagnostic and management codes. Outcomes included all-cause hospitalisation (number and duration) and mortality. We used Poisson, negative binomial, linear, and Cox proportional hazards models, adjusting for demographic and socioeconomic factors, adding interaction terms to examine if ethnicity, deprivation, and urbanity were associated with outcomes. Results: We included 9,010 individuals with MS and 78,121 matched controls. Over a mean follow-up of 13.2 years, people with MS had over twice the incidence of DM compared with controls (adjusted incidence rate ratio [aIRR]=2.26, 95% CI: 1.96 to 2.61, p<0.001). Among people with MS, incident DM was associated with higher hospitalisation rates (aIRR=1.82, 95%CI: 1.47 to 2.28, p<0.001), longer hospitalisation duration (median 18 vs 4 days, adjusted beta;=0.53, 95%CI: 0.41 to 0.65, p<0.001), and increased all-cause mortality when incident DM was modelled as a time-varying exposure (adjusted hazard ratio=1.46, 95%CI: 1.17 to 1.82, p<0.001), compared to those who did not develop DM. Similar patterns were observed among controls (hospitalisation rates: aIRR = 2.96, 95% CI 2.63 to 3.23, p<0.001; hospitalisation duration: adjusted {beta} = 0.93, 95% CI: 0.86 to 0.99, p<0.001; mortality [time-varying]: HR = 1.50, 95% CI: 1.27 to 1.77, p<0.001). The relationship between DM and increased hospitalisation was stronger in rural areas among those with MS and stronger in White groups among controls. Conclusions: People with MS are more likely to be diagnosed with DM, resulting in greater all-cause hospitalisation and all-cause mortality. This highlights the importance of equitable screening, prevention, and management of DM in people living with MS, with particular attention to geographical health inequalities.

Objective To map national Parkinsons disease (PD) research capability to inform an inclusive delivery strategy for a large-scale clinical trial. Background Few people with PD participate in clinical trials, particularly from under-served populations. The Edmond J Safra Accelerating Clinical Trials in PD initiative (EJS ACT-PD) aims to deliver an inclusive multi-arm multi-stage (MAMS) disease modification PD trial. Methods A survey disseminated to National Health Service (NHS) hospitals assessed PD research capability regarding trial experience, rater expertise, trial facilities and specialist investigations. A process was developed to categorise sites into 3 tiers, with tier 1 having the least PD-research capability or experience, and tier 3 being experienced specialist centres. We mapped tiers to PD prevalence, social deprivation and ethnic diversity to identify infrastructure gaps. We developed trial delivery strategies to facilitate rapid and inclusive recruitment. Results Out of 97 survey responses, 43 sites were categorised as tier 1, 33 as tier 2 and 21 as tier 3. Diversity and social deprivation index were higher for tier 3 sites (predominantly urban). A greater proportion of tier 1 and 2 sites were situated in areas of higher PD prevalence (predominantly rural). Ninety one percent of sites reported experience with remote trial delivery methods. Our delivery strategy included: initial trial set-up at tier 3 sites to enable rapid and ethnically diverse recruitment; core funded staff within strategic sites to develop regional solutions for inclusive trial participation and to enable research opportunity provision in areas where currently very little exists, and a hybrid delivery model of in-person and remote study visits, ensuring maximal acceptability and deliverability. Conclusions The mapping of current PD research delivery capability has allowed us to develop a trial delivery strategy that will broaden the provision of research participation opportunity to under-served groups. It has also enabled existing infrastructure to be maximised while mitigating identified gaps.

