Zuranolone for the Treatment of Adults With Major Depressive Disorder: A Randomized, Placebo‐Controlled Phase 3 Trial
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VIEW CORRECTIONPublication: American Journal of Psychiatry
Abstract
Objective:
This study assessed the efficacy and safety of a 14-day treatment course of once-daily zuranolone 50 mg, an investigational oral positive allosteric modulator of the γ-aminobutyric acid type A (GABAA) receptor, for the treatment of major depressive disorder.
Methods:
Patients 18–64 years of age with severe major depressive disorder were enrolled in this randomized, double-blind, placebo-controlled trial. Patients self-administered zuranolone 50 mg or placebo once daily 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. Safety and tolerability were assessed by incidence of adverse events.
Results:
Of 543 randomized patients, 534 (266 in the zuranolone group, 268 in the placebo group) constituted the full analysis set. Compared with patients in the placebo group, patients in the zuranolone group demonstrated a statistically significant improvement in depressive symptoms at day 15 (least squares mean change from baseline HAM-D score, −14.1 vs. −12.3). Numerically greater improvements in depressive symptoms for zuranolone versus placebo were observed by day 3 (least squares mean change from baseline HAM-D score, −9.8 vs. −6.8), which were sustained at all visits throughout the treatment and follow-up periods of the study (through day 42, with the difference remaining nominally significant through day 12). Two patients in each group experienced a serious adverse event; nine patients in the zuranolone group and four in the placebo group discontinued treatment due to adverse events.
Conclusions:
Zuranolone at 50 mg/day elicited a significantly greater improvement in depressive symptoms at day 15, with a rapid time to effect (day 3). Zuranolone was generally well tolerated, with no new safety findings compared with previously studied lower dosages. These findings support the potential of zuranolone in treating adults with major depressive disorder.
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History
Received: 20 May 2022
Revision received: 14 December 2022
Revision received: 3 February 2023
Accepted: 14 February 2023
Published online: 3 May 2023
Published in print: September 01, 2023
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Competing Interests
Dr. Clayton has received grant support from Daré Bioscience, Janssen, Otsuka, Praxis Precision Medicines, Relmada Therapeutics, and Sage Therapeutics; she has received advisory board or consulting fees from AbbVie, Brii Biosciences, Fabre-Kramer, Janssen Research and Development, MindCure Health, Mycomedica Life Sciences, Ovoca Bio, Praxis Precision Medicines, PureTech Health, Reunion Neuroscience (formerly Field Trip Health), S1 Biopharma, Sage Therapeutics, Takeda/Lundbeck, Vella Bioscience, and WCG MedAvante-ProPhase; she has received royalties from Ballantine Books/Random House, the Changes in Sexual Functioning Questionnaire, and Guilford Publications; and she holds shares/restricted stocks in Euthymics, Mediflix, and S1 Biopharma. Dr. Parikh has served as a consultant for Aifred, Assurex, Boehringer Ingelheim, Janssen, Mensante, NeonMind, Sage Therapeutics, and Takeda; he has received speaking honoraria from CANMAT and Otsuka and CME honoraria from Otsuka; he has received research grants from Assurex, the Canadian Institutes for Health Research, the Ethel and James Flinn Foundation, Janssen, Merck, the Ontario Brain Institute, Sage Therapeutics, and Takeda; and he holds shares in Mensante and NeonMind. Dr. Iosifescu has served as a consultant for Alkermes, Allergan, Angelini, Axsome, Biogen, Boehringer Ingelheim, the Centers for Psychiatric Excellence, Clexio, Jazz, Lundbeck, Neumora, Otsuka, Precision Neuroscience, Relmada, Sage Therapeutics, and Sunovion, and he has received grant support (paid to his institutions) from Alkermes, AstraZeneca, BrainsWay, LiteCure, NeoSync, Otsuka, Roche, and Shire. Ms. Forrestal and Dr. Kotecha are employees of Biogen and may hold stock. Drs. Lasser, Doherty, Jonas, and Jung are employees of Sage Therapeutics and may hold stock and/or stock options. Dr. Jonas serves as a board member for Sage Therapeutics. Dr. Kanes is currently an employee of Ancora Bio and was an employee of Sage Therapeutics at the time this trial was conducted and is a shareholder of Sage Therapeutics.
Funding Information
This study was funded by Sage Therapeutics and Biogen. Medical writing support was provided by Ryan Coleman, Ph.D., of AlphaBioCom and funded by Sage Therapeutics and Biogen.
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