Background: Antibiotics and antidepressants are commonly co-prescribed, yet it remains unclear whether antibiotic exposure around the initiation of antidepressant treatment is associated with later development of difficult-to-treat depression. In this study, we used routine care electronic health records to test whether antibiotic prescriptions in proximity to starting a first-line antidepressant are associated with subsequent treatment escalation to difficult-to-treat options. Methods: We ran a propensity score–matched retrospective cohort study using de-identified electronic health records from the TriNetX US Collaborative Network. We included adults aged 18–65 years with a coded diagnosis of depression (ICD-10 F32–F34) who received their first antidepressant prescription (index date). We excluded individuals with lifetime bipolar disorder or psychotic disorders and those with any of the outcomes of interest on or before the index date. Antibiotic exposure was defined as at least one antibiotic prescription in a window from 1 year before to 3 months after the index antidepressant prescription; follow-up started at the end of this window and continued for up to 5 years. The primary outcome was difficult-to-treat depression, defined as first recorded use of ketamine or esketamine, tricyclic antidepressants, monoamine oxidase inhibitors, lithium augmentation, or electroconvulsive therapy. Propensity scores were estimated using logistic regression, and exposed and unexposed patients were matched 1:1 using a greedy nearest-neighbour algorithm. We used Kaplan–Meier methods with log-rank tests and estimated 5-year restricted mean time lost (RMTL) ratios, with prespecified sensitivity analyses. Negative control outcomes were used to assess residual confounding. Outcomes: In the matched cohort (n=783,406; 391,703 antibiotic-exposed and 391,703 unexposed), antibiotic exposure was associated with higher risk of difficult-to-treat depression (RMTL ratio 1.09, 95% CI 1.07-1.11; p<0.0001) over 5 years. Associations were strongest for ketamine/esketamine (1.17, 1.13-1.20; p<0.0001) and tricyclic antidepressants (1.05, 1.02-1.08; p=0.0006). Negative control outcomes showed no association. When exposure was restricted to topical-only antibiotics, the association was null (RMTL ratio 1.06, 95% CI 0.93–1.20, p=0.389), suggesting that the signal is specific to systemically absorbed antibiotics. Findings were robust in all other prespecified sensitivity analyses, including exclusion of antibiotic prescriptions within ±7 days of index. Interpretation: Our findings suggest that recent antibiotic exposure at the time of antidepressant initiation may help identify patients at higher subsequent risk of treatment escalation to difficult-to-treat depression. Given that both antibiotics and antidepressants are commonly prescribed, findings could have important implications at the population level.

An estimated 5% of cases of first-episode psychosis are due to rare and sometimes reversible causes that can be identified through diagnostic investigations that are currently less common in psychiatry, e.g. lumbar puncture, specialised brain imaging and genetic testing. The current clinical practice of the use of such technologies, however, raises several challenging ethical questions. Drawing on our multidisciplinary perspective spanning psychiatry, neurology, philosophy, neuroscience, sociology and medical ethics from three countries, we identify emerging ethical issues in the diagnosis of rare causes of psychosis. We group challenges thus: (a) diagnostic justice, (b) moral responsibility and (c) unintended consequences of diagnostic work-up. Justice challenges surrounded the role of (a) 'luck', (b) social capital and (c) prior psychiatric diagnoses in determining access to work-up. Moral responsibility challenges surround the extent to which (a) clinicians are expected to know the red flags and work-up for rare or ultra-rare causes; and (b) those running health systems should enable knowledgeable clinicians to provide the requisite work-up. Challenges related to unintended consequences include the risk of pursuing work-up of rare causes to reinforce (a) psychiatric exceptionalism and (b) paternalistic decision-making that doesn't allow space for patient preferences. Finally, we reflect on unresolved issues and future directions.

