Need for Head-to-Head Adjunctive MDD Data, With Leslie Citrome, MD

A network meta-analysis presented as a late-breaking session at the 2026 Neuroscience Education Institute (NEI) Spring Congress in Kissimmee, Florida, suggested lumateperone (CAPLYTA) demonstrated favorable efficacy outcomes and limited weight gain and akathisia risk compared with other FDA-approved adjunctive atypical antipsychotics for major depressive disorder (MDD).

However, in an interview with HCPLive, investigator Leslie Citrome, MD, MPH, a clinical professor of psychiatry and behavioral sciences at New York Medical College, said direct comparative data remain needed to clarify differences between therapies in clinical practice. He said that clinicians should interpret the findings within the context of indirect evidence and the broader limitations of registrational clinical trial populations.

“The limitation that’s really key is that not all studies that were done were included—only those that led to approval by the FDA and that are mentioned in product labeling,” Citrome said.

The analysis indirectly compared lumateperone with aripiprazole, brexpiprazole, cariprazine, and quetiapine XR using placebo plus antidepressant therapy as a common comparator across 10 randomized placebo-controlled registrational trials. Citrome and colleagues reported lumateperone showed the greatest effect size across 4 efficacy outcomes, including Montgomery-Åsberg Depression Rating Scale (MADRS) change from baseline (mean difference, -4.71; 95% credible interval [CrI], -5.78 to -3.63), MADRS response (odds ratio [OR], 2.33; 95% CrI, 1.77 to 3.05), MADRS remission (OR, 2.22; 95% CrI, 1.57 to 3.07), and Clinical Global Impression-Severity (CGI-S) (-0.60; 95% CrI, -0.74 to -0.46) improvements.

According to Citrome, another important limitation involves the characteristics of patients enrolled in randomized controlled trials, which may differ from those of patients routinely seen in practice. Clinical trial participants must provide informed consent, attend scheduled visits, and often receive compensation for participation, creating what he described as a “quasi-artificial environment.”

Patients with suicidal ideation or elevated suicide risk are also commonly excluded from adjunctive MDD trials, potentially limiting generalizability to more complex real-world populations.

“The patients that are in the study may differ somewhat from the patients in practice, but in general, we would expect the same treatment effects overall,” Citrome said.

The findings were not unexpected to Citrome, who noted he has previously evaluated lumateperone using measures such as number needed to treat and number needed to harm. However, he suggested many practicing clinicians may still find the comparative differences among adjunctive atypical antipsychotics notable.

“The average clinician who’s not aware of this research may be a little bit surprised that these drugs are not all the same, and they’re not interchangeable,” Citrome said.

The network meta-analysis found lumateperone demonstrated no statistically significant weight gain relative to placebo plus antidepressant therapy and was the only treatment evaluated with akathisia risk comparable to placebo. Somnolence risk remained greater than placebo, consistent with the broader adjunctive atypical antipsychotic class.

Citrome emphasized that treatment selection in MDD remains individualized and should account for patient preferences and prior adverse event experiences, particularly related to weight gain, akathisia, sedation, and somnolence.

“If you’re looking for a particular drug for a particular person, you must take into account the person’s own values and preferences,” he said.

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 others.

Watch part 1 here: Lumateperone Ranked Favorably Among Adjunctive MDD Therapies, With Leslie Citrome, MD

References

CAPLYTA® (lumateperone) showed greatest improvement across key efficacy outcomes among adjunctive MDD treatments in new network meta-analysis. JNJ.com. Published May 4, 2026. Accessed May 12, 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