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AXS-05 reduced depressive symptoms more than placebo over 6 weeks in adults with major depressive disorder. The primary endpoint, change in MADRS total score at week 6, was −15.9 points with dextromethorphan-bupropion versus −12.0 points with placebo, for a least-squares mean difference of −3.87 points (95% CI, −1.39 to −6.36; P=.002).

The authors also reported statistically significant benefits versus placebo at every assessed time point, starting at week 1.

AXS-05 separated from placebo by week 1 on depressive symptoms. At week 1, the least-squares mean change from baseline in MADRS total score was −7.20 with dextromethorphan-bupropion versus −4.97 with placebo, a difference of −2.23 points (95% CI, −0.60 to −3.86; P=.007).

By week 2, the difference increased to −3.44 points on MADRS (−11.09 vs −7.66; 95% CI, −1.40 to −5.47; P<.001).

Yes. AXS-05 produced higher remission and response rates than placebo. Remission, defined as MADRS total score ≤10, occurred in 16.9% of patients receiving dextromethorphan-bupropion versus 7.5% receiving placebo at week 2 (treatment difference, 9.4%; 95% CI, 1.9%–16.8%; P=.013).

At week 6, remission rates were 39.5% versus 17.3% (treatment difference, 22.2%; 95% CI, 11.7%–32.7%; P<.001), and clinical response, defined as at least 50% reduction in MADRS total score, was 54.0% versus 34.0% (treatment difference, 20.0%; 95% CI, 8.4%–31.6%; P<.001).

The most common adverse events with AXS-05 were dizziness, nausea, headache, somnolence, and dry mouth. Adverse events during treatment occurred in 61.7% of patients receiving dextromethorphan-bupropion and 45.1% of patients receiving placebo.

Adverse events leading to discontinuation occurred in 6.2% of the dextromethorphan-bupropion group versus 0.6% of the placebo group.

In this trial, AXS-05 was not associated with psychotomimetic effects, weight gain, or increased sexual dysfunction. The authors also reported no suicide-related adverse events or suicidal behaviors on the Columbia-Suicide Severity Rating Scale in either treatment group.

One patient in each group reported suicidal ideation without intent at week 6 on the C-SSRS.

GEMINI was a phase 3, randomized, double-blind, placebo-controlled trial conducted over 6 weeks at 40 US centers. A total of 327 patients were randomized 1:1 to dextromethorphan-bupropion 45 mg-105 mg or placebo; patients received study medication once daily for 3 days and then twice daily thereafter.

The modified intent-to-treat population included 156 patients in the dextromethorphan-bupropion group and 162 in the placebo group.

The study enrolled adults aged 18–65 years with nonpsychotic major depressive disorder of at least moderate severity. Patients had to have a major depressive episode lasting at least 4 weeks, a MADRS total score of 25 or higher, and a CGI-S score of 4 or higher.

Key exclusions included bipolar disorder, psychotic disorder, panic disorder, obsessive-compulsive disorder, treatment-resistant depression defined as at least 2 adequate failed antidepressant treatments in the current episode, alcohol or substance use disorder within the past year, clinically significant suicide risk, and history of seizure disorder.

Yes. The authors reported broader benefits beyond clinician-rated depression scores. At all time points, least-squares mean improvements from baseline on the QIDS-SR-16, MADRS-6, and Q-LES-Q-SF were statistically significantly greater with dextromethorphan-bupropion than with placebo, and the percentage of patients much or very much improved on the PGI-I was also significantly higher.

Improvement on the Sheehan Disability Scale was statistically significantly greater with dextromethorphan-bupropion at week 2 and at every time point thereafter; the article notes that P values for these non-key secondary endpoints are nominal because multiplicity adjustment was not applied.

The main limitations were restricted generalizability and short duration. The trial excluded patients with psychotic or other psychiatric disorders, alcohol or substance use disorders, clinically significant suicide risk, and significant medical comorbidities, and it prohibited certain concomitant medications, which may limit how broadly the findings apply.

The study was conducted at experienced trial sites with frequent assessments that may not reflect general practice, dropout was higher in the dextromethorphan-bupropion group than placebo (24.1% vs 10.4%), multiplicity adjustments were applied only to key secondary endpoints, and treatment duration was limited to 6 weeks.

The combination was designed to increase dextromethorphan exposure by slowing its metabolism. The article states that dextromethorphan is an uncompetitive NMDA receptor antagonist and a σ1 receptor agonist, but its clinical utility has been limited by rapid and extensive metabolism through CYP2D6, yielding subtherapeutic plasma levels.

In AXS-05, the bupropion component serves to increase plasma dextromethorphan concentrations by inhibiting its metabolism.