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Treatment-resistant symptoms occur in about a third of patients with schizophrenia and are associated with a substantial reduction in their quality of life. The development of new treatment options for clozapine-resistant schizophrenia constitutes a crucial, unmet need in psychiatry. Additionally, an overview of past and possible future research avenues to optimise the early detection, diagnosis, and management of clozapine-resistant schizophrenia is unavailable. In this Health Policy, we discuss the ongoing challenges associated with clozapine-resistant schizophrenia faced by patients and health-care providers worldwide to improve the understanding of this condition. We then revisit several clozapine guidelines, the diagnostic tests and treatment options for clozapine-resistant schizophrenia, and currently applied research approaches in clozapine-resistant schizophrenia. We also suggest methodologies and targets for future research, divided into innovative nosology-oriented field trials (eg, examining dimensional symptom staging), translational approaches (eg, genetics), epidemiological research (eg, real-world studies), and interventional studies (eg, non-traditional trial designs incorporating lived experiences and caregivers' perspectives). Finally, we note that low-income and middle-income countries are under-represented in studies on clozapine-resistant schizophrenia and propose an agenda to guide multinational research on the cause and treatment of clozapine-resistant schizophrenia. We hope that this research agenda will empower better global representation of patients living with clozapine-resistant schizophrenia and ultimately improve their functional outcomes and quality of life., Competing Interests: Declaration of interests JL has received honoraria from Otsuka, Janssen, Lundbeck, and Sumitomo Pharmaceuticals. CUC has been a consultant or advisor to, or has received honoraria from AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo, Boehringer Ingelheim, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Janssen (Johnson & Johnson), Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Newron, Noven, Otsuka, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Seqirus, SK Life Science, Sunovion, Sun Pharma, Supernus, Takeda, Teva, and Viatris. He has provided expert testimony for Janssen and Otsuka. He has served on a data safety monitoring board for Lundbeck, Relmada, Reviva, Rovi, Supernus, and Teva. He has received grant support from Janssen and Takeda. He has received royalties from UpToDate and is also a stock option holder of Cardio Diagnostics, Mindpax, LB Pharma, and Quantic. ROC has received research funding (awarded to his institution) from Roche and Alkermes, is a consultant to Saladax Biomedical, and is a speaker for Clinical Care Options. ST has received speaker honoraria from Otsuka, Mochida, Takeda, Meiji, Eisai, Sumitomo, Viatris, and Teijin. JT has participated in research projects funded by grants from Janssen-Cilag and Eli Lilly awarded to his institution. He also reports personal fees from Eli Lilly, Evidera, Janssen-Cilag, Lundbeck, Mediuutiset, Otsuka, Sidera, and Suvovion; and he is a consultant to HLS Therapeutics, Orion, and WebMed Global. AH is co-editor of the German Association for Psychiatry, Psychotherapy and Psychosomatics schizophrenia treatment guidelines and first author of the World Federation of Societies of Biological Psychiatry schizophrenia treatment guidelines. He has been on the advisory boards and has received speaker fees from Janssen, Lundbeck, and Otsuka. EW has been on the advisory boards of Recordati. JMG-D is funded by a grant from Ministerio de Ciencia y Tecnología (Colombia), and has been a consultant for, received honoraria from, or been on the speakers or advisory boards of Janssen, Eurofarma, Servier, Sanofi, Lilly, and Pfizer. DSh is an expert advisor to the National Institute for Health and Care Excellence (NICE) centre for guidelines; the views expressed in this Health Policy are the authors' and not those of NICE. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: Treatment-resistant schizophrenia (TRS) is associated with significant impairment of functioning and high treatment costs. Identification of patients at high risk of TRS at the time of their initial diagnosis may significantly improve clinical outcomes and minimise social and functional disability. We aim to develop a prognostic model for predicting the risk of developing TRS in patients with first-episode schizophrenia and to examine its potential utility and acceptability as a clinical decision tool., Methods and Analysis: We will use two well-characterised longitudinal UK-based first-episode psychosis cohorts: Aetiology and Ethnicity in Schizophrenia and Other Psychoses and Genetics and Psychosis for which data have been collected on sociodemographic and clinical characteristics. We will identify candidate predictors for the model based on current literature and stakeholder consultation. Model development will use all data, with the number of candidate predictors restricted according to available sample size and event rate. A model for predicting risk of TRS will be developed based on penalised regression, with missing data handled using multiple imputation. Internal validation will be undertaken via bootstrapping, obtaining optimism-adjusted estimates of the model's performance. The clinical utility of the model in terms of clinically relevant risk thresholds will be evaluated using net benefit and decision curves (comparative to competing