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

Abstract Background Treatments for MDD that 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 MDD. The dextromethorphan component of an sigma-1 agonist. bupropion serves primarily to increase the bioavailability dextromethorphan. Objective To evaluate effect in improving Methods GEMINI (N=327) was randomized, double-blind, placebo-controlled, 6-week study, which randomized adults (dextromethorphan HBr 45 mg- HCl 105 mg) or placebo, twice daily. primary endpoint change from baseline MADRS total score at Week 6. A post-hoc analysis conducted determine impact versus placebo on 5-item anhedonia subscale (MAS). Results Baseline MAS scores were 19.8 19.6 group, respectively. At 1, treatment resulted significant mean reduction 4.44 2.69 points (p< 0.001). 6, 9.70 compared 7.22 (p=0.001). Response rates (≥ 50% improvement) significantly greater 1 0.001) every time point thereafter. Treatment generally safe well tolerated. most common adverse events dizziness, nausea, headache, diarrhea, somnolence, dry mouth. Conclusions rapidly reduced as symptoms. Funding Axsome Therapeutics