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-4199200 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 completionrates were 81% on SEP-4199 200 mg/d, 88% on 400 mg/d, and 86% on placebo. SEP-4199 had low rates ofindividual adverse events (<8%) and minimal effects on weight and lipids; median increases in prolactin were+83.6 mu g/L on 200 mg/d, +95.2 mu g/L on 400 mg/d compared with 0.0 mu g/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.