A phase III trial revealed that adding lumateperone (Caplyta) to existing antidepressant regimens significantly alleviated depressive symptoms in individuals with major depressive disorder (MDD). The study, involving 484 patients, demonstrated that adjunctive lumateperone led to a notable improvement in Montgomery-Åsberg Depression Rating Scale (MADRS) total scores compared to placebo (least square mean difference -4.9, P <0.0001). These findings were presented by Willie Earley, MD, of Intra-Cellular Therapies at Psych Congress in Boston.
Rapid and Sustained Efficacy
"The efficacy was significant as early as day 8 and continued to the end of study at day 43," Dr. Earley noted in his poster presentation, highlighting the rapid onset and sustained effect of lumateperone.
Background on Lumateperone
Lumateperone, an atypical antipsychotic, was initially approved by the FDA for adults with schizophrenia in December 2019. It subsequently received approval in December 2021 for bipolar I or II-related depressive episodes, both as a monotherapy and as an adjunct to lithium or valproate. The drug's mechanism of action involves simultaneous modulation of serotonin, dopamine, and glutamate neurotransmission.
Study Design and Patient Population
The study enrolled adults aged 18-65 with a DSM-5 diagnosis of MDD who had shown an inadequate response to one or two prior antidepressant courses. Inadequate response was defined as less than a 50% improvement after at least 6 weeks of antidepressant monotherapy, as measured by the Antidepressant Treatment Response Questionnaire. Participants were required to be experiencing a major depressive episode with a MADRS total score of ≥24 and a Quick Inventory of Depressive symptomatology-Self Report-16 item (QIDS-SR-16) score of ≥14. The average baseline MADRS total score was 30.4, and the Clinical Global Impressions-Severity scale (CGI-S) score was 4.7.
The treatment arm predominantly consisted of female (66%) and white (75%) participants, with an average age of 45. The majority were on a selective serotonin reuptake inhibitor (SSRI) (65%) compared to a serotonin-norepinephrine reuptake inhibitor (SNRI) (29%).
Treatment Outcomes
Patients were randomized to receive either 42 mg of lumateperone (n=241) or placebo, in addition to their existing antidepressant. Beyond the improvement in MADRS scores, the lumateperone group also exhibited significant enhancements in CGI-S scores (least square mean difference -0.7, P <0.0001), a key secondary endpoint. Additionally, lumateperone-treated patients experienced a 2.4-point reduction in QIDS-SR-16 total score from a baseline of 18.1 (P <0.0001).
Safety and Tolerability
Treatment-emergent adverse events (TEAEs) were more frequent in the lumateperone group (58%) compared to placebo (46.5%), with serious AEs being uncommon in both groups (0.4%). Commonly reported TEAEs in the lumateperone group included dry mouth, fatigue, and tremor (≥5% of patients).
Despite some reports of tremor, there were "no notable changes" in extrapyramidal symptoms (EPS), as measured by the Abnormal Involuntary Movement Scale, Barnes Akathisia Rating Scale, and Simpson-Angus Scale. EPS-related TEAEs, per a broad Medical Dictionary for Regulatory Activities query, occurred in 6.2% of the lumateperone arm versus 2.9% of the placebo arm.
Importantly, no deaths or suicidal behavior were reported during the study. Emergent suicidal ideation was also lower in the lumateperone arm (1.4% vs 3.5%).
Cardiometabolic Profile
Weight and BMI remained stable in both groups throughout the study. Furthermore, there were no clinically relevant mean increases in cardiometabolic measures with lumateperone compared to placebo, including total cholesterol, HDL cholesterol, LDL, triglycerides, glucose, insulin, and prolactin.
Implications and Future Directions
"These results suggest lumateperone 42 mg adjunctive to antidepressant therapy is a promising new treatment option for adults with major depressive disorder with inadequate response to prior antidepressant therapy," Earley and colleagues concluded. Intra-Cellular Therapies anticipates submitting a supplemental new drug application for the adjunctive treatment of major depressive disorder by the end of 2024.
