It's frustrating for both patients and doctors when depression treatments fall short, and unfortunately, this is a common problem. The seminal STAR*D trial, for example, found that two-thirds of depressed patients didn't achieve remission with first-line treatments, and those who responded only did so after eight weeks of treatment (Trivedi MH et al, Am J Psychiatry 2006;163:28–40). We need new treatment strategies that can improve, and accelerate, response rates.

Medications targeting the glutamatergic system appear promising. One such example is dextromethorphan, but it's metabolized too quickly to have a beneficial effect. Bupropion inhibits dextromethorphan's breakdown, so by pairing dextromethorphan with extended-release bupropion in one tablet, dextromethorphan's bioavailability and half-life increase sufficiently for it to have a therapeutic effect. (Bupropion's own antidepressant effects don't hurt either.)

This multisite, randomized, double-blind trial assessed a combination tablet of dextromethorphan-bupropion (AXS-05, now marketed as Auvelity) versus sustained-release bupropion in patients aged 18–65 (n=80) diagnosed with moderate to severe major depressive disorder (MDD). Participants received either dextromethorphan-bupropion (45 mg/105 mg tablet; n=43) or bupropion alone (105 mg tablet; n=37) once daily for the first 3 days, then twice daily for 6 weeks. Treatment responses were evaluated using weekly Montgomery-Åsberg Depression Rating Scale (MADRS) scores.

Results

Dextromethorphan-bupropion produced a significantly greater, and faster, reduction of depressive symptoms compared to bupropion alone. For example, at week 2, 47% of dextromethorphan-bupropion patients reached remission, versus 16% of bupropion patients. Response rates (defined as 50% decrease in MADRS score from baseline) were 61% with dextromethorphan-bupropion compared to 41% with bupropion at 6 weeks. The combo was well tolerated, with adverse events comparable to the bupropion group.

Limitations of the study included its short duration and the exclusion of patients with comorbid psychiatric or medical disorders. The study was also industry funded.

A 2023 review summarized eight clinical trials of dextromethorphan-bupropion for MDD, bipolar depression, and treatment-resistant depression. It concluded that the evidence was solid for MDD but mixed for the latter two conditions (Parincu Z and Iosifescu DV, Expert Rev Neurother 2023;23(3):205–212).