Stefan Leucht1,2, Sofia Bauer1,3, Spyridon Siafis1, Tasnim Hamza4, Hui Wu1,5, Johannes Schneider-Thoma1, Georgia Salanti4, John M Davis6,7. 1. Department of Psychiatry and Psychotherapy, Technical University of Munich, School of Medicine, Munich, Germany. 2. Institute of Psychiatry, Psychology and Neuroscience, Department of Psychiatry, Department of Psychosis Studies, King's College London, London, United Kingdom. 3. Ludwig-Maximilians-Universität München, Munich, Germany. 4. Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland. 5. Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China. 6. Psychiatric Institute, University of Illinois at Chicago. 7. Department of Psychiatry, Johns Hopkins University, Baltimore, Maryland.
Abstract
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.
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.
Authors: Xenia M Hart; Christoph Hiemke; Luzie Eichentopf; Xenija M Lense; Hans Willi Clement; Andreas Conca; Frank Faltraco; Vincenzo Florio; Jessica Grüner; Ursula Havemann-Reinecke; Espen Molden; Michael Paulzen; Georgios Schoretsanitis; Thomas G Riemer; Gerhard Gründer Journal: Psychopharmacology (Berl) Date: 2022-10-05 Impact factor: 4.415
Authors: Heidi Taipale; Antti Tanskanen; Jurjen J Luykx; Marco Solmi; Stefan Leucht; Christoph U Correll; Jari Tiihonen Journal: Schizophr Bull Date: 2022-06-21 Impact factor: 7.348