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Background: Clozapine is an antipsychotic drug with unique efficacy, and it is the only recommended treatment for treatment-resistant schizophrenia (TRS: failure to respond to at least two different antipsychotics). However, clozapine is also associated with a range of adverse effects which restrict its use, including blood dyscrasias, for which haematological monitoring is required. As treatment resistance is recognised earlier in the illness, the question of whether clozapine should be prescribed in children and young people is increasingly important. However, most research to date has been in older, chronic patients, and evidence regarding the efficacy and safety of clozapine in people under age 25 is lacking. The CLEAR (CLozapine in EARly psychosis) trial will assess whether clozapine is more effective than treatment as usual (TAU), at the level of clinical symptoms, patient rated outcomes, quality of life and cost-effectiveness in people below 25 years of age. Additionally, a nested biomarker study will investigate the mechanisms of action of clozapine compared to TAU., Methods and Design: This is the protocol of a multi-centre, open label, blind-rated, randomised controlled effectiveness trial of clozapine vs TAU (any other oral antipsychotic monotherapy licenced in the British National Formulary) for 12 weeks in 260 children and young people with TRS (12-24 years old)., Aim and Objectives: The primary outcome is the change in blind-rated Positive and Negative Syndrome Scale scores at 12 weeks from baseline. Secondary outcomes include blind-rated Clinical Global Impression, patient-rated outcomes, quality of life, adverse effects, and treatment adherence. Patients will be followed up for 12 months and will be invited to give consent for longer term follow-up using clinical records and potential re-contact for further research. For mechanism of action, change in brain magnetic resonance imaging (MRI) biomarkers and peripheral inflammatory markers will be measured over 12 weeks., Discussion: The CLEAR trial will contribute knowledge on clozapine effectiveness, safety and cost-effectiveness compared to standard antipsychotics in young people with TRS, and the results may guide future clinical treatment recommendation for early psychosis., Trial Registration: ISRCTN Number: 37176025, IRAS Number: 1004947., Trial Status: In set-up. Protocol version 4.0 01/08/23. Current up to date protocol available here: https://fundingawards.nihr.ac.uk/award/NIHR131175# /., (© 2024. The Author(s).)

