• Michael E Thase, Arielle D Stanford, Asli Memisoglu, William Martin, Amy Claxton, J Alexander Bodkin, Madhukar H Trivedi, Maurizio Fava, Miao Yu, and Sanjeev Pathak.
• Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania School of Medicine, 3535 Market Street, Suite 670, Philadelphia, PA, 19104-3309, USA. thase@mail.med.upenn.edu.
• Neuropsychopharmacology. 2019 Dec 1; 44 (13): 2268-2276.

AbstractBuprenorphine/samidorphan (BUP/SAM; ALKS 5461) is an investigational opioid system modulator for the adjunctive treatment of patients with major depressive disorder (MDD), who did not respond adequately to prior antidepressant therapy (ADT). FORWARD-2, an open-label extension study, assessed long-term safety and tolerability of adjunctive BUP/SAM treatment in these patients. Patients from four short-term trials and de novo patients were enrolled; all had confirmed MDD and a current major depressive episode lasting 2-24 months. Patients were treated with an established ADT for ≥8 weeks before receiving sublingual, adjunctive BUP/SAM 2 mg/2 mg for up to 52 weeks. Safety (primary objective) was assessed via adverse events (AEs), the Columbia-Suicide Severity Rating Scale, and the Clinical Opiate Withdrawal Scale (COWS). Exploratory evaluation of efficacy was done using the Montgomery-Åsberg Depression Rating Scale (MADRS). Of 1485 patients, 50% completed the study and 11% discontinued due to AEs. AEs of nausea, headache, constipation, dizziness, and somnolence, each occurred in ≥10% of patients. There was no evidence of increased suicidal ideation or behavior. Euphoria-related AEs were uncommon (1.2%). Following abrupt BUP/SAM discontinuation, "drug withdrawal" AEs were infrequent (0.4%), and the incidence of COWS categorical worsening after abrupt drug discontinuation was low (6.5%). Improvements in mean MADRS scores were maintained until study end, suggesting durability of antidepressant effect in patients continuing treatment. BUP/SAM was generally well tolerated, with a low risk of abuse and an AE profile consistent with those seen in placebo-controlled studies. Withdrawal reports were uncommon and of limited clinical impact.

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