strategies). Consultation with patients and clinical stakeholders will determine potential thresholds of risk for treatment decision-making. The acceptability of embedding the model as a clinical tool will be explored using qualitative focus groups with up to 20 clinicians in total from early intervention services. Clinicians will be recruited from services in Stafford and London with the focus groups being held via an online platform., Ethics and Dissemination: The development of the prognostic model will be based on anonymised data from existing cohorts, for which ethical approval is in place. Ethical approval has been obtained from Keele University for the qualitative focus groups within early intervention in psychosis services (ref: MH-210174). Suitable processes are in place to obtain informed consent for National Health Service staff taking part in interviews or focus groups. A study information sheet with cover letter and consent form have been prepared and approved by the local Research Ethics Committee. Findings will be shared through peer-reviewed publications, conference presentations and social media. A lay summary will be published on collaborator websites., Competing Interests: Competing interests: DS is expert advisor to the NICE centre for guidelines. The views expressed are the authors’ and not those of NICE., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: When psychosis emerges in young people there is a risk of poorer outcomes, and access to evidence-based treatments is paramount. The current evidence base is limited. Antipsychotic medications show only a small benefit over placebo, but young people experience more side effects than adults. There is sparse evidence for psychological intervention. Research is needed to determine the clinical effectiveness and cost-effectiveness of psychological intervention versus antipsychotic medication versus a combined treatment for adolescents with psychosis., Objectives: The objective of Managing Adolescent first-episode Psychosis: a feasibility Study (MAPS) was to determine the feasibility of conducting a definitive trial to answer the question of clinical effectiveness and cost-effectiveness of these three treatment options., Design: This was a prospective, randomised, open-blinded, evaluation feasibility trial with a single blind. Participants were allocated 1 : 1 : 1 to receive antipsychotic medication, psychological intervention or a combination of both. A thematic qualitative study explored the acceptability and feasibility of the trial., Setting: Early intervention in psychosis services and child and adolescent mental health services in Manchester, Oxford, Lancashire, Sussex, Birmingham, Norfolk and Suffolk, and Northumberland, Tyne and Wear., Participants: People aged 14-18 years experiencing a first episode of psychosis either with an International Classification of Diseases , Tenth Revision, schizophrenia spectrum diagnosis or meeting the entry criteria for early intervention in psychosis who had not received antipsychotic medication or psychological intervention within the last 3 months., Interventions: Psychological intervention involved up to 26 hours of cognitive-behavioural therapy and six family intervention sessions over 6 months, with up to four booster sessions. Antipsychotic medication was prescribed by the participant's psychiatrist in line with usual practice. Combined treatment was a combination of psychological intervention and antipsychotic medication., Main Outcome Measures: The primary outcome was feasibility (recruitment, treatment adherence and retention). We used a three-stage progression criterion to determine feasibility. Secondary outcomes were psychosis symptoms, recovery, anxiety and depression, social and educational/occupational functioning, drug and alcohol use, health economics, adverse/metabolic side effects and adverse/serious adverse events., Results: We recruited 61 out of 90 (67.8%; amber zone) potential participants (psychological intervention, n  = 18; antipsychotic medication, n  = 22; combined treatment, n  = 21). Retention to follow-up was 51 out of 61 participants (83.6%; green zone). In the psychological intervention arm and the combined treatment arm, 32 out of 39 (82.1%) participants received six or more sessions of cognitive-behavioural therapy (green zone). In the combined treatment arm and the antipsychotic medication arm, 28 out of 43 (65.1%) participants received antipsychotic medication for 6 consecutive weeks (amber zone). There were no serious adverse events related to the trial and one related adverse event. Overall, the number of completed secondary outcome measures, including health economics, was small., Limitations: Medication adherence was determined by clinician report, which can be biased. The response to secondary outcomes was low, including health economics. The small sample size obtained means that the study lacked statistical power and there will be considerable uncertainty regarding estimates of treatment effects., Conclusions: It is feasible to conduct a trial comparing psychological intervention with antipsychotic medication and a combination treatment in young people with psychosis with some adaptations to the design, including adaptations to collection of health economic data to determine cost-effectiveness., Future Work: An adequately powered definitive trial is required to provide robust evidence., Trial Registration: Current Controlled Trials ISRCTN80567433., 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. 25, No. 4. See the NIHR Journals Library website for further project information.

