BACKGROUND: Postpartum depression (PPD) is a common and potentially severe condition frequently managed in primary care, where delayed treatment adversely affects maternal and infant outcomes. Neuroactive steroid therapies targeting γ-aminobutyric acid type A receptors represent a novel therapeutic class. Brexanolone, the first FDA-approved treatment for PPD, required prolonged inpatient administration and was withdrawn from the U.S. market in 2025. Zuranolone is currently the only FDA-approved medication specifically indicated for PPD, offering a short-course oral treatment suitable for outpatient use. This review evaluated the efficacy of zuranolone and its applicability in primary care practice.
METHODS: This evidence-based review was conducted in accordance with PRISMA 2020 guidelines. A search was performed using PubMed, from 2021 to January 2026. Search terms “zuranolone,” “postpartum depression”. Eligible studies were randomized, double-blind, placebo-controlled trials enrolling adults with PPD, baseline 17-item Hamilton Depression Rating Scale (HAMD-17) scores. Two phase 3 trials (ROBIN and SKYLARK; n=349) were included. These trials enrolled women aged 18-45 years, ≤6 months postpartum, with severe postpartum depression (HAMD-17 score ≥26) and onset in the third trimester or within 4 weeks postpartum. Participants were randomized 1:1 to receive zuranolone (30 mg in ROBIN, n=153; 50 mg in SKYLARK, n=196) or placebo.
RESULTS: For the primary outcome, both trials demonstrated statistically significant superiority over placebo at day 15, with mean HAMD-17 score reductions favoring zuranolone by −4.2 points in ROBIN (95% CI −6.9 to −1.5; P=0.003) and −4.0 points in SKYLARK (95% CI −6.3 to −1.7; P0.001). Antidepressant effects emerged by day 3 and were sustained through day 45. For secondary outcomes, response rates at day 15 were 72% with zuranolone versus 48% with placebo in ROBIN, and remission rates were 45% versus 23% (number needed to treat of 5 for both). Zuranolone also improved anxiety symptoms (HAM-A) and maternal functioning (Barkin Index). Adverse events were predominantly CNS-related, and were generally mild to moderate.
CONCLUSION: Zuranolone offers rapidly acting, short-course oral treatment for severe postpartum depression and represents a meaningful therapeutic advance for primary care. Its use, however, is limited by high cost, variable insurance coverage, restriction to severe PPD populations, controlled substance classification, limited long-term data, and the absence of head-to-head comparisons with selective serotonin reuptake inhibitors or psychotherapy. Further research is needed to clarify comparative effectiveness, cost-effectiveness, patient selection, and long-term outcomes.