Impact of AXS-05 (DEXTROMETHORPHANBUPROPION), an Oral NMDA Receptor Antagonist, on Anhedonic Symptoms in Major Depressive Disorder

Background. Treatments forMDDthat can improve both overall depressive and anhedonic symptoms are urgently needed. AXS‐05 (dextromethorphan‐bupropion) is a novel, oral, investigational NMDA receptor antagonist with multimodal activity being developed for MDD. The dextromethorphan component of AXS‐05 is anNMDAreceptor antagonist and a sigma‐1 receptor agonist. The bupropion component of AXS‐05 serves primarily to increase the bioavailability of dextromethorphan. Objective. To evaluate the effect of AXS‐05 in improving anhedonic symptoms in MDD. Methods. GEMINI (N=327) was a randomized, double‐blind, placebo‐controlled, 6‐week study, which randomized adults with MDD to AXS‐05 (dextromethorphan HBr 45 mg‐ bupropion HCl 105 mg) or placebo, twice daily. The primary endpoint was change from baseline in the MADRS total score at Week 6. A post‐hoc analysis was conducted to determine the impact of AXS‐05 versus placebo on the 5‐item MADRS anhedonia subscale (MAS). Results. Baseline MAS scores were 19.8 and 19.6 in the AXS‐05 and placebo group, respectively. At Week 1, AXS‐05 treatment resulted in a significant mean reduction from baseline in the MAS score of 4.44 versus 2.69 points for placebo (p< 0.001). At Week 6, the mean reduction from baseline in the MAS was 9.70 for AXS‐05 compared to 7.22 for placebo (p=0.001). Response rates (≥50%MAS improvement) were significantly greater for AXS‐05 compared to placebo at Week 1 (p< 0.001) and at every time point thereafter. Treatment with AXS‐05 was generally safe and well tolerated. The most common adverse events being dizziness, nausea, headache, diarrhea, somnolence, and dry mouth. Conclusions. Treatment with AXS‐05 rapidly and significantly reduced anhedonic symptoms as well as overall depressive symptoms.