Background: Evidence for the effectiveness of treatments in early-onset psychosis is sparse. Current guidance for the treatment of early-onset psychosis is mostly extrapolated from trials in adult populations. The UK National Institute for Health and Care Excellence has recommended evaluation of the clinical effectiveness and cost-effectiveness of antipsychotic drugs versus psychological intervention (cognitive behavioural therapy [CBT] and family intervention) versus the combination of these treatments for early-onset psychosis. The aim of this study was to establish the feasibility of a randomised controlled trial of antipsychotic monotherapy, psychological intervention monotherapy, and antipsychotics plus psychological intervention in adolescents with first-episode psychosis., Methods: We did a multicentre pilot and feasibility trial according to a randomised, single-blind, three-arm, controlled design. We recruited participants from seven UK National Health Service Trust sites. Participants were aged 14-18 years; help-seeking; had presented with first-episode psychosis in the past year; were under the care of a psychiatrist; were showing current psychotic symptoms; and met ICD-10 criteria for schizophrenia, schizoaffective disorder, or delusional disorder, or met the entry criteria for an early intervention for psychosis service. Participants were assigned (1:1:1) to antipsychotics, psychological intervention (CBT with optional family intervention), or antipsychotics plus psychological intervention. Randomisation was via a web-based randomisation system, with permuted blocks of random size, stratified by centre and family contact. CBT incorporated up to 26 sessions over 6 months plus up to four booster sessions, and family intervention incorporated up to six sessions over 6 months. Choice and dose of antipsychotic were at the discretion of the treating consultant psychiatrist. Participants were followed up for a maximum of 12 months. The primary outcome was feasibility (ie, data on trial referral and recruitment, session attendance or medication adherence, retention, and treatment acceptability) and the proposed primary efficacy outcome was total score on the Positive and Negative Syndrome Scale (PANSS) at 6 months. Primary outcomes were analysed by intention to treat. Safety outcomes were reported according to as-treated status, for all patients who had received at least one session of CBT or family intervention, or at least one dose of antipsychotics. The study was prospectively registered with ISRCTN, ISRCTN80567433., Findings: Of 101 patients referred to the study, 61 patients (mean age 16·3 years [SD 1·3]) were recruited from April 10, 2017, to Oct 31, 2018, 18 of whom were randomly assigned to psychological intervention, 22 to antipsychotics, and 21 to antipsychotics plus psychological intervention. The trial recruitment rate was 68% of our target sample size of 90 participants. The study had a low referral to recruitment ratio (around 2:1), a high rate of retention (51 [84%] participants retained at the 6-month primary endpoint), a high rate of adherence to psychological intervention (defined as six or more sessions of CBT; in 32 [82%] of 39 participants in the monotherapy and combined groups), and a moderate rate of adherence to antipsychotic medication (defined as at least 6 consecutive weeks of exposure to antipsychotics; in 28 [65%] of 43 participants in the monotherapy and combined groups). Mean scores for PANSS total at the 6-month primary endpoint were 68·6 (SD 17·3) for antipsychotic monotherapy (6·2 points lower than at randomisation), 59·8 (13·7) for psychological intervention (13·1 points lower than at randomisation), and 62·0 (15·9) for antipsychotics plus psychological intervention (13·9 points lower than at randomisation). A good clinical response at 6 months (defined as ≥50% improvement in PANSS total score) was achieved in four (22%) of 18 patients receiving antipsychotic monotherapy, five (31%) of 16 receiving psychological intervention, and five (29%) of 17 receiving antipsychotics plus psychological intervention. In as-treated groups, serious adverse events occurred in eight [35%] of 23 patients in the combined group, two [13%] of 15 in the antipsychotics group, four [24%] of 17 in the psychological intervention group, and four [80%] of five who did not receive any treatment. No serious adverse events were considered to be related to participation in the trial., Interpretation: This trial is the first to show that a head-to-head clinical trial comparing psychological intervention, antipsychotics, and their combination is safe in young people with