REVIEW OF: Tabuteau H et al, Am J Psychiatry 2022;179(7):490–499

STUDY TYPE: Randomized double-blind controlled trial 

It’s frustrating for both patients and doctors when depression treatments fall short, and unfortunately, this is a common problem. Remember the STAR*D trial? It 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 badly need new treatment strategies that can improve and accelerate response rates.

Medications targeting the glutamatergic system appear promising. One example is dextromethorphan, but it’s metabolized too quickly to have a beneficial effect. Bupropion inhibits dextromethorphan’s breakdown, so by pairing both medications, dextromethorphan’s bioavailability and half-life increase sufficiently for it to have a therapeutic effect. 

This multisite, randomized, double-blind trial assessed a new combination tablet of dextromethorphan-bupropion (AXS-05, now marketed as Auvelity) compared to sustained-release bupropion in patients ages 18–65 (n=80) diagnosed with moderate to severe major depressive disorder. Participants received either dextromethorphan-bupropion (45 mg/105 mg tablet, n=43) or bupropion only (105 mg tablet, n=37). Treatment was once daily for the first three days, followed by twice-daily administration for six weeks. Treatment responses were evaluated using weekly Montgomery-Åsberg Depression Rating Scale (MADRS) measurements.

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 vs 16% of bupropion-only patients. Response rates (defined as a 50% decrease in MADRS score from baseline) were 61% with dextromethorphan-bupropion compared to 41% with bupropion at six weeks. The medication was well tolerated, and adverse events were comparable to the bupropion group.

Limitations of the study include the short duration and the exclusion of patients with comorbid psychiatric disorders or medical comorbidities. Another concern is that Axsome Therapeutics (Auvelity’s producer) funded the study. The authors mention that Axsome’s involvement was to make sure all the investigators were qualified and appropriately trained to administer the rating scales.

CARLAT TAKE 

A dextromethorphan-bupropion combination tablet was fast acting, effective, and well tolerated in treating major depression. We’d like to see the research replicated with larger sample sizes, for longer durations, and free of industry funding. The FDA seems to see dextromethorphan-bupropion as a promising treatment for major depression, as it granted breakthrough therapy designation to this combination tablet in March 2019. However, keep in mind that dextromethorphan is a medication with misuse potential, commonly utilized by adolescents and some adults with a history of substance misuse. Therefore, we recommend prudence when contemplating dextromethorphan-bupropion in patients with a history of substance use disorders. Be on the lookout for further evidence regarding this new treatment for depression.