Evaluation of AXS-05 (dextromethorphan-bupropion) in Major Depressive Disorder Using the Interest-Activity Domain

Abstract: Background: Individuals with major depressive disorder (MDD) with loss of interest and reduced activity respond poorly to serotonergic antidepressants. AXS-05 (dextromethorphan-bupropion) is an oral N-methyl-D-aspartate receptor antagonist and sigma-1 receptor agonist FDA-approved for treating MDD in adults, with bupropion primarily serving to increase dextromethorphan bioavailability. We explored the effects of baseline interest-activity symptoms on depression outcomes and efficacy of AXS-05 in improving interest-activity domain scores. Methods: AXS-05 was evaluated in two double-blind, randomized, controlled, 6-week trials in individuals with MDD: GEMINI (Nf327; placebo-controlled) and ASCEND (Nf80; active-controlled with bupropion). In both, changes in Montgomery-Asberg Depression Rating Scale (MADRS) and Quick Inventory of Depressive Symptomatology (QIDS) compared to control were primary/secondary efficacy measures. Data were pooled and interest-activity domain score was calculated by summation of applicable MADRS (concentration, lassitude, and inability to feel) and QIDS items (concentration, interest, and energy – doubled for equal weight). Results: Higher baseline impairment in interest-activity was associated with less improvement in MADRS total score in the control group (P=0.037). Baseline interest-activity was not significantly associated with either MADRS total score in the AXS-05 group (P=0.787) or MADRS change from baseline with AXS-05 at any week (all P>0.184). The estimated marginal mean improvement in the interest-activity domain for AXS-05 versus control was significant at every timepoint, including Week 1 (P=0.001) and Week 6 (P=0.007). Common adverse reactions with AXS-05 were dizziness, headache, diarrhea, somnolence, dry mouth, sexual dysfunction, and hyperhidrosis. Conclusions: AXS-05 reduced depressive symptoms regardless of baseline interest-activity and significantly improved interest-activity symptoms versus control.Short Description: In people with MDD, low interest, reduced activity, indecisiveness, and lack of enjoyment are associated with poor response to serotonergic antidepressants. This post hoc analysis evaluated the interest-activity symptom score, a newer measure derived from MADRS and QIDS-SR. AXS-05, an oral NMDA receptor antagonist and sigma-1 receptor agonist, significantly improved interest-activity symptom scores versus control. These results suggest that AXS-05 may be an effective treatment option in individuals with MDD with impaired interest and activity.Name of Sponsoring Organization(s): Axsome Therapeutics