first-episode psychosis. However, the feasibility of a larger trial is unclear because of site-specific recruitment challenges, and amendments to trial design would be needed for an adequately powered clinical and cost-effectiveness trial that provides robust evidence., Funding: National Institute for Health Research., (Copyright © 2020 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: Adolescent-onset psychosis is associated with more severe symptoms and poorer outcomes than adult-onset psychosis. The National Institute for Clinical Excellence (NICE) recommend that adolescents with first episode psychosis (FEP) should be offered a combination of antipsychotic medication (APs), cognitive behavioural therapy (CBT) and family intervention (FI). The evidence for APs in treating psychosis is limited in adolescents compared to adults. Nevertheless, it indicates that APs can reduce overall symptoms in adolescents but may cause more severe side effects, including cardiovascular and metabolic effects, than in adults. CBT and FI can improve outcomes in adults, but there are no studies of psychological interventions (PI) in patients under 18 years old. Given this limited evidence base, NICE made a specific research recommendation for determining the clinical and cost effectiveness of APs versus PI versus both treatments for adolescent FEP., Methods/design: The current study aimed to establish the feasibility and acceptability of conducting such a trial by recruiting 14-18-year-olds with a first episode of psychosis into a feasibility prospective randomised open blinded evaluation (PROBE) design, three-arm, randomised controlled trial of APs alone versus PI alone versus a combination of both treatments. We aimed to recruit 90 participants from Early Intervention and Child and Adolescent Mental Health Teams in seven UK sites. APs were prescribed by participants' usual psychiatrists. PI comprised standardised cognitive behavioural therapy and family intervention sessions., Discussion: This is the first study to compare APs to PI in an adolescent population with FEP. Recruitment finished on 31 October 2018. The study faced difficulties with recruitment across most sites due to factors including clinician and service-user treatment preferences., Trial Registration: Current controlled trial with ISRCTN, ISRCTN80567433 . Registered on 27 February 2017.

Background: Little evidence is available for head-to-head comparisons of psychosocial interventions and pharmacological interventions in psychosis. We aimed to establish whether a randomised controlled trial of cognitive behavioural therapy (CBT) versus antipsychotic drugs versus a combination of both would be feasible in people with psychosis., Methods: We did a single-site, single-blind pilot randomised controlled trial in people with psychosis who used services in National Health Service trusts across Greater Manchester, UK. Eligible participants were aged 16 years or older; met ICD-10 criteria for schizophrenia, schizoaffective disorder, or delusional disorder, or met the entry criteria for an early intervention for psychosis service; were in contact with mental health services, under the care of a consultant psychiatrist; scored at least 4 on delusions or hallucinations items, or at least 5 on suspiciousness, persecution, or grandiosity items on the Positive and Negative Syndrome Scale (PANSS); had capacity to consent; and were help-seeking. Participants were assigned (1:1:1) to antipsychotics, CBT, or antipsychotics plus CBT. Randomisation was done via a secure web-based randomisation system (Sealed Envelope), with randomised permuted blocks of 4 and 6, stratified by gender and first episode status. CBT incorporated up to 26 sessions over 6 months plus up to four booster sessions. Choice and dose of antipsychotic were at the discretion of the treating consultant. Participants were followed up for 1 year. The primary outcome was feasibility (ie, data about recruitment, retention, and acceptability), and the primary efficacy outcome was the PANSS total score (assessed at baseline, 6, 12, 24, and 52 weeks). Non-neurological side-effects were assessed systemically with the Antipsychotic Non-neurological Side Effects Rating Scale. Primary analyses were done by intention to treat; safety analyses were done on an as-treated basis. The study was prospectively registered with ISRCTN, number ISRCTN06022197., Findings: Of 138 patients referred to the study, 75 were recruited and randomly assigned-26 to CBT, 24 to antipsychotics, and 25 to antipsychotics plus CBT. Attrition was low, and retention high, with only four withdrawals across all groups. 