Key Takeaways

From the Authors As published in the article
  1. Standard-of-care antidepressants are often associated with treatment-limiting adverse effects and can require weeks or months to produce effects, potentially resulting in negative outcomes, including decreased likelihood of remission and nonadherence.
  2. A short-term course of a monotherapy or adjunctive treatment that leads to rapid response, is generally well tolerated, and maintains effect over 6 months would be a paradigm shift in treatment options.
Extended Takeaways
  1. In the modified full analysis set, the phase 3 trial was negative at the prespecified primary endpoint: day 15 HDRS-17 change was −12.5 (0.68) with zuranolone 30 mg versus −11.1 (0.59) with placebo, with an LSM (SE) difference of −1.4 [0.89] (P = .116).
  2. The signal with zuranolone 30 mg was concentrated early in treatment, with significant HDRS-17 separation from placebo 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.
  3. Patients with more severe baseline depression appeared more likely to show benefit: in those with HDRS-17 ≥ 24, zuranolone 30 mg produced a day 15 LSM (SE) change of −13.6 [0.8] versus −11.4 [0.71] for placebo, with an LSM (SE) difference of −2.3 [1.05] (P = .032).
  4. Nonadherence may have diluted efficacy estimates, as 30/338; 8.9% of patients assigned to zuranolone had no measurable postbaseline plasma concentration; excluding these patients yielded a significant day 15 advantage for zuranolone 30 mg versus placebo (LSM [SE] difference: −1.8 [0.92], P = .049).
  5. The 20 mg dose did not separate from placebo in the primary analysis or in exploratory post hoc analyses, arguing against 20 mg as an effective target dose in major depressive disorder under this study design.
  6. Tolerability was broadly similar to placebo over the double-blind period, with TEAEs in 54.7% of the zuranolone 30 mg group versus 48.9% with placebo and discontinuations due to TEAEs of 2.1% versus 3.2%; no TEAEs of loss of consciousness were reported.
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