Abstract
The endogenous opioid system is thought to play an important role in the regulation of mood. Buprenorphine/samidorphan (BUP/SAM) combination is an investigational opioid system modulator for adjunctive treatment of major depressive disorder (MDD). To confirm results from early studies, we report the efficacy and safety of BUP/SAM as adjunctive treatment in patients with MDD and an inadequate response to antidepressant therapy (ADT) in FORWARD-4 and FORWARD-5: two phase 3, randomized, double-blind, placebo-controlled studies that utilized the same sequential parallel-comparison design. Efficacy was measured using the Montgomery–Åsberg Depression Rating Scale (MADRS). FORWARD-5 achieved the primary endpoint and demonstrated that adjunctive BUP/SAM 2 mg/2 mg was superior to placebo (average difference change from baseline to week 3 through end of treatment [EOT] in MADRS-6 and −10 versus placebo: −1.5, P = 0.018; −1.9, P = 0.026, respectively). FORWARD-4 did not achieve the primary endpoint (change from baseline in MADRS-10 at week 5 versus placebo: –1.8, P = 0.109), although separate analyses showed significant treatment differences at other timepoints using traditional, regulatory-accepted endpoints such as reduction in MADRS-10 at EOT. The pooled analysis of the two studies demonstrated consistently greater reduction in MADRS-10 scores from baseline for BUP/SAM 2 mg/2 mg versus placebo at multiple timepoints including EOT and average change from baseline to week 3 through EOT (–1.8, P = 0.010; –1.8, P = 0.004, respectively). The overall effect size (Hedges’ g) in the pooled analyses for MADRS-10 change from baseline to EOT was 0.22. Overall, BUP/SAM was generally well tolerated, with most adverse events (AEs) being mild or moderate in severity. The most common AEs, occurring in ≥5% of patients in the BUP/SAM 2 mg/2 mg treatment group, which was more frequently than the placebo group, included nausea, constipation, dizziness, vomiting, somnolence, fatigue, and sedation. There was minimal evidence of abuse, and no evidence of dependence or opioid withdrawal by AEs or objective measures. This report describes adjunctive BUP/SAM 2 mg/2 mg combination, a therapy with a novel opioidergic mechanism of action, as a potential new treatment option for patients with MDD who have an inadequate response to currently available ADT.
Highlights
Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.Major depressive disorder (MDD) is associated with significant morbidity [1], and is a leading cause of global disability, affecting some 300 million people worldwide [2]
Incidences of serious adverse events (AEs) were low in both. The data from these two FORWARD trials support the view that the BUP/SAM combination represents a promising potential adjunctive treatment for patients with MDD, acting through a novel, opioidergic mechanism of action compared with current antidepressant therapies
In the FORWARD-5 study, adjunctive BUP/SAM 2 mg/2 mg consistently reduced depression symptomatology compared to placebo across multiple timepoints in patients continuing their current antidepressant therapy (ADT) and met the primary endpoints of reducing core and overall depression symptoms
Summary
Major depressive disorder (MDD) is associated with significant morbidity [1], and is a leading cause of global disability, affecting some 300 million people worldwide [2]. Predominant pharmacotherapies approved for treatment of Corporal Michael Crescenz Veterans Affairs Medical Center, Philadelphia, PA, USA 3 University of Texas Southwestern Medical Center, Dallas, TX, USA 4 Alkermes, Inc., Waltham, MA, USA. Opioid system modulation with buprenorphine/samidorphan combination for major depressive disorder: two. BUP/SAM (2 mg/2 mg) Placebo + ADT.
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