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Background: Early warning signs monitoring by service users with schizophrenia has shown promise in preventing relapse but the quality of evidence is low. We aimed to establish the feasibility of undertaking a definitive randomised controlled trial to determine the effectiveness of a blended digital intervention for relapse prevention in schizophrenia., Methods: This multicentre, feasibility, cluster randomised controlled trial aimed to compare Early signs Monitoring to Prevent relapse in psychosis and prOmote Well-being, Engagement, and Recovery (EMPOWER) with treatment as usual in community mental health services (CMHS) in Glasgow and Melbourne. CMHS were the unit of randomisation, selected on the basis of those that probably had five or more care coordinators willing to participate. Participants were eligible if they were older than 16 years, had a schizophrenia or related diagnosis confirmed via case records, were able to provide informed consent, had contact with CMHS, and had had a relapse within the previous 2 years. Participants were randomised within stratified clusters to EMPOWER or to continue their usual approach to care. EMPOWER blended a smartphone for active monitoring of early warning signs with peer support to promote self-management and clinical triage to promote access to relapse prevention. Main outcomes were feasibility, acceptability, usability, and safety, which was assessed through face-to-face interviews. App usage was assessed via the smartphone and self-report. Primary end point was 12 months. Participants, research assistants and other team members involved in delivering the intervention were not masked to treatment conditions. Assessment of relapse was done by an independent adjudication panel masked to randomisation group. The study is registered at ISRCTN (99559262)., Findings: We identified and randomised eight CMHS (six in Glasgow and two in Melbourne) comprising 47 care coordinators. We recruited 86 service users between Jan 19 and Aug 8, 2018; 73 were randomised (42 [58%] to EMPOWER and 31 [42%] to treatment as usual). There were 37 (51%) men and 36 (49%) women. At 12 months, main outcomes were collected for 32 (76%) of service users in the EMPOWER group and 30 (97%) of service users in the treatment as usual group. Of those randomised to EMPOWER, 30 (71%) met our a priori criterion of more than 33% adherence to daily monitoring that assumed feasibility. Median time to discontinuation of these participants was 31·5 weeks (SD 14·5). There were 29 adverse events in the EMPOWER group and 25 adverse events in the treatment as usual group. There were 13 app-related adverse events, affecting 11 people, one of which was serious. Fear of relapse was lower in the EMPOWER group than in the treatment as usual group at 12 months (mean difference -7·53 (95% CI -14·45 to 0·60; Cohen's d -0·53)., Interpretation: A trial of digital technology to monitor early warning signs blended with peer support and clinical triage to detect and prevent relapse appears to be feasible, safe, and acceptable. A further main trial is merited., Funding: UK National Institute for Health Research Health Technology Assessment programme and the Australian National Health and Medical Research Council., Competing Interests: Declaration of interests AIG reports personal fees from University of Manchester, personal fees from University of Exeter, personal fees from British Association for Behavioural and Cognitive Psychotherapies and other interests with UK National Health Service (NHS) Education for Scotland outside the submitted work. JA, SL, and SB report other interests with CareLoop Health, outside the submitted work. SB reports grants from the Medical Research Council and UK National Institute for Health Research (NIHR) during the conduct of the study. SL reports grants from the UK Medical Research Council (MRC) during the conduct of the study. JA reports grants from MRC, Engineering and Physical Sciences Research Council, Economic and Social Research Council, NIHR, and the US National Institute for Health, and was a Fellow of the Alan Turing Institute during the conduct of the study. AB reports personal fees from Bayer, Merck, Janssen, Novartis, Sword Health, Amgen, and Daiichi Sankyo outside the submitted work. JF reports grants from National Health and Medical Research Council (Australia) during the conduct of the study and other interests with Melbourne Health (NorthWestern Mental Health) outside the submitted work. HMcL reports grants from NIHR Health Technology Assessment (HTA) during the conduct of the study, and grants with Academy of Medical Sciences, Glasgow Children's Hospital Charity, and Scotland's Chief Scientist's Office. CM reports grants from National Health and Medical Research Council (Australia) during the conduct of the study. JN reports grants from the University of Aberdeen and the University of Edinburgh during the conduct of the study and declares membership of the following NIHR boards: Cardio Pulmonary Resusitation decision making committee; HTA commissioning board; HTA commissioning sub-board (expression of interest); HTA funding boards policy group; HTA general board; HTA post-board funding teleconference; NIHR clinical trials unit standing advisory committee; NIHR HTA and Efficacy Mechanism Evaluation editorial board; pre-exposure prophylaxis impact review panel. PF is a member of the HTA mental health prioritisation panel. CW reports grants from NIHR during the conduct of the study and from the Royal College of Psychiatrists, and other interests with Five Areas outside the submitted work. AY reports an NIHR Senior Investigator Grant. JG reports grants from the National Health Medical Research Council. