Lumateperone Shows Broad Symptom Benefit for MDD, With Michael E. Thase, MD

New analyses of adjunctive lumateperone (CAPLYTA) move beyond remission rates to address questions clinicians routinely face regarding symptom-specific benefits, long-term safety, and where the medication may fit in the adjunctive treatment strategy for major depressive disorder (MDD), according to Michael E. Thase, MD, of the University of Pennsylvania.1

“To make a long story short, the improvement is consistent across all of the symptoms,” Thase told HCPLive. “The least improvement was seen on the suicide item, but that's not because it doesn't reduce suicidal ideation. It's because… It's not a good idea to have such a patient in a placebo-controlled trial in which they might not get an active medicine for 6 or 8 weeks. So, I would look at that as not a meaningful finding. And even on that item, there was improvement. It just wasn't nominally quite as much [of an] improvement. So, benefit is broad. It's across symptom domains. It includes relief of anxiety and anxious arousal. It includes improvement of sleep…[and] improvement in life satisfaction.”

The US Food & Drug Administration (FDA) approved lumateperone as an adjunctive treatment for MDD, announced by Johnson & Johnson on November 6, 2025.2 Since then, investigators conducted further research on remission rates and the safety of lumateperone for this treatment indication.

The analyses pooled short-term data from multiple randomized, placebo-controlled trials in patients with MDD who had an inadequate response to antidepressant therapy (ADT).1 In these studies, lumateperone 42 mg plus ADT significantly improved Montgomery–Åsberg Depression Rating Scale (MADRS) remission rates by day 43 compared with placebo plus ADT (25.5% vs 13.6%; P <.0001). Complete remission, reflecting near-total symptom resolution, occurred in 10.6% of lumateperone-treated patients versus 5.6% of placebo-treated patients (P <.01), demonstrating meaningful early symptom improvement in this difficult-to-treat population.

Long-term outcomes from a separate trial and open-label extension showed that 44.1% of patients achieved complete remission, and 65.4% reached remission at some point during the study. Subgroup analyses indicated that these benefits were consistent across age, baseline disease severity, and concomitant antidepressant type.1

Beyond overall MADRS improvement, lumateperone demonstrated efficacy across individual symptom domains. Thase noted that all 10 MADRS items—including mood, sleep disturbance, anxiety, and hedonic capacity—showed improvement. Sleep and anxiety improvements were particularly relevant given their contribution to functional impairment and relapse risk. Additional measures outside the MADRS, including life satisfaction and standard anxiety scales, further supported the medication’s broad multidimensional impact.1

Long-term tolerability was also favorable. Six-month follow-up revealed minimal weight gain, low rates of sexual dysfunction, and few neurologic adverse effects, such as akathisia or extrapyramidal symptoms. Thase emphasized that these findings support the safety of continued treatment.1

“It's one thing not to have weight gain over six weeks. It's another not to have meaningful weight gain over six months,” Thase said. “The 6-month data are very reassuring about the safety profile of this medication.”

Given these results, lumateperone could be considered after failure of a second antidepressant trial, and future evidence may support its evaluation earlier in the adjunctive sequence. Remaining questions focus on very long-term outcomes, particularly tardive dyskinesia, though real-world experience in bipolar depression suggests a very low risk.1

“I've been excited about this medication since I don't treat very many people with schizophrenia. When I began to see this used for treatment of bipolar depression, I couldn't wait to have it approved for adjunctive therapy for people with non bipolar depression, because I knew that it had a really good, favorable profile and that it helped a meaningful proportion of patients. So I just want to say I'm delighted that we have it available, and I look forward to having broader use of it than I've had previously.

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

1. Thase M. Adjunctive Lumateperone Improves Remission Rates in MDD, With Michael E. Thase, MD. HCPLive. Published on January 19, 2026. Accessed on January 19, 2026. https://www.hcplive.com/view/adjunctive-lumateperone-improves-remission-rates-mdd-michael-e-thase-md

2. FDA approval of CAPLYTA® (lumateperone) has the potential to reset treatment expectations, offering hope for remission in adults with major depressive disorder. JNJ.com. Published November 6, 2025. Accessed on January 19, 2026. https://www.jnj.com/media-center/press-releases/fda-approval-of-caplyta-lumateperone-has-the-potential-to-reset-treatment-expectations-offering-hope-for-remission-in-adults-with-major-depressive-disorder