Introduction: At least one in four people treated by the primary care improving access to psychological therapies (IAPT) programme in England experiences distressing psychotic experiences (PE) in addition to common mental disorder (CMD). These individuals are less likely to achieve recovery. IAPT services do not routinely screen for nor offer specific treatments for CMD including PE. The Tailoring evidence-based psychological therapY for People with common mental disorder including Psychotic EXperiences study will evaluate the clinical and cost-effectiveness of an enhanced training for cognitive behavioural therapists that aims to address this clinical gap., Methods and Analysis: This is a multisite, stepped-wedge cluster randomised controlled trial. The setting will be IAPT services within three mental health trusts. The participants will be (1) 56-80 qualified IAPT cognitive behavioural therapists and (2) 600 service users who are triaged as appropriate for cognitive behavioural therapy in an IAPT service and have PE according to the Community Assessment of Psychic Experiences-Positive 15-items Scale. IAPT therapists will be grouped into eight study clusters subsequently randomised to the control-intervention sequence. We will obtain pseudonymous clinical outcome data from IAPT clinical records for eligible service users. We will invite service users to complete health economic measures at baseline, 3, 6, 9 and 12-month follow-up. The primary outcome will be the proportion of patients with common mental disorder psychotic experiences who have recovered by the end of treatment as measured by the official IAPT measure for recovery., Ethics and Dissemination: The study received the following approvals: South Central-Berkshire Research Ethics Committee on 28 April 2020 (REC reference 20/SC/0135) and Health Research Authority (HRA) on 23 June 2020. An amendment was approved by the Ethics Committee on 01 October 2020 and HRA on 27 October 2020. Results will be made available to patients and the public, the funders, stakeholders in the IAPT services and other researchers., Trial Registration Number: ISRCTN93895792., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Background: People with psychosis have high rates of trauma, with a post-traumatic stress disorder (PTSD) prevalence rate of approximately 15%, which exacerbates psychotic symptoms such as delusions and hallucinations. Pilot studies have shown that trauma-focused (TF) psychological therapies can be safe and effective in such individuals. This trial, the largest to date, will evaluate the clinical effectiveness of a TF therapy integrated with cognitive behaviour therapy for psychosis (TF-CBTp) on post-traumatic stress symptoms in people with psychosis. The secondary aims are to compare groups on cost-effectiveness; ascertain whether TF-CBTp impacts on a range of other meaningful outcomes; determine whether therapy effects endure; and determine acceptability of the therapy in participants and therapists., Methods: Rater-blind, parallel arm, pragmatic randomised controlled trial comparing TF-CBTp + treatment as usual (TAU) to TAU only. Adults (N = 300) with distressing post-traumatic stress and psychosis symptoms from five mental health Trusts (60 per site) will be randomised to the two groups. Therapy will be manualised, lasting 9 months (m) with trained therapists. We will assess PTSD symptom severity (primary outcome); percentage who show loss of PTSD diagnosis and clinically significant change; psychosis symptoms; emotional well-being; substance use; suicidal ideation; psychological recovery; social functioning; health-related quality of life; service use, a total of four times: before randomisation; 4 m (mid-therapy); 9 m (end of therapy; primary end point); 24 m (15 m after end of therapy) post-randomisation. Four 3-monthly phone calls will be made between 9 m and 24 m assessment points, to collect service use over the previous 3 months. Therapy acceptability will be assessed through qualitative interviews with participants (N = 35) and therapists (N = 5-10). An internal pilot will ensure integrity of trial recruitment and outcome data, as well as therapy protocol safety and adherence. Data will be analysed following intention-to-treat principles using generalised linear mixed models and reported according to Consolidated Standards of Reporting Trials-Social and Psychological Interventions Statement., Discussion: The proposed intervention has the potential to provide significant patient benefit in terms of reductions in distressing symptoms of post-traumatic stress, psychosis, and emotional problems; enable clinicians to implement trauma-focused therapy confidently in this population; and be cost-effective compared to TAU through reduced service use., Trial Registration: ISRCTN93382525 (03/08/20)., (© 2022. The Author(s).)

Objective: Many people with psychotic experiences do not develop psychotic disorders, yet those who seek help demonstrate high clinical complexity and poor outcomes. In this systematic review and meta-analysis, we evaluated the effectiveness and cost-effectiveness of psychological interventions for people with psychotic experiences., Method: We searched 13 databases for studies of psychological interventions for adults with psychotic experiences, but not psychotic disorders. Our outcomes were the proportion of participants remitting from psychotic experiences (primary); changes in positive and negative psychotic symptoms, depression, anxiety, functioning, distress, and quality of life; and economic outcomes (secondary). We analysed results using multilevel random-effects meta-analysis and narrative synthesis., Results: A total of 27 reports met inclusion criteria. In general, there was no strong evidence for the superiority of any one intervention. Five studies reported on our primary outcome, though only two reports provided randomised controlled trial evidence that psychological intervention (specifically, cognitive behavioural therapy) promoted remission from psychotic experiences. For secondary outcomes, we could only meta-analyse trials of cognitive behavioural therapy. We found that cognitive behavioural therapy was more effective than treatment as usual for reducing distress (pooled standardised mean difference: -0.24; 95% confidence interval = [-0.37, -0.10]), but no more effective than the control treatment for improving any other outcome. Individual reports indicated that cognitive behavioural therapy, mindfulness-based cognitive therapy, sleep cognitive behavioural therapy, systemic therapy, cognitive remediation therapy, and supportive treatments improved at least one clinical or functional outcome. Four reports included economic evaluations, which suggested cognitive behavioural therapy may be cost-effective compared with treatment as usual., Conclusion: Our meta-analytic findings were primarily null, with the exception that cognitive behavioural therapy may reduce the distress associated with psychotic experiences. Our analyses were limited by scarcity of studies, small samples and variable study quality. Several intervention frameworks showed preliminary evidence of positive outcomes; however, the paucity of consistent evidence for clinical and functional improvement highlights a need for further research into psychological treatments for psychotic experiences., Prospero Protocol Registration Number: CRD42016033869.