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Relapse is a major determinant of outcome for people with a diagnosis of schizophrenia. Early warning signs frequently precede relapse. A recent Cochrane Review found low-quality evidence to suggest a positive effect of early warning signs interventions on hospitalisation and relapse., Objective: How feasible is a study to investigate the clinical effectiveness and cost-effectiveness of a digital intervention to recognise and promptly manage early warning signs of relapse in schizophrenia with the aim of preventing relapse?, Design: A multicentre, two-arm, parallel-group cluster randomised controlled trial involving eight community mental health services, with 12-month follow-up., Settings: Glasgow, UK, and Melbourne, Australia., Participants: Service users were aged > 16 years and had a schizophrenia spectrum disorder with evidence of a relapse within the previous 2 years. Carers were eligible for inclusion if they were nominated by an eligible service user., Interventions: The Early signs Monitoring to Prevent relapse in psychosis and prOmote Wellbeing, Engagement, and Recovery (EMPOWER) intervention was designed to enable participants to monitor changes in their well-being daily using a mobile phone, blended with peer support. Clinical triage of changes in well-being that were suggestive of early signs of relapse was enabled through an algorithm that triggered a check-in prompt that informed a relapse prevention pathway, if warranted., Main Outcome Measures: The main outcomes were feasibility of the trial and feasibility, acceptability and usability of the intervention, as well as safety and performance. Candidate co-primary outcomes were relapse and fear of relapse., Results: We recruited 86 service users, of whom 73 were randomised (42 to EMPOWER and 31 to treatment as usual). Primary outcome data were collected for 84% of participants at 12 months. Feasibility data for people using the smartphone application (app) suggested that the app was easy to use and had a positive impact on motivations and intentions in relation to mental health. Actual app usage was high, with 91% of users who completed the baseline period meeting our a priori criterion of acceptable engagement (> 33%). The median time to discontinuation of > 33% app usage was 32 weeks (95% confidence interval 14 weeks to ∞). There were 8 out of 33 (24%) relapses in the EMPOWER arm and 13 out of 28 (46%) in the treatment-as-usual arm. Fewer participants in the EMPOWER arm had a relapse (relative risk 0.50, 95% confidence interval 0.26 to 0.98), and time to first relapse (hazard ratio 0.32, 95% confidence interval 0.14 to 0.74) was longer in the EMPOWER arm than in the treatment-as-usual group. At 12 months, EMPOWER participants were less fearful of having a relapse than those in the treatment-as-usual arm (mean difference -4.29, 95% confidence interval -7.29 to -1.28). EMPOWER was more costly and more effective, resulting in an incremental cost-effectiveness ratio of £3041. This incremental cost-effectiveness ratio would be considered cost-effective when using the National Institute for Health and Care Excellence threshold of £20,000 per quality-adjusted life-year gained., Limitations: This was a feasibility study and the outcomes detected cannot be taken as evidence of efficacy or effectiveness., Conclusions: A trial of digital technology to monitor early warning signs that blended with peer support and clinical triage to detect and prevent relapse is feasible., Future Work: A main trial with a sample size of 500 (assuming 90% power and 20% dropout) would detect a clinically meaningful reduction in relapse (relative risk 0.7) and improvement in other variables (effect sizes 0.3-0.4)., Trial Registration: This trial is registered as ISRCTN99559262., Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 26, No. 27. See the NIHR Journals Library website for further project information. Funding in Australia was provided by the National Health and Medical Research Council (APP1095879).

Background: Clozapine (clozaril, Mylan Products Ltd) is a first-choice treatment for people with schizophrenia who have a poor response to standard antipsychotic medication. However, a significant number of patients who trial clozapine have an inadequate response and experience persistent symptoms, called clozapine-resistant schizophrenia (CRS). There is little evidence regarding the clinical effectiveness of pharmacological or psychological interventions for this population., Objectives: To evaluate the clinical effectiveness and cost-effectiveness of cognitive-behavioural therapy (CBT) for people with CRS and to identify factors predicting outcome., Design: The Focusing on Clozapine Unresponsive Symptoms (FOCUS) trial was a parallel-group, randomised, outcome-blinded evaluation trial. Randomisation was undertaken using permuted blocks of random size via a web-based platform. Data were analysed on an intention-to-treat (ITT) basis, using random-effects regression adjusted for site, age, sex and baseline symptoms. Cost-effectiveness analyses were carried out to determine whether or not CBT was associated with a greater number of quality-adjusted life-years (QALYs) and higher costs than treatment as usual (TAU)., Setting: Secondary care mental health services in five cities in the UK., Participants: People with CRS aged ≥ 16 years, with an International Classification of Diseases , Tenth Revision (ICD-10) schizophrenia spectrum diagnoses and who are experiencing psychotic symptoms., Interventions: Individual CBT included up to 30 hours of therapy delivered over 9 months. The comparator was TAU, which included care co-ordination from secondary care mental health services., Main Outcome Measures: The primary outcome was the Positive and Negative Syndrome Scale (PANSS) total score at 21 months and the primary secondary outcome was PANSS total score at the end of treatment (9 months post randomisation). The health benefit measure for the economic evaluation was the QALY, estimated from the EuroQol-5 Dimensions, five-level version (EQ-5D-5L), health status measure. Service use was measured to estimate costs., Results: Participants were allocated to CBT ( n  = 242) or TAU ( n  = 245). There was no significant difference between groups on the