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

Kristina M Deligiannidis; Samantha Meltzer-Brody; Handan Gunduz-Bruce; James Doherty; Jeffrey Jonas; Sigui Li; Abdul J Sankoh; Christopher Silber; Andrew D Campbell; Brian Werneburg; Stephen J Kanes; Robert Lasser

doi:10.1001/jamapsychiatry.2021.1559

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

Deligiannidis KM, Meltzer-Brody S, Gunduz-Bruce H, Doherty J, Jonas J, Li S, Sankoh AJ, Silber C, Campbell AD, Werneburg B, Kanes SJ, Lasser R

Published September 2021 JAMA psychiatry, 78(9), 951-959

DOI 10.1001/jamapsychiatry.2021.1559 PMID 34190962 PMC PMC8246337

RRM Academy Synopsis

Zuranolone reduced postpartum depression symptoms more than placebo

A double-blind randomized trial of 153 women with postpartum depression found that by day 15, depression scores fell more with zuranolone than with placebo. At day 15, scores were down by 50% or more in 72 out of 100 women on zuranolone and 48 out of 100 on placebo. Anxiety scores also fell more with zuranolone at day 15.

Key Findings

On the 17-item Hamilton Rating Scale for Depression (HAMD-17), scores fell 17.8 points with zuranolone and 13.6 with placebo at day 15 (difference, −4.2; 95% CI, −6.9 to −1.5).
The HAMD-17 difference favored zuranolone from day 3 (−2.7; 95% CI, −5.1 to −0.3) through day 45 (−4.1; 95% CI, −6.7 to −1.4), 4 weeks after treatment ended.
Day-15 response (a HAMD-17 score drop of 50% or more) was 72% (53 of 74) on zuranolone and 48% (35 of 73) on placebo (odds ratio, 2.6; 95% CI, 1.3-5.2).
Day-15 remission (a HAMD-17 score of 7 or less) was 45% (33 of 74) on zuranolone and 23% (17 of 73) on placebo (odds ratio, 2.5; 95% CI, 1.2-5.2).
Each group had 1 serious adverse event, a confusional state with zuranolone and pancreatitis with placebo. Somnolence (drowsiness) affected 15% (12 of 78) on zuranolone against 11% (8 of 73) on placebo.

Interpretation

The trial was phase 3, double-blind and randomized. Chance assigned women to zuranolone or a matching placebo, and the dispensing pharmacy staff were the only study staff who knew the assignments. Participants were women with postpartum depression at 27 US sites, aged 18 to 45 and up to 6 months after delivery. Their major depressive episode, without psychosis, began in the third trimester or within 4 weeks of delivery, and the baseline HAMD-17 score had to be 26 or higher. Participants had to stop breastfeeding from just before the first dose until 7 days after the last. The authors note that benefit beyond day 45, when follow-up ended, is unknown.

RRM Context

RRM seeks the root cause of postpartum mood problems and considers the whole woman, including the hormonal changes of pregnancy and the time after birth. The authors describe postpartum depression as likely having several causes. They name large changes in a steroid that acts on the brain around birth as one potential factor.

Our editorial summary of this paper, not the article's abstract.

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.

Topics

Therapeutics › Hormonal Agents › Progesterone and Progestins · Postpartum › Mental Health › Postpartum Depression

Kristina M Deligiannidis, Samantha Meltzer-Brody, Handan Gunduz-Bruce, James Doherty, Jeffrey Jonas, Sigui Li, Abdul J Sankoh, Christopher Silber, Andrew D Campbell, Brian Werneburg, Stephen J Kanes, Robert Lasser

K Deligiannidis, Sam Meltzer-Brody, S Meltzer-Brody, H Gunduz-Bruce, Jim Doherty, Jimmy Doherty, J Doherty, Jeff Jonas, J Jonas, S Li, A Sankoh, Chris Silber, C Silber, Andy Campbell, Drew Campbell, A Campbell, B Werneburg, Steve Kanes, S Kanes, Bob Lasser, Rob Lasser, Bobby Lasser, R Lasser

PMID 34190962 34190962 DOI 10.1001/jamapsychiatry.2021.1559 10.1001/jamapsychiatry.2021.1559 Deligiannidis et al. 2021, Deligiannidis 2021

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

Zuranolone reduced postpartum depression symptoms more than placebo

Key Findings

Interpretation

RRM Context

Abstract

Topics

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