REVIEW OF: Maji S et al, Psychiatry Res 2024;342:116257

STUDY TYPE: Randomized, double-blind, placebo-controlled clinical trial

Dextromethorphan is best known as an over-the-counter cough suppressant, but it also acts as an NMDA receptor antagonist (like ketamine) and modulates serotonin and norepinephrine. It’s already paired with bupropion in the combo pill Auvelity, where bupropion’s CYP2D6 inhibition prolongs the action of 90 mg of dextromethorphan. This study investigated lower doses of dextromethorphan with SSRIs for early augmentation in mild to moderate MDD.

Researchers randomly assigned 60 adults—about half under 35—to receive either 30 mg/day of dextromethorphan or a placebo for 8 weeks. All had been depressed for about 6–7 weeks and had started SSRIs (the equivalent of 50 mg of sertraline) within 4 weeks. Patients with a history of substance use were excluded. The primary outcome was change in Montgomery–Åsberg Depression Rating Scale (MADRS) score. Secondary measures included response (≥ 50% improvement), remission (MADRS < 7), Clinical Global Impression Scale (CGI) scores, and tolerability.

Patients receiving dextromethorphan showed a significantly greater MADRS reduction, with a large effect size (Cohen’s d = 1.05) and nearly double the response and remission rates of patients receiving placebo. CGI improvements were also significantly better. The treatment was well tolerated, with no serious adverse events. Improvement was most pronounced in those with moderate depression and in patients receiving sertraline; however, the effects of paroxetine and fluoxetine were hard to study given the low sample size.

CARLAT TAKE
If you want to add dextromethorphan to an antidepressant, bupropion is currently the only FDA-approved option. However, this single-center study investigating recent episodes of depression in a relatively young population also supports the use of 30 mg of SSRIs. Paroxetine and fluoxetine inhibit CYP2D6, but sertraline doesn’t, so it’s unfortunate that this trial didn’t have the power to detect differences between individual SSRIs. If you try this off label, the simplest and cheapest approach is OTC immediate-release dextromethorphan, rather than combination cough products.