A Randomized, Double-blind, Placebo-controlled Proof-of-Concept Trial to Evaluate the Efficacy and Safety of Non-racemic Amisulpride (SEP-4199) for the Treatment of Bipolar I Depression.

BACKGROUND Non-racemic amisulpride (SEP-4199) is an 85:15 ratio of aramisulpride:esamisulpride with a 5-HT7 and D2 receptor binding profile optimized for the treatment of bipolar depression. The aim of this study was to evaluate the efficacy and safety of SEP-4199 for the treatment of bipolar depression. METHODS Patients meeting DSM-5 criteria for bipolar I depression were randomized to 6 weeks of double-blind, placebo-controlled treatment with SEP-4199 200 mg/d or 400 mg/d. The primary endpoint was change in the Montgomery-Asberg Depression Rating Scale (MADRS) at Week 6. The primary efficacy analysis population consisted of patients in Europe and US (n=289); the secondary efficacy analysis population (ITT; n=337) included patients in Japan. RESULTS Endpoint improvement in MADRS total score was observed on both the primary analysis for SEP-4199 200 mg/d (P=0.054; effect size [ES], 0.31) and 400 mg/d (P=0.054; ES, 0.29), and on the secondary (full ITT) analysis for SEP-4199 200 mg/d (P=0.016; ES, 0.34) and 400 mg/d (P=0.024; ES, 0.31). Study completion rates were 81% on SEP-4199 200 mg/d, 88% on 400 mg/d, and 86% on placebo. SEP-4199 had low rates of individual adverse events (<8%) and minimal effects on weight and lipids; median increases in prolactin were +83.6 μg/L on 200 mg/d, +95.2 μg/L on 400 mg/d compared with 0.0 μg/L on placebo. LIMITATIONS The study excluded patients with bipolar II depression and serious psychiatric or medical comorbidity. CONCLUSION Study results provide preliminary proof of concept, needing confirmation in subsequent randomized trials, for the efficacy of non-racemic amisulpride in bipolar depression.