Major depressive disorder (MDD) is a debilitating, chronic, biologically-based condition. Limitations of current pharmacotherapy include high rates of inadequate response, and suboptimal time to response which can be up to 6-8 weeks with current oral agents. These antidepressants act mainly via monoamine mechanisms. There is an urgent need for faster-acting, more effective, and mechanistically novel treatments. AXS-05 (dextromethorphan-bupropion modulated delivery tablet) is a novel, oral, investigational NMDA receptor antagonist with multimodal activity. AXS-05 utilizes a proprietary formulation and doses of dextromethorphan and bupropion, and metabolic inhibition technology, to modulate the delivery of the components. The dextromethorphan component of AXS-05 is an uncompetitive NMDA receptor antagonist and sigma-1 receptor agonist, and the bupropion component serves to increase the bioavailability of dextromethorphan. ASCEND was a Phase 2, randomized, double-blind, active-controlled, multi-center, U.S. trial. Adult subjects (N=80) with a confirmed diagnosis of moderate-severe MDD were treated either with AXS-05 (dextromethorphan 45 mg-bupropion 105 mg) (n=43), or the active comparator bupropion (105 mg) (n=37), twice daily for 6 weeks. The primary endpoint was the change from baseline in the MADRS total score, calculated at each study timepoint and averaged (overall treatment effect). On the primary endpoint, AXS-05 demonstrated a statistically significant mean reduction from baseline in the MADRS total score over the 6-week treatment period of 13.7 points versus 8.8 for bupropion (p<0.001). At Week 6, AXS-05 demonstrated a 17.2 point reduction in the MADRS total score compared to a 12.1 point reduction for bupropion (p=0.013). AXS-05 rapidly improved depressive symptoms, with a statistically significant improvement over bupropion on the CGI-I scale at Week 1 (p=0.045). Starting at Week 1, AXS-05 achieved superiority over bupropion on the MADRS total score, with statistical significance achieved at Week 2 and maintained thereafter. At Week 6, 47% of AXS-05 patients achieved remission compared with 16% of bupropion patients (p=0.004). The most common AEs in the AXS-05 group were nausea, dizziness, dry mouth, decreased appetite, and anxiety. AXS-05 was not associated with psychotomimetic effects, weight gain, or increased sexual dysfunction. Based on these rapid and substantial antidepressant effects versus bupropion, AXS-05 has the potential to address the urgent need for rapidly-acting, more effective and mechanistically novel antidepressants.