BACKGROUND:N-methyl-D-aspartate receptor (NMDAR)-antibody encephalitis is a life-threatening neuropsychiatric disorder requiring prompt immunotherapy. The earliest features are mental-state changes, often mistaken for primary psychosis. Improved clinical differentiation could assist rational diagnostic investigation and expedite immunotherapy. Inspired by patients' and relatives' lived experience, we aimed to explore the psychiatric phenotype of NMDAR-antibody encephalitis and the features common to and distinct from real-world episodes of psychosis. METHODS:In this international, multicentre, retrospective phenotypic analysis we collected data on episodes of NMDAR-antibody encephalitis from specialised neurology services in Europe (UK, Germany, and Sweden) and the USA. For comparison, we collected similar data from de-identified accepted referrals to a UK early intervention in psychosis service, including consecutively presenting cases (unselected psychosis) and a group defined by having been assessed and admitted to hospital under the Mental Health Act (selected psychosis). Additionally, we included episodes of postpartum psychosis from a mother and baby unit in the Netherlands. In our mental-state inventory we included core features from ICD-11, the Bush-Francis catatonia score, and the Neuropsychiatric Inventory encompassing anxiety, depression, mania, schizophrenia, catatonia, and also more granular transdiagnostic behavioural features including those common to neuropsychiatric and neurobehavioural syndromes, such as delirium and dementia. Ethnicity data were not available. We compared and visualised the neuropsychiatric phenotype of these cohorts. FINDINGS:We collected data from 100 episodes of NMDAR-antibody encephalitis from 96 patients between 2010 and 2022 (median age 22 years, female:male ratio 3·80), 135 episodes of psychosis from 135 patients between 2018 and 2019 (median age 27 years, female:male ratio 0·75), and ten episodes of postpartum psychosis from ten patients between 2005 and 2012 (median age 30 years, all female sex). Psychopathology in NMDAR-antibody encephalitis was abundant (92 [92%] of 100 episodes) and ultra-rapid in onset (median 1 day [95% CI 1-1; IQR 1-7]) versus unselected primary psychoses (median 180 days [120-210; 91-365]; p<0·0001). 21 (36%) of 58 mental-state features, including catatonic and visual hallucinations, were over-represented in NMDAR-antibody encephalitis and 12 (21%) were under-represented, including features typical of affective (eg, elated mood, flight of ideas, grandiose delusions) and non-affective psychoses (eg, thought broadcasting, thought withdrawal, paranoid delusions; false discovery rate threshold <0·05). Typically, in NMDAR-antibody encephalitis, the complexity sequentially evolved from mood to psychotic to catatonic predominance within 2 weeks. INTERPRETATION:NMDAR-antibody encephalitis has a rapid-onset, complex, and dynamic neuropsychiatric phenotype, sufficiently distinctive to drive a clinical approach to differentiation. FUNDING:UK NIHR, Wellcome, and UK Medical Research Council (MRC)/UK Research and Innovation.

Survivors of encephalitis frequently experience chronic neuropsychiatric sequelae, yet the prevalence and patterns of mental health outcomes remain poorly characterized. We conducted a systematic review and meta-analysis to quantify the prevalence of psychiatric and behavioural symptoms following encephalitis. We also aimed to compare infectious with autoimmune encephalitis, explore specific aetiological associations as well as age-related differences. Following PRISMA guidelines, MEDLINE, EMBASE, PsycINFO, CINAHL, and PubMed were searched through 13 December 2024. Observational studies reporting psychiatric outcomes ≥3 months post-encephalitis were included. Two reviewers independently screened titles/abstracts and extracted data on symptom prevalence, study design, aetiology, and demographics. Random-effects meta-analyses estimated pooled prevalence of depression, anxiety, disinhibition, emotional instability, and other neuropsychiatric domains. Subgroup analyses compared infectious versus autoimmune causes and paediatric versus adult cohorts. Meta-regression assessed the influence of follow-up duration, sex percentage and cohort age. One hundred one studies (n = 4703 patients; weighted mean age 36.5 years) met inclusion. Across all aetiologies, pooled prevalence estimates included: depression, 26.9% (95% CI 22.2-32.3%); anxiety, 22.8% (95% CI 14.2-32.0%); disinhibition, 20.5% (95% CI 15.1-27.3%); emotional instability, 22.9% (95% CI 15.6-32.4%). Infectious encephalitis demonstrated higher rates of mood symptoms (75.2% versus 30.9% in autoimmune; P < 0.001). Meta-regression revealed that follow-up duration, mean cohort age, and female proportion influenced the prevalence of several neuropsychiatric symptoms. Heterogeneity was substantial across analyses, reflecting aetiologic, methodological, and demographic diversity in included studies. Psychiatric sequelae following encephalitis occur at rates comparable to neurological complications, with depression, anxiety, disinhibition, and emotional instability each affecting at least one-quarter of survivors. The substantial heterogeneity across studies highlights the need for prospective comparative cohorts, consistent diagnostic criteria, and the development of a standardized mental health outcome set to improve both care and research.