prespecified primary outcome [PANSS total score at 21 months was 0.89 points lower in the CBT arm than in the TAU arm, 95% confidence interval (CI) -3.32 to 1.55 points; p  = 0.475], although PANSS total score at the end of treatment (9 months) was significantly lower in the CBT arm (-2.40 points, 95% CI -4.79 to -0.02 points; p  = 0.049). CBT was associated with a net cost of £5378 (95% CI -£13,010 to £23,766) and a net QALY gain of 0.052 (95% CI 0.003 to 0.103 QALYs) compared with TAU. The cost-effectiveness acceptability analysis indicated a low likelihood that CBT was cost-effective, in the primary and sensitivity analyses (probability < 50%). In the CBT arm, 107 participants reported at least one adverse event (AE), whereas 104 participants in the TAU arm reported at least one AE (odds ratio 1.09, 95% CI 0.81 to 1.46; p  = 0.58)., Conclusions: Cognitive-behavioural therapy for CRS was not superior to TAU on the primary outcome of total PANSS symptoms at 21 months, but was superior on total PANSS symptoms at 9 months (end of treatment). CBT was not found to be cost-effective in comparison with TAU. There was no suggestion that the addition of CBT to TAU caused adverse effects. Future work could investigate whether or not specific therapeutic techniques of CBT have value for some CRS individuals, how to identify those who may benefit and how to ensure that effects on symptoms can be sustained., Trial Registration: Current Controlled Trials ISRCTN99672552., Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 23, No. 7. See the NIHR Journals Library website for further project information., Competing Interests: Anthony P Morrison reports personal fees from the provision of training workshops in cognitive–behavioural therapy (CBT) for psychosis and royalties from books on the topic, outside the submitted work. Andrew Gumley reports grants from the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme (grant number 13/15/04) outside the submitted work. Douglas Turkington reports personal fees from Insight–CBT partnership (Insight Healthcare, Newcastle upon Tyne), outside the submitted work. Gemma Shields reports grants from NIHR during the conduct of the study. Graeme MacLennan reports grants from the NIHR HTA programme during the conduct of the study. Hamish J MacLeod reports that he occasionally provides CBT for psychosis workshops and receives fees for this work. John Norrie reports personal fees from the NIHR Editors Board and grants from NIHR HTA General Board Deputy Chairperson, outside the submitted work, and has membership of the HTA Funding Boards Policy Group and Pre-Exposure Prophylaxis Impact Review Panel. Linda Davies reports grants from the NIHR HTA programme during the conduct of the study. Paul French has membership of the HTA prioritisation Panel. Paul Hutton reports that he sits on an Expert Steering Group for Professor Jill Stavert’s Centre for Mental Health and Incapacity Law Rights and Policy at Edinburgh Napier University, and that he is a member of a committee developing National Institute for Health and Care Excellence (NICE) guidelines on supporting decision-making for people who may lack mental capacity. Robert Dudley reports receiving a NIHR Comprehensive Local Research Network Greenshoots award to fund time to support his contribution to the FOCUS (Focusing on Clozapine Unresponsive Symptoms) trial, royalties from Guilford Press and personal fees from Trinity College Dublin, outside the submitted work. Samantha Bowe reports personal fees from Pennine Care NHS Foundation Trust and personal fees from Cheshire & Wirral Partnership NHS Foundation Trust, outside the submitted work. Thomas RE Barnes reports personal fees from Sunovion (Marlborough, MA, USA) and Otsuka (Tokyo, Japan)/Lundbeck (Copenhagen, Denmark), outside the submitted work.

Background: Obesity is a major challenge for people with schizophrenia.AimsWe assessed whether STEPWISE, a theory-based, group structured lifestyle education programme could support weight reduction in people with schizophrenia., Method: In this randomised controlled trial (study registration: ISRCTN19447796), we recruited adults with schizophrenia, schizoaffective disorder or first-episode psychosis from ten mental health organisations in England. Participants were randomly allocated to the STEPWISE intervention or treatment as usual. The 12-month intervention comprised four 2.5 h weekly group sessions, followed by 2-weekly maintenance contact and group sessions at 4, 7 and 10 months. The primary outcome was weight change after 12 months. Key secondary outcomes included diet, physical activity, biomedical measures and patient-related outcome measures. Cost-effectiveness was assessed and a mixed-methods process evaluation was included., Results: Between 10 March 2015 and 31 March 2016, we recruited 414 people (intervention 208, usual care 206) with 341 (84.4%) participants completing the trial. At 12 months, weight reduction did not differ between groups (mean difference 0.0 kg, 95% CI -1.6 to 1.7, P = 0.963); physical activity, dietary intake and biochemical measures were unchanged. STEPWISE was well-received by participants and facilitators. The healthcare perspective incremental cost-effectiveness ratio was £246 921 per quality-adjusted life-year gained., Conclusions: Participants were successfully recruited and retained, indicating a strong interest in weight interventions; however, the STEPWISE intervention was neither clinically nor cost-effective. Further research is needed to determine how to manage overweight and obesity in people with schizophrenia.Declaration of interestR.I.G.H. received fees for lecturing, consultancy work and attendance at conferences from the following: Boehringer Ingelheim, Eli Lilly, Janssen, Lundbeck, Novo Nordisk, Novartis, Otsuka, Sanofi, Sunovion, Takeda, MSD. M.J.D. reports personal fees from Novo Nordisk, Sanofi-Aventis, Lilly, Merck Sharp & Dohme, Boehringer Ingelheim, AstraZeneca, Janssen, Servier, Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceuticals