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Jump to Key Points Adding lumateperone to antidepressant therapy was associated with improved sexual function compared to placebo in patients with major depressive disorder (MDD), a new analysis showed.
After 6 weeks of treatment, both men and women reported improvements in sexual functioning, pleasure, and arousal, which appear to be mediated through improvement in depressive symptoms, the investigators noted.
“Adjunctive lumateperone 42 mg improves depressive symptoms without worsening sexual function, suitable for patients with MDD with inadequate antidepressant therapy response seeking to avoid sexual dysfunction as an adverse effect of treatment,” lead author Anita Clayton, MD, professor and chair of psychiatry and neurobehavioral sciences at the University of Virginia in Charlottesville, and colleagues wrote.
The study was published online on September 2 in The Journal of Clinical Psychiatry.
- Adjunctive lumateperone 42 mg + antidepressant improved MDD symptoms at 6 weeks.
- CSFQ-14 sexual function improved vs placebo; LSMD 2.7, ES 0.38, P<.0001.
- Benefit seen across ages/sexes; clinically meaningful only in women.
- Baseline sexual dysfunction common: 82.5%; scores unchanged if absent at baseline.
- ~66.2% of sexual-function effect mediated by depressive symptom improvement.
Common Comorbidity in MDD
Lumateperone, an atypical antipsychotic, was initially approved by the FDA in 2019 for schizophrenia. It was later approved for bipolar disorder and, in 2025, as an adjunctive treatment for MDD.
Sexual dysfunction is a common comorbidity of MDD, affecting an estimated 68% of patients, researchers noted.
“Sexual dysfunction in MDD is underreported and can be worsened by first-line treatments,” researchers noted. Because this is a common reason for treatment discontinuation, “treatments with minimal sexual adverse effects are needed.”
To better understand the drug’s effects on sexual function, researchers conducted a post hoc analysis of a phase 3, double-blind, randomized controlled trial of patients with treatment-resistant MDD.
The analysis was performed on the trial’s intention-to-treat (ITT) population (mean age, 46 years; 69.6% women; 95.4% White). Patients received daily doses of either 42 mg of lumateperone (n = 242) or placebo (n = 238), in addition to antidepressant treatment. ITT patients received one or more doses of either drug. At baseline, 82.5% reported sexual dysfunction.
Sexual function was assessed by the 14-item Changes in Sexual Functioning Questionnaire (CSFQ-14). A change of 2-3 points compared to placebo was classed as a clinically meaningful improvement in sexual functioning. The primary endpoint was the change in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score from baseline to 6 weeks.
Improvement Across Ages and Sexes
Adjunctive treatment with lumateperone led to significantly greater improvement in the MADRS total score at day 43 than with placebo, meeting the primary endpoint.
Compared to placebo, adjunctive treatment with lumateperone was associated with significant improvement in the CSFQ-14 total score at 6 weeks (least-squares mean difference [LSMD], 2.7; effect size [ES], 0.38; P < .0001).
Researchers noted improvements in CSFQ-14 scores across all age groups and sexes, although the improvement was only clinically meaningful in women (LSMD, 3.5; ES, 0.47; P < .0001). Both sexes had significant increases in pleasure and arousal.
Patients with sexual dysfunction at baseline showed significant improvement (LSMD, 3.1; ES, 0.42; P < .0001), and CSFQ-14 scores remained unchanged among those with no sexual dysfunction at the study outset.
In an exploratory analysis, the investigators found that an estimated 66.2% of the treatment effect on sexual functioning scores was mediated through improvements in MADRS total scores.
“These findings suggest that improvement in depressive symptoms, which were observed for the primary efficacy outcome, may also be associated with improvement in sexual functioning,” they wrote.
Limitations of the study were that the long-term effects of lumateperone on sexual functioning may not have been captured, as well as potential bias from self-report measures. In addition, the investigators urged caution in drawing conclusions from the results among men due to the smaller sample size, among other factors.
The study was funded by Intra-Cellular Therapies, which was responsible for the design, analysis, interpretation, and publication of the research. See the study for the full list of author disclosures.
