BACKGROUND: Clozapine is recommended by national and international guidelines for people with treatment-resistant schizophrenia. However, available meta-analyses of randomised controlled trials have not shown superior efficacy of clozapine when compared with other second-generation antipsychotics, with heterogeneity identified between the original studies. We aimed to use individual patient data (IPD) to account for potential reasons of variability and to synthesise an adjusted estimate for the difference in efficacy between clozapine and other second-generation antipsychotics for treatment-resistant schizophrenia. METHODS: In this systematic review and IPD meta-analysis, we searched the Cochrane Schizophrenia Group's Study-Based Register from inception to Jan 24, 2024, and previous reviews for blinded randomised controlled trials comparing clozapine with other second-generation antipsychotics in participants with treatment-resistant schizophrenia. Trials were eligible if they included patients with treatment-resistant schizophrenia and had a duration of at least 6 weeks. IPD were requested from trial investigators. The primary outcome was change in overall schizophrenia symptoms as measured by the Positive and Negative Syndrome Scale (PANSS) between clozapine and other second-generation antipsychotics after 6-8 weeks of treatment. The effect size measure for the primary outcome was mean difference with 95% credible interval (CrI). We fitted a Bayesian random-effects IPD meta-regression model that included duration of illness, baseline severity, and sex as potential prognostic factors or treatment effect modifiers. Confidence in the evidence was assessed using Grading of Recommendations, Assessment, Development, and Evaluation (GRADE). People with lived experience of mental illness were involved in this study. This study is registered with PROSPERO, CRD42021254986. FINDINGS: We screened 13 876 references and included 19 studies with data for 1599 participants; IPD were available for 12 of 19 trials (n=1052; mean age 37·67 years [SD 11·24; range 10-66]; 348 [33·08%] women and 704 [66·92%] men). Data on ethnicity were not available. The estimated mean difference in change from baseline PANSS total score was -0·64 points (95% CrI -3·97 to 2·63; τ=2·68) in favour of other second-generation antipsychotics. Shorter duration of illness and higher baseline severity were prognostic factors associated with a larger reduction in symptoms, but neither those factors nor sex were found to modify the relative effect between clozapine and other second-generation antipsychotics. The confidence in the evidence was graded as very low. INTERPRETATION: This IPD meta-analysis found a small and uncertain advantage of other second-generation antipsychotics, mainly olanzapine and risperidone, and so did not provide evidence for superior efficacy of clozapine compared with other second-generation antipsychotics in treatment-resistant schizophrenia. It is limited by unavailability of IPD for some studies, uncaptured sources of variance, and uncertainty due to premature study discontinuation. Given the side-effects of clozapine, the observed uncertainty regarding clozapine's superiority warrants prudent use and further research. FUNDING: German Ministry of Education and Research.

Beckley Psytech Oxford UK; School of Medicine University of Maryland Baltimore MD USA

Bündnis für psychisch erkrankte Menschen Munich Germany

Department of Clinical Research University of Bern Bern Switzerland; Institute of Social and Preventive Medicine University of Bern Bern Switzerland

Department of Psychiatry and Behavioral Sciences Northwestern Feinberg School of Medicine Chicago IL USA

Department of Psychiatry and Behavioral Sciences University of Minnesota Minneapolis MN USA

Department of Psychiatry and Psychotherapy Florence Nightingale Hospital Düsseldorf Germany

Department of Psychiatry and Psychotherapy Hamburg Eppendorf University Hamburg Germany

Department of Psychiatry and Psychotherapy School of Medicine and Health Technical University of Munich Munich Germany; German Center for Mental Health Munich Germany

Department of Psychiatry and Psychotherapy School of Medicine and Health Technical University of Munich Munich Germany; German Center for Mental Health Munich Germany; Neuropsychiatry and Laboratory of Molecular Psychiatry Charité Medical University Berlin and German Center for Neurodegenerative Diseases Berlin Germany; University of Edinburgh and UK Dementia Research Institute Edinburgh UK

Department of Psychiatry and Psychotherapy University of Leipzig Leipzig Germany; Department of Psychiatry Psychotherapy and Psychosomatics Rudolf Virchow Klinikum Glauchau Glauchau Germany

Department of Psychiatry Lausanne University Hospital and University of Lausanne Prilly Lausanne Switzerland

Faculty of Biology Medicine and Health The University of Manchester Manchester UK

Faculty of Medicine in Pilsen Charles University Pilsen Czech Republic

Finnish Institute for Health and Welfare Helsinki Finland

Institute of Social and Preventive Medicine University of Bern Bern Switzerland

Institute of Social and Preventive Medicine University of Bern Bern Switzerland; Graduate School for Health Sciences University of Bern Bern Switzerland

Maryland Psychiatric Research Center Baltimore MD USA

Psychiatric Institute University of Illinois at Chicago Chicago IL USA; Maryland Psychiatric Research Center Baltimore MD USA

SUNY Downstate Health Sciences Center New York NY USA

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