Background Restrictive interventions are used in the treatment of some people with severe mental disorders such as psychosis - including psychiatric intensive care unit (PICU) admission, seclusion and restraint. Early Intervention in Psychosis (EIP) service input may improve outcomes in psychosis, but it is unclear whether specific components of EIP care reduce the need for restrictive practice.Aims To examine associations between EIP care components, demographic characteristics and restrictive interventions.Method We conducted a retrospective cohort study of 14 874 people who used EIP services in England, using linked data from the National Clinical Audit of Psychosis and the Mental Health Services Data Set. We examined associations between EIP components and time to PICU admission (primary outcome) alongside seclusion/physical restraint/injected chemical restraint/requests for police assistance (secondary outcomes), using multilevel Cox regression, adjusting for demographic factors and clustering by service.Results Higher hazards of restrictive interventions were observed among men, younger people and several minority ethnic groups. Individuals eligible for clozapine who were not offered it (hazard ratio 1.51, 95% CI 1.20-1.91) or refused it (hazard ratio 1.46, 95% CI 1.02-2.10) had higher hazards of PICU admission than those not eligible, whereas those who were eligible for clozapine and received it did not. There was weaker evidence of similar effects on hazards of physical restraint and seclusion. Receipt of CBT for psychosis was associated with reduced hazards of PICU admission (hazard ratio 0.80, 95% CI 0.67-0.95) and physical restraint (hazard ratio 0.68, 95% CI 0.47-0.98). Substance use was associated with increased hazards of PICU admission and requests for police assistance, although substance use interventions appeared to partially mitigate this.Conclusions Marked demographic disparities exist in the use of restrictive practice. Specific EIP care components may be associated with reductions. Strengthening evidence-based EIP provision and addressing structural inequalities may support progress towards less coercive and more equitable care.

INTRODUCTION:Early Intervention in Psychosis (EIP) services in England are commissioned to provide up to 3 years' support to people experiencing first episode psychosis, but the optimal duration remains debated. This qualitative study aimed to explore how decisions about EIP duration are made and experienced by multiple stakeholders. METHODS:Qualitative longitudinal study comprising semi-structured interviews with EIP Service Users (SUs), carers, EIP practitioners, GPs, and mental health service commissioners; follow-up interviews with SUs 6-11 months later. Data were collected between September 2022 and September 2024 and informed by information power. Data were thematically analysed by a multidisciplinary team. Patient and carer involvement and engagement were integral to the study. RESULTS:The 3-year time limit of contact with EIP teams was thought to work well when SUs felt supported and ready for discharge, but constrained shared decision making when they did not. Some participants described early discharge before 3 years, either as a negotiated decision based on wellness and readiness to move on or as a consequence of poor engagement. Others reported extended care beyond 3 years in response to individual needs or delays in transfer to Community Mental Health Teams (CMHTs). This flexibility in duration varied across teams and trusts. Well-managed, relational care was viewed as key to effective discharge. CONCLUSION:Flexible, person-centred episodes of care and collaborative discharge planning, supported by effective coordination between EIP, primary care, and CMHTs, are essential to sustaining relational practice and ensuring smoother transitions.

