Clinical Summary
Clinical Summary: Zuranolone in Major Depressive Disorder: Results From MOUNTAIN—A Phase 3, Multicenter, Double-Blind, Randomized, Placebo-Controlled Trial
Many patients with major depressive disorder need faster symptom relief than standard antidepressants typically provide, but rapid-acting options must still show durable benefit and acceptable tolerability. This trial tests whether a 14-day oral course of zuranolone can deliver that rapid benefit in adult outpatients with major depressive disorder.
Design
a randomized, double-blind, parallel-group, placebo-controlled, phase 3 trial
N
A total of 581 patients were randomized; 570 (98.1%) received ≥ 1 dose of study drug
Population
adult outpatients with MDD
Duration
a screening period of ≤ 28 days, a 14-day treatment period, a 4-week observation period, and an extended follow-up period through day 182 (6 months) after the last dose of zuranolone
Key Findings
- The primary endpoint was negative: at day 15, zuranolone 30 mg had an LSM (SE) CFB in HDRS-17 of −12.5 (0.68) vs −11.1 (0.59) for placebo (LSM [SE] difference: −1.4 [0.89]; P = .116); zuranolone 20 mg was −11.5 (0.62) vs placebo with an LSM (SE) difference of −0.4 [0.85] (P = .664).
- Zuranolone 30 mg separated from placebo early on HDRS-17, with statistically significant CFB at day 3 (−8.3 [0.47] vs −6.7 [0.46]; P = .016), day 8 (−9.9 [0.60] vs −7.8 [0.53]; P = .008), and day 12 (−11.9 [0.65] vs −9.9 [0.57]; P = .018), but not after day 15.
- Among patients with more severe disease (HDRS-17 ≥ 24), post hoc analysis showed a significant day 15 benefit with zuranolone 30 mg: LSM (SE) −13.6 (0.8) vs −11.4 (0.71) for placebo, with an LSM (SE) difference of −2.3 [1.05] (P = .032).
- When patients with no measurable plasma zuranolone concentration (30/338; 8.9%) were excluded, zuranolone 30 mg showed a significant day 15 HDRS-17 advantage vs placebo: LSM (SE) −13.0 (0.72) vs −11.1 (0.59), with an LSM (SE) difference of −1.8 [0.92] (P = .049).
- Tolerability was similar across groups during the double-blind period: TEAEs occurred in 54.7% with zuranolone 30 mg, 50.5% with zuranolone 20 mg, and 48.9% with placebo; TEAEs leading to treatment discontinuation were 2.1%, 1.6%, and 3.2%, respectively.
Clinical Bottom Line
A 14-day course of zuranolone did not beat placebo on the prespecified day 15 primary endpoint in this phase 3 major depressive disorder trial. The clinical signal was an early but not sustained benefit with zuranolone 30 mg, with greater separation in patients with more severe baseline depression and in those with measurable drug exposure.
Practice Implications
- Do not interpret MOUNTAIN as evidence that zuranolone 20 mg is effective in major depressive disorder; the 20 mg dose did not show significant differences from placebo at any assessment time point in the post hoc analyses.
- If considering rapid-onset neuroactive steroid treatment strategies in major depressive disorder, focus on the early-treatment window: zuranolone 30 mg showed significant HDRS-17 improvement by day 3, day 8, and day 12, but not at day 15 in the primary analysis.
- Assess baseline severity when weighing likely benefit, because patients with HDRS-17 ≥ 24 had a larger and statistically significant day 15 separation from placebo with zuranolone 30 mg (LSM [SE] difference: −2.3 [1.05]; P = .032).
- Adherence matters with short-course treatment: 30/338; 8.9% of patients assigned to zuranolone had no measurable postbaseline plasma concentration, and excluding these patients changed the day 15 result for zuranolone 30 mg to statistical significance (P = .049).