40 (78%) of 51 participants allocated to CBT attended six or more sessions. Of the 49 participants randomised to antipsychotics, 11 (22%) were not prescribed a regular antipsychotic. Median duration of total antipsychotic treatment was 44·5 weeks (IQR 26-51). PANSS total score was significantly reduced in the combined intervention group compared with the CBT group (-5·65 [95% CI -10·37 to -0·93]; p=0·019). PANSS total scores did not differ significantly between the combined group and the antipsychotics group (-4·52 [95% CI -9·30 to 0·26]; p=0·064) or between the antipsychotics and CBT groups (-1·13 [95% CI -5·81 to 3·55]; p=0·637). Significantly fewer side-effects, as measured with the Antipsychotic Non-neurological Side Effects Rating Scale, were noted in the CBT group than in the antipsychotics (3·22 [95% CI 0·58 to 5·87]; p=0·017) or antipsychotics plus CBT (3·99 [95% CI 1·36 to 6·64]; p=0·003) groups. Only one serious adverse event was thought to be related to the trial (an overdose of three paracetamol tablets in the CBT group)., Interpretation: A head-to-head clinical trial of CBT versus antipsychotics versus the combination of the two is feasible and safe in people with first-episode psychosis., Funding: National Institute for Health Research., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Excess deaths from cardiovascular disease are a major contributor to the significant reduction in life expectancy experienced by people with schizophrenia. Important risk factors in this are smoking, alcohol misuse, excessive weight gain and diabetes. Weight gain also reinforces service users' negative views of themselves and is a factor in poor adherence with treatment. Monitoring of relevant physical health risk factors is frequently inadequate, as is provision of interventions to modify these. These guidelines review issues surrounding monitoring of physical health risk factors and make recommendations about an appropriate approach. Overweight and obesity, partly driven by antipsychotic drug treatment, are important factors contributing to the development of diabetes and cardiovascular disease in people with schizophrenia. There have been clinical trials of many interventions for people experiencing weight gain when taking antipsychotic medications but there is a lack of clear consensus regarding which may be appropriate in usual clinical practice. These guidelines review these trials and make recommendations regarding appropriate interventions. Interventions for smoking and alcohol misuse are reviewed, but more briefly as these are similar to those recommended for the general population. The management of impaired fasting glycaemia and impaired glucose tolerance ('pre-diabetes'), diabetes and other cardiovascular risks, such as dyslipidaemia, are also reviewed with respect to other currently available guidelines.These guidelines were compiled following a consensus meeting of experts involved in various aspects of these problems. They reviewed key areas of evidence and their clinical implications. Wider issues relating to primary care/secondary care interfaces are discussed but cannot be resolved within guidelines such as these., (© The Author(s) 2016.)

The National Audit of Schizophrenia (NAS) examined the quality of care received in England and Wales. Part of the audit set out to determine whether six prescribing standards, set by the national clinical guidelines for schizophrenia, were being implemented and to prompt improvements in care. Mental Health Trusts and Health Boards provided data obtained from case-notes for adult patients living in the community with schizophrenia or schizoaffective disorder. An audit of practice tool was developed for data collection. Most of the 5055 patients reviewed were receiving pharmacological treatment according to national guidelines. However, 15.9% of the total sample (95%CI: 14.9-16.9) were prescribed two or more antipsychotics concurrently and 10.1% of patients (95%CI: 9.3-10.9) were prescribed medication in excess of recommended limits. Overall 23.7% (95%CI: 22.5-24.8) of patients were receiving clozapine. However, there were many with treatment resistance who had no clear reason documented as to why they had not had a trial of clozapine (430/1073, 40.1%). In conclusion, whilst most people were prescribed medication in accordance with nationally agreed standards, there was considerable variation between service providers. Antipsychotic polypharmacy, high dose prescribing and clozapine underutilisation in treatment resistance were all key concerns which need to be further addressed., (Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.)

