ANXIOLYTIC EFFECTS OF DEXTROMETHORPHAN-BUPROPION (45MG/105MG): POST HOC ANALYSES ACROSS TRIALS IN MAJOR DEPRESSIVE DISORDER

Background

Anxiety is common in major depressive disorder (MDD), with anxious distress reported in 45-78% of patients and associated with poorer outcomes. Dextromethorphanbupropion (45mg/105mg) is an NMDA receptor antagonist and sigma-1 agonist approved for MDD in adults. Here we evaluate anxiolytic efficacy of dextromethorphan-bupropion across trials performed in patients with MDD.

Methods

Post hoc analyses were conducted using data from 4 clinical trials of dextromethorphan-bupropion: ASCEND and GEMINI (6-week, double-blind, randomized controlled trials [RCTs] vs bupropion or placebo) and COMET and EVOLVE (open-label studies up to 15 months). Anxiety symptoms were assessed via the Hamilton Anxiety Rating Scale (HAM-A) (EVOLVE) and the Montgomery-Åsberg Depression Rating Scale (MADRS) Inner Tension item (all studies), as well as a MADRS anxiety and vegetative symptoms subscale (comprised of the Inner Tension, Concentration Difficulties, Reduced Sleep, and Reduced Appetite items) capturing interconnected features of MDD. Anxiety treatment-emergent adverse events (TEAEs) were examined.

Results

In EVOLVE, dextromethorphan-bupropion significantly reduced HAM-A scores from baseline (15.6) by 3.4±5.34 (mean±SD) and 10.2±6.33 at Week 1 and Month 12 (P < 0.001). Remission of anxiety symptoms occurred in 78.3% of participants at Month 12. HAM-A correlated with Inner Tension (ρ=0.57-0.62). Open-label studies showed significant mean reductions in Inner Tension (EVOLVE: −0.86, −2.48; COMET: −0.83, −2.10 at Week 1 and Month 12; all P < 0.001), as well as the anxiety and vegetative subscale (EVOLVE: −2.96, −9.46; COMET: −2.84, −9.28 at Week 1 and Month 12, respectively; all P < 0.001). In RCTs, dextromethorphan-bupropion significantly improved Inner Tension versus control groups at Week 6 (GEMINI: Δ=0.37; ASCEND: Δ=1.19); the anxiety and vegetative subscale also showed significant improvement (GEMINI: Δ=1.41; ASCEND: Δ=2.22)(all P < 0.05). Anxiety TEAEs were infrequent, with an absolute prevalence of 0.9-2.1% across groups, and were generally transient (median duration: 4-44 days), with few discontinuations.

Conclusions

In this post hoc analysis, dextromethorphan-bupropion was associated with clinically meaningful, sustained improvement in anxiety symptoms in adults with MDD. Anxiety-related TEAEs were infrequent. These findings are supportive of dextromethorphanbupropion use in patients with MDD and anxiety symptoms.