Effect of Zuranolone vs Placebo in Postpartum Depression: A Randomized Clinical Trial

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.

Conflict of interest statement

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.

Figures

Figure 1.. CONSORT Diagram

The 122 patients who were considered screen failures were screened but deemed ineligible for the study. Two patients randomized to placebo each received in error 1 dose of zuranolone, 30 mg (1 patient on day 1 and the other on day 3). Both were logged as such for safety analysis, but the patients received placebo at all other time points. Therefore, the safety population included 78 patients treated with zuranolone and 73 patients treated with placebo. Two patients were randomized but did not receive dosing (zuranolone, n = 1 [withdrawal]; placebo, n = 1 [noncompliance]), and 1 patient in the placebo group did not complete a postbaseline efficacy assessment, resulting in an efficacy population of 76 patients in the zuranolone group and 74 patients in the placebo group.

Figure 2.. Least-Squares Mean (LSM) Change From Baseline in the 17-Item Hamilton Rating Scale for Depression (HAMD-17) Score

Treatment with zuranolone, 30 mg, achieved the primary end point of a significant change from baseline HAMD-17 total score at day 15 compared with placebo using mixed-effects model for repeated measures. HAMD-17 total score at time points other than day 15 were secondary end points, not adjusted for multiplicity and therefore reported as point estimates, which also showed sustained improvements for the zuranolone group compared with the placebo group. aP = .03. bP = .01. cP = .003.

Figure 3.. HAMD-17 Response, HAMD-17 Remission, and LSM Change From Baseline in HAM-A Scores

Key secondary end points were not adjusted for multiplicity, and P values are reported as point estimates. A, Treatment with zuranolone, 30 mg, resulted in a greater percentage of patients achieving 17-item Hamilton Rating Scale for Depression (HAMD-17) response (days 8, 15, and 45) and HAMD-17 remission (days 3, 15, and 45) compared with placebo. HAMD-17 response is defined as a 50% or greater reduction in total score from baseline, and HAMD-17 remission is defined as total score of 7 or less. B, Sustained improvements in anxiety symptoms as assessed by Hamilton Rating Scale for Anxiety (HAM-A) were observed across the treatment and follow-up periods in the zuranolone group compared with the placebo group. LSM indicates least-squares mean. aP = .02. bP = .01. cP = .005. dP = .009. eP = .001. fP = .006. gP < .001.