The first controlled trial of the combination therapy shows its benefit in 6-week depressive symptom improvement versus lone bupropion.
Investigative therapy dextromethorphan-bupropion (AXS-05) provided significantly improved major depression symptoms versus lone sustained-release bupropion while remaining tolerable in adult patients over 6 weeks, according to new phase 2 trial findings.
In a randomized, double-blind, multi center, parallel-group study of the NMDA/sigma-1 receptor antagonist combination therapy, investigators observed significant improvements in the Montgomery-Asberg Depression Rating Scale (MADRS) of adults with major depression treated with dextromethorphan-bupropion versus those treated with lone antidepressant bupropion.
The new findings from the ASCEND trial contribute to the clinical profile of the Axsome Therapeutics agent, which previously received breakthrough therapy designation by the US Food and Drug Administration (FDA). They also offer differentiated outcomes for clinical assessment of depression—a field which due to increasing rates of placebo-controlled assessments has reported an approximate 50% clinical trial signal response rate in the last 25 years, according to the investigators.
Led by chief executive officer Herriot Tabuteau, MD, the Axsome research team sought to compare mean MADS score change in patients randomized to either dextromethorphan-bupropion or bupropion from baseline to each week of treatment through 6 weeks.
“Currently approved oral antidepressants work primarily via monoamine pathways,” investigators explained. “Partial or inadequate response is common with these agents, and they typically take several weeks to produce clinically meaningful effects.”
Their assessment included patients aged 18-65 years old with a diagnosis of major depressive disorder of moderate to greater severity. Patients were randomized to either 45 mg/105 mg dextromethorphan-bupropion tablet or 105 mg bupropion, taken once-daily for the first 3 days then twice daily thereafter, for 6 weeks.
Patient diagnoses and disease severity were confirmed by an independent assessor, and all patients received ≥1 study medication dose and ≥1 post-baseline assessment.
Of the 97 patients randomized in the trial, 17 did not have a confirmed diagnosis and severity based on the independent assessment—leaving 80 patients randomized to either dextromethorphan-bupropion (n = 43) or bupropion (n = 37).
The MADRS is a 10-item clinician-led questionnaire that scores patients on a scale from 0 - 60, with greater scores representing more severe depression. Tabuteau and colleagues sought secondary endpoints including ≥50% reduction from baseline in MADRS total score, representing clinical response, and MADRS total scores of ≤10, representing remission.
At 6 weeks, investigators observed a mean reduction of 13.7 points in MADRS score from baseline among patients treated with dextromethorphan-bupropion, versus just 8.8 points in the comparator group—a mean difference of 4.9 points (95% CI, -3.1 to -6.8). In fact, patients treated with the investigative drug reported significantly greater MADRS reductions starting at week 2 and every week thereafter.
Patients treated with dextromethorphan-bupropion also reported significantly greater remission rates beginning at week 2 and continuing through the study (46.5% vs 16.2%; mean difference, 30.3; 95% CI, 11.2 - 49.3). Another 60.5% of patients treated with dextromethorphan-bupropion achieved the response rate, versus 40.5% of patients treated with bupropion (mean difference, 19.9; 95% CI, -1.6 to 41).
Commonly observed adverse events with the investigative drug included dizziness, nausea, dry mouth, decreased appetite and anxiety; investigators observed no associations with psychotomimetic effects, unlike other NMDA receptor antagonists.
Investigators described the benefit of care as “rapid, substantial, and statistically significant” in treating the primary endpoints of major depression symptoms in adults versus lone bupropion.
“Dextromethorphan-bupropion demonstrated a rapid onset of effect on depressive symptoms and global measures, with statistically significant improvements compared with bupropion observed starting at week 2 on several measures, despite the small sample size of the study,” they wrote. "The team concluded that ASCEND, the first controlled trial for dextromethorphan-bupropion in patients with depression, showed clinically meaningful improvements against the active comparator.
"ASCEND is one of the pivotal efficacy trials that forms the basis of our (New Drug Application) for AXS-05 in depression, which is currently under review by the FDA,” Tabuteau said in a statement. “Axsome is positioned to move expeditiously to make this product available to patients as quickly as possible, should it be approved."
The study, “Effect of AXS-05 (Dextromethorphan-Bupropion) in Major Depressive Disorder: A Randomized Double-Blind Controlled Trial,” was published online in The American Journal of Psychiatry.