Lumateperone Tops Efficacy in Adjunctive Treatment for MDD, Review Finds
Key Clinical Summary
- A JAMA Psychiatry network meta-analysis compared 5 US Food and Drug Administration (FDA)–approved atypical antipsychotics used adjunctively for major depressive disorder (MDD).
- Lumateperone demonstrated the highest efficacy for depressive symptom reduction, while aripiprazole showed the best overall acceptability profile.
- Investigators reported clinically meaningful differences in efficacy, tolerability, and discontinuation rates that may inform treatment selection and sequencing.
A new systematic review and network meta-analysis published in JAMA Psychiatry evaluated the comparative efficacy and acceptability of the 5 US Food and Drug Administration (FDA)–approved atypical antipsychotics used as adjunctive therapy for major depressive disorder (MDD).
“Most adults living with major depressive disorder (MDD) fail to achieve remission with conventional antidepressants,” Robert S. McIntyre, MD, Department of Psychiatry, University of Toronto, and study coauthors wrote in the study abstract.
The investigators, which include Psych Congress faculty members Joseph F. Goldberg, MD, and Christoph U. Correll, MD, found significant differences among agents, with lumateperone ranking highest for efficacy and aripiprazole demonstrating the most favorable acceptability profile.
Study Findings
The analysis included 22 short-term clinical studies involving 10,962 participants with MDD who had inadequate response to conventional antidepressants. Researchers assessed adjunctive treatment with aripiprazole, brexpiprazole, cariprazine, lumateperone, and quetiapine extended release (XR) compared with placebo.
Investigators conducted database searches using PubMed/MEDLINE, PsycINFO, Embase, and the Cochrane Library from inception through July 15, 2025. The primary outcomes were efficacy, defined as at least a 50% reduction in Montgomery-Åsberg Depression Rating Scale scores, and acceptability, measured by all-cause discontinuation.
Lumateperone demonstrated the largest efficacy effect size, with a risk ratio (RR) of 1.72 (95% credible interval [CrI], 1.40-2.15). Aripiprazole ranked second for efficacy with a risk ratio of 1.53 (95% CrI, 1.32-1.77), followed by brexpiprazole at 1.38 (95% CrI, 1.18-1.65). Cariprazine (RR, 1.20; 95% CrI, 1.07-1.36) and quetiapine XR 9 (RR, 1.15; 95% CrI, 0.96-1.35) showed smaller effects.
For acceptability, aripiprazole ranked highest (RR, 1.16, 95% Crl, 0.89-1.50), followed by cariprazine (RR, 1.44; 95% Crl, 1.15-1.82) and brexpiprazole (RR, 1.47; 95% Crl, 1.18-1.85). Lumateperone demonstrated the lowest acceptability (RR, 2.30; 95% Crl, 1.45-3.84). despite its strong efficacy signal. Secondary outcomes, including symptomatic remission and weight gain, generally aligned with the primary efficacy and tolerability findings.
The authors concluded that atypical antipsychotics approved for adjunctive treatment of MDD “exhibit differential efficacy, acceptability, and tolerability relevant to treatment selection and sequencing.”
Clinical Implications
Major depressive disorder remains a major clinical challenge, with many patients failing to achieve remission with antidepressant monotherapy. Adjunctive atypical antipsychotics are commonly used in practice, but comparative evidence among approved agents has been limited.
The findings may help clinicians individualize treatment decisions by balancing symptom improvement against tolerability and discontinuation risk. Lumateperone’s higher efficacy could make it attractive for patients with persistent depressive symptoms, while aripiprazole’s favorable acceptability profile may support longer-term adherence in clinical practice.
The analysis also highlights the importance of considering adverse effects when selecting adjunctive therapy. Weight gain and tolerability concerns remain clinically relevant in patients with MDD who often require prolonged treatment exposure.
Investigators additionally identified a significant evidence gap regarding maintenance efficacy. Most included studies were short-term, and the authors noted the absence of adequate and well-controlled long-term trials evaluating sustained benefit with adjunctive atypical antipsychotics in MDD.
Expert Commentary
The study authors reported that FDA-approved atypical antipsychotics for MDD “should be simultaneously considered” according to efficacy and acceptability outcomes. They also emphasized that differences among agents may have practical implications for treatment sequencing in patients with inadequate antidepressant response.
Reference
