The American College of Clinical Gynecology recommends consideration of brexanolone or zuranolone in postpartum patients with onset of moderate-to-severe perinatal depression in the third trimester or within 4 weeks postpartum.
Background
Postpartum depression (PPD) is an episode of major depression that occurs during pregnancy or within 12 months after delivery per the World Health Organization.1 It is estimated that 10% to 15% of women in developed countries are impacted by PPD following childbirth.1 For mild-to-moderate PPD, psychotherapy is considered first-line therapy.1,2 In severe PPD or if symptoms are not sufficiently responsive to psychotherapy, antidepressants may be required.1,2
First-line antidepressants include selective serotonin reuptake inhibitors (SSRIs) with escitalopram or sertraline being reasonable first-line medications if there is no pharmacotherapy history.1,3 However, no antidepressants are FDA approved for the treatment of PPD. The first FDA-approved medication for PPD was brexanolone (Zulresso; Sage Therapeutics) in 2019, followed by the first oral medication, zuranolone (Zurzuvae; Sage Therapeutics, Biogen), in 2023.4,5
Comparing Brexanolone and Zuranolone6,7
Clinical Trial Data
Brexanolone
Three randomized controlled trials to assess the efficacy of brexanolone were summarized into 1 meta-analysis. Patients with PPD were included in these trials if they were no later than 6 months postpartum with a diagnosis of moderate PPD [17-item Hamilton Depression Rating Scale (HAMD-17) score of 20 to 25] in 1 study or severe PPD (HAMD-17 score of 26 or higher) in 2 studies. The meta-analysis found that treatment with brexanolone resulted in greater treatment response compared to placebo starting at 24 hours [risk ratio (RR), 1.34; 95% CI 1.03 to 1.73] and lasting until day 7 (RR, 1.32; 95% CI 1.01 to 1.73).8
Zuranolone
Efficacy of zuranolone was demonstrated in 2 double-blind, randomized, placebo-controlled trials. Patients included had onset of severe PPD (HAMD-17 score of 26 or higher) during the third trimester of pregnancy or within 4 weeks postpartum. The primary end point in both studies was the change in HAMD-17 score from baseline to day 17 for zuranolone vs placebo. One study assessed zuranolone 30 mg daily and the second assessed zuranolone 50 mg daily for 2 weeks.9,10
In the zuranolone 30 mg study, there was a significant improvement in day 15 HAMD-17 score with zuranolone compared to placebo (−17.8 vs −13.6; difference, −4.2; 95% CI, −6.9 to −1.5) with sustained differences in HAMD-17 scores from day 3 through day 45 for zuranolone.9 In the zuranolone 50 mg study, treatment with zuranolone demonstrated a significant improvement in HAMD-17 score at day 15 (−15.6 vs. −11.6; difference, −4.0; 95% CI, −6.3 to −1.7) and also at days 3, 28, and 45.10
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Application to Clinical Practice
The American College of Clinical Gynecology recommends consideration of brexanolone or zuranolone in postpartum patients with onset of moderate-to-severe perinatal depression in the third trimester or within 4 weeks postpartum.3,11 Benefits of brexanolone include its rapid onset of action, but challenges include its limited access, high cost, need to hold breastfeeding during treatment, requirement to monitor the infusion inpatient, and lack of efficacy data beyond 30 days. Due to these risks, it may be logical to consider brexanolone for treatment-refractory PPD, but it has not been studied for efficacy in this indication.3 Like brexanolone, a benefit of zuranolone includes the rapid resolution of symptoms, but zuranolone does not require inpatient monitoring. Zuranolone comes with risks of suicidal thoughts or behavior, sedation, lack of data in breastfeeding, and no efficacy data after 45 days.11