Dose-effect trajectory of lumateperone in schizophrenia: Evidence from a systematic review and meta-analysis of randomized controlled trials

Background: The optimal dose of lumateperone for treating schizophrenia remains unclear. We examined its dose-response relationship for efficacy and acceptability. Methods: We searched major databases (e.g. PubMed, EMBASE, Cochrane), and grey literature from inception to January 20, 2025 (INPLASY202510038) for randomized controlled trials (RCTs) comparing lumateperone with placebo in schizophrenia. We excluded non-peer-reviewed studies and those lacking a placebo group or involved non-schizophrenic patients. The Cochrane Risk of Bias Tool was used for risk of bias assessment. We used a one-step dose-response meta-analysis (DRMA) with a random-effects model to calculate the effect sizes as standardized mean differences (SMDs) and risk ratios (RRs) with 95 % confidence intervals (CIs). Results: 688 patients from two RCTs received placebo or lumateperone. Lumateperone 42 mg significantly improved the Positive and Negative Syndrome Scale (PANSS) total score (SMD = −0.29, 95 % CI: −0.47 to −0.10), PANSS positive symptom score (SMD = −0.41, 95 % CI: −0.64 to −0.18), and responder rate (RR = 1.52, 95 % CI: 1.16–2.01), as well as marginally improved the PANSS negative symptom score (SMD = −0.17, 95 % CI: −0.34–0.01). Higher doses (>42–63 mg) were associated with increased rates of oral dryness/thirst, nausea/vomiting, somnolence, and dizziness. No dose-response relationship was found for dropout rates, headache, or extrapyramidal symptoms. A limitation of this study is the small number of available RCTs. Conclusions: Lumateperone 42 mg appears to offer the most favorable balance of efficacy and side effects for the treatment of schizophrenia.