Efficacy and Tolerability of Lumateperone in Acute Bipolar Depression: A Systematic Review and Meta-analysis

Background: Second-generation antipsychotics are currently recommended as either monotherapy/adjunctive treatment for bipolar depression (BDep) as per most of the international guidelines. In 2021, the United States Food and Drug Administration approved the use of lumateperone, either as monotherapy or adjunctive to a mood stabilizer, for the treatment of acute BDep. The study aims to assess the efficacy and tolerability of lumateperone for acute BDep compared to placebo, including differential efficacy as monotherapy versus adjunct to mood stabilizer. Methods: A systematic review of randomized double-blind placebo-controlled trials evaluating lumateperone as monotherapy or adjunct to mood stabilizers for acute BDep was carried out. The inclusion criteria included English-language research with outcomes assessed between 6 and 12 weeks that compared lumateperone as a monotherapy or adjunct to a placebo. Remission and response rates were the primary outcome indicators. The secondary outcomes comprised the standardized mean differences (SMDs) in changes from baseline to endpoint on the Montgomery–Åsberg Depression Rating Scale (MADRS), overall dropout rate, and dropout rate attributable to adverse effects. Binary and continuous outcomes were analyzed using RevMan 5.4 software, applying the Mantel–Haenszel method for binary data and the inverse variance method for continuous data. PROSPERO has this study registered (CRD420250653338). Results: Five studies were eligible for systematic review. Only three studies, totaling 1,094 patients, were eligible for the meta-analysis. Lumateperone showed significantly higher response rates than placebo (Odds ratio = 1.59, 95% confidence interval [CI]: 1.25–2.04; Z = 3.70; P < 0.001). SMDs of MADRS scores from baseline were −0.38 (95% CI: −0.56, −0.19, Z = 4.06, P < 0.001), indicating efficacy of lumateperone over placebo. The dropout rate attributable to adverse effects was higher in the lumateperone arm, but no significant increase in overall dropout rate compared to placebo. Heterogeneity was significant. Subgroup analysis revealed that lumateperone as monotherapy had better efficacy compared to when used as an adjunctive treatment. Conclusion: In acute BDep, lumateperone showed superior efficacy compared with placebo; monotherapy was found to be better than adjunct to mood stabilizer. There was no significant increase in overall dropout rate with lumateperone compared to placebo. Future research should assess its potential as a preventive treatment for depressive episodes in bipolar disorder.