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

• Main Authors: Deng, L. (Author), Fava, M. (Author), Hopkins, S.C (Author), Kent, J. (Author), Koblan, K.S (Author), Loebel, A. (Author), Tsai, J. (Author)
• Format: Article
• Language: English
• Published: Elsevier B.V. 2022
• Subjects: Agents, Antidepressive; amisulpride; Amisulpride; bipolar disorder; Bipolar disorder; Bipolar Disorder; controlled study; depression; Depression; Depressive disorder; Diagnostic and Statistical Manual of Mental Disorders; double blind procedure; Double-Blind Method; Enantiomer; human; Humans; randomized controlled trial; Serotonin 7 receptor; treatment outcome; Treatment Outcome
• Online Access: View Fulltext in Publisher

 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. © 2021