Background: Many people who have common mental disorders, such as depression and anxiety, also have some psychotic experiences. These experiences are associated with higher clinical complexity, poor treatment response, and negative clinical outcomes. Psychological interventions have the potential to improve outcomes for people with psychotic experiences. The aims of this systematic review are to (1) synthesise the evidence on the effectiveness and cost-effectiveness of psychological interventions to reduce psychotic experiences and their associated distress and (2) identify key components of effective interventions., Methods: Our search strategy will combine terms for (1) psychological interventions, (2) psychotic experiences, and (3) symptoms associated with psychotic experiences. We will search the following online databases: MEDLINE, Embase, PsycINFO, all Cochrane databases, British Nursing Index (BNI), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Health Management Information Consortium (HMIC), Education Resources Information Center (ERIC), and EconLit. Our primary outcome is the proportion of people who recovered or remitted from psychotic experiences after the intervention. Our secondary outcomes are changes in positive psychotic symptoms, negative psychotic symptoms, depression, anxiety, functioning (including social, occupational, and academic), quality of life, and cost-effectiveness. Two independent reviewers will judge each study against pre-specified inclusion and exclusion criteria and will extract study characteristics, outcome data, and intervention components. Risk of bias and methodological quality will be assessed using the Effective Public Health Practice Project Quality Assessment Tool for Quantitative Studies and the Drummond Checklist. Results will be synthesised using random-effects meta-analysis and narrative synthesis., Discussion: The identification of effective psychological interventions and of specific components associated with intervention effectiveness will augment existing evidence that can inform the development of a new, tailored intervention to improve outcomes related to psychotic symptoms, anxiety and depression, distress, functioning, and quality of life., Systematic Review Registration: PROSPERO CRD42016033869.

Background: General practitioners are usually the first health professionals to be contacted by people with early signs of psychosis. We aimed to assess whether increased liaison between primary and secondary care improves the clinical effectiveness and cost-effectiveness of detection of people with, or at high risk of developing, a first psychotic illness., Methods: Our Liaison and Education in General Practices (LEGs) study was a cluster-randomised controlled trial of primary care practices (clusters) in Cambridgeshire and Peterborough, UK. Consenting practices were randomly allocated (1:1) to a 2 year low-intensity intervention (a postal campaign, consisting of biannual guidelines to help identify and refer individuals with early signs of psychosis) or a high-intensity intervention, which additionally included a specialist mental health professional who liaised with every practice and a theory-based educational package. Practices were not masked to group allocation. Practices that did not consent to be randomly assigned comprised a practice-as-usual (PAU) group. The primary outcome was number of referrals of patients at high risk of developing psychosis to the early intervention service per practice site. New referrals were assessed clinically and stratified into those who met criteria for high risk or first-episode psychotic illness (FEP; together: psychosis true positives), and those who did not fulfil such criteria for psychosis (false positives). Referrals from PAU practices were also analysed. We assessed cost-effectiveness with decision analytic modelling in terms of the incremental cost per additional true positive identified. The trial is registered at the ISRCTN registry, number ISRCTN70185866., Findings: Between Dec 22, 2009, and Sept 7, 2010, 54 of 104 eligible practices provided consent and between Feb 16, 2010, and Feb 11, 2011, these practices were randomly allocated to interventions (28 to low intensity and 26 to high intensity); the remaining 50 practices comprised the PAU group. Two high-intensity practices were excluded from the analysis. In the 2 year intervention period, high-intensity practices referred more FEP cases than did low-intensity practices (mean 1.25 [SD 1.2] for high intensity vs 0.7 [0.9] for low intensity; incidence rate ratio [IRR] 1.9, 95% CI 1.05-3.4, p=0.04), although the difference was not statistically significant for individuals at high risk of psychosis (0.9 [1.0] vs 0.5 [1.0]; 2.2, 0.9-5.1, p=0.08). For high risk and FEP combined, high-intensity practices referred both more true-positive (2.2 [1.7] vs 1.1 [1.7]; 2.0, 1.1-3.6, p=0.02) and false-positive (2.3 [2.4] vs 0.9 [1.2]; 2.6, 1.3-5.0, p=0.005) cases. Referral patterns did not differ between low-intensity and PAU practices. Total cost per true-positive referral in the 2 year follow-up was £26,785 in high-intensity practices, £27,840 in low-intensity practices, and £30,007 in PAU practices., Interpretation: This intensive intervention to improve liaison between primary and secondary care for people with early signs of psychosis was clinically and cost effective., Funding: UK National Institute for Health Research., (Copyright © 2015 Perez et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.)