Background. Nascent findings suggest that people with attention-deficit/hyperactivity disorder (ADHD) experience higher rates of mortality. To date, study samples have been insufficiently well-characterized to examine the mechanisms via which this neurodevelopmental condition elevates mortality risk. Methods. We used data from the 2007 and 2011 waves of the US National Health Interview Survey, a general population-based cohort study comprising 52097 adults (28675 women) aged 18 years or older at baseline. ADHD diagnosis and an array of demographic, socioeconomic, lifestyle, and co-morbidity (somatic and psychiatric) covariates were self-reported. Findings. At baseline, compared with unaffected individuals, participants with ADHD were more likely to be socioeconomically disadvantaged, smoke cigarettes, consume alcohol, and report symptoms of psychological distress. A median 7.75 years of mortality surveillance (range: 7.25-12.25) gave rise to 6597 deaths from all-causes. After adjustment for age, sex, ethnicity, and survey year, ADHD was associated with a markedly elevated risk of death (hazard ratio [95% confidence interval]: 1.58 [1.20-2.09]). Statistical adjustment for socioeconomic circumstances (11% attenuation), physical co-morbidities (15%), and lifestyle factors (17%) had only a modest impact on the ADHD-death gradient, with the greatest explanatory power apparent for symptoms of depression and anxiety (58%). The magnitude of the association of ADHD with mortality was commensurate to that for several well-established risk factors such as poverty (1.66 [1.55-1.78]), hypertension (1.41 [1.32-1.51]), and diabetes (1.71 [1.59-1.85]) but somewhat lower than cigarette smoking (2.51 [2.29-2.76]) after controlling for age, sex, ethnicity, and survey year. Associations between ADHD and cause-specific mortality from cardiovascular disease, cancer, and chronic respiratory disease were inconclusive. Interpretation. In the present study, the influence of ADHD on total mortality appears to be largely embodied via a series of malleable characteristics, particularly mental illness. If confirmed elsewhere, these results raise the possibility that risk factor modification via standard pharmacological and behavioral interventions could help reduce rates of premature mortality in this patient group. Funding. This paper received no direct funding. GDB is supported by the UK Medical Research Council (MR/P023444/1) and the US National Institute on Aging (1R56AG052519-01, 1R01AG052519-01A1).

INTRODUCTION Severe acute brain injury (stroke, traumatic brain injury or hypoxic-ischemic encephalopathy; SABI) is increasingly recognized as a chronic condition with care and communication needs beyond the initial hospitalization. This study aimed to characterize post-acute care patterns among SABI survivors, focusing on healthcare utilization and outpatient communication. METHODS Data were collected from a prospective cohort of hospitalized SABI patients using surveys, chart reviews, and the ED Information Exchange database. Socioeconomic disadvantage was assessed using the Area Deprivation Index (ADI), and qualitative analysis of outpatient notes examined conversations around palliative care needs and goals-of-care. RESULTS Two-thirds of patients (140/222) survived until discharge, primarily to nursing facilities (39%) or inpatient rehabilitation (38%). Among 109 with one-year follow-up, there were 89 hospitalizations, 104 ED visits, and 28 deaths. Patients from the most disadvantaged neighborhoods had significantly higher odds of rehospitalization or ED use within 30 days (OR 3.37, p=0.036). ADI was not linked to one-year utilization. seen outpatient by primary care (40%), neurology/neurosurgery (57%), and palliative care (1%), but conversations rarely revisited prognosis or goals-of-care. CONCLUSIONS Our findings highlight the need for improved long-term care planning and communication, particularly for socioeconomically disadvantaged survivors of SABI.

Background. Psychotic-like experiences (PLEs) index early risk for psychotic disorders and are consistently associated with childhood trauma, yet underlying biological mechanisms remain poorly understood. DNA methylation (DNAm) may capture the biological embedding of early adversity, while adolescent exposures such as cannabis use may modify these processes. We examined epigenome-wide associations of childhood trauma and PLEs, tested the moderating role of early cannabis use, and evaluated DNAm as a potential mediator. Methods. We analysed data from the Avon Longitudinal Study of Parents and Children (ALSPAC), a UK population-based birth cohort. Childhood trauma was assessed prospectively and retrospectively. Epigenome-wide DNAm was measured in peripheral blood at ~17 years using the Illumina 450K array, and PLEs were assessed at 18 using a structured interview. Epigenome-wide association studies were conducted for trauma-DNAm and DNAm-PLEs associations in the final sample (n = 1,457), adjusting for demographic, biological, and technical covariates. Differentially methylated regions (DMRs) were identified using DMRff, followed by functional enrichment analyses. Cannabis use at 15.5 was modelled as a moderator with multiple imputation for missing data. Mediation was tested using the Divide-Aggregate Composite-null Test (DACT). Results. Childhood trauma was associated with widespread DNAm differences, primarily at the regional level, with enrichment in pathways related to cellular stress responses. In contrast, DNAm associated with PLEs was more limited and implicated loci involved in epigenetic regulatory processes. These signatures were largely distinct, and there was no evidence supporting mediation after multiple testing correction. Incorporating cannabis use altered the pattern and extent of DNAm associations, with stronger and more significant signals observed at both CpG and regional levels, although these did not translate into evidence of mediation. Conclusion. Childhood trauma and PLEs show distinct DNAm signatures in adolescence, with trauma-related DNAm reflecting broad stress-related processes and PLE-associated DNAm implicating regulatory mechanisms. We found little evidence that DNAm mediates the trauma-PLE association. Instead, adolescent exposures, particularly cannabis use, may distinctly influence trauma-related epigenetic variation with limited detectable downstream effects on PLEs. These findings support a context-dependent model of epigenetic risk and highlight the need for larger longitudinal studies to clarify causal pathways linking early adversity to psychosis.