In resource-limited settings, improving care for mental, neurological and substance misuse (MNS) disorders is essential. This study evaluated the feasibility and effectiveness of implementing all adult modules of the WHO mental health Gap Action Programme Intervention Guide (mhGAP-IG) in primary healthcare (PHC) in rural Kenya through training non-specialist primary healthcare workers. We conducted a stepped-wedge cluster randomized trial across 127 public primary care facilities in Kilifi County, Kenya. Facilities were grouped into 16 clusters and randomly assigned to one of 16 monthly intervention start dates between August 2021 and November 2022. All clusters began in the control condition and sequentially crossed over to the intervention. The intervention comprised a 10-day mhGAP-IG training followed by quarterly supportive supervision. The primary outcome was the monthly rate of clinical consultations for MNS disorders per 100,000 outpatient consultations. Secondary outcomes included healthcare worker stigma and patient-level measures of illness severity, disability, and quality of life. A total of 172 healthcare workers were trained, and 5,320,423 adult outpatient consultations were recorded. Compared to the control period, the monthly rate of epilepsy diagnoses increased from 191.35 to 395.49 per 100,000 consultations (crude absolute increase 204.13 per 100,000), with an adjusted intervention effect of β = 119.19 (95% CI 34.70-203.67; p = 0.006). Depression diagnoses increased from 1.41 to 15.24 per 100,000 consultations (crude increase 13.82 per 100,000; β = 9.70, 95% CI 5.69-13.71; p < 0.001), dementia from 0.25 to 5.58 (crude increase 5.33 per 100,000; β = 4.11, 95% CI 2.51-5.71; p < 0.001), and substance misuse disorders from 0.04 to 2.14 (crude increase 2.10 per 100,000; β = 1.78, 95% CI 0.95-2.61; p < 0.001). Although crude increases were observed for psychosis (18.55 to 49.38 per 100,000), suicidality (0.17 to 0.46), and a decrease for other mental health complaints (108.44 to 81.15), the adjusted intervention effects for these outcomes were not statistically significant. Healthcare worker stigma and patient outcomes improved significantly. Large-scale implementation of mhGAP-IG in rural Kenyan PHC was feasible and associated with improved detection of MNS disorders and better provider and patient outcomes. Further studies in diverse settings are needed to assess generalizability. TRIAL REGISTRATION:Pan African Clinical Trials registry [PACTR202011741472301].

Objectives People experiencing homelessness (PEH) face multiple barriers to seeking healthcare and have poorer health outcomes. Point of care tests (POCTs) provide a potential solution to improving access to diagnostics for this population. This survey aimed to understand if these technologies could address unmet needs in primary care for PEH.Design and setting An online survey was circulated via dedicated inclusion healthcare newsletters to professionals providing community-based care for PEH in England. The survey focused on experiences of diagnostics and opinions on the use of POCTs for this population.Participants Thirty-two healthcare workers participated, including GPs, nurses and other allied practitioners from 13 different Integrated Care Boards across England.Analysis Descriptive analyses were performed using standard statistical parameters. A reflexive thematic analysis was performed on free-text responses.Results There was evidence of current POCT use but with marked variation across services as to which tests are available. Healthcare workers were overwhelmingly positive about the potential for POCTs, with rapid results facilitating prompt diagnosis and management, increasing likelihood of engagement. C reactive protein testing was considered as the test, which could confer the most benefit to acute care, with renal function and troponin also being discussed, whereas tests to determine cardiometabolic risk were thought to have the most patient benefit in chronic care. Point of care ultrasound for diagnosis of respiratory pathologies and deep vein thrombosis and POCTs for malnutrition were suggested as potential future technologies to address unmet healthcare needs.Conclusion The majority of responders expressed that enhancing the provision of POCTs would be beneficial, both in acute and chronic care scenarios, due to the benefits of getting rapid results and reducing the need for repeat appointments or onward referral for diagnostics.

