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The FDA approved combination dextromethorphan and bupropion extended-release tablets (Auvelity) for adults with major depressive disorder (MDD), announced on Friday.

Dextromethorphan-bupropion is an oral N-methyl D-aspartate (NMDA) receptor antagonist, and "represents the first new oral non-monoamine-based mechanism of action approved to treat major depressive disorder in over sixty years," Maurizio Fava, MD, of Massachusetts General Hospital in Boston, said in a statement from the drugmaker.

Support for the approval came via the phase III GEMINI clinical program, in which patients saw an average 16.6-point reduction in Montgomery-Åsberg Depression Rating Scale scores from baseline versus an 11.9-point reduction for placebo (P=0.002) -- meeting the trial's primary endpoint.

Patients on dextromethorphan-bupropion (45 mg/105 mg) also saw a significant improvement in depression rating within the first week of treatment (-7.3 vs -4.9 for placebo, P=0.007) -- meeting the trial's key secondary endpoint -- and were maintained throughout the 6-week trial.

Dextromethorphan -- used most commonly as a cough suppressant -- acts as the antagonist of the NMDA receptor, as well as an ionotropic glutamate receptor and a sigma-1 receptor agonist. Bupropion, an aminoketone and CYP2D6 inhibitor, increases and prolongs the blood levels of dextromethorphan, which together modulate glutamatergic neurotransmission.

The starting dose of the treatment is one tablet once daily in the morning, then twice daily after 3 days, separated by at least 8 hours in between doses.

According to the label, patients should have their blood pressure checked prior to treatment, as well as be screened for a history of bipolar disorder, mania, or hypomania, and to determine if patients are receiving any other medications that contain bupropion or dextromethorphan.

The label also carries a boxed warning regarding suicidal thoughts and behaviors.

The most common side effects included dizziness, headache, diarrhea, feeling sleepy, dry mouth, sexual function problems, and excessive sweating.

Another NMDA receptor antagonist -- esketamine (Spravato) -- is approved for treatment-resistant depression and MDD, but is only available as a nasal spray.

Axsome said dextromethorphan and bupropion extended-release tablets are expected to hit U.S. shelves by the end of 2022.

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