Objective: ADHD has been associated with obesity indicators, including BMI, across the lifespan. A possible mechanism linking ADHD and BMI is binge eating. Previous research has found associations between ADHD, binge eating and BMI. However, the role of genetic and environmental influences on these associations remains unclear. Method: We utilized data from the Twins Early Development Study (TEDS), comprising 3,675 monozygotic and 7,063 dizygotic twin pairs. ADHD symptoms in childhood and adolescence were assessed using parent-reported questionnaires. Adult ADHD symptoms were measured using both self-report and parent-report questionnaires. Phenotypic mediation models examined whether binge eating mediated the association between ADHD and BMI, without controlling for genetic confounding. Subsequently, the etiological architecture underlying the associations among the three traits across childhood, adolescence, and adulthood were investigated by incorporating genetic and environmental influences into the models. Results: Binge eating significantly mediated the association between ADHD symptoms and BMI in both adolescence and adulthood. However, these mediation effects were no longer present once genetic and environmental influences were incorporated into the models. The best-fitting model in childhood, adolescence and adulthood was Cholesky decomposition models, where covariance between traits was explained by shared aetiology. Conclusions: This twin study reveals shared liability across ADHD, binge eating, and BMI. The mediating role of binge eating in the relationship between ADHD symptoms and BMI was largely confounded by shared genetic influences. Intervention strategies could focus more on common underlying behavioural and self-regulatory mechanisms across these traits, as well as placing more emphasis on symptom patterns within families.

Background: Major depressive disorder (MDD) is clinically heterogeneous, hindering identification of reproducible biomarkers. Using a semi-supervised machine learning approach, HYDRA, we previously identified two neuroanatomical dimensions from structural MRI in medication-free MDD from COORDINATE-MDD consortium. These dimensions (D1, D2) showed differential responses to selective serotonin reuptake inhibitor (SSRI) antidepressants and placebo. External replication in UK Biobank linked D2, characterized by widespread subtle neuroanatomical reductions, to an immuno-metabolic profile. Here, we examined whether these dimensions are detectable early in the course of illness. Methods: We applied the pre-trained model to structural MRI data from the multisite PRONIA cohort, comprising individuals with recent-onset depression (ROD; n = 377; mean age 25.8 years, SD 6.0; 51.3% female) and healthy controls (n = 267; mean age 25.5 years, SD 6.4; 61.0% female). Participants were assigned to clusters (C1, C2) corresponding to the previously identified dimensions (D1, D2). Clusters were compared on clinical symptom profiles, peripheral inflammatory markers, and in a subset (n = 107), proteomic ageing indices. Results: Two neuroanatomical clusters were identified in PRONIA. C1 (n = 265) showed higher negative symptom severity and elevated interleukin-2 levels. C2 (n = 140) was associated with higher residual proteomic age. Overall depressive symptom severity did not differ significantly between clusters. Conclusions: Neuroanatomical dimensions of MDD are reproducible and detectable at illness onset. Associations with negative symptom severity, inflammatory signalling, and proteomic ageing suggest these dimensions capture biologically meaningful heterogeneity early in depression. These findings support a biologically informed framework for stratified treatment approaches in MDD.

