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Original Investigation
August 18, 2021

Examination of Dosing of Antipsychotic Drugs for Relapse Prevention in Patients With Stable Schizophrenia: A Meta-analysis

Author Affiliations
  • 1Department of Psychiatry and Psychotherapy, Technical University of Munich, School of Medicine, Munich, Germany
  • 2Institute of Psychiatry, Psychology and Neuroscience, Department of Psychiatry, Department of Psychosis Studies, King’s College London, London, United Kingdom
  • 3Ludwig-Maximilians-Universität München, Munich, Germany
  • 4Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland
  • 5Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
  • 6Psychiatric Institute, University of Illinois at Chicago
  • 7Department of Psychiatry, Johns Hopkins University, Baltimore, Maryland
JAMA Psychiatry. Published online August 18, 2021. doi:10.1001/jamapsychiatry.2021.2130
Key Points

Question  What are the optimum doses for relapse prevention in patients with stable schizophrenia?

Findings  In this meta-analysis of 26 studies including 4776 participants, doses higher than approximately 5-mg/d risperidone equivalent were not associated with more efficacy. However, increasing doses were associated with more adverse events.

Meaning  In this study, even low doses of antipsychotics appear to have some association with efficacy for relapse prevention in schizophrenia; however, clinicians may need to be cautious when they decrease doses at the lower dose end because further decreases of dose are accompanied by disproportionally higher relapse risk.


Importance  The doses of antipsychotic drugs needed for relapse prevention in schizophrenia is a debated issue.

Objective  To examine dose-response findings in a meta-analysis of randomized clinical trials.

Data Sources  Studies were identified through the Cochrane Schizophrenia Group’s Study-Based Register of Trials (March 9, 2020), PubMed (January 1, 2021), and previous reviews. First authors and/or pharmaceutical companies were contacted for additional information.

Study Selection  Two reviewers independently selected randomized clinical trials that compared fixed doses of a second-generation antipsychotic, haloperidol, or fluphenazine for relapse prevention in patients with stable schizophrenia.

Data Extraction and Synthesis  Using the Preferred Reporting Items for Systematic Reviews and Meta-analyses guideline, all parameters in duplicate were extracted and frequentist dose-response random-effects meta-analyses were conducted.

Main Outcomes and Measures  Study-defined relapse (primary outcome), rehospitalization, Positive and Negative Syndrome Scale or Brief Psychiatric Rating Scale total score reduction from baseline, all-cause discontinuation, and dropouts due to adverse events.

Results  Evidence from 72 dose arms from 26 studies with 4776 participants was analyzed. The efficacy-related dose-response curves had a hyperbolic shape meaning that the probability to relapse decreased rapidly with doses of up to 5-mg/d risperidone equivalent (relative relapse risk, 0.43; 95% CI, 0.31-0.57; standardized mean difference for Positive and Negative Syndrome Scale total score reduction, −0.55; 95% CI, −0.68 to −0.41), but flattened thereafter. In contrast, dropouts due to adverse events continued to increase beyond this dose (relative risk at 5 mg/d, 1.38; 95% CI, 0.87-2.55; relative risk at 15 mg/d, 2.68; 95% CI, 1.49-4.62). In a subgroup analysis of patients in remission, a plateau was reached earlier, at approximately 2.5-mg/d risperidone equivalent.

Conclusions and Relevance  The findings of this meta-analysis suggest that doses higher than approximately 5-mg/d risperidone equivalent may provide limited additional benefit for relapse prevention but more adverse events. For patients in remission or who are receiving high-potency first-generation antipsychotics, doses as low as 2.5-mg/d risperidone equivalent may be sufficient. However, caution is needed at this low dose end when further decreases of dose may be accompanied by a disproportionally higher relapse risk. Moreover, the observations are averages, and factors such as slow or rapid metabolism, age, illness stage, comorbidities, and drug-drug interactions suggest that individual patients will often need higher or lower doses.

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