Adjunctive lumateperone (ITI-007) in the treatment of bipolar depression: Results from a randomized placebo-controlled clinical trial.

OBJECTIVE: This phase 3, randomized, double-blind, placebo-controlled study (NCT02600507) evaluated the efficacy and safety of lumateperone adjunctive therapy to lithium or valproate in patients with bipolar depression. METHODS: Patients (18-75 years) with bipolar I or bipolar II disorder experiencing a major depressive episode (MDE), with inadequate therapeutic response to lithium or valproate, were randomized 1:1:1 to 6 weeks adjunctive therapy with lumateperone 28 mg (n = 176), lumateperone 42 mg (n = 177), or placebo (n = 176). The primary and key secondary efficacy endpoints were change from baseline to Day 43 in Montgomery-Åsberg Depression Rating Scale (MADRS) Total score and the Clinical Global Impression Scale-Bipolar Version-Severity Scale (CGI-BP-S) depression subscore. Safety assessments included adverse events, laboratory evaluations, vital signs, extrapyramidal symptoms (EPS), and suicidality. RESULTS: Patients treated with adjunctive lumateperone 42 mg showed significantly greater improvement compared with adjunctive placebo in MADRS Total score (LS mean difference vs placebo [LSMD], -2.4; p = 0.02) and CGI-BP-S depression subscore (LSMD, -0.3; p = 0.01), while adjunctive lumateperone 28 mg showed numerical improvement in MADRS Total score (LSMD, -1.7; p = 0.10) and improvement in the CGI-BP-S depression subscore (LSMD, -0.3; p = 0.04). Adjunctive lumateperone treatment was well tolerated; treatment-emergent adverse events reported at rates >5% and twice placebo for lumateperone 42 mg were somnolence (11.3%), dizziness (10.7%), and nausea (8.5%), with minimal risk of EPS, metabolic abnormalities, or increased prolactin. CONCLUSIONS: Lumateperone 42-mg treatment adjunctive to lithium or valproate significantly improved depression symptoms and was generally well tolerated in patients with MDEs associated with either bipolar I or bipolar II disorder.