What are the optimum doses for relapse prevention in patients with stable schizophrenia?
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.
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.
The doses of antipsychotic drugs needed for relapse prevention in schizophrenia is a debated issue.
To examine dose-response findings in a meta-analysis of randomized clinical trials.
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.
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.
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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Leucht S, Bauer S, Siafis S, et al. Examination of Dosing of Antipsychotic Drugs for Relapse Prevention in Patients With Stable Schizophrenia: A Meta-analysis. JAMA Psychiatry. Published online August 18, 2021. doi:10.1001/jamapsychiatry.2021.2130
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