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Effect of Zuranolone vs Placebo in Postpartum DepressionA Randomized Clinical Trial

Educational Objective
To demonstrate the efficacy and safety of zuranolone, a neuroactive steroid γ-aminobutyric acid receptor–positive allosteric modulator, in postpartum depression (PPD).

1 Credit CME

JAMA Psychiatry

September 1, 2021

Original Investigation

Article Information and Disclosures

Kristina M. Deligiannidis, MD^1,2;

Samantha Meltzer-Brody, MD, MPH³;

Handan Gunduz-Bruce, MD, MBA⁴;

Abdul J. Sankoh, PhD⁴;

Christopher Silber, MD⁴;

Andrew D. Campbell, PhD⁴;

Brian Werneburg, PhD⁴;

Stephen J. Kanes, MD, PhD⁴;

Robert Lasser, MD, MBA⁴

Author Affiliations

¹Department of Psychiatry, Zucker Hillside Hospital, Glen Oaks, New York
²Feinstein Institutes for Medical Research, Northwell Health, Manhasset, New York
³Department of Psychiatry, University of North Carolina School of Medicine, Chapel Hill
⁴Sage Therapeutics, Inc, Cambridge, Massachusetts

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Key Points

Question Does treatment with zuranolone reduce depressive symptoms in female individuals experiencing postpartum depression?

Findings In this phase 3, double-blind, randomized, placebo-controlled trial of 151 adult women with postpartum depression, patients taking daily zuranolone for 2 weeks displayed greater statistically significant reductions in depressive symptoms compared with placebo at day 15, assessed by change from baseline in the 17-item Hamilton Rating Scale for Depression. Reductions in depressive symptoms were observed by day 3 and sustained at all measured time points through day 45.

Meaning Zuranolone provided significant reductions in depressive symptoms and was generally well tolerated, supporting its further development in the treatment of postpartum depression.

Abstract

Importance Postpartum depression (PPD) is one of the most common medical complications during and after pregnancy, negatively affecting both mother and child.

Objective To demonstrate the efficacy and safety of zuranolone, a neuroactive steroid γ-aminobutyric acid receptor–positive allosteric modulator, in PPD.

Design, Setting, and Participants This phase 3, double-blind, randomized, outpatient, placebo-controlled clinical trial was conducted between January 2017 and December 2018 in 27 enrolling US sites. Participant were women aged 18 to 45 years, 6 months or fewer post partum, with PPD (major depressive episode beginning third trimester or ≤4 weeks postdelivery), and baseline 17-item Hamilton Rating Scale for Depression (HAMD-17) score of 26 or higher. Analysis was intention to treat and began December 2018 and ended March 2019.

Interventions Randomization 1:1 to placebo:zuranolone, 30 mg, administered orally each evening for 2 weeks.

Main Outcomes and Measures Primary end point was change from baseline in HAMD-17 score for zuranolone vs placebo at day 15. Secondary end points included changes from baseline in HAMD-17 total score at other time points, HAMD-17 response (≥50% score reduction) and remission (score ≤7) rates, Montgomery-Åsberg Depression Rating Scale score, and Hamilton Rating Scale for Anxiety score. Safety was assessed by adverse events and clinical assessments.

Results Of 153 randomized patients, the efficacy set comprised 150 patients (mean [SD] age, 28.3 [5.4] years), and 148 (98.7%) completed treatment. A total of 76 patients were randomized to placebo, and 77 were randomized to zuranolone, 30 mg. Zuranolone demonstrated significant day 15 HAMD-17 score improvements from baseline vs placebo (−17.8 vs −13.6; difference, −4.2; 95% CI, −6.9 to −1.5; P = .003). Sustained differences in HAMD-17 scores favoring zuranolone were observed from day 3 (difference, −2.7; 95% CI, −5.1 to −0.3; P = .03) through day 45 (difference, −4.1; 95% CI, −6.7 to −1.4; P = .003). Sustained differences at day 15 favoring zuranolone were observed in HAMD-17 response (odds ratio, 2.63; 95% CI, 1.34-5.16; P = .005), HAMD-17 score remission (odds ratio, 2.53; 95% CI, 1.24-5.17; P = .01), change from baseline for Montgomery-Åsberg Depression Rating Scale score (difference, −4.6; 95% CI, −8.3 to −0.8; P = .02), and Hamilton Rating Scale for Anxiety score (difference, −3.9; 95% CI, −6.7 to −1.1; P = .006). One patient per group experienced a serious adverse event (confusional state in the zuranolone group and pancreatitis in the placebo group). One patient in the zuranolone group discontinued because of an adverse event vs none for placebo.

Conclusions and Relevance In this randomized clinical trial, zuranolone improved the core symptoms of depression as measured by HAMD-17 scores in women with PPD and was generally well tolerated, supporting further development of zuranolone in the treatment of PPD.

Trial Registration ClinicalTrials.gov Identifier: NCT02978326

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Article Information

Corresponding Author: Kristina M. Deligiannidis, MD, Division of Psychiatry Research, Zucker Hillside Hospital, 75-59 263rd St, Glen Oaks, NY 11004 (kdeligian1@northwell.edu).