Objectives: For children and adolescents, the adverse effects from antipsychotic medicines exaggerate the already considerable burden of having a serious mental illness. Many of these young people face a future not only limited by stigmatizing psychiatric illness but also a life restricted and shortened by physical ill-health, particularly cardiovascular disease and type-2 diabetes. This review focuses on bridging the current gap between available evidence and practice guidelines and policies., Method: Following an extensive literature search, key papers focusing on the evidence of the nature and occurrence of metabolic morbidity in children and adolescents following the use of antipsychotic medication were included., Results: There is growing evidence to suggest that some of the key antecedents of metabolic syndrome occur soon after diagnosis and initiation of antipsychotic medication, and they accumulate over time., Conclusion: While guidelines and policies around the monitoring of metabolic syndrome in children and adolescents with mental illness receiving antipsychotic medication are limited, an opportunity lies in altering the trajectory towards cardiovascular disease and type-2 diabetes by early recognition and intervention to reduce cardiometabolic risk rather than waiting until disease end-points are reached later in life.

There is uncertainty with regard to the appropriate use of metformin for the prevention and management of second-generation antipsychotic-induced weight gain and metabolic abnormalities. We aim to systematically review the primary literature and to provide recommendations with regard to the use of metformin in psychiatric populations prescribed second-generation antipsychotics. The authors undertook a literature search of Medline, EMBASE, and PsycINFO using the search terms; antipsychotic OR atypical antipsychotic AND weight AND metformin. Narrative review was undertaken without additional statistical analysis. The search provided 198 results from which 10 original research papers were identified: six randomized controlled trials and one open-label study for adults and two randomized controlled trials and one open-label study for children and adolescents. Four meta-analyses were also identified. We concluded that if weight gain occurs after second-generation antipsychotic initiation, despite lifestyle intervention, metformin should be considered. Further studies with adequate statistical power are required to determine the efficacy of metformin in those with chronic psychotic illness.

The article offers the authors' insight regarding the use of metformin for the cardiometabolic protection in psychosis. They state that a lifestyle programme to prevent weight gain at initiation of antipsychotic treatment is essential to tackle or prevent cardiometabolic risk. They suggest that the metformin combined with a lifestyle programme could be used for severely mentally ill when antipsychotic agents are initiated.

This presentation will highlight how the early phase of major mental illness may provide a critical window of opportunity in which to prevent future life-restricting and life-shortening physical comorbidities. Despite many recent advances in our understanding of severe mental illnesses, those affected still lose 15–20 years of life on average compared to the general population. Most premature deaths arise from the same common disorders that affect the general population such as cardiovascular disease, infections and cancers. Of these cardiovascular diseases is now the single biggest cause, far greater than suicide. Shockingly the mortality gap is still widening as the reduction in CVD morbidity and mortality seen in the general population over the last three decades continues to elude people with severe mental illnesses, for whom the prevalence of CVD, obesity and diabetes are now of epidemic proportion. And yet, much of this epidemic can be predicted. High rates of tobacco use, physical inactivity and poor nutrition point to underlying health inequalities. Furthermore, initiation of antipsychotic treatment is associated with aggressive weight gain and metabolic disturbance from the early phase of psychosis, and yet often these adverse effects remain unmonitored and untreated. This presentation will argue that these potentially modifiable risk factors provide natural targets for prevention from the onset of psychosis and its treatment. Extending the early intervention paradigm to embrace a far more holistic body & mind approach is overdue. [ABSTRACT FROM AUTHOR]

A reply to a letter to the editor is presented which discusses the potential benefits of metformin coadministered with antipsychotic medications.