Background: Whole-population linked administrative data platforms provide an opportunity to generate evidence on early life multidimensional disadvantage to inform resourcing and service provision to families with complex needs. Methods: We used individual-level de-identified data from nine administrative data sources included in the Better Evidence Better Outcomes Linked Data (BEBOLD) platform. The population included all children born in South Australia between 2004-2011 (n=143,083), and their parents. We described the prevalence and distribution of multiple disadvantages affecting children from the 12 months before birth to age 5. Eleven domains of parental disadvantage were created: economic, education, access to services, mental health, substance misuse, smoking during pregnancy, domestic and family violence, health, child protection contact, justice system contact, and death. We investigated the concordance of our measure with an area-level socioeconomic measure used in government reporting. Results: One in two children (48%) were exposed to at least one disadvantage domain, and one in seven (14%) were exposed to three or more domains before age five. Economic disadvantage was most prevalent, affecting one in four (27%) children, of which 75% were exposed to additional forms of disadvantage. Substance misuse, domestic and family violence, and justice system contact were the least likely domains to occur in isolation. Only 54.4% who experienced five or more disadvantage domains were classified in the area-level socioeconomic measure's 'most disadvantaged' quintile. Conclusion: Early life exposure to parental disadvantage can be highly multidimensional. Measurement across different systems is important for informing coordinated service provision for families with complex needs.

In the past two decades, the focus on genome-wide association studies in large samples of unrelated patients has overshadowed family genetic studies. Therefore, little is still known about the levels and effects of the transmission of polygenic risk scores (PRS) among familial cases of schizophrenia (SZ) or bipolar disorder (BD) and their unaffected relatives. Prior research has shown that PRS are elevated in both patients and young individuals at familial risk for BD and SZ. We sought to study the transmission of PRS in affected multigenerational families and non-affected adult relatives (NAARs) with or without other non-mood nonpsychotic DSM-IV diagnoses and unrelated non-affected individuals from the same population. We genotyped 1,117 participants divided in 48 families from the Eastern Quebec Schizophrenia and Bipolar Disorder Kindreds. PRSs for both SZ and BD were computed using Multivariate Lassosum. For both SZ PRS and BD PRS, SZ and BD cases present higher PRS compared to controls, replicating previous findings. Regardless of a diagnosis of other non-psychotic and non-mood conditions, NAARs presented higher PRS than the unrelated cohort. Crucially, a subset of families presented consistently low PRS transmission profiles across generations, falling below expectations from our polygenic inheritance model. When the effect of individual PRs is accounted for, we observed sex-specific associations between familial PRS and patients' symptom dimensions. Our results clearly demonstrate that polygenic inheritance alone does not adequately explain disease transmission in families. Such an approach may also clarify why some families exhibit dense clustering of cases despite minimal polygenic burden.

Background: Obsessive-compulsive disorder (OCD) is characterized by disturbing thoughts (obsessions) that initiate anxiety-reducing thoughts or behaviors (compulsions). For patients with treatment-resistant OCD (tr-OCD), neuromodulation techniques, like capsulotomy (a lesion in the anterior limb of the internal capsule) and deep brain stimulation (DBS), have emerged as interventions that likely regulate connectivity between the prefrontal cortex (PFC) and subcortical targets. Three patients (Cap-DBS1-3) underwent a failed capsulotomy followed by successful DBS. Here, we aimed to understand the brain connections disrupted by failed capsulotomy vs modulated by successful DBS. Methods: We used diffusion-weighted magnetic resonance imaging (dMRI) tractography in a control cohort with tr-OCD (n=12) and in two of the Cap-DBS patients themselves to determine connectivity profiles of the capsulotomy, volume of tissue activated (VTA), and potentially necessary tracts (VTA minus capsulotomy tracts). We used whole-brain, PFC-focused, and subcortically-focused tractography algorithms to fully explore the space of possible connections. Results: Capsulotomy regions-of-interest (ROIs) connected with a variety of PFC and subcortical regions. VTA ROIs and potentially necessary tracts had limited and inconsistent PFC connectivity but substantial subcortical connectivity. While correlated to the average OCD connectome (r = 0.214, 95% CI [0.177, 0.251]; r = 0.756, 95% CI [0.739, 0.772]), the Cap-DBS connectomes had many edges that were stronger (z-score > 3). Conclusions: The connectivity profile of potentially necessary tracts for successful DBS treatment after failed capsulotomy revealed a surprising proportion of subcortical regions and inconsistent PFC involvement, highlighting an often-ignored set of connections that may be critical to effective DBS.