Accepted for Publication: May 5, 2021.

Published Online: June 30, 2021. doi:10.1001/jamapsychiatry.2021.1559

Author Contributions: Drs Deligiannidis and Gunduz-Bruce had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Gunduz-Bruce, Doherty, Jonas, Li, Sankoh, Campbell, Kanes.

Acquisition, analysis, or interpretation of data: Deligiannidis, Meltzer-Brody, Gunduz-Bruce, Jonas, Li, Sankoh, Silber, Werneburg, Kanes, Lasser.

Drafting of the manuscript: Deligiannidis, Meltzer-Brody, Doherty, Sankoh, Campbell, Werneburg, Kanes, Lasser.

Critical revision of the manuscript for important intellectual content: Deligiannidis, Meltzer-Brody, Gunduz-Bruce, Doherty, Jonas, Li, Silber, Campbell, Werneburg, Kanes.

Statistical analysis: Li, Sankoh, Silber.

Obtained funding: Campbell.

Administrative, technical, or material support: Deligiannidis, Meltzer-Brody, Gunduz-Bruce, Jonas, Li, Silber, Campbell, Werneburg, Kanes.

Supervision: Gunduz-Bruce, Doherty, Jonas, Sankoh, Silber, Campbell, Kanes, Lasser.

Conflict of Interest Disclosures: Dr Deligiannidis reported grants from Sage Therapeutics, Inc, during the conduct of the study; personal fees from Sage Therapeutics, Inc (ad hoc consulting), grants from Vorso Corporation, grants from Sage Therapeutics, Inc (outside the submitted work), nonfinancial support from Sage Therapeutics, Inc (travel reimbursement), and grants from National Institutes of Health outside the submitted work. Dr Meltzer-Brody reported grants from Sage Therapeutics, Inc, to the University of North Carolina at Chapel Hill during the conduct of the study; grants from Janssen and Sage Therapeutics, Inc, to the University of North Carolina Chapel Hill; and personal fees from WebMD/MedScape outside the submitted work. Dr Gunduz-Bruce reports a patent for PCT/US2018/050012 pending. Dr Kanes reports a patent for use of neuroactive steroids in treatment of postpartum depression pending. Ms Li and Drs Gunduz-Bruce, Doherty, Jonas, Sankoh, Werneburg, Kanes, and Lasser are employees of Sage Therapeutics, Inc, and hold stock/stock options. Drs Campbell and Silber were employees of Sage Therapeutics, Inc, at the time the study was conducted and own stock/stock options in the company.

Funding/Support: This trial was funded by Sage Therapeutics, Inc.

Role of the Funder/Sponsor: During the peer review process, both Sage Therapeutics, Inc, and their collaboration partner Biogen had the opportunity to review and comment on this manuscript; however, the authors had full editorial control of the manuscript and provided final approval on all content.

Meeting Presentations: Aspects of this study have been presented at the 2019 Anxiety and Depression Association of America annual meeting; March 30, 2019; Chicago, Illinois; the 2019 American Society of Clinical Psychopharmacology Annual Meeting; May 28, 2019; Scottsdale, Arizona; the Massachusetts General Hospital Clinical Trials Network Institute VII Annual Symposium; June 29, 2019; Rome, Italy; 32nd European College of Neuropsychopharmacology Congress; September 9, 2019; Copenhagen, Denmark; 11th Annual National Network of Depression Centers Conference; September 24, 2019; Ann Arbor, Michigan; the International College of Neuropsychopharmacology meeting; October 4, 2019; Athens, Greece; 19th Congress of the International Society of

Psychosomatic Obstetrics and Gynaecology; October 12, 2019; The Hague, Netherlands; Marcé of North America 2019 Conference; October 26, 2019; Chapel Hill, North Carolina; 58th Annual Meeting of the American College of Neuropsychopharmacology; December 10 and 11, 2019; Orlando, Florida; Congrès de l’Encéphale 2020; January 23, 2020; Paris, France; 40th Annual Society for Maternal-Fetal Medicine Meeting; February 6, 2020; Grapevine, Texas; joint congress of the Working Group on Neuropsychopharmacology and Pharmacopsychiatry and the German Society for Biological Psychiatry; March 4, 2020; Berlin, Germany; American Society of Clinical Psychopharmacology Annual Meeting; May 29, 2020; virtual; Society of Biological Psychiatry Annual Meeting; May 1, 2020; virtual; European College of Neuropsychopharmacology Annual Meeting; September 12, 2020; virtual; Psych Congress Annual Meeting; September 10, 2020; virtual.

Additional Contributions: We thank members of the Sage Therapeutics, Inc, clinical operations team, including Tressa Gamache, MS; Corey Leonardi, BS; and Amanda Moore, MSHS, for the planning, management, and execution of the clinical trial. We also thank Kathryn Wall, PhD, at Boston Strategic Partners (supported by Sage Therapeutics, Inc), and Michael Craig, MSc, at Sage Therapeutics, Inc, for editorial support. Compensation was not received outside of standard salary and stock/stock options.

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Effect of Zuranolone vs Placebo in Postpartum DepressionA Randomized Clinical Trial

Novel Oral Drug Rapidly Treats Postpartum Depression

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