Background: Compulsory admission to psychiatric hospitals may be distressing, disruptive to patients and families, and associated with considerable cost to the health service. Improved patient experience and cost reductions could be realised by providing cost-effective crisis planning services., Methods: Economic evaluation within a multi-centre randomised controlled trial comparing Joint Crisis Plans (JCP) plus treatment as usual (TAU) to TAU alone for patients aged over 16, with at least one psychiatric hospital admission in the previous two years and on the Enhanced Care Programme Approach register. JCPs, containing the patient's treatment preferences for any future psychiatric emergency, are a form of crisis intervention that aim to mitigate the negative consequences of relapse, including hospital admission and use of coercion. Data were collected at baseline and 18-months after randomisation. The primary outcome was admission to hospital under the Mental Health Act. The economic evaluation took a service perspective (health, social care and criminal justice services) and a societal perspective (additionally including criminal activity and productivity losses)., Findings: The addition of JCPs to TAU had no significant effect on compulsory admissions or total societal cost per participant over 18-months follow-up. From the service cost perspective, however, evidence suggests a higher probability (80%) of JCPs being the more cost-effective option. Exploration by ethnic group highlights distinct patterns of costs and effects. Whilst the evidence does not support the cost-effectiveness of JCPs for White or Asian ethnic groups, there is at least a 90% probability of the JCP intervention being the more cost-effective option in the Black ethnic group., Interpretation: The results by ethnic group are sufficiently striking to warrant further investigation into the potential for patient gain from JCPs among black patient groups., Trial Registration: Current Controlled Trials ISRCTN11501328.

Background: The early detection and referral to specialized services of young people at ultra-high risk (UHR) for psychosis may reduce the duration of untreated psychosis and, therefore, improve prognosis. General practitioners (GPs) are usually the healthcare professionals contacted first on the help-seeking pathway of these individuals., Methods/design: This is a cluster randomized controlled trial (cRCT) of primary care practices in Cambridgeshire and Peterborough, UK. Practices are randomly allocated into two groups in order to establish which is the most effective and cost-effective way to identify people at UHR for psychosis. One group will receive postal information about the local early intervention in psychosis service, including how to identify young people who may be in the early stages of a psychotic illness. The second group will receive the same information plus an additional, ongoing theory-based educational intervention with dedicated liaison practitioners to train clinical staff at each site. The primary outcome of this trial is count data over a 2-year period: the yield - number of UHR for psychosis referrals to a specialist early intervention in psychosis service - per primary care practice., Discussion: There is little guidance on the essential components of effective and cost-effective educational interventions in primary mental health care. Furthermore, no study has demonstrated an effect of a theory-based intervention to help GPs identify young people at UHR for psychosis. This study protocol is underpinned by a robust scientific rationale that intends to address these limitations., Trial Registration: Current Controlled Trials ISRCTN70185866.

