New phase 3 study data on lumateprone (Caplyta) as adjunctive therapy for patients with major depressive disorder and anxious distress has reached primary and secondary endpoints. Study 501 (NCT04985942) met primary endpoints for lumateperone plus antidepressant therapy, with Montgomery-Asberg Depression Rating Scale (MADRS) scores improving for patients with major depressive disorder (MDD) and anxious distress who received the drug as an adjunct.1
Eligible participants were adults aged 18-65 with a diagnosis of MDD (based on DSM-5 criteria) who had inadequate response to 1 or 2 courses of antidepressant therapy, were experiencing a major depressive episode (MADRS score 24 or higher and Clinical Global Impression Scale Severity (CGIS) 4 or higher), and had a Quick Inventory of Depressive Symptomatology Self Report 16 item score of 14 or higher. Inadequate response to antidepressant therapy was defined as less than 50% improvement with antidepressant monotherapy for 6 or more weeks, as measured by the Antidepressant Treatment Response Questionnaire. Patient population included 481 participants in the modified intent to treat group, with 207 (43%) having anxious distress at baseline. Two-hundred thirty-nine participants received adjunctive lumateperone and 242 received adjunctive placebo.
The primary endpoint for lumateperone and antidepressant therapy was met, with results of significantly higher MADRS score improvements from baseline to day 43, as compared with placebo. Lumateperone as an adjunct improved MADRS scores in patients with anxious distress, with improvement almost reaching statistical significance after day 8 (P=.0510) and achieved significance at day 15 (P=.0044). Key secondary endpoints were also met with the treatment group showing significantly greater CGIS improvement compared with placebo (P<.0001). Response and remission rates were also significantly greater for lumateperone plus antidepressant therapy vs placebo.
Lumateperone also improved MADRS inner tension single-item score from baseline to day 43, compared with placebo (P<.0001). General Anxiety Disorder 7 (GAD-7) total scores also improved with lumateperone in treatment vs placebo (P<.0001). The drug had a favorable safetry profile in patients with MDD who had inadequate antidepressant therapy response.
Patients were randomly assigned to 6-week oral administration of lumateperone 42 mg in combination with antidepressant therapy or to placebo plus antidepressant therapy. MADRS scores were evaluated at baseline and days 8, 15, 22, 29, 36 and 43.
Lumateperone is currently approved by the US Food and Drug Administration (FDA) as an antipsychotic to treat schizophrenia and for depressive episodes associated with bipolar disorder 1 and 2 as both monotherapy and adjunctive therapy with lithium or valproate. It has a novel mechanism of action as a modulator of serotonin, dopamine, and glutamate. The drug is a 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.2
For patients with anxious distress, the combination of lumateperone and antidepressant therapy showed significant and clinically meaningful efficacy as compared with adjunctive placebo. “These results suggest lumateperone 42 mg adjuntive to [antidepressant therapy] is a promising new treatment option for adults with MDD and anxious stress with inadequate response to [antidepressant therapy],” investigators noted.
References
1. Durgam S, Earley WR, Kozauer SG, et al. Lumateperone as adjunctive therapy in patients with major depressive disorder and anxious distress. Poster presented at: Psych Congress; September 17-21, 2025; San Diego, CA. Accessed September 18, 2025.
2. Mechanism of action and pharmacology. CAPLYTA HCP. Accessed September 18, 2025. https://www.caplytahcp.com/mechanism-of-action