Dextromethorphan-bupropion safe and effective treatment for major depression: Study

USA: Dextromethorphan-bupropion (AXS-05) is efficient in improving depressive symptoms in patients with major depression compared to bupropion alone and is generally well-tolerated, according to data from a phase-2 trial published in The American Journal of Psychiatry.

Major depressive disorder (MDD), also known as clinical depression is one of the most common mental disorders worldwide. It is characterized by persistently depressed mood or loss of interest in activities, causing significant impairment in daily life and may prove to be potentially life-threatening. Medicines to relieve symptoms and psychotherapy are effective in such patients. Altered glutamatergic neurotransmission is implicated in the pathogenesis of major depressive disorder. AXS-05 (dextromethorphan-bupropion) is a novel, oral NMDA receptor antagonist and sigma-1 receptor agonist, which utilizes inhibition of CYP2D6 to increase its bioavailability.

Herriot Tabuteau, Chief Executive Officer of Axsome, USA, and colleagues conducted a phase 2 trial to assess the efficacy and safety of dextromethorphan-bupropion in the treatment of major depressive disorder compared to the active comparator sustained-release bupropion

Researchers enrolled 80 patients, aged 18-65 years with a diagnosis of a major depressive disorder of moderate or greater severity for the study. Patients were randomly assigned to receive either dextromethorphan-bupropion (45 mg/105 mg tablet) or bupropion (105 mg tablet), once daily for the first 3 days and twice daily thereafter, for a total of 6 weeks.

The primary endpoint was set as the overall treatment effect on the Montgomery-Åsberg Depression Rating Scale (MADRS) score (average of the change from baseline for weeks 1–6). MADRS score was assessed in all randomized patients whose diagnosis and severity were confirmed by an independent assessor and who received at least one dose of study medication and had at least one postbaseline assessment.

Key findings of the trial include:

• MADRS score was significantly greater with dextromethorphan-bupropion than with bupropion (−13.7 points vs. −8.8 points).

• Remission rates were significantly greater with dextromethorphan-bupropion at week 2 and every time point thereafter (week 6: 46.5% vs. 16.2%).

• Response rates (≥50% decrease in MADRS score from baseline) at week 6, were 60.5% with dextromethorphan-bupropion and 40.5% with bupropion.

• Dextromethorphan-bupropion presented adverse events like dizziness, nausea, dry mouth, decreased appetite, and anxiety but it was not associated with psychotomimetic effects, weight gain, or sexual dysfunction.

The authors conclude that dextromethorphan-bupropion (AXS-05) has proved its efficiency in improving depressive symptoms in patients with major depression without any major adverse events.

Dextromethorphan-bupropion (AXS-05) has shown promising results as a future potential treatment for patients with major depressive disorder, the authors wrote.

Reference:

Tabuteau H, Jones A, Anderson A, Jacobson M, Iosifescu DV. Effect of AXS-05 (Dextromethorphan-Bupropion) in Major Depressive Disorder: A Randomized Double-Blind Controlled Trial. Am J Psychiatry. 2022 Jul;179(7):490-499. doi: 10.1176/appi.ajp.21080800. Epub 2022 May 18. PMID: 35582785.