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Psychiatry Research Review
Psychiatry Research Review

Released: November 18, 2021

Expiration: November 17, 2022

Sanjay Gupta
Sanjay Gupta, MD
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Treatment of Postpartum Depression With Zuranolone: A Randomized Clinical Trial Using a Placebo

Deligiannidis K, et al. JAMA Psychiatry. 2021;78:951-959.

Background
Postpartum depression (PPD) is a common but underdiagnosed and undertreated medical complication that negatively affects mothers, their children, and their partners. This study evaluated the efficacy and safety of zuranolone, a γ-aminobutyric acid receptor–positive allosteric modulator, in women diagnosed with PPD.

Methods
The trial was a double-blind, placebo-controlled, and randomized phase III study of 153 women conducted at 27 US sites between January 2017 and December 2018. Patients were randomized 1:1 to receive a placebo or 30 mg of zuranolone, which was administered orally each evening for 2 weeks. Enrolled women were between 18 and 45 years of age and were 6 months or fewer postpartum. PPD was defined as an episode of major depression beginning in the third trimester or ≤4 weeks after delivery, with a score of ≥26 on the 17-item Hamilton Rating Scale for Depression (HAMD-17). The primary endpoint of the study was the change from baseline in HAMD-17 score on Day 15. Secondary efficacy endpoints included changes in HAMD-17 score from baseline to Days 3, 8, 21, and 45; the rate of ≥50% score reductions in HAMD-17; and the rate of HAMD-17 remission (total score ≤7). The safety and tolerability of zuranolone were evaluated using adverse events (AE) and clinical assessments.

Results
The Day 15 primary endpoint was met, as women who received zuranolone had a statistically significant reduction in HAMD-17 score (from baseline) compared with women who received a placebo. The benefit from zuranolone was sustained from Day 3 through all measured time points. Day 15 secondary endpoints also favored zuranolone over a placebo, with 72% of women achieving ≥50% HAMD-17 score reduction compared with 48% for placebo. Remission was achieved at Day 15 by 45% of the women who received zuranolone compared with 23% for the women receiving a placebo. In the zuranolone group, 1 woman discontinued treatment due to an AE, but no patients in the placebo group discontinued treatment due to an AE. One woman from each group experienced a serious AE; a woman in the zuranolone group experienced a confusional state, and a woman in the placebo group experienced pancreatitis.

Conclusions
As measured by changes in HAMD-17 scores, zuranolone significantly improved the symptoms of depression and was generally well tolerated in women with PPD.

Clinical Commentary
PPD depression affects 11% of women in the postpartum period and often goes undetected. In this phase III trial, zuranolone was well tolerated and significantly improved depressive symptoms in women with PPD, based on the use of rating scales. In this study, Black (41%) and Hispanic (21%) women were represented at higher levels than in previous studies. Zuranolone was given for 14 days, and there was nonmedication follow-up until Day 45 (4 weeks after stopping drug) for both the medication and the placebo groups.

Zuranolone is an investigational drug that is a positive allosteric modulator of the γ-aminobutyric acid type A receptor. This drug has been developed as an improvement on allopregnanolone (brexanolone), which is given by intravenous infusion. This drug can be given orally and has a terminal half-life of 16-23 hours, allowing for once-daily administration.

Clinical Insights

  • Zuranolone worked as early as 3 days, separating from placebo and the sustained efficacy was still noted on Day 45, 4 weeks after cessation of medication treatment.
  • Using a patient-reported measure of postpartum maternal functioning, zuranolone meaningfully improved maternal functioning on Day 45.
  • Increased suicidal ideation or behavior was not observed.
  • Four weeks after drug cessation, 75% of patients in the zuranolone group achieved a response compared with 57% of patients in the placebo group. Remission rates were 53% and 30%, respectively.
  • The most common AEs in patients receiving zuranolone were somnolence (15%), headache (9%), and dizziness (8%). The majority were in the mild to moderate range.

Summary
In March 2019, the FDA approved brexanolone, the first agent approved for PPD. Brexanolone is given as an intravenous infusion over 60 hours in a specialized setting under a Risk Evaluation and Mitigation Strategy program. If zuranolone is approved, the advantage would be that it is an oral tablet and will have reduced administration costs. Zuranolone currently has breakthrough therapy status from the FDA, and healthcare professionals should stay tuned for more information and potential FDA approval.

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