International Inc.; and, grants from Novo Nordisk, Sanofi-Aventis, Lilly, Boehringer Ingelheim, Janssen. K.K. has received fees for consultancy and speaker for Novartis, Novo Nordisk, Sanofi-Aventis, Lilly, Servier and Merck Sharp & Dohme. He has received grants in support of investigator and investigator-initiated trials from Novartis, Novo Nordisk, Sanofi-Aventis, Lilly, Pfizer, Boehringer Ingelheim and Merck Sharp & Dohme. K.K. has received funds for research, honoraria for speaking at meetings and has served on advisory boards for Lilly, Sanofi-Aventis, Merck Sharp & Dohme and Novo Nordisk. D.Sh. is expert advisor to the NICE Centre for guidelines; board member of the National Collaborating Centre for Mental Health (NCCMH); clinical advisor (paid consultancy basis) to National Clinical Audit of Psychosis (NCAP); views are personal and not those of NICE, NCCMH or NCAP. J.P. received personal fees for involvement in the study from a National Institute for Health Research (NIHR) grant. M.E.C. and Y.D. report grants from NIHR Health Technology Assessment, during the conduct of the study; and The Leicester Diabetes Centre, an organisation (employer) jointly hosted by an NHS Hospital Trust and the University of Leicester and who is holder (through the University of Leicester) of the copyright of the STEPWISE programme and of the DESMOND suite of programmes, training and intervention fidelity framework that were used in this study. S.R. has received honorarium from Lundbeck for lecturing. F.G. reports personal fees from Otsuka and Lundbeck, personal fees and non-financial support from Sunovion, outside the submitted work; and has a family member with professional links to Lilly and GSK, including shares. F.G. is in part funded by the National Institute for Health Research Collaboration for Leadership in Applied Health Research & Care Funding scheme, by the Maudsley Charity and by the Stanley Medical Research Institute and is supported by the by the Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London.

Background: Obesity is twice as common in people with schizophrenia as in the general population. The National Institute for Health and Care Excellence guidance recommends that people with psychosis or schizophrenia, especially those taking antipsychotics, be offered a healthy eating and physical activity programme by their mental health care provider. There is insufficient evidence to inform how these lifestyle services should be commissioned., Objectives: To develop a lifestyle intervention for people with first episode psychosis or schizophrenia and to evaluate its clinical effectiveness, cost-effectiveness, delivery and acceptability., Design: A two-arm, analyst-blind, parallel-group, randomised controlled trial, with a 1 : 1 allocation ratio, using web-based randomisation; a mixed-methods process evaluation, including qualitative case study methods and logic modelling; and a cost-utility analysis., Setting: Ten community mental health trusts in England., Participants: People with first episode psychosis, schizophrenia or schizoaffective disorder., Interventions: Intervention group: (1) four 2.5-hour group-based structured lifestyle self-management education sessions, 1 week apart; (2) multimodal fortnightly support contacts; (3) three 2.5-hour group booster sessions at 3-monthly intervals, post core sessions. Control group: usual care assessed through a longitudinal survey. All participants received standard written lifestyle information., Main Outcome Measures: The primary outcome was change in weight (kg) at 12 months post randomisation. The key secondary outcomes measured at 3 and 12 months included self-reported nutrition (measured with the Dietary Instrument for Nutrition Education questionnaire), objectively measured physical activity measured by accelerometry [GENEActiv (Activinsights, Kimbolton, UK)], biomedical measures, adverse events, patient-reported outcome measures and a health economic assessment., Results: The trial recruited 414 participants (intervention arm: 208 participants; usual care: 206 participants) between 10 March 2015 and 31 March 2016. A total of 341 participants (81.6%) completed the trial. A total of 412 participants were analysed. After 12 months, weight change did not differ between the groups (mean difference 0.0 kg, 95% confidence interval -1.59 to 1.67 kg; p  = 0.964); physical activity, dietary intake and biochemical measures were unchanged. Glycated haemoglobin, fasting glucose and lipid profile were unchanged by the intervention. Quality of life, psychiatric symptoms and illness perception did not change during the trial. There were three deaths, but none was related to the intervention. Most adverse events were expected and related to the psychiatric illness. The process evaluation showed that the intervention was acceptable, with participants valuing the opportunity to interact with others facing similar challenges. Session feedback indicated that 87.2% of participants agreed that the sessions had met their needs. Some indicated the desire for more ongoing support. Professionals felt that the intervention was under-resourced and questioned the long-term sustainability within current NHS settings. Professionals would have preferred greater access to participants' behaviour data to tailor the intervention better. The incremental cost-effectiveness ratio from the health-care perspective is £246,921 per quality-adjusted life-year (QALY) gained and the incremental cost-effectiveness ratio from the societal perspective is £367,543 per QALY gained., Conclusions: Despite the challenges of undertaking clinical research in this population, the trial successfully recruited and retained participants, indicating a high level of interest in weight management interventions; however, the STEPWISE intervention was neither clinically effective nor cost-effective. Further research will be required to define how overweight and obesity in people with schizophrenia should be managed. The trial results suggest that lifestyle