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Clinical Trial
. 2023 Sep 1;180(9):668-675.
doi: 10.1176/appi.ajp.20220785. Epub 2023 Jul 26.

Zuranolone for the Treatment of Postpartum Depression

Kristina M Deligiannidis  1 , Samantha Meltzer-Brody  1 , Bassem Maximos  1 , E Quinn Peeper  1 , Marlene Freeman  1 , Robert Lasser  1 , Amy Bullock  1 , Mona Kotecha  1 , Sigui Li  1 , Fiona Forrestal  1 , Nilanjana Rana  1 , Manny Garcia  1 , Bridgette Leclair  1 , James Doherty  1
Affiliations
Clinical Trial

Zuranolone for the Treatment of Postpartum Depression

Kristina M Deligiannidis et al. Am J Psychiatry. .

Abstract

Objective: Postpartum depression (PPD) is a common perinatal complication with adverse maternal and infant outcomes. This study investigated the efficacy and safety of zuranolone, a positive allosteric modulator of synaptic and extrasynaptic GABAA receptors and neuroactive steroid, as an oral, once-daily, 14-day treatment course for patients with severe PPD.

Methods: In this double-blind phase 3 trial, women with severe PPD were randomized in a 1:1 ratio to receive zuranolone 50 mg/day or placebo for 14 days. The primary endpoint was change from baseline in total score on the 17-item Hamilton Depression Rating Scale (HAM-D) at day 15; key secondary endpoints were change from baseline in HAM-D score at days 3, 28, and 45 and change from baseline in Clinical Global Impressions severity (CGI-S) score at day 15. Adverse events were monitored.

Results: Among 196 patients randomized (zuranolone, N=98; placebo, N=98), 170 (86.7%) completed the 45-day study. Treatment with zuranolone compared with placebo resulted in statistically significant improvement in depressive symptoms at day 15 (least squares mean [LSM] change from baseline in HAM-D score, -15.6 vs. -11.6; LSM difference, -4.0, 95% CI=-6.3, -1.7); significant improvement in depressive symptoms was also reported at days 3, 28, and 45. CGI-S score at day 15 significantly improved with zuranolone compared with placebo. The most common adverse events (≥10%) with zuranolone were somnolence, dizziness, and sedation. No loss of consciousness, withdrawal symptoms, or increased suicidal ideation or behavior were observed.

Conclusions: In this trial, zuranolone demonstrated significant improvements in depressive symptoms and was generally well tolerated, supporting the potential of zuranolone as a novel, rapid-acting oral treatment for PPD.

Trial registration: ClinicalTrials.gov NCT04442503.

Keywords: Mood Disorders-Postpartum; Pharmacotherapy.

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Conflict of interest statement

Dr. Deligiannidis has served as a consultant for Brii Biosciences, Gerbera Therapeutics, GH Research, Neuroscience Software, Reunion Neuroscience, and Sage Therapeutics; she has received grants from Sage Therapeutics, awarded to Zucker Hillside Hospital/Feinstein Institutes for Medical Research (related to clinical trials of brexanolone and zuranolone), and grants from NIH and Vorso Corporation; and she has received royalties from an NIH employee invention. Dr. Meltzer-Brody has received grant funding from Janssen, awarded to the University of North Carolina Chapel Hill, grants from NIH and the Patient-Centered Outcomes Research Institute, and grants and other research funding from Sage Therapeutics, awarded to the University of North Carolina at Chapel Hill; and she has received personal fees from WebMD/Medscape. Dr. Maximos has received grants from Sage Therapeutics related to the zuranolone clinical trial; he has served as a consultant for Evofem Biosciences; and he may hold stock in Sage Therapeutics. Dr. Peeper holds stock in Sage Therapeutics. Dr. Freeman conducts research with the Massachusetts General Hospital (MGH) National Pregnancy Registry and, as an employee of MGH, works with the MGH Clinical Trials Network and Institute, which received research funding from multiple pharmaceutical companies and NIMH; current sponsors of the MGH National Pregnancy Registry include Alkermes, Eisai, Johnson & Johnson/Janssen Pharmaceuticals, Otsuka America Pharmaceutical, Sage Therapeutics, Sunovion Pharmaceuticals, Supernus Pharmaceuticals, and Teva Pharmaceutical Industries; she is a research investigator for Sage Therapeutics; she serves on advisory boards for independent data safety and monitoring committees for Beckley Psytech, Brainify, Eliem, Everly Health, Janssen (Johnson & Johnson), Neurocrine, Novartis, Relmada, Sage Therapeutics, and Tibi Health; she has participated in Everly Health Educational activities (speaking, planning): WebMD, Medscape, Pri-Med, and Postpartum Support International; and she has received royalties from the MGH Scale and the Massachusetts General Hospital Female Reproductive Lifecycle and Hormones Questionnaire. Dr. Lasser, Dr. Bullock, Ms. Li, and Dr. Doherty are employees of Sage Therapeutics, and may hold stock and/or stock options. Dr. Rana and Dr. Garcia were employees of Sage Therapeutics at the time of the study and development of the manuscript, and may hold stock and/or stock options. Dr. Kotecha, Ms. Forrestal, and Dr. Leclair are employees of Biogen, and may hold stock.

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