EFFECTS OF DEXTROMETHORPHAN-BUPROPION (45MG/105MG) IN PARTICIPANTS WITH MAJOR DEPRESSIVE DISORDER AND ANXIOUS DISTRESS

Background

Anxiety is a prevalent feature of major depressive disorder (MDD), with anxious distress reported in 45-78% of patients. The DSM-5 ‘with anxious distress’ specifier requires ≥2 of 5 symptoms during a depressive episode: feeling keyed up or tense, feeling unusually restless, difficulty concentrating due to worry, fear that something awful may happen, and feeling that one might lose control. Anxiety symptoms in MDD are associated with a decreased response to traditional antidepressant treatments. Dextromethorphan-bupropion (45 mg/105 mg) (DM-BUP; Auvelity®) is an NMDA receptor antagonist, sigma-1 receptor agonist, and CYP2D6 inhibitor approved for the treatment of MDD in adults. Here, we examine the antidepressant efficacy of DM-BUP in people with MDD and anxious distress.

Methods

This post‑hoc subgroup analysis used data from the 6‑week, Phase 3, double‑blind, randomized GEMINI trial evaluating DM-BUP versus placebo in adults (18-65 years) with MDD (MADRS ≥25). The primary endpoint was change from baseline in MADRS total score at Week 6; other prespecified endpoints included MADRS response (≥50% reduction) and MADRS remission (≤10). Participants with anxiety were eligible provided anxiety had not been the primary clinical concern within 6 months before screening. Anxious distress (proxy definition) required meeting at ≥2 of the following: MADRS Concentration Difficulties ≥3 with QIDS Concentration Difficulties ≥2; MADRS Inner Tension ≥3; QIDS Restlessness ≥2. Continuous outcomes were analyzed using mixed models for repeated measures and categorical outcomes via chi‑square tests; P‑values were nominal. Safety assessments included TEAEs (≥5% incidence) and discontinuations.

Results

Among participants with anxious distress (DM BUP n=115/156; placebo n=102/161), DM-BUP produced greater reductions in MADRS total score versus placebo at all timepoints, with least squares mean (±SE) differences of −3.20 ± 0.99, −4.08 ± 1.23, −5.21 ± 1.34, −5.82 ± 1.39, and −5.12 ± 1.56 at Weeks 1, 2, 3, 4, and 6, respectively (all P ≤ 0.001). DM-BUP treatment resulted in higher response rates at all visits (≥50% reduction in MADRS total score; all P < 0.05) and higher remission rates from Week 2 onward (MADRS total score ≤10; all P < 0.01). CGI‑S scores improved from Week 1 onward with DM-BUP versus placebo (all P < 0.01), along with higher CGI‑I improvement rates at Weeks 1-4 (all P < 0.05). DM‑BUP was associated with improvement in patient-reported outcomes, including Q-LES-Q and SDS at all timepoints. A greater proportion of participants reported being Much/Very Much Better on the PGI‑I with DM-BUP versus placebo at all visits (Week 6: 39.1% vs 26.5%; P = 0.048). Across participants in the GEMINI trial, the most common TEAEs were dizziness, nausea, headache, diarrhea, somnolence, and dry mouth. Anxiety‑related TEAEs were uncommon (4.3% DM-BUP vs 1.2% placebo), and discontinuations due to anxiety were low (1.9% vs 0%).

Conclusions

DM-BUP demonstrated robust antidepressant efficacy in participants with MDD and anxious distress, showing improvements in MADRS severity, response, and remission compared to placebo. Clinician‑rated global impressions and patient‑reported outcomes also showed improvements. DM-BUP was generally well‑tolerated, with low rates of anxiety‑related discontinuations. Overall, these findings support DM-BUP as a clinically meaningful and well‑tolerated treatment option for patients with MDD and anxious distress.