programmes for people with schizophrenia may need greater resourcing than for other populations, and interventions that have been shown to be effective in other populations, such as people with diabetes mellitus, are not necessarily effective in people with schizophrenia., Trial Registration: Current Controlled Trials ISRCTN19447796., Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 22, No. 65. See the NIHR Journals Library website for further project information., Competing Interests: Richard IG Holt received fees for lecturing, consultancy work and attendance at conferences from the following companies: Boehringer Ingelheim (Ingelheim am Rhein, Germany), Eli Lilly and Company (Indianapolis, IN, USA), Janssen Pharmaceutica (Beerse, Belgium), Lundbeck (Copenhagen, Denmark), Novo Nordisk (Bagsværd, Denmark), Novartis (Basel, Switzerland), Otsuka Pharmaceutical Co., Ltd (Tokyo, Japan), Sanofi-Aventis (Paris, France) and Sunovion Pharmaceuticals, Inc. (Marlborough, MA, USA). Paul French is a member of the National Institute for Health Research (NIHR) Health Technology Assessment Mental, Psychological and Occupational Health funding panel. Melanie J Davies and Kamlesh Khunti are members of a NIHR Clinical Trials Unit. Melanie J Davies reports personal fees from Novo Nordisk, Sanofi-Aventis, Eli Lilly and Company, Merck Sharp & Dohme (Kenilworth, NJ, USA), Boehringer Ingelheim, AstraZeneca (Cambridge, UK), Janssen Pharmaceutica, Servier Laboratories (Neuilly-sur-Seine, France), Mitsubishi Tanabe Pharma Corporation (Tokyo, Japan) and Takeda Pharmaceuticals International Inc. (Canton of Zürich, Switzerland) and grants from Novo Nordisk, Sanofi-Aventis, Eli Lilly and Company, Boehringer Ingelheim and Janssen Pharmaceutica. Kamlesh Khunti has received fees for consultancy and being a speaker for Novartis, Novo Nordisk, Sanofi-Aventis, Eli Lilly and Company, Servier Laboratories and Merck Sharp & Dohme. He has received grants in support of investigator and investigator-initiated trials from Novartis, Novo Nordisk, Sanofi-Aventis, Eli Lilly and Company, Pfizer (New York, NY, USA), Boehringer Ingelheim and Merck Sharp & Dohme. Kamlesh Khunti has also received funds for research and honoraria for speaking at meetings, and has served on advisory boards for Eli Lilly and Company, Sanofi-Aventis, Merck Sharp & Dohme and Novo Nordisk. David Shiers is an expert advisor to the National Institute for Health and Care Excellence (NICE) centre for guidelines, a board member of the National Collaborating Centre for Mental Health (NCCMH) and a clinical advisor (on a paid consultancy basis) to the National Clinical Audit of Psychosis (NCAP); any views given in this report are personal and not those of NICE, NCCMH or NCAP. David Shiers reports personal fees from the Wiley-Blackwell publication Promoting Recovery in Early Psychosis, 2010 (ISBN 978-1-4051-4894-8), as he is a joint editor in receipt of royalties. John Pendelbury received personal fees for involvement in the study from a NIHR grant; he reports personal fees from the Greater Manchester Mental Health NHS foundation trust outside the submitted work and has published papers in the area of weight management and physical health related to mental health. Marian E Carey and Yvonne Doherty report being employed by the Leicester Diabetes Centre, an organisation (employer) jointly hosted by a NHS hospital trust and the University of Leicester and which is the holder (through the University of Leicester) of the copyright of the STEPWISE programme and of the Diabetes Education and Self-Management for Ongoing and Newly Diagnosed (DESMOND) suite of programmes, training and intervention fidelity framework that were used in this study. Fiona Gaughran reports personal fees from Otsuka and Lundbeck and personal fees and non-financial support from Sunovion, outside the submitted work, and has a family member with professional links to Eli Lilly and Company and GlaxoSmithKline (Brentford, UK), including shares.

Background: Although clozapine is the treatment of choice for treatment-refractory schizophrenia, 30-40% of patients have an insufficient response, and others are unable to tolerate it. Evidence for any augmentation strategies is scarce. We aimed to determine whether cognitive behavioural therapy (CBT) is an effective treatment for clozapine-resistant schizophrenia., Methods: We did a pragmatic, parallel group, assessor-blinded, randomised controlled trial in community-based and inpatient mental health services in five sites in the UK. Patients with schizophrenia who were unable to tolerate clozapine, or whose symptoms did not respond to the drug, were randomly assigned 1:1 by use of randomised-permuted blocks of size four or six, stratified by centre, to either CBT plus treatment as usual or treatment as usual alone. Research assistants were masked to allocation to protect against rater bias and allegiance bias. The primary outcome was the Positive and Negative Syndrome Scale (PANSS) total score at 21 months, which provides a continuous measure of symptoms of schizophrenia; PANSS total was also assessed at the end of treatment (9 months). The primary analysis was by randomised treatment based on intention to treat, for all patients for whom data were available. This study was prospectively registered, number ISRCTN99672552. The trial is closed to accrual., Findings: From Jan 1, 2013, to May 31, 2015, we randomly assigned 487 participants to either CBT and treatment as usual (n=242) or treatment as usual alone (n=245). Analysis included 209 in the CBT group and 216 in the treatment as usual group. No difference occurred in the primary outcome (PANSS total at 21 months, mean difference -0·89, 95% CI -3·32 to 1·55; p=0·48), although the CBT group improved at the end of treatment (PANSS total at 9 months, mean difference -2·40, -4·79 to -0·02; p=0·049). During the trial, 107 (44%) of 242 participants in the CBT arm and 104 (42%) of 245 in the treatment as usual arm had at least one adverse event (odds ratio 1·09, 95% CI 0·81 to 