In this episode, we discuss the evidence, safety, and place in therapy of Auvelity® (dextromethorphan-bupropion), a newly approved antidepressant with a unique mechanism of action and interesting pharmacokinetic considerations. Key Concepts Auvelity® (bupropion-dextromethorphan) was FDA approved in 2022 for major depressive disorder (MDD). The bupropion component inhibits CYP2D6 metabolism and increases serum concentrations of dextromethorphan. The proposed mechanism of benefit in MDD is via dextromethorphan (as an NMDA antagonist) and possibly with bupropion (as a dopamine/norepinephrine reuptake inhibitor). Although the bupropion component in Auvelity® is being used for its drug interaction, the dose is a therapeutic dose and carries several warnings and precautions, including the risk of seizure and hypertension. In short (6-week) clinical trials, Auvelity® improved depression symptoms quickly (within 1-2 weeks), which is faster than many other antidepressants. Auvelity® is associated with dizziness, anxiety, hyperhidrosis, nausea, headache, diarrhea, and dry mouth. As a CYP2D6 inhibitor, the bupropion component of Auvelity® will cause drug interactions with many other medications, including some antidepressants, antipsychotics, and opioid analgesics (among others). References Iosifescu DV, Jones A, O'Gorman C, et al. Efficacy and Safety of AXS-05 (Dextromethorphan-Bupropion) in Patients With Major Depressive Disorder: A Phase 3 Randomized Clinical Trial (GEMINI). J Clin Psychiatry. 2022;83(4):21m14345. Published 2022 May 30. doi:10.4088/JCP.21m14345 Tabuteau H, Jones A, Anderson A, Jacobson M, Iosifescu DV. Effect of AXS-05 (Dextromethorphan-Bupropion) in Major Depressive Disorder: A Randomized Double-Blind Controlled Trial. Am J Psychiatry. 2022;179(7):490-499. doi:10.1176/appi.ajp.21080800 Kotlyar M, Brauer LH, Tracy TS, et al. Inhibition of CYP2D6 activity by bupropion. J Clin Psychopharmacol. 2005;25(3):226-229. doi:10.1097/01.jcp.0000162805.46453.e3