Background:Early Intervention in Psychosis services improves outcomes for young people with psychosis, but 25% disengage in the first 12 months with costs to their mental health. Objectives:To refine a toolkit and training and evaluate effectiveness, implementation, and cost-effectiveness of the Early Youth Engagement-2 intervention to reduce disengagement. Design:Cluster randomised controlled trial with economic and process evaluation. Randomisation:Randomisation at team level stratified by site. Masking:Research assistants, outcome assessors and statisticians were masked to treatment allocation for the primary disengagement and cost-effectiveness outcomes. Participants and teams administering the interventions were unmasked. Setting:Twenty Early Intervention in Psychosis teams in five sites across England. Participants:A total of 1027 young people (14-35 years) with first-episode psychosis (F20-29, 31; ICD-10); 20-282 Early Intervention in Psychosis staff. Intervention:Team-based motivational engagement (Early Youth Engagement-2) intervention, delivered by Early Intervention in Psychosis clinicians alongside standardised Early Intervention in Psychosis, supported by the implementation toolkit (training, website and booklet series). Comparison:Standardised Early Intervention in Psychosis, including National Institute for Health and Care Excellence guidelines approved interventions. Main outcome measures:Primary outcome - time to disengagement over 26 months (days from date of allocation to care co-ordinator to date of last contact following refusal to engage with service, or lack of response to contact for consecutive 3-month period). Secondary outcomes - mental health, recovery, quality of life, service use, at 6 and 12 months. Economic outcomes - National Health Service mental healthcare costs, wider societal care costs, clinical and social outcomes over 12 months; cost-effectiveness. Process evaluation outcomes - fidelity to the Early Youth Engagement-2 model, implementation process scores, therapeutic alliance, qualitative outcomes. Results:Disengagement was 16% across both arms. The multivariable Cox regression on 1005 participants estimated an adjusted hazard ratio for Early Youth Engagement-2 + standardised Early Intervention in Psychosis (n = 652) versus standardised Early Intervention in Psychosis service alone (n = 375) of 1.07 (95% confidence interval 0.76 to 1.49; p = 0.713). There were no observed differences between arms for any secondary outcomes. The health economic evaluation indicated lower mean mental healthcare costs of -£788 (95% CI -£3571 to £1994) and marginally improved mental health states for intervention participants. Early Youth Engagement-2 participants spent 30 more days per year in education and training (95% CI 1.52 to 53.68; probability positive outcome for the intervention: 99%), but these outcomes must be viewed very cautiously as only 22% of the sample provided data. The process evaluation revealed heterogeneous implementation fidelity and constant pressure to adapt to widespread disruption from COVID-19. There was no effect on therapeutic alliance: the most likely active change mechanism was through psychoeducation. Limitations:Lower than expected disengagement, high loss to follow-up and impact of COVID-19 on fidelity, implementation and outcomes. Conclusions:In the primary clinical effectiveness analysis, 95% confidence limits ruled out a reduction of more than 24% in the risk of disengagement with the Early Youth Engagement-2 intervention. In a cost-effectiveness analysis, estimates fell in the direction of dominance of the Early Youth Engagement-2 intervention (reduced costs, marginally better mental health states). Future work:Dissemination of the booklet and website resources and an adapted version of the model as stand-alone tools for use in good-practice routine Early Intervention in Psychosis care. Study registration:This study is registered as ISRCTN 51629746. Funding:This award was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme (NIHR award ref: 16/31/87) and is published in full in Health and Social Care Delivery Research; Vol. 13, No. 33. See the NIHR Funding and Awards website for further award information.