1·46; p=0·58). Only two (1%) of 242 participants in the CBT arm and one (<1%) of 245 in the treatment as usual arm had a trial-related serious adverse event., Interpretation: At 21-month follow-up, CBT did not have a lasting effect on total symptoms of schizophrenia compared with treatment as usual; however, CBT produced statistically, though not clinically, significant improvements on total symptoms by the end of treatment. There was no indication that the addition of CBT to treatment as usual caused adverse effects. The results of this trial do not support a recommendation to routinely offer CBT to all people who meet criteria for clozapine-resistant schizophrenia; however, a pragmatic individual trial might be indicated for some., Funding: National Institute for Health Research Technology Assessment programme., (Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: For around a third of people with a diagnosis of schizophrenia, the condition proves to respond poorly to treatment with many typical and atypical antipsychotics. This is commonly referred to as treatment-resistant schizophrenia. Clozapine is the only antipsychotic with convincing efficacy for people whose symptoms are considered treatment-resistant to antipsychotic medication. However, 30-40 % of such conditions will have an insufficient response to the drug. Cognitive behavioural therapy has been shown to be an effective treatment for schizophrenia when delivered in combination with antipsychotic medication, with several meta-analyses showing robust support for this approach. However, the evidence for the effectiveness of cognitive behavioural therapy for people with a schizophrenia diagnosis whose symptoms are treatment-resistant to antipsychotic medication is limited. There is a clinical and economic need to evaluate treatments to improve outcomes for people with such conditions., Methods/design: A parallel group, prospective randomised, open, blinded evaluation of outcomes design will be used to compare a standardised cognitive behavioural therapy intervention added to treatment as usual versus treatment as usual alone (the comparator group) for individuals with a diagnosis of schizophrenia for whom an adequate trial of clozapine has either not been possible due to tolerability problems or was not associated with a sufficient therapeutic response. The trial will be conducted across five sites in the United Kingdom., Discussion: The recruitment target of 485 was achieved, with a final recruitment total of 487. This trial is the largest definitive, pragmatic clinical and cost-effectiveness trial of cognitive behavioural therapy for people with schizophrenia whose symptoms have failed to show an adequate response to clozapine treatment. Using a prognostic risk model, baseline information will be used to explore whether there are identifiable subgroups for which the treatment effect is greatest., Trial Registration: Current Controlled Trials ISRCTN99672552 . Registered 29(th) November 2012.

Background and Objectives: Cognitive behaviour therapy (CBT) for psychosis has been shown to be effective, but there are recent suggestions that it is less efficacious than initially thought. Metacognitive therapy (MCT), which focuses on metacognitive mechanisms, has led to positive results in other disorders, but has yet to be evaluated in people with schizophrenia spectrum diagnoses. This study evaluates the feasibility of MCT for people with psychotic disorders., Methods: Ten participants with schizophrenia spectrum disorders received up to 12 sessions of MCT in an open trial. Outcomes included psychiatric symptoms measured using the PANSS, at baseline, 9 months (end of treatment) and at 12 months (follow-up), as well as dimensions of hallucinations and delusions, emotional dysfunction, self-rated recovery, social functioning and metacognitive beliefs., Results: T-tests and Wilcoxon's signed ranks tests revealed significant beneficial effects on several outcomes at end-of-treatment and follow-up. Cohen's d effect sizes were moderate to large (for PANSS total, d = 1.0 at end of treatment; d = 0.95 at follow-up). A response rate analysis found 50% and 40% of participants achieved at least a 25% reduction in PANSS total scores by end of therapy and follow-up, respectively. Exploratory analyses revealed that metacognitive beliefs significantly changed over treatment and follow-up periods., Limitations: This study had no control group and was not randomised; therefore, it is likely that effect sizes were inflated., Conclusions: This study provides preliminary evidence that MCT is a feasible treatment for people with psychosis. An adequately powered randomised controlled trial is warranted., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Decline in social functioning occurs in individuals who later develop psychosis., Aims: To investigate whether baseline differences in disability are present in those who do and those who do not make a transition to psychosis in a group clinically at high risk and whether disability is a risk factor for transition., Method: Prospective multicentre, naturalistic field study with an 18-month follow-up period on 245 help-seeking individuals clinically at high risk. Disability was assessed with the Disability Assessment Schedule of the World Health Organization (WHODAS-II)., Results: At baseline, the transition group displayed significantly greater difficulties in making new friends (z = -3.40, P = 0.001), maintaining a friendship (z =-3.00, P = 0.003), dealing with people they do not know (z =-2.28, P = 0.023) and joining community activities (z =-2.0, P = 0.05) compared with the non-transition group. In Cox regression, difficulties in getting along with people significantly contributed to the prediction of transition to psychosis in our sample (β = 0.569, s.e. = 0.184, Wald = 9.548, P = 0.002, hazard ratio (HR) = 1.767, 95% CI 1.238-2.550)., Conclusions: Certain domains of social disability might contribute to the prediction of psychosis in a sample clinically at high risk.

