Dextromethorphan-bupropion relieves symptoms in major depressive disorder

Treatment with dextromethorphan-bupropion (AXS-05) significantly improves depressive symptoms relative to bupropion alone and is well tolerated in patients with major depression, results of a phase II trial have shown.

A team of investigators conducted this randomized, double-blind, multicentre, parallel-group trial to compare AXS-05 with the active comparator sustained-release bupropion in adult patients diagnosed with moderate or severe major depressive disorder. Patients were randomly assigned to receive either AXS-05 (45 mg/105 mg tablet) or bupropion (105 mg tablet), once daily for the first 3 days and twice daily thereafter, for a total of 6 weeks.

Overall treatment effect on Montgomery-Åsberg Depression Rating Scale (MADRS) score (average of the change from baseline for weeks 1–6), the primary outcome, was assessed in all patients whose diagnosis and severity were confirmed by an independent assessor and who received at least one dose of the study drug and had at least one postbaseline assessment.

Eighty patients met the eligibility criteria (AXS-05, n=43; bupropion, n=37). Over weeks 1‒6, the AXS-05 group demonstrated a significantly greater mean change from baseline in MADRS score than did the bupropion group (‒13.7 vs ‒8.8 points; least-square mean difference, ‒4.9, 95 percent confidence interval [CI], ‒3.1 to ‒6.8).

MADRS score change was also significantly greater with AXS-05 than with bupropion at week 2 and every time point thereafter (week 6: ‒17.3 vs ‒12.1 points; least-squares mean difference, ‒5.2, 95 percent CI, ‒1.1 to ‒9.3).

Likewise, patients on AXS-05 had significantly higher remission rates at week 2 and every time point afterwards (week 6: 46.5 percent vs 16.2 percent; least-squares mean difference, 30.3 percent, 95 percent CI, 11.2‒49.4), as well as better response rates (≥50-percent decrease in MADRS score from baseline) at week 6 (60.5 percent vs 40.5 percent; least-squares mean difference, 19.9 percent, 95 percent CI, ‒1.6 to 41).

The AXS-05 group also had more favourable secondary outcomes. The most common adverse events in this cohort were dizziness, nausea, dry mouth, decreased appetite, and anxiety. AXS-05 showed no association with psychotomimetic effects, weight gain, or sexual dysfunction.

“Altered glutamatergic neurotransmission is implicated in the pathogenesis of major depressive disorder,” the investigators said. “AXS-05 is an oral NMDA receptor antagonist and sigma-1 receptor agonist, which utilizes inhibition of CYP2D6 to increase its bioavailability.”