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Rapid Antidepressant Effects and MADRS Item Improvements With AXS-05 (DEXTROMETHORPHAN-BUPROPION), an Oral NMDA Receptor Antagonist in Major Depressive Disorder: Results From Two Randomized Double-Blind, Controlled Trials

Published online by Cambridge University Press:  14 April 2023

Amanda Jones
Affiliation:
Axsome Therapeutics, New York, NY, USA
Caroline Streicher
Affiliation:
Axsome Therapeutics, New York, NY, USA
Shawn Alter
Affiliation:
Axsome Therapeutics, New York, NY, USA
Zachariah Thomas
Affiliation:
Axsome Therapeutics, New York, NY, USA
Herriot Tabuteau
Affiliation:
Axsome Therapeutics, New York, NY, USA
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Abstract

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Background

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 an NMDA receptor antagonist and a sigma-1 receptor agonist. The bupropion component of AXS-05 serves primarily to increase the bioavailability of dextromethorphan.

Methods

AXS-05 was evaluated in two double-blind, randomized, controlled, 6-week trials. The GEMINI trial (N=327) was placebo-controlled and the ASCEND trial (N=80) used bupropion as the control. Here we focus on efficacy in the first 2 weeks of treatment and present a pooled analysis of the individual items of the MADRS for AXS-05 as compared to control.

Results

In GEMINI, starting at Week 1, AXS 05 was superior (p < 0.05) to placebo on: mean MADRS improvement (7.3 vs. 4.9), MADRS response (15% vs. 7%), CGI-I (22% vs. 13%), CGI-S (0.7 vs. 0.4) and Q-LES-Q-SF (9.0% vs. 5.8%). At Week 2, AXS-05 was also statistically superior to placebo on MADRS remission (17% vs.8%) and on the SDS (6.8 vs. 4.5).

In ASCEND, from Week 2, AXS-05 was superior (p< 0.05) to bupropion on: mean MADRS improvement (12.5vs. 7.8), MADRS remission (26% vs. 3%), and CGI-S (1.41 vs. 0.9).

At Week 1, treatment with AXS-05 resulted in greater improvements (p< 0.05) in reported sadness, inner tension, inability to feel, pessimistic thoughts, and suicidal thoughts, as compared to control. At Week 6, AXS-05 demonstrated significant improvements over control on seven of the ten MADRS items.

In the GEMINI trial, the most commonly reported adverse events were dizziness, nausea, headache, diarrhea, somnolence, and dry mouth.

Conclusions

Treatment with AXS-05 resulted in rapid and broad antidepressant efficacy.

Funding

Axsome Therapeutics

Type
Abstracts
Copyright
© The Author(s), 2023. Published by Cambridge University Press