Background: Negative beliefs regarding task performance have been shown to correlate with negative symptom severity in patients with chronic schizophrenia. We conducted a pilot study to determine whether the association also exists in individuals at ultra-high risk of psychosis., Sampling and Methods: The sample consisted of 38 individuals at ultra-high risk of psychosis and 51 controls. All participants completed the Abbreviated Dysfunctional Attitudes Scale; the ultra-high-risk participants were assessed with the Positive and Negative Syndrome Scale., Results: High-risk participants endorsed negative performance beliefs to a greater extent than controls and these beliefs were associated with greater negative symptom severity, independent of depression and positive symptoms., Conclusions: The findings are consistent with previous results in chronic patients, and suggest that negative performance beliefs may be a promising psychological factor worthy of further attention in individuals at high risk of psychosis. Longitudinal research with more comprehensive assessment is needed to elucidate the potential role of negative performance beliefs in this population., (Copyright 2009 S. Karger AG, Basel.)

There have been recent advances in the ability to identify people at high risk of developing psychosis. This has led to interest in the possibility of preventing the development of psychosis. A randomized controlled trial compared cognitive therapy (CT) over 6 months with monthly monitoring in 58 patients meeting criteria for ultrahigh risk of developing a first episode of psychosis. Participants were followed up over a 3-year period. Logistic regression demonstrated that CT significantly reduced likelihood of being prescribed antipsychotic medication over a 3-year period, but it did not affect transition to psychosis defined using the Positive and Negative Syndrome Scale (PANSS) or probable Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnosis. However, exploratory analyses revealed that CT significantly reduced the likelihood of making progression to psychosis as defined on the PANSS over 3 years after controlling for baseline cognitive factors. Follow-up rate at 3 years was 47%. There appear to be enduring benefits of CT over the long term, suggesting that it is an efficacious intervention for people at high risk of developing psychosis.

Background: Psychotic disorders are severe and prevalent mental health conditions associated with long-term disability, reduced quality of life, and substantial economic costs. Early Intervention in Psychosis (EIP) services aim to provide timely and comprehensive treatment for psychotic disorders, and EIP service input is associated with improved outcomes. However, there is limited understanding of the specific components of EIP care that contribute to these improvements. There is significant nationwide variability in the commissioning and delivery of EIP, with individuals receiving different packages of components from different services. In this study, we seek to explore associations between EIP components and clinically significant outcomes, in order to understand the mechanisms underlying improved psychosis care. Methods: This national retrospective cohort study will utilize data from the 2019 National Clinical Audit of Psychosis (NCAP), examining the care received by 10,560 individuals treated by EIP services in England. Exposure data from the NCAP, capturing the components of care delivered by EIP services, will be linked with outcome data from routine NHS Digital datasets over a three-year follow-up period. This will be the first study to use this method to examine this population in England. The primary outcomes will be surrogate measures of relapse of psychosis (hospital admission and referral to community-based crisis intervention services). Secondary outcomes include duration of admissions, emergency hospital attendances, episodes of detention under the Mental Health Act, and all-cause mortality. We will use multilevel regression to examine associations between exposures and outcome events. We will handle missing data using appropriate imputation techniques. Discussion: This study aims to provide valuable insights into the long-term effects of variations in EIP service delivery. The study involves a large, diverse cohort including individuals treated by every EIP service in England. While there are limitations inherent in the observational nature of the study, any associations identified will be of great relevance to clinicians, researchers, and policymakers seeking to optimize EIP care. The results will enable more targeted treatment planning, resource allocation, and potential innovations in EIP care, ultimately leading to improved prognoses for people experiencing psychosis. [ABSTRACT FROM AUTHOR]

Aims and Methods To examine whether national initiatives have led to improvements in the physical health of people with psychosis. Secondary analysis of a national audit of services for people with psychosis. Proportions of patients in 'good health' according to seven measures, and one composite measure derived from national standards, were compared between multiple rounds of data collection. Results The proportion of patients in overall 'good health' under the care of 'Early Intervention in Psychosis' teams increased from 2014-2019, particularly for measures of smoking, alcohol and substance use. There was no overall change in the proportion of patients in overall 'good health' under the care of 'Community Mental Health Teams' from 2011-2017. However, there were improvements in alcohol use, blood glucose and lipid levels. Clinical implications There have been modest improvements in the health of people with psychosis over the last nine years. Continuing efforts are required to translate these improvements into reductions in premature mortality. [ABSTRACT FROM AUTHOR]

Aims: Ongoing NICE guidance recommends research on the clinical and cost effectiveness of psychological treatment alone, compared to antipsychotic medication and compared to psychological treatment and antipsychotic medication combined. The COMPARE study (Cognitive behaviour therapy or Medication for Psychosis- A Randomised Evaluation) was a pilot trial designed to inform a definitive trial to answer this question. Method: COMPARE was a single-site pilot randomised controlled trial to compare a standardised Cognitive Behaviour Therapy (CBT) intervention to treatment with antipsychotic medication (APs) and a combined treatment (CBT plus APs) in adults with psychosis. Participants were assessed using the Positive and Negative Syndrome Scale (PANSS) and followed up at 6, 12, 24 and 52 weeks. The primary outcomes were recruitment and retention of participants. We surveyed a wider population of staff and service users to further inform feasibility of a definitive trial. Results: We report the characteristics of the recruited sample at baseline (n = 75) and results from surveys. Conclusions: The study recruited to target demonstrating it is feasible to identify and recruit participants to a study of this kind. The survey results also suggest that such trials are feasible. [ABSTRACT FROM AUTHOR]

