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Lumateperone Ranked Favorably Among Adjunctive MDD Therapies, With Leslie Citrome, MD
A study suggested lumateperone demonstrated favorable efficacy outcomes and limited weight gain and akathisia risk compared with other adjunctive antipsychotics for MDD.
Lumateperone (CAPLYTA) demonstrated the largest effect size across 4 key efficacy outcomes in a network meta-analysis comparing FDA-approved adjunctive atypical antipsychotics for major depressive disorder (MDD), according to findings presented at the 2026 Neuroscience Education Institute (NEI) Spring Congress in Kissimmee, Florida.
The analysis, which evaluated 10 randomized placebo-controlled registrational trials, found lumateperone was favored for Montgomery-Åsberg Depression Rating Scale (MADRS) change from baseline, MADRS response, MADRS remission, and Clinical Global Impression-Severity (CGI-S) change from baseline when indirectly compared with other approved adjunctive therapies for adults with MDD. Investigators also reported no statistically significant weight gain relative to placebo plus antidepressant therapy and no clinically relevant increase in akathisia risk.
In an interview with HCPLive, Leslie Citrome, MD, MPH, clinical professor of psychiatry & behavioral sciences at the New York Medical College, said the findings offer clinicians a comparative context in a treatment landscape lacking direct head-to-head trials among adjunctive atypical antipsychotics.
“The importance of this network meta-analysis is to provide information about where these different interventions stand relative to each other,” Citrome said. “Because there’s no head-to-head comparison amongst these drugs in randomized controlled clinical trials, we depend on other clinical trials in order to get this information.”
The network meta-analysis used placebo plus antidepressant therapy as a common comparator to indirectly evaluate lumateperone alongside aripiprazole, brexpiprazole, cariprazine, and quetiapine XR. According to Citrome, the shared design structure across registrational trials allowed investigators to estimate comparative efficacy and tolerability despite differences in individual studies.
The analysis showed lumateperone had the greatest placebo-adjusted effect size for MADRS improvement among the therapies evaluated (MADRS change from baseline: mean difference, -4.71; 95% credible interval [CI], -5.78 to -3.63). Citrome noted clinicians often interpret these findings beyond statistical significance alone, focusing instead on the magnitude of symptomatic improvement and the likelihood that patients achieve clinically meaningful outcomes.
“This means, on average, maybe you do have a better chance of achieving remission or response,” Citrome said. “It doesn’t mean that you’re guaranteed success each time, though. This is an average.”
Clinical response in the analysis was defined as a ≥ 50% reduction in MADRS score from baseline, while remission was generally defined as a MADRS score ≤ 10. Citrome said these endpoints better reflect the outcomes clinicians seek in practice than rating-scale changes alone (MADRS response: odds ratio [OR], 2.33; 95% CI, 1.77 to 3.05) and MADRS remission (OR, 2.22; 95% CI, 1.57 to 3.07).
The network meta-analysis also evaluated safety and tolerability outcomes frequently associated with adjunctive atypical antipsychotic use, including weight gain, akathisia, and somnolence.
According to the findings, lumateperone demonstrated no clinically relevant change in weight (from baseline: MD -0.08; 95% CI -0.30 to 0.13) and ranked most favorably among all evaluated therapies for weight-related outcomes, including ≥ 7% weight gain from baseline (OR, 0.41; 95% CI, 0.04 to 1.42). Citrome emphasized the importance of minimizing metabolic burden in long-term MDD management.
“Many patients are concerned about weight gain that they would attribute to the medicines that are prescribed to them,” Citrome said.
The analysis additionally found lumateperone was the only treatment comparable to placebo for akathisia risk (OR 3.78; 95% CI, 0.40 to 17.17). Citrome noted akathisia can complicate clinical assessment because patients may interpret symptoms as worsening anxiety rather than medication-related inner restlessness.
“That inner restlessness that people experience can often be confused with anxiety,” he said. “People don’t understand why they feel more anxious despite being treated for their depression.”
Citrome added clinicians frequently weigh 3 adverse events when selecting adjunctive atypical antipsychotics for MDD: clinically meaningful weight gain, akathisia, and sedation or somnolence, all of which can affect adherence and daily functioning.
Although lumateperone demonstrated favorable outcomes for weight gain and akathisia in the analysis, the risk of somnolence remained greater than that of the placebo, consistent with other adjunctive atypical antipsychotics included in the comparison.
Citrome said the findings reinforce the importance of individualized treatment selection based on patient history, prior treatment response, and tolerability preferences.
“I’m glad that there are many choices out there,” he said. “If one doesn’t work, use the other.”
Editor’s note: Relevant disclosures for Citrome include H. Lundbeck A S, Axsome Therapeutics, Alkermes, Otsuka America Pharmaceutical, E.R. Squibb & Sons, Neurocrine Biosciences, Teva Pharmaceutical, and more.
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