Background: The CRIMSON (CRisis plan IMpact: Subjective and Objective coercion and eNgagement) study is an individual level, randomised controlled trial that compared the effectiveness of Joint Crisis Plans (JCPs) with treatment as usual for people with severe mental illness. The JCP is a negotiated statement by a patient of treatment preferences for any future psychiatric emergency, when he or she might be unable to express clear views. We assessed whether the additional use of JCPs improved patient outcomes compared with treatment as usual., Methods: Patients were eligible if they had at least one psychiatric admission in the previous 2 years and were on the Enhanced Care Programme Approach register. The study was done with 64 generic and specialist community mental health teams in four English mental health care provider organisations (trusts). Hypotheses tested were that, compared with the control group, the intervention group would experience: fewer compulsory admissions (primary outcome); fewer psychiatric admissions; shorter psychiatric stays; lower perceived coercion; improved therapeutic relationships; and improved engagement. We stratified participants by centre. The research team but not participants nor clinical staff were masked to allocation. This study is registered with ClinicalTrials.gov, number ISRCTN11501328., Findings: 569 participants were randomly assigned (285 to the intervention group and 284 to the control group). No significant treatment effect was seen for the primary outcome (56 [20%] sectioned in the control group and 49 [18%] in the JCP group; odds ratio 0·90 [95% CI 0·58-1·39, p=0·63]) or any secondary outcomes, with the exception of an improved secondary outcome of therapeutic relationships (17·3 [7·6] vs 16·0 [7·1]; adjusted difference -1·28 [95% CI -2·56 to -0·01, p=0·049]). Qualitative data supported this finding., Interpretation: Our findings are inconsistent with two earlier JCP studies, and show that the JCP is not significantly more effective than treatment as usual. There is evidence to suggest the JCPs were not fully implemented in all study sites, and were combined with routine clinical review meetings which did not actively incorporate patients' preferences. The study therefore raises important questions about implementing new interventions in routine clinical practice., Funding: Medical Research Council UK and the National Institute for Health Research., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objective: To investigate the cost effectiveness of joint crisis plans, a form of advance agreement for people with severe mental illness., Design: Single blind randomised controlled trial., Setting: Eight community mental health teams in southern England., Participants: 160 people with a diagnosis of psychotic illness or non-psychotic bipolar disorder who had been admitted to hospital at least once within the previous two years., Intervention: Joint crisis plan formulated by the patient, care coordinator, psychiatrist, and project worker containing contact information, details of illnesses, treatments, relapse indicators, and advance statements of preferences for care for future relapses. Control group was standardised service information., Main Outcome Measures: Admission to hospital; service use over 15 months., Results: Use of a joint crisis plan was associated with less service use and lower costs on average than in the standardised service information group, but differences were not significant. Total costs during follow-up were 7264 pounds sterling (10,616 euros, 13,560 dollars) for each participant with a joint crisis plan and 8359 pounds sterling (12,217 euros, 15,609 dollars) for each participant with standardised service information (mean difference 1095 pounds sterling; 95% confidence interval -2814 to 5004). Cost effectiveness acceptability curves, used to explore uncertainty in estimates of costs and effects, suggest there is a greater than 78% probability that joint crisis plans are more cost effective than standardised service information in reducing the proportion of patients admitted to hospital., Conclusion: Joint crisis plans produced a non-significant decrease in admissions and total costs. Though the cost estimates had wide confidence intervals, the associated uncertainty suggests there is a relatively high probability of the plans being more cost effective than standardised service information for people with psychotic disorders.

Purpose: Data on the process of mental health care is scant. Most studies focus on services at their inception when activity may be atypical and then usually present data only mean values for the reported variables over the whole study period. We aimed to test whether care delivery changes over time, and to describe any changes at the individual patient and team levels., Methods: Process data on 272 patients in three new intensive case management (ICM) teams were collected over 2 years. Interventions were prospectively recorded using clinician-derived categories. Changes over time are described at both patient and team level., Results: The number of contacts and the proportion of face-to-face activity were remarkably constant after the first month at the patient level. The proportion of 'psychiatric' interventions (main focus on medication or a specific 'mental health' intervention performed) increased greatly after the first 6 months. The care activity received by individual patients varied considerably. Overall, teams varied significantly in the extent to which their activity rates were sustained over time., Conclusions: New ICM teams deliver highly individualised care with more marked differences in treatment patterns between patients in the same team than mean differences between teams. The early 'engagement' period is marked by a greater focus on social care. There is evidence of differences in sustainability of the services by site.