Physical exercise is increasingly recognized as an important component of psychiatric care, although the feasibility of implementing exercise in residential care settings is not well understood. We evaluated the feasibility of a 10-week intervention of weekly fitness classes (delivered by a personal trainer) and other exercise activities using a mixed-methods approach. This was offered to across four residential care services, to all 51 residents who had severe mental illness (SMI). Of these, 27.5% consented to the exercise intervention. Participants averaged 87.6 min of moderate-to-vigorous exercise per-week, although fitness classes were poorly attended, and 35.7% dropped-out over 10 weeks. Of those who completed the intervention, increased physical activity was associated with significantly reduced negative symptoms. In conclusion, implementing exercise interventions in residential psychiatric care is challenging; given that supervised exercise classes may not be appealing to many residents, while unsupervised exercise is poorly adhered to. Future interventions should consider that better tailored exercise programs are required to adequately confront motivational issues, and to account for participant preference in order to increase engagement. [ABSTRACT FROM AUTHOR]

Background: People with schizophrenia are two to three times more likely to be overweight than the general population. The UK National Institute of Health and Care Excellence (NICE) recommends an annual physical health review with signposting to, or provision of, a lifestyle programme to address weight concerns and obesity. The purpose of this randomised controlled trial is to assess whether a group-based structured education programme can help people with schizophrenia to lose weight. Methods: Design: a randomised controlled trial of a group-based structured education programme. Setting: 10 UK community mental health trusts. Participants: 396 adults with schizophrenia, schizoaffective, or first-episode psychosis who are prescribed antipsychotic medication will be recruited. Participants will be overweight, obese or be concerned about their weight. Intervention: participants will be randomised to either the intervention or treatment as usual (TAU). The intervention arm will receive TAU plus four 2.5-h weekly sessions of theory-based lifestyle structured group education, with maintenance contact every 2 weeks and ‘booster’ sessions every 3 months. All participants will receive standardised written information about healthy eating, physical activity, alcohol and smoking. Outcomes: the primary outcome is weight (kg) change at 1 year post randomisation. Secondary outcomes, which will be assessed at 3 and 12 months, include: the proportion of participants who maintained or reduced their weight; waist circumference; body mass index; objectively measured physical activity (wrist accelerometer); self-reported diet; blood pressure; fasting plasma glucose, lipid profile and HbA1c (baseline and 1 year only); health-related quality of life (EQ-5D- 5L and RAND SF-36); (adapted) brief illness perception questionnaire; the Brief Psychiatric Rating Scale; the Client Service Receipt Inventory; medication use; smoking status; adverse events; depression symptoms (Patient Health Questionnaire-9); use of weight-loss programmes; and session feedback (intervention only). Outcome assessors will be blind to trial group allocation. Qualitative interviews with a subsample of facilitators and invention-arm participants will provide data on intervention feasibility and acceptability. Assessment of intervention fidelity will also be performed. Discussion: The STEPWISE trial will provide evidence for the clinical and cost-effectiveness of a tailored intervention, which, if successful, could be implemented rapidly in the NHS. [ABSTRACT FROM AUTHOR]

Background: STEPWISE is a theory-informed self-management education programme that was co-produced with service users, healthcare professionals and interventionists to support weight loss for people with schizophrenia. We report the process evaluation to inform understanding about the intervention and its effectiveness in a randomised controlled trial (RCT) that evaluated its efficacy. Methods: Following the UK Medical Research Council (MRC) Guidelines for developing and evaluating complex interventions, we explored implementation quality. We considered causal mechanisms, unanticipated consequences and contextual factors associated with variation in actual and intended outcomes, and integrated treatment fidelity, using the programme theory and a pipeline logic model. We followed a modified version of Linnan and Steckler's framework and single case design. Qualitative data from semi-structured telephone interviews with service-users (n = 24), healthcare professionals delivering the intervention (n = 20) and interventionists (n = 7) were triangulated with quantitative process and RCT outcome data and with observations by interventionists, to examine convergence within logic model components. Results: Training and course materials were available although lacked co-ordination in some trusts. Healthcare professionals gained knowledge and some contemplated changing their practice to reflect the (facilitative) 'style' of delivery. They were often responsible for administrative activities increasing the burden of delivery. Healthcare professionals recognised the need to address antipsychotic-induced weight gain and reported potential value from the intervention (subject to the RCT results). However, some doubted senior management commitment and sustainability post-trial. Service-users found the intervention highly acceptable, especially being in a group of people with similar experiences. Service-users perceived weight loss and lifestyle benefits; however, session attendance varied with 23% (n = 47) attending all group-sessions and 17% (n = 36) attending none. Service-users who lost weight wanted closer monitoring and many healthcare professionals wanted to monitor outcomes (e.g. weight) but it was outside the intervention design. No clinical or cost benefit was demonstrated from the intermediate outcomes (RCT) and any changes in RCT outcomes were not due to the intervention. Conclusions: This process evaluation provides a greater understanding of why STEPWISE was unsuccessful in promoting weight loss during the clinical trial. Further research is required to evaluate whether different levels of contact and objective monitoring can support people with schizophrenia to lose weight. Trial registration: ISRCTN, ISRCTN19447796. Registered 20 March 2014. [ABSTRACT FROM AUTHOR]