How-To Guides

No—the phase 3 MOUNTAIN trial did not meet its primary endpoint. At day 15, change from baseline in HDRS-17 was not significantly different from placebo for either dose: zuranolone 30 mg had an LSM (SE) change of −12.5 (0.68) versus −11.1 (0.59) with placebo (LSM difference −1.4 [0.89]; P=.116), and zuranolone 20 mg had an LSM (SE) change of −11.5 (0.62) (LSM difference vs placebo −0.4 [0.85]; P=.664).

Zuranolone 30 mg showed an early signal of improvement, with statistically significant separation from placebo on HDRS-17 by day 3, day 8, and day 12. The LSM (SE) change from baseline was −8.3 (0.47) versus −6.7 (0.46) at day 3 (P=.016), −9.9 (0.60) versus −7.8 (0.53) at day 8 (P=.008), and −11.9 (0.65) versus −9.9 (0.57) at day 12 (P=.018) for zuranolone 30 mg versus placebo, respectively.

Those between-group differences were not significant after day 15 in the main analysis.

In post hoc analysis, zuranolone 30 mg was associated with greater benefit in patients with more severe baseline depression, defined as HDRS-17 ≥24. In that subgroup, day 15 HDRS-17 change from baseline was −13.6 (0.8) with zuranolone 30 mg versus −11.4 (0.71) with placebo, for an LSM (SE) difference of −2.3 [1.05] (P=.032).

The same subgroup also showed significant differences at day 3, day 8, day 12, and day 21 in the post hoc analysis.

Yes. The authors reported that 30 of 338 patients assigned to zuranolone (8.9%) had no measurable postbaseline plasma zuranolone concentration, which could indicate nonadherence. When those patients were excluded, zuranolone 30 mg showed a significant day 15 advantage over placebo on HDRS-17: LSM (SE) change from baseline was −13.0 (0.72) versus −11.1 (0.59), with an LSM (SE) difference of −1.8 [0.92] (P=.049).

Among patients who had both baseline HDRS-17 ≥24 and measurable plasma zuranolone concentration, the day 15 LSM (SE) difference versus placebo was −2.6 [1.08] (P=.018).

No clear efficacy signal was shown for zuranolone 20 mg in this trial. It did not separate from placebo on the primary endpoint at day 15, with an LSM (SE) difference of −0.4 [0.85] (P=.664), and the authors reported that patients who received zuranolone 20 mg did not show any significant differences from placebo at any assessment time point in the exploratory post hoc analyses.

With zuranolone 30 mg, HDRS-17 response rates were significantly higher than placebo at day 8 and day 12, but not at day 15. Response was 33.8% versus 23.0% at day 8 (P=.024) and 43.5% versus 32.7% at day 12 (P=.034) for zuranolone 30 mg versus placebo.

At day 15, HDRS-17 response rates were 50.3% with zuranolone 30 mg, 42.8% with zuranolone 20 mg, and 42.6% with placebo; these day 15 comparisons were not significant versus placebo. HDRS-17 remission rates at day 15 were 31.4%, 23.0%, and 23.4%, respectively, and the only statistically significant remission difference reported was for zuranolone 30 mg versus placebo at day 12.

Zuranolone was generally well tolerated, and overall treatment-emergent adverse event rates were similar across groups: 54.7% with zuranolone 30 mg, 50.5% with zuranolone 20 mg, and 48.9% with placebo during the double-blind period. The most common adverse events in the 30 mg group were fatigue (6.8%), somnolence (6.8%), headache (6.3%), diarrhea (6.3%), dizziness (5.7%), sedation (4.7%), and nausea (3.6%).

TEAEs leading to treatment discontinuation were 2.1% with zuranolone 30 mg, 1.6% with zuranolone 20 mg, and 3.2% with placebo, and no TEAEs of loss of consciousness were reported.

The study did not find worsening of sexual dysfunction with zuranolone 30 mg, and there were no significant differences versus placebo in change from baseline on the CSFQ-14 in either females or males at days 15, 28, and 42. The incidence of weight increase or weight gain was also low, with related adverse events reported in 1 patient in the zuranolone 30-mg group, 1 patient in the 20-mg group, and 4 patients in the placebo group.

MOUNTAIN was a phase 3, multicenter, randomized, double-blind, parallel-group, placebo-controlled trial conducted at 55 US sites. Adults aged 18–65 years with major depressive disorder were randomized 1:1:1 to zuranolone 20 mg, zuranolone 30 mg, or placebo taken once daily in the evening with food for 14 days.

The study included a screening period of up to 28 days, a 14-day treatment period, a 4-week observation period, and extended follow-up through day 182. A total of 581 patients were randomized, and 570 received at least 1 dose of study drug.

The main limitations were a robust placebo response, mid-study changes to eligibility criteria, and uncertainty about adherence in some participants. The authors noted that the trial required amendment to better enroll patients with the intended severity of depression, and about 9% of patients taking zuranolone 30 mg did not have detectable plasma zuranolone concentration, which could limit interpretation of the efficacy results.

They also stated that the stringent inclusion and exclusion criteria may limit generalizability, and although follow-up lasted 6 months, patients could not receive repeat treatment courses if another depressive episode occurred, limiting conclusions about real-world long-term use.