Conference Coverage

Dextromethorphan/bupropion combo is remarkably fast-acting antidepressant



– A novel investigational oral combination of dextromethorphan and bupropion achieved a strikingly rapid and clinically meaningful reduction in depressive symptoms in patients with major depressive disorder in a phase 2, active comparator–controlled study, Cedric O’Gorman, MD, reported at the annual congress of the European College of Neuropsychopharmacology.

This agent, known for now as AXS-05, demonstrated a significantly greater improvement in depressive symptoms than bupropion alone at week 1 – the earliest assessment – and the between-group difference continued to grow over the course of the 6-week, double-blind randomized trial. Thus, AXS-05 shows the potential to help meet the widely recognized need for faster-acting, higher-response antidepressant therapies than are currently available, observed Dr. O’Gorman, senior vice president for clinical development and medical affairs at Axsome Therapeutics in New York.

AXS-05 has multimodal mechanisms of action. As a result, it is not only in late-stage clinical development for major depressive disorder, but also for nicotine dependence and agitation in patients with Alzheimer’s disease.

Dextromethorphan is an NMDA (N-methyl-D-aspartate)–receptor antagonist, a serotonin and norepinephrine reuptake inhibitor, a sigma-1–receptor agonist, and a nicotinic-receptor antagonist. Bupropion, too, is a nicotinic-receptor antagonist. In addition, it’s a dopamine and norepinephrine reuptake inhibitor, and it boosts plasma levels of dextromethorphan by inhibiting its metabolism, the psychiatrist explained.

The phase 2, double-blind clinical trial included 80 patients with confirmed major depressive disorder who were experiencing an acute moderate to severe depressive episode. Slightly more than half of them had a history of three or more prior depressive episodes. Their mean baseline Montgomery-Åsberg Depression Rating Scale (MADRS) total score was 32, with a mean Clinical Global Impressions-Severity (CGI-S) score of 4.5 on a 1-7 scale. Participants were randomized to 45 mg dextromethorphan/105 mg bupropion or to 105 mg of bupropion-only, twice daily for 6 weeks.

The primary study endpoint was the average weekly change in MADRS score from baseline to week 6. The difference was highly significant: 13.7 points in the AXS-05 group, 8.8 with bupropion. At week 6, the AXS-05 group averaged a 17.2-point reduction from baseline in MADRS total score, compared with a 12.1-point decrease in controls. The between-group difference numerically favored AXS-05 at week 1, achieving statistically significant superiority from week 2 on. At week 6, 47% of the AXS-05 group had achieved clinical remission as defined by a MADRS score of 10 or less, as did 16% of the bupropion group.

At week 1 – again, the earliest assessment – 18% of AXS-05-treated patients were rated much or very much improved on the CGI, as were 3% of bupropion-treated controls. At week 6, 59% of the AXS-05 group and 27% of controls were rated very much improved.

Twelve percent of patients in both study arms discontinued treatment because of adverse events, none serious. The most common adverse events in the dextromethorphan/bupropion group were nausea, dizziness, dry mouth, reduced appetite, and anxiety. There were no instances of weight gain, sexual dysfunction, or psychomimetic effects.

Two phase 3, double-blind, 6-week RCTs of AXS-05 in depression are ongoing. STRIDE 1 includes 250 patients with treatment-resistant depression randomized to AXS-05 or bupropion. GEMINI is a study of 300 patients with major depressive disorder assigned to AXS-05 or placebo.

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