BACKGROUND:Psychotic disorders are severe mental health conditions frequently associated with long-term disability, reduced quality of life and premature mortality. Early Intervention in Psychosis (EIP) services aim to provide timely, comprehensive packages of care for people with psychotic disorders. However, it is not clear which components of EIP services contribute most to the improved outcomes they achieve. AIMS:We aimed to identify associations between specific components of EIP care and clinically significant outcomes for individuals treated for early psychosis in England. METHOD:This national retrospective cohort study of 14 874 EIP individuals examined associations between 12 components of EIP care and outcomes over a 3-year follow-up period, by linking data from the National Clinical Audit of Psychosis (NCAP) to routine health outcome data held by NHS England. The primary outcome was time to relapse, defined as psychiatric inpatient admission or referral to a crisis resolution (home treatment) team. Secondary outcomes included duration of admissions, detention under the Mental Health Act, emergency department and general hospital attendances and mortality. We conducted multilevel regression analyses incorporating demographic and service-level covariates. RESULTS:Smaller care coordinator case-loads and the use of clozapine for eligible people were associated with reduced relapse risk. Physical health interventions were associated with reductions in mortality risk. Other components, such as cognitive-behavioural therapy for psychosis (CBTp), showed associations with improvements in secondary outcomes. CONCLUSIONS:Smaller case-loads should be prioritised and protected in EIP service design and delivery. Initiatives to improve the uptake of clozapine should be integrated into EIP care. Other components, such as CBTp and physical health interventions, may have specific benefits for those eligible. These findings highlight impactful components of care and should guide resource allocation to optimise EIP service delivery.

BACKGROUND:Scalable assessment tools for precision psychiatry are of increasing clinical interest. One clinical risk assessment that might be improved by such approaches is assessment of violence perpetration risk. This is an important adverse outcome to reduce for some people presenting to services for first-episode psychosis. A prediction tool (Oxford Mental Illness and Violence (OxMIV)) has been externally validated in these services, but clinical acceptability and role need to be examined and developed. AIMS:This study aimed to understand clinical use of the OxMIV tool to support violence risk management in early intervention in psychosis services in terms of acceptability to clinicians, patients and carers, practical feasibility, perceived utility, impact and role. METHOD:A mixed methods approach integrated quantitative data on utility and patterns of use of the OxMIV tool over 12 months in two services with qualitative data from interviews of 20 clinicians and 12 patients and carers. RESULTS:The OxMIV tool was used 141 times, mostly in new assessments. Required information was available, with only family history items scored unknown to any notable degree. The OxMIV tool was deemed helpful by clinicians in most cases, especially if there were previous risk concerns. It was acceptable practically, and broadly for the service, for which its concordance with clinical judgement was important. Patients and carers thought it could improve openness. There was some limited impact on plans for clinical support. CONCLUSIONS:The OxMIV tool met an identified clinical need to support clinical assessment for violence risk. Linkage to intervention pathways is a research priority.

BACKGROUND:There is a significant mortality gap between the general population and people with psychosis. Completion rates of regular physical health assessments for cardiovascular risk in this group are suboptimal. Point-of-care testing (POCT) for diabetes and hyperlipidaemia - providing an immediate result from a finger-prick - could improve these rates. AIMS:To evaluate the impact on patient-clinician encounters and on physical health check completion rates of implementing POCT for cardiovascular risk markers in early intervention in psychosis (EIP) services in South East England. METHOD:A mixed-methods, real-world evaluation study was performed, with 40 POCT machines introduced across EIP teams in all eight mental health trusts in South East England from March to May 2021. Clinician training and support was provided. Numbers of completed physical health checks, HbA1c and lipid panel blood tests completed 6 and 12 months before and 6 months after introduction of POCT were collected for individual patients. Data were compared with those from the South West region, which acted as a control. Clinician questionnaires were administered at 2 and 8 months, capturing device usability and impacts on patient interactions. RESULTS:Post-POCT, South East England saw significant increases in HbA1c testing (odds ratio 2.02, 95% CI 1.17-3.49), lipid testing (odds ratio 2.38, 95% CI 1.43-3.97) and total completed health checks (odds ratio 3.61, 95% CI 1.94-7.94). These increases were not seen in the South West. Questionnaires revealed improved patient engagement, clinician empowerment and patients' preference for POCT over traditional blood tests. CONCLUSIONS:POCT is associated with improvements in the completion and quality of physical health checks, and thus could be a tool to enhance holistic care for individuals with psychosis.

