Adjunctive Atypical Antipsychotics in Major Depressive Disorder: Comparing Efficacy and Tolerability

Leslie Citrome, MD, discussed the comparative efficacy and tolerability of adjunctive atypical antipsychotics for the treatment of major depressive disorder (MDD), with particular focus on lumatperone, the most recently approved agent in this class.

Citrome began by noting the absence of head-to-head randomized controlled trials comparing adjunctive atypical antipsychotics against one another for MDD. He argued that the next best evidence comes from network meta-analysis, which pools regulatory approval trial data, all of which share a placebo arm, to enable indirect comparisons. Citrome identified lumatperone as demonstrating a larger effect size versus placebo than the other available adjunctive agents.¹ He emphasized that statistical significance alone (P < 0.05) is insufficient for clinical interpretation, explaining: "a statistically significant result may not be clinically relevant, and for that, we need effect size—what is the size of the treatment effect?" He described his preference for calculating number needed to treat and number needed to harm from odds ratios for response and remission, noting he was actively working on such a project.

Citrome devoted significant attention to tolerability, which he said has been the focus of his research for the past 20 years. He underscored that each available agent carries a distinct adverse effect profile and advocated for individualized shared decision-making around weight gain, akathisia, and sedation. From the network meta-analysis, he highlighted that lumatperone demonstrated an absence of both weight gain and akathisia versus placebo—advantages that may favor its selection for patients in whom those adverse effects are a concern, despite its intermediate sedation profile.²

Citrome also raised a critical point about timing: in the pivotal approval trials, the average patient had been ill for over 12 months prior to receiving adjunctive therapy. He stated that "atypical antipsychotics added to antidepressants work, and it's just a shame that they're used so late in the course of treatment," advocating for earlier incorporation into treatment planning to maximize the likelihood of achieving response and remission.

In the absence of direct comparative data, Citrome endorsed real-world evidence—including EHR-linked practice patterns, medication discontinuation rates, and hospitalization outcomes—as a complementary source of practice-based guidance.

Dr Citrome is a clinical professor of psychiatry and behavioral sciences at New York Medical College in Valhalla, New York.

References

1. Duerr HA. Lumateperone ranks highest among adjunctive MDD therapies in first network meta-analysis. Psychiatric Times. May 4, 2026. https://www.psychiatrictimes.com/view/lumateperone-ranks-highest-among-adjunctive-mdd-therapies-in-first-network-meta-analysis

2. Caplyta (lumateperone) showed greatest improvement across key efficacy outcomes among adjunctive MDD treatments in new network meta-analysis. Press release. May 4, 2026. https://www.jnj.com/media-center/press-releases/caplyta-lumateperone-showed-greatest-improvement-across-key-efficacy-outcomes-among-adjunctive-mdd-treatments-in-new-network-meta-analysis