The American journal of psychiatryDec 1, 2025

Lumateperone added to treatment in major depression: Results from a late-stage controlled trial

Psychedelic Science Weekly Brief ↗PubMed ↗DOI ↗

Updated Apr 3, 2026

Abstract

Lumateperone 42 mg plus antidepressant therapy significantly improved depression symptoms with a least squares mean difference of -4.5 in the MADRS total score compared to placebo plus antidepressant therapy.

The treatment group showed a statistically significant reduction in the MADRS total score at day 43 compared to the placebo group.
Improvements were also observed in the Clinical Global Impressions Scale severity score, with a least squares mean difference of -0.5.
Patient-reported symptoms improved significantly, with a total score difference of -2.2 on the Quick Inventory of Depressive Symptomatology.
Common treatment-emergent adverse events included dizziness, somnolence, and dry mouth, occurring in at least 5% of the lumateperone group.
The discontinuation rate due to adverse events was higher in the lumateperone group (12.4%) compared to the placebo group (0.8%).
Extrapyramidal symptoms and cardiometabolic abnormalities were minimally observed and comparable between both treatment groups.

Simplified

OBJECTIVE: This phase 3, randomized, double-blind, placebo-controlled trial evaluated lumateperone 42 mg (a simultaneous modulator of serotonin, dopamine, and glutamate neurotransmission) adjunctive to antidepressant therapy (ADT) in patients with major depressive disorder (MDD) and inadequate ADT response.

METHODS: Participants were adults (ages 18-65 years) who had-defined MDD and inadequate response to one to two ADTs in the current depressive episode and a Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≥24. Patients were randomized in a 1:1 ratio to 6 weeks of oral placebo plus ADT (N=238) or lumateperone 42 mg plus ADT (N=242), once daily in the evening; the ADT was the latest drug to which they had inadequate response (i.e., <50% improvement). Primary and key secondary outcomes were change from baseline to day 43 in MADRS total score and Clinical Global Impressions Scale severity (CGI-S) score. Safety measures included adverse events, extrapyramidal symptoms, laboratory assessments, and suicidal ideation and behavior. DSM-5

RESULTS: Lumateperone+ADT met primary and key secondary endpoints, significantly improving MADRS total score (least squares mean difference [LSMD] versus placebo=-4.5; effect size=-0.56) and CGI-S score (LSMD=-0.5; effect size=-0.51) versus placebo+ADT at day 43. Patient-reported depression significantly improved with lumateperone+ADT versus placebo+ADT at day 43 (16-item Quick Inventory of Depressive Symptomatology-Self-Report, total score: LSMD=-2.2; effect size=-0.45). Lumateperone+ADT was generally well tolerated. The most common treatment-emergent adverse events (≥5%, twice the rate in the placebo+ADT group) were dizziness, somnolence, dry mouth, nausea, diarrhea, and fatigue; 12.4% versus 0.8% of patients discontinued treatment due to treatment-emergent adverse events in the lumateperone+ADT arm versus the placebo+ADT arm. There was minimal risk of extrapyramidal symptoms. Cardiometabolic abnormalities and weight gain were similar between the lumateperone+ADT arm and the placebo+ADT arm. Emergence of suicidal ideation was low.

CONCLUSIONS: Patients receiving lumateperone 42 mg plus ADT had statistically significant and clinically meaningful improvement in depression symptoms and disease severity compared with those receiving placebo+ADT. Lumateperone+ADT was generally safe and well tolerated in patients with MDD with inadequate ADT response.

Funding

Competing interests

Drs. Durgam, Earley, Kozauer, Mo, Lakkis, and Edwards are full-time employees of Intra-Cellular Therapies, and may hold equity in the company. Dr. Kornstein receives research support from NIH and the National Science Foundation, and she has served as a consultant for AbbVie, Arrivo Bioventures, Biogen, Eli Lilly, Engrail Therapeutics, Intra-Cellular Therapies, Gerbera, Lipocine, Relmada, Reunion Neuroscience, and Sage Therapeutics. Dr. Fava has received research support from AbbVie, Acadia Pharmaceuticals, Aditum Bio Management Company, Allergan, Alkermes, Altimate Health Corporation, Alto Neuroscience, Ancora Bio, Angelini, Aptinyx, Arbor Pharmaceuticals, Avanir, Axsome, Benckiser Pharmaceuticals, BioClinica, Biogen, Biohaven, BioShin, Cambridge Science Corporation, Centrexion Therapeutics Corporation, Cerecor, Cybin IRL, Damona Pharmaceuticals, EmbarkNeuro, Eliem Therapeutics, Gate Neurosciences, Genomind, Gentelon, Gerbera Therapeutics, Happify, Johnson & Johnson, Lundbeck, Marinus Pharmaceuticals, Medpace, Methylation Sciences, Millennium Pharmaceutics, Minerva Neurosciences, Neuralstem, Neurocrine Biosciences, NeuroRX, Novaremed, NIDA, NIH, NIMH, Novartis, Otsuka, PCORI, Pfizer, Premiere Research International, Praxis Precision Medicines, Protagenic Therapeutics, Relmada Therapeutics, Reckitt, Shenox Pharmaceuticals, Stanley Medical Research Institute, Taisho, Takeda, University of Michigan, Vistagen, WinSanTor, and Xenon Pharmaceuticals; he has served as a consultant for Revival Therapeutics and Sensorium Therapeutics; he has equity holdings in Compellis, Neuromity, Psy Therapeutics, Revival Therapeutics, and Sensorium Therapeutics; he has patents for sequential parallel comparison design, licensed by MGH to Pharmaceutical Product Development, LLC (PPD) (US_7840419, US_7647235, US_7983936, US_8145504, US_8145505), a patent application for a combination of ketamine plus scopolamine in major depressive disorder, licensed by MGH to Biohaven, and patents for pharmacogenomics of depression treatment with folate (US_9546401, US_9540691); copyright for the MGH Cognitive and Physical Functioning Questionnaire, the Sexual Functioning Inventory, the Antidepressant Treatment Response Questionnaire, Discontinuation-Emergent Signs and Symptoms, the Symptoms of Depression Questionnaire, and SAFER; and he has copyrights with Belvoir, Lippincott Williams & Wilkins, Wolters Kluwer, and World Scientific Publishing.

PubMed

Lumateperone added to treatment in major depression: Results from a late-stage controlled trial

Abstract

Funding

Competing interests

You found one interesting study. We’ll send the next 7.

What Lands in Your Inbox Each Week:

Recent issues from the psychedelic science brief

Abstract

Funding

Competing interests

Related papers

You found one interesting study. We’ll send the next 7.

What Lands in Your Inbox Each Week:

Recent issues from the psychedelic science brief