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A systematic review and meta-analysis of clozapine response rates in schizophrenia

Nature Mental Health (2026)Cite this article

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Abstract

Clozapine is the gold standard for treatment-resistant schizophrenia (TRS) and demonstrates superior efficacy in non-TRS. Clozapine response rates have been quantified in TRS, but comparable data for non-TRS groups are sparse. Here we conducted a single-group meta-analysis of randomized controlled trials evaluating clozapine monotherapy efficacy across the schizophrenia spectrum, irrespective of treatment resistance. Primary outcomes included response rates (≥20% Positive and Negative Syndrome Scale (PANSS) reduction) and absolute/percentage PANSS score changes. Secondary analyses examined ≥50% PANSS reduction rates, author-defined remission criteria and imputed response rates across multiple thresholds (0–75% reduction). Meta-regression and subgroup analyses explored the impact of predefined variables. Sixty randomized controlled trials were included: 27 in non-TRS patients and 33 in TRS. In non-TRS, we found an 81% response rate (95% confidence interval (CI) 69% to 89%), with mean PANSS reductions of 31.1 points (95% CI −38.0 to −24.2), representing a 48.3% improvement (95% CI −57.9% to −38.7%). In TRS, we found a 63% response rate (95% CI 56% to 69%), with mean reductions of 22.4 PANSS points (95% CI −27.4 to −17.4) equating to 31.3% improvement (95% CI −37.1% to −25.6%). Studies with a longer illness duration showed a nonlinear association with worse outcomes. Response declined steeply in the first illness decade (odds ratio 0.80 per year, 95% CI 0.71 to 0.91), from >90% at illness onset to ~46% by year 10, before stabilizing with no further time-dependent effects. This meta-analysis provides robust evidence for clozapine’s efficacy across all stages of schizophrenia. The duration-of-illness effect underscores the importance of prompt treatment initiation. Clinicians and researchers should consider clozapine earlier in the treatment algorithm and maintain therapeutic optimism even in chronic cases, as substantial response rates persist.

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Fig. 1: PRISMA flowchart of screening and study selection process.
Fig. 2: Forest plot of pooled response rates, defined as ≥20% symptom reduction from baseline in non-TRS and TRS.
Fig. 3: Pooled response rates in non-TRS and TRS, according to three response definitions.
Fig. 4: Nonlinear meta-regression of PANSS percentage reduction against duration of illness (in years).
Fig. 5: Piecewise mixed-effects meta-regression modeling response rates against illness duration (in years) with a clinically informed 10-year cutoff.
Fig. 6: Forest plot of pooled response rates across four treatment resistance groups: first-episode schizophrenia versus chronic versus nonresponse to ≥1 prior antipsychotic versus nonresponse to ≥2 prior antipsychotics.

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Data availability

The data supporting this analysis are derived from published summary statistics; all sources are presented in the ‘Table of included trials’ in Supplementary Section 5.

Code availability

Code used for analysis is available via GitHub at https://github.com/samaramyrto-bit/Clozapine-response-rates-Samara-2026.

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Acknowledgements

A.N. was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation; grant number NI 2226/1-1 and Project-ID 499552394 – SFB 1597). We thank all study authors who responded to our data requests for our team’s previous reviews.

Author information

Authors and Affiliations

  1. Department of Psychiatry, Faculty of Medicine, University of Thessaly, Larisa, Greece

    Myrto Samara, Elisavet Pinioti, Nikos Christodoulou & Andreas S. Lappas

  2. Centre for Trials Research, Cardiff University, Cardiff, UK

    Eleni Glarou

  3. Division of Population Medicine, School of Medicine, Cardiff University, Cardiff, UK

    Eleni Glarou

  4. Laboratory of Hygiene, Social and Preventive Medicine and Medical Statistics, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece

    Adriani Nikolakopoulou

  5. Institute of Medical Biometry and Statistics, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany

    Adriani Nikolakopoulou

  6. Technical University of Munich, TUM School of Medicine and Health, Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar, Munich, Germany

    Spyridon Siafis & Stefan Leucht

  7. German Center for Mental Health (DZPG), partner site München/Augsburg, Munich, Germany

    Spyridon Siafis & Stefan Leucht

  8. Department of Geriatric Psychiatry, Aneurin Bevan University Health Board, Newport, UK

    Andreas S. Lappas

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Contributions

M.S.: conceptualization, methodology, formal data analysis, data curation, visualization, investigation, writing (original draft), writing (review and editing), project administration, study screening, study quality assessment. M.S. had full access to all data in the study. E.G.: study screening, study quality assessment, writing (review and editing). E.P.: study screening, study quality assessment, writing (review and editing). A.N.: methodology, formal data analysis, writing (review and editing). N.C.: writing (review and editing). S.S.: writing (review and editing). S.L.: writing (review and editing). A.S.L.: supervision, methodology, study search, validation of study screening, writing (review and editing). All authors reviewed and approved the submission of the final paper.

Corresponding author

Correspondence to Myrto Samara.

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Competing interests

M.S. has received honoraria as a consultant/advisor and/or for lectures from Recordati, Lundbeck and Viatris. S.L. has received honoraria as a consultant/advisor and/or for lectures from Angelini, Böhringer Ingelheim, Geodon and Richter, Janssen, Johnson&Johnson, Lundbeck, LTS Lohmann, MSD, Otsuka, Recordati, Sanofi Aventis, Sandoz, Sunovion, TEVA, Eisai, Rovi, Medichem, and Mitsubishi. The other authors declare no competing interests.

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Samara, M., Glarou, E., Pinioti, E. et al. A systematic review and meta-analysis of clozapine response rates in schizophrenia. Nat. Mental Health (2026). https://doi.org/10.1038/s44220-026-00604-w

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