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Clinical Trial
. 2019 Dec;44(13):2268-2276.
doi: 10.1038/s41386-019-0451-3. Epub 2019 Jun 29.

Results from a long-term open-label extension study of adjunctive buprenorphine/samidorphan combination in patients with major depressive disorder

Michael E Thase  1 , Arielle D Stanford  2 , Asli Memisoglu  2 , William Martin  2 , Amy Claxton  2 , J Alexander Bodkin  3   4 , Madhukar H Trivedi  5 , Maurizio Fava  4   6 , Miao Yu  2 , Sanjeev Pathak  2
Affiliations
Clinical Trial

Results from a long-term open-label extension study of adjunctive buprenorphine/samidorphan combination in patients with major depressive disorder

Michael E Thase et al. Neuropsychopharmacology. 2019 Dec.

Abstract

Buprenorphine/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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Figures

Fig. 1
Fig. 1
a Mean MADRS scores over time and b proportion of patients achieving remission during BUP/SAM treatment. Data were based on observed cases. Week 0 refers to baseline of this study and was the baseline for patients without prior BUP/SAM exposure. PBL refers to the prior baseline for those patients with prior BUP/SAM exposure, i.e., their baseline from study FORWARD-1, FORWARD-3, FORWARD-4, or FORWARD-5. Each subsequent week refers to week of study visit during FORWARD-2 and corresponds to week since BUP/SAM initiation for patients with no prior BUP/SAM exposure. Remission was defined as Montgomery–Åsberg Depression Rating Scale score ≤ 10. BUP/SAM buprenorphine/samidorphan, MADRS Montgomery–Åsberg Depression Rating Scale, PBL prior baseline
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