Abstract
BACKGROUND: The optimal antipsychotic doses for achieving efficacy in acute schizophrenia spectrum disorders have been investigated but uncertainties remained. We conducted one-stage dose-response meta-analyses to elucidate the dose-response relationships of antipsychotics in acute schizophrenia by utilizing a larger amount of information than two-stage approach. METHODS: We searched Cochrane Schizophrenia Group's register until 13.01.2025 and PubMed until 19.01.2026 for fixed-dose studies investigating 20 antipsychotics regardless of their formulations in adults and in children/adolescents with acute schizophrenia. The primary outcome was overall schizophrenia symptoms, summarized using standardized mean difference (SMD). We conducted one-stage random-effects dose-response meta-analyses with restricted cubic splines, analyzing each drug separately and all drugs combined. We evaluated confidence in the evidence using GRADE. People with lived experience were not involved. The protocol was registered with PROSPERO (CRD42020181467). FINDINGS: We included 131 studies with 40,715 participants analyzed (for adults, mean age 39.24 years, 31.8% females; for children/adolescents, 15.68 years, 45.1% females; ethnicity data not available). Dose-response curves of most antipsychotics on overall symptoms in people with acute exacerbations of schizophrenia were hyperbolic, reaching plateau within the lower-to-medium approved dose ranges, around 3-5 mg risperidone dose equivalents. There was low to very low certainty of evidence regarding the dose-response relationships of amisulpride, blonanserin, cariprazine, clozapine, haloperidol, lumateperone and ziprasidone. We did not find enough studies to conduct dose-response meta-analysis for olanzapine/samidorphan, xanomeline/trospium, and zotepine. Dose-response curves did not clearly differ in children and adolescents, but data were sparse and with low or very low certainty. INTERPRETATION: Antipsychotics typically exert the majority of their therapeutic effects at doses within the lower to middle range of their recommended doses. While this finding provides a general reference for clinical use, individual variability is expected in practice. Further investigation is required to elucidate the influence of potential effect modifiers on the dose-response relationships. FUNDING: This meta-analysis was conducted within the framework of a larger project funded by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG; grant #468853597) and within activities of the German Center for Mental Health (Deutsches Zentrum für Psychische Gesundheit, DZPG), Munich-Augsburg partner site, funded by the Federal Ministry of Research, Technology and Space (BMFTR, grant #01EE2303B). This study was also partly funded by the SENSHIN Medical Research Foundation grant given to YF.