Background: Little is known about the determinants of violence in women with psychosis., Aims: To identify predictors of violence in a community sample of women with chronic psychosis., Method: The 2-year prevalence of physical assault was estimated for a sample of 304 women with psychosis. Baseline socio-demographic and clinical factors were used to identify predictors of assault., Results: The 2-year prevalence of assault in the sample was 17%. Assaultive behaviour was associated with previous violence (OR=5.87,95% CI 2.42-14.25), non-violent convictions (OR=2.63,95% CI 1.17-5.93), victimization (OR=2.46, 95% CI1.02-5.93), African-Caribbean ethnicity (OR=2.24,95% CI1.02-4.77), cluster B personality disorder (OR=2.66, 95% CI1.11-6.38) and high levels of unmet need (OR=1.17,95% CI1.01-1.35). An interaction between African-Caribbean ethnicity and cluster B personality disorder was identified in relation to violent outcome. Violent women were found to be more costly to services., Conclusions: Nearly a fifth of community-dwelling women with chronic psychosis committed assault over a period of 2 years. Six independent risk factors were found to predict violence.

Objective: Alcohol misuse in psychotic patients is common and leads to poor treatment outcome. This study examines the relationship between alcohol consumption and cost of care in patients with a severe psychotic illness., Method: Patient care was evaluated over 2 years for 708 patients. Patient reported alcohol consumption was evaluated at initial interview. The outcome measure was cost of care over 2 years., Results: There was no difference in mean cost of care between non-drinkers, moderate and heavy drinkers. Increased alcohol consumption (measured as a continuous variable, adjusted for baseline characteristics) was associated with lower cost of care., Conclusion: Heavier alcohol consumers did not incur more treatment costs and may, indeed, cost less than other patients. This may reflect higher levels of drinking being associated with better overall functioning, poorer engagement with services or exclusion from services., (Copyright Blackwell Munksgaard 2002.)

Background: Many factors influence the type and quantity of services received by patients and, thus, the total cost of care. Knowledge of these factors can aid budgetary and service-planning decisions., Aims: To investigate factors that influence the cost of caring for patients with severe psychotic illness., Method: Univariate and multivariate analyses were used to examine associations between baseline characteristics and subsequent 2-year total direct costs in 667 patients from the UK 700 case management trial., Results: Significantly more money was spent on younger patients, those with longer duration of illness, those who had spent less time living independently and those who had spent longer in hospital for psychiatric reasons., Conclusions: Total costs of caring for patients with severe psychotic illness appear to be influenced to a large extent by age, duration of illness and past levels of dependence on statutory services. The strength of these relationships is greater than the impact of illness severity.

Background: Little research has been carried out on the benefits of intensive case management (ICM) for people with borderline IQ and severe mental illness., Aims: To compare outcome and costs of care of patients with severe psychotic illness with borderline IQ to patients of normal IQ and to assess whether ICM is more beneficial for the former than for the latter., Method: The study utilises data from the UK700 multi-centre randomised controlled trial of case management. The main outcome measure was the number of days spent in hospital for psychiatric reasons. Secondary outcomes were costs of care and clinical outcome., Results: ICM was significantly more beneficial for borderline-IQ patients than those of normal IQ in terms of reductions in days spent in hospital, hospital admissions, total costs and needs and increased satisfaction., Conclusions: ICM appears to be a cost-effective strategy for a subgroup of patients with severe psychosis with cognitive deficits.

Background: Studies of intensive case management (ICM) for patients with psychotic illnesses have produced conflicting results in terms of outcome. Negative results have sometimes been attributed to a failure to deliver differing patterns of care., Aims: To test whether the actual care delivered in a randomised clinical trial of ICM v. standard case management (the UK700 trial) differed significantly., Method: Data on 545 patients' care were collected over 2 years. All patient contacts and all other patient-centred interventions (e.g. telephone calls, carer contacts) of over 15 minutes were prospectively recorded. Rates and distributions of these interventions were compared., Results: Contact frequency was more than doubled in the ICM group. There were proportionately more failed contacts and carer contacts but there was no difference in the average length of individual contacts or the proportion of contacts in the patients' homes., Conclusions: The failure to demonstrate outcome differences in the UK700 study is not due to a failure to vary the treatment process. UK standard care contains many of the characteristics of assertive outreach services and differences in outcome may require that greater attention be paid to delivering evidence-based interventions.