The U.S. Food and Drug Administration (FDA) has approved lumateperone (Caplyta) as an adjunctive therapy with antidepressants for the treatment of major depressive disorder (MDD) in adults.
Lumateperone was approved by the FDA previously for the treatment of schizophrenia and depressive episodes associated with bipolar I and II disorders. Lumateperone is a potent serotonin 5-HT2A receptor antagonist, a dopamine D2 receptor presynaptic partial agonist and postsynaptic antagonist, a D1 receptor–dependent indirect modulator of glutamatergic AMPA and NMDA currents, and a serotonin reuptake inhibitor. Lumateperone has negligible binding to H1, 5-HT2C, and muscarinic receptors, which may limit weight gain.(Figure 1).
The effectiveness of lumateperone, as adjunctive therapy with antidepressants, for the treatment of major depressive disorder (MDD) in adults was established in two 6-week, randomized, double-blind, placebo-controlled, multi-center trials in adult patients who met DSM-5 criteria for MDD, with or without symptoms of anxiety who had inadequate response to one to two courses of prior antidepressant therapy (Study 501 NCT04985942 and Study 502 NCT05061706).
The studies enrolled adults (18-65 years) who met DSM-5 criteria for MDD with inadequate response to 1-2 antidepressant therapies in the current depressive episode and had Montgomery-Åsberg Depression Rating Scale (MADRS) Total score =24, Clinical Global Impression Scale-Severity (CGI-S) score =4, and Quick Inventory of Depressive Symptomatology-Self Report-16 item (QIDS-SR-16) score =14.
Primary and key secondary endpoints were the change from baseline to Day 43 in MADRS Total score and CGI-S score, respectively. In both studies, lumateperone 42 mg adjunctive to antidepressant therapy met the primary endpoint, with significant improvement in depressive symptoms vs placebo plus antidepressant therapy and was generally well tolerated.
In Study 501, lumateperone adjunctive to antidepressant therapy was associated with significantly greater reductions from baseline to day 43 in MADRS total score (least-squares mean difference [LSMD], -4.9; P < .0001) and CGI-S score (LSMD, -0.7; P < .0001) than placebo.
Safety/Tolerability:
- Generally well tolerated; most AEs mild/moderate
- Common AEs (=5%): dry mouth (10.8%), fatigue (9.5%), tremor (5%)
- Minimal weight gain, cardiometabolic effects, prolactin changes, EPS
- Low suicidal ideation rates (1.4% vs 3.5% placebo)
In Study 502, lumateperone 42 mg adjunctive to antidepressant provided a 4.5-point reduction on the MADRS at week 6 compared to placebo, meaning the trial met its primary endpoint. It also met the key secondary endpoint of change from baseline on the CGI-S at week 6.
Other FDA-approved adjunctive treatment options for MDD are serotonin–dopamine antagonists & partial agonists (Table 1) that have safety and tolerability concerns that impact short- and long-term medication adherence, including weight gain, cardiometabolic disturbances, and extrapyramidal symptoms (EPS).
References:
Durgam S et al. J Clin Psychiatry 2025;86(4):25m15848 Abstract.
Durgam S et al. J Clin Psychopharmacol 2025;45(2):67-75. Abstract.
Durgam S et al. Poster presented at the 38th European College of Neuropsychopharmacology (ECNP) Annual Congress, October 11-14, 2025, Amsterdam, The Netherlands.
Durgam S, et al. Poster presented at: Psych Congress Annual Meeting, October 29-November 2, 2024, Boston, MA