Safety and Tolerability of Adjunctive Lumateperone for the Treatment of Major Depressive Disorder: A Pooled Analysis of Two Randomized Placebo-Controlled Trials.

BACKGROUND AND

OBJECTIVES

Lumateperone, a simultaneous modulator of serotonin, dopamine, and glutamate neurotransmission, demonstrated efficacy and safety as adjunctive therapy in two phase III, randomized, double-blind, placebo-controlled trials in patients with major depressive disorder with inadequate antidepressant therapy (ADT) response. The objective of this pooled analysis of Studies 501 and 502 was to investigate the safety and tolerability of lumateperone 42 mg + ADT.

METHODS

Data were pooled from two studies that enrolled adults (aged 18-65 years) with Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition-defined major depressive disorder with inadequate response to one to two ADTs in the current depressive episode (Montgomery-Åsberg Depression Rating Scale Total score ≥ 24; Clinical Global Impression-Severity score ≥ 4). Patients were randomized to 6 weeks of oral lumateperone 42 mg + ADT or placebo + ADT. Safety measures included adverse events, body morphology, cardiometabolic parameters, prolactin levels, extrapyramidal symptoms (EPS), and suicidality.

RESULTS

The pooled population comprised 964 patients (lumateperone + ADT, n = 483; placebo + ADT, n = 481). Treatment-emergent adverse events (TEAEs) occurred in 68.1% and 45.1% of the lumateperone + ADT and placebo + ADT groups, respectively. Treatment discontinuation because of an adverse event occurred in 8.7% of the lumateperone + ADT group and 0.8% of the placebo + ADT group. The most common TEAEs (≥ 5%, greater than twice placebo + ADT) were dizziness, dry mouth, somnolence, nausea, fatigue, and diarrhea. Of patients experiencing TEAEs, the majority (96.3%) had events of mild or moderate severity. Potentially clinically significant weight increase (≥ 7%) occurred in 0.4% and 1.3% of the lumateperone + ADT and placebo + ADT groups, respectively. Changes in cardiometabolic parameters and prolactin levels were minimal and similar to placebo + ADT. No notable changes occurred in EPS-related scales. EPS-related TEAEs occurred in 5.8% and 1.7% of lumateperone + ADT and placebo + ADT groups, respectively. The most common EPS-related TEAE was tremor (lumateperone + ADT, 3.9%; placebo + ADT, 0.2%), which had a mean duration of 11.9 days in the lumateperone + ADT group. Emergence of suicidal ideation was infrequent (lumateperone + ADT, 1.6%; placebo + ADT, 2.5%).

CONCLUSIONS

Lumateperone 42 mg + ADT had a good safety profile and was generally well tolerated in this pooled analysis, with low risks of weight gain, cardiometabolic abnormalities, and EPS with short-term treatment but with higher discontinuation rates because of adverse events (8.7%) versus placebo + ADT, in patients with major depressive disorder with inadequate ADT response.

CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT04985942 (registered 22 July, 2021); NCT05061706 (registered 20 September, 2021).