FDA Approves Oral Treatment for Postpartum Depression

In August 2023, the FDA approved zuranolone (Zurzuvae) for the treatment of adults with postpartum depression (PPD).¹ Zuranolone is an allosteric modulator of γ-aminobutyric acid A receptors.

Efficacy

FDA approval was based on the results of 2 multicenter, randomized, double-blind, placebo-controlled studies (study 1 [NCT04442503] and study 2 [NCT02978326]) evaluating the efficacy of zuranolone for the treatment of women with PPD.^2,3

Eligible participants experienced a major depressive episode that met Diagnostic and Statistical Manual of Mental Disorders criteria during the period between the third trimester of pregnancy and 4 weeks after delivery. Participants could maintain treatment with concomitant oral antidepressants if stable doses of these medications were achieved at least 30 days prior to baseline assessment.

In both studies, the change in Hamilton Depression Rating Scale (HAMD-17) total score at baseline and on day 15 served as the primary end point; both studies assessed the change in HAMD-17 score at additional times as a secondary end point. Participants were randomly assigned to receive zuranolone 50 mg once daily (n = 98) or placebo (n = 98) in study 1 and zuranolone 30 mg once daily (n = 77) or placebo (n = 76) in study 2. All participants administered doses in the evening for 14 days. Participants who were not able to tolerate the dose of zuranolone were permitted to administer a reduced dose for the remainder of the treatment period (40 mg in study 1 and 20 mg in study 2).

Participants were followed for a minimum of 4 weeks after the 14-day treatment course. In findings from both studies, participants in the zuranolone group demonstrated statistically significant improvements in depressive symptoms measured as changes in HAMD-17 scores compared with participants administered placebo (study 1: –15.6 vs –11.6; study 2: –17.8 vs –13.6).2,3

Safety

Zuranolone safety was evaluated in a group of 349 women. The most common adverse reactions occurring among 5% or less of participants in the zuranolone group included somnolence, dizziness, sedation, diarrhea, and infection. Somnolence is the most common adverse reaction leading to treatment discontinuation.

Zuranolone has central nervous system (CNS) depressant effects that can impair mental alertness. Patients should not engage in potentially hazardous activities or drive until 12 hours after zuranolone administration. Dosage reduction or discontinuation of zuranolone may be necessary to manage these CNS depressant effects. Patients taking other concomitant CNS depressants or strong CYP3A4 inhibitors also require a reduced dose of zuranolone. Coadministration with CYP3A4 inducers should be avoided, as this may decrease the efficacy of zuranolone. Zuranolone may cause suicidal thoughts and behavior. Providers and patients must monitor for worsening depression, which may require a change in treatment strategy.

Zuranolone may cause fetal harm. Patients should be advised of the risk of fetal exposure to zuranolone in utero. Zuranolone is present in low levels in human milk. There are no data on the effects of zuranolone on a breastfed infant and limited data on the effects on milk production.

Dosing and Administration

Zuranolone is available in 20-mg, 25-mg, and 30-mg capsules for oral administration. The recommended zuranolone dose is 50 mg once daily in the evening for 14 days. Zuranolone should be taken with a fat-containing food or meal. The recommended dose for patients with severe hepatic impairment or moderate to severe renal impairment is 30 mg daily in the evening. Safety and effectiveness beyond 14 days have not been established. If a dose is missed, patients should take the next dose at the regular time. Patients should not take extra capsules to make up for the missed dose.

READ MORE: Mental and Behavioral Health Resource Center

References

1. Zuranolone. Package insert. Sage Therapeutics Inc; 2023.

2. Deligiannidis KM, Meltzer-Brody S, Gunduz-Bruce H, et al. Effect of zuranolone vs placebo in postpartum depression: a randomized clinical trial. JAMA Psychiatry. 2021;78(9):951-959. doi:10.1001/jamapsychiatry.2021.1559

3. Deligiannidis KM, Meltzer-Brody S, Maximos B, et al. Zuranolone for the treatment of postpartum depression. Am J Psychiatry. 2023;180(9):668-675. doi:10.1176/appi.ajp.20220785