INTRODUCTION:Early Intervention in Psychosis (EIP) services in England offer up to 3 years' time-limited support to people experiencing early psychosis. Service users (SUs) are discharged to primary care, a community mental health team (CMHT), or other specialist mental health service. The aim of this study is to explore the SU and carer journey through discharge from EIP and into the early post-discharge period. METHODS:Qualitative longitudinal study comprising semi-structured interviews with SUs and carers at, or shortly after, discharge from EIP, and follow-up interviews with SUs 6-11 months later. Data collection conducted between January 2023-September 2024 and informed by information power. Data were thematically analysed by a multidisciplinary team. RESULTS:SUs and carers expressed their desire to be actively involved in EIP discharge planning and decision-making. They contrasted close relationships with EIP practitioners with inaccessibility of care and difficulties navigating healthcare systems after discharge. Some SUs described feelings of abandonment and expressed a wish for transitional support, and proactive, relationship-based care post-discharge. Carers played an important role as patient advocates but were rarely offered support themselves. CONCLUSION:Improved collaboration is needed between SUs, carers and primary care/CMHT practitioners in the build-up to EIP discharge. There should be proactive contact from primary care at the point of discharge and in the early post-discharge period. Carer needs are often overlooked; primary care could utilise the 'carers register' and proactively offer support. PATIENT OR PUBLIC CONTRIBUTION:Patient and carer involvement and engagement was key to all stages of this study. The research team met regularly with our two co-investigators with lived experience (as a service user and a carer), who contributed to data analysis and writing this paper. We worked closely with our patient and carer advisory group, EXTEND-ing, throughout the research process. They helped formulate research questions, co-designed topic guides and participant information sheets, and contributed to data analysis and interpretation.

BACKGROUND:Early intervention in psychosis (EIP) services improve outcomes for young people, but approximately 30% disengage. AIMS:To test whether a new motivational engagement intervention would prolong engagement and whether it was cost-effective. METHOD:We conducted a multicentre, single-blind, parallel-group, cluster randomised controlled trial involving 20 EIP teams at five UK National Health Service (NHS) sites. Teams were randomised using permuted blocks stratified by NHS trust. Participants were all young people (aged 14-35 years) presenting with a first episode of psychosis between May 2019 and July 2020 (N = 1027). We compared the novel Early Youth Engagement (EYE-2) intervention plus standardised EIP (sEIP) with sEIP alone. The primary outcome was time to disengagement over 12-26 months. Economic outcomes were mental health costs, societal costs and socio-occupational outcomes over 12 months. Assessors were masked to treatment allocation for primary disengagement and cost-effectiveness outcomes. Analysis followed intention-to-treat principles. The trial was registered at ISRCTN51629746. RESULTS:Disengagement was low at 15.9% overall in standardised stand-alone services. The adjusted hazard ratio for EYE-2 + sEIP (n = 652) versus sEIP alone (n = 375) was 1.07 (95% CI 0.76-1.49; P = 0.713). The health economic evaluation indicated lower mental healthcare costs linked to reductions in unplanned mental healthcare with no compromise of clinical outcomes, as well as some evidence for lower societal costs and more days in education, training, employment and stable accommodation in the EYE-2 group. CONCLUSIONS:We found no evidence that EYE-2 increased time to disengagement, but there was some evidence for its cost-effectiveness. This is the largest study to date reporting positive engagement, health and cost outcomes in a total EIP population sample. Limitations included high loss to follow-up for secondary outcomes and low completion of societal and socio-occupational data. COVID-19 affected fidelity and implementation. Future engagement research should target engagement to those in greatest need, including in-patients and those with socio-occupational goals.

Summary The National Institute for Health and Care Research has enabled the integration of world-leading science with clinical practice in the UK’s National Health Service, and has saved lives and improved lives as a result. However, this integration has not extended to mental health services. The case is made for a National Institute for Mental Health Research (NIMHR) to address this inequity.