Dextromethorphan/bupropion (Auvelity) is an oral, fixed-dose combination developed by Axsome Therapeutics for major depressive disorder, Alzheimer's disease agitation, and smoking cessation. Dextromethorphan is an NMDA receptor antagonist and sigma-1 receptor agonist; bupropion is an antidepressant and CYP2D6 inhibitor that increases dextromethorphan's bioavailability. The drug received US approval in August 2022 for treating MDD in adults. This article summarizes the development milestones leading to that approval, including clinical trials and regulatory steps.
Many patients with mood disorders such as major depressive disorder and bipolar depression do not respond well to standard antidepressants, creating a need for new treatments. Dysfunction in the brain's glutamate system is thought to play a role in these disorders. Subanesthetic doses of racemic (R,S)-ketamine, a glutamatergic modulator, have been observed to produce rapid reductions in depressive symptoms. This has led to investigation of other glutamate-modulating agents, including broad modulators, glycine site modulators, NMDA receptor antagonists, metabotropic glutamate receptor modulators, and mTORC1 activators. Most are in early development and have shown modest effects compared to (R,S)-ketamine and esketamine, though some have more favorable characteristics. The most promising agents appear to be those targeting ionotropic glutamate receptors.