Efficacy and Safety of AXS-05 (Dextromethorphan-Bupropion) in Patients With Major Depressive Disorder

Abstract

Abstract Objective: Altered glutamatergic neurotransmission has been implicated in the pathogenesis of depression. This trial evaluated the efficacy and safety of AXS-05 (dextromethorphan-bupropion), an oral NMDA receptor antagonist and σ1 receptor agonist, in the treatment of major depressive disorder (MDD). Methods: This double-blind, Phase 3 trial, was conducted between June 2019 and December 2019. Patients with a DSM-5 diagnosis of MDD were randomized in a 1:1 ratio to receive dextromethorphan-bupropion (45 mg-105 mg tablet) or placebo, orally (once daily for days 1-3, twice daily thereafter) for 6 weeks. The primary endpoint was the change from baseline to week 6 in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Other efficacy endpoints and variables included MADRS changes from baseline at week 1 and 2, clinical remission (MADRS score ≤ 10), clinical response (≥ 50% reduction in MADRS score from baseline), clinician- and patient-rated global assessments, Quick Inventory of Depressive Symptomology-Self-Rated, Sheehan Disability Scale, and quality of life measures. Results: A total of 327 patients were randomized: 163 patients to dextromethorphan-bupropion and 164 patients to placebo. Mean baseline MADRS total scores were 33.6 and 33.2 in the dextromethorphan-bupropion and placebo groups, respectively. The least-squares mean change from baseline to week 6 in MADRS total score was -15.9 points in the dextromethorphan-bupropion group and -12.0 points in the placebo group (least-squares mean difference, -3.87; 95% confidence interval [CI], -1.39 to -6.36; P<0.001). Dextromethorphan-bupropion was superior to placebo for MADRS improvement at all timepoints including week 1 (P=0.007) and week 2 (P<0.001). Remission was achieved by 39.5% of patients with dextromethorphan-bupropion versus 17.3% with placebo (least-squares mean difference, 22.2; 95% CI, 11.7 to 32.7; P<0.001), and clinical response by 54.0% versus 34.0%, respectively (least-squares mean difference, 20.0%; 95% CI, 8.4%, 31.6%; P<0.001), at week 6. Results for most secondary endpoints were significantly better with dextromethorphan-bupropion than with placebo at almost all timepoints (eg, CGI-S least-squares mean difference at week 6, -0.48; 95% CI, -0.48 to -0.79; P=0.002). The most common adverse events in the dextromethorphan-bupropion group were dizziness, nausea, headache, somnolence, and dry mouth. Dextromethorphan-bupropion was not associated with psychotomimetic effects, weight gain, or increased sexual dysfunction. Conclusions: In this Phase 3 trial in patients with MDD, treatment with dextromethorphan-bupropion (AXS-05) resulted in significant improvements in depressive symptoms compared to placebo starting one week after treatment initiation, and was generally well tolerated. Clinical Trial Registration ClinicalTrials.gov Identifier: NCT04019704