Adjunctive Lumateperone Improves Remission Rates in MDD, With Michael E. Thase, MD

Achieving sustained remission remains a central challenge in the management of major depressive disorder (MDD), particularly for patients who fail to respond adequately to antidepressant therapy (ADT) alone. New pooled analyses evaluating lumateperone 42 mg as an adjunct to ADT provide encouraging evidence for both short-term efficacy and long-term durability, as discussed by Michael E. Thase, MD, of the University of Pennsylvania, in a recent interview.

“[Patients who do not respond easily to antidepressants are not only at grave risk for continuing to suffer and continuing to do poorly at work and in their social roles, but they are also more likely to then become chronically depressed,” Thase told HCPLive. “It's not just enough to help them feel better over 6 weeks or 8 weeks or in the short run, but it's really important for the benefits to be sustained and for the treatment benefit not to dissipate.”

He provided the example of weight gain, which can appear relatively small in 6 weeks but large over 6 months.

“I'm glad to say that in the long term…the benefits were sustained,” Thase continued. “People did, on average, continue to improve if they had not had a full remission with the first 6 weeks of treatment [and] that that could happen with continued treatment. There was very little cost for the continued treatment in terms of the risk of weight gain or the development of new side effects.”

In pooled short-term studies, presented at the American College of Neuropsychopharmacology (ACNP) Annual Meeting in the Bahamas from January 12 – 15, 2026, lumateperone 42 mg plus ADT demonstrated significantly greater Montgomery–Åsberg Depression Rating Scale (MADRS) total score remission rates compared with placebo plus ADT by day 43 (25.5% vs 13.6%; P <.0001). Complete remission was achieved by 10.6% of patients receiving lumateperone versus 5.6% of those receiving placebo, highlighting the clinical relevance of early symptom resolution in patients with an inadequate response to ADT (P <.01). In a separate long-term trial, complete remission was achieved by 44.1% of patients.

During the open-label phase, 65.4% of patients achieved remission. In each subgroup analysis, over 55% of patients receiving lumateperone plus ADT achieved remission at the end of the trial. Remission rates were similar despite age, ADT treatment, or baseline disease severity.

Tolerability further distinguishes lumateperone from other adjunctive options. Across studies, treatment was associated with minimal weight gain, low discontinuation rates, and a favorable neurologic safety profile, with little evidence of akathisia or extrapyramidal symptoms—concerns that often limit long-term use of other adjunctive agents.

“I want clinicians to know that we not only have a new therapy that's been approved for this purpose now, lumateperone has been approved for several years for the treatment of schizophrenia, but now it's approved for the adjunctive treatment of major depressive disorder and that it is effective… [and] effective relatively quickly,” Thase said. “There's only a single therapeutic dose, 42 milligrams, so it's easy to get the dose right. It's really well tolerated; very few patients drop out there. There's little, if [any], weight gain associated with the treatment. Patients are unlikely to have uncomfortable, neurologic side effects such as restlessness or stiffness…We're delighted that the results turned out so well.”

Relevant disclosures for Thase include Otsuka Pharmaceutical, Janssen Scientific Affairs, E.R. Squibb & Sons, Eli Lilly and Company, H. Lundbeck A S, Boehringer Ingelheim International GmbH, and ITI, Inc. (d/b/a Intra-Cellular Therapies, Inc.).

References

Bhagwagar Z, Durgam S, Earley W, et al. Remission with lumateperone 42 mg adjunctive to antidepressant therapy in patients with Major Depressive Disorder: Analysis of Short-Term and Long-Term Trials. Presented at the American College of Neuropsychopharmacology (ACNP) Annual Meeting in Bahamas from January 12 – 15, 2026