Zuranolone in Postpartum Depression

Postpartum depression (PPD) is a serious and often underdiagnosed mood disorder with limited treatment options.¹ It is characterized by intense feelings of sadness, lack of interest, and suicidal ideation following childbirth. This can be associated with poor maternal and infant bonding, low rates of breastfeeding initiation, and adverse effects on the mother’s health.²

Image credit: Jelena Stanojkovic | stock.adobe.com

In a 2018 report by the CDC, researchers found that 13% of surveyed women with a recent live birth reported depressive symptoms during the postpartum period.² Although there is no definitive single cause of PPD, hormone changes may contribute to PPD.³ During pregnancy, allopregnanolone, a naturally occurring progesterone metabolite and neurosteroid, acts as a potent modulator of the GABA-A receptor in the brain to decrease stress exposure and provide neurogenesis for the fetus.³ After delivery, allopregnanolone levels decrease drastically, which has been shown to be correlated with PPD.⁴

PPD Management

In 2023, zuranolone (Zurzuvae; Sage Therapeutics, Inc; Biogen Inc) became the first oral medication to be FDA approved for the treatment of PPD, following the success of the SKYLARK trial (NCT04442503).5,6 Prior to zuranolone, the only medication FDA approved to treat PPD was brexanolone (Zulresso; Sage Therapeutics, Inc). Although efficacious, brexanolone administration requires a 60-hour in-hospital intravenous infusion, which may not be readily accessible or convenient for some patients.⁶

The American College of Obstetricians and Gynecologists recommends the consideration of zuranolone in the postpartum period for depression that has onset in either the third trimester or within 4 weeks post partum. It is a once-daily, 50-mg tablet taken every evening for a 14-day treatment course. It can provide patients with rapid relief of symptoms by day 3 and can be used alone or as an adjunct to other oral antidepressant therapy.^7,8 Although the mechanism of action for zuranolone is currently not fully understood, it is thought to be related to its positive allosteric modulation of GABA-A receptors.⁸ It mimics the stabilizing effect of allopregnanolone by restoring inhibitory tone that may have been lost after delivery.

Zuranolone carries a boxed warning for impaired ability to drive because of its depressant effects on the central nervous system. Patients should be advised to abstain from driving and engaging in other potentially hazardous activities for at least 12 hours after taking zuranolone.

Future Directions

Although zuranolone has acquired FDA approval for PPD, its use in major depressive disorder (MDD) remains under investigation. As one of the most common mental disorders in the world, MDD has a lifetime prevalence of 12%.⁹ MDD is defined as an individual having a loss of interest and/or feeling down, hopeless, or depressed for a minimum of 2 weeks.^9,10

A randomized, placebo-controlled phase 3 trial compared a zuranolone group of 266 patients to a placebo group with 268 patients. The trial enrolled patients aged 18 to 64 years with severe MDD who self-administered zuranolone 50 mg or placebo once daily for 14 days. The primary end point was change from baseline in total score on the 17-item Hamilton Depression Rating Scale at day 15.¹¹

The trial showed that a 14-day course of zuranolone in adults with MDD resulted in significantly greater improvement in depressive symptoms at day 15 (least square mean of –14.1 vs –12.3, P = .01). Like its use in PPD, patients reported an average time to effect of 3 days, which is significantly shorter than the 4 to 6 weeks required for selective serotonin reuptake inhibitors.⁹ Two patients in each group experienced a serious adverse event, and 9 patients in the zuranolone group and 4 in the placebo group discontinued treatment due to adverse events.¹¹

As additional studies unfold, the role of zuranolone in treating MDD remains one to watch closely. Its proven success in PPD stands as a promising example of how it could reshape the way clinicians approach mood disorders in clinical practice.

REFERENCES

1. Carlson K, Mughal S, Azhar Y, Siddiqui W. Perinatal Depression. In: StatPearls. StatPearls Publishing; 2025. Accessed April 17, 2025. https://www.ncbi.nlm.nih.gov/books/NBK519070/

2. Bauman BL, Ko JY, Cox S, et al. Vital signs: postpartum depressive symptoms and provider discussions about perinatal depression—United States, 2018. MMWR Morb Mortal Wkly Rep.2020;69(19):575-581. doi:10.15585/mmwr.mm6919a2

3. Schiller CE, Meltzer-Brody S, Rubinow DR. The role of reproductive hormones in postpartum depression. CNS Spectr. 2015;20(1):48-59. doi:10.1017/S1092852914000480

4. Brunton PJ, Russell JA, Hirst JJ. Allopregnanolone in the brain: protecting pregnancy and birth outcomes. Prog Neurobiol. 2014;113:106-136. doi:10.1016/j.pneurobio.2013.08.005

5. Walton N, Maguire J. Allopregnanolone-based treatments for postpartum depression: why/how do they work? Neurobiol Stress. 2019;11:100198. doi:10.1016/j.ynstr.2019.100198

6. FDA approves first oral treatment for postpartum depression. News release. FDA. August 4, 2023. Updated August 22, 2023. Accessed April 17, 2025. https://www.fda.gov/news-events/pressannouncements/fda-approves-first-oral-treatment-postpartum-depression

7. FDA approves Zurzuvae (zuranolone), the first and only oral treatment approved for women with postpartum depression, and issues a complete response letter for major depressive disorder. News release. Biogen Inc. August 4, 2023. Accessed April 17, 2025. https://investors.biogen.com/newsreleases/news-release-details/fda-approves-zurzuvaetm-zuranolone-first-and-only-oral-treatment

8. Zuranolone for the treatment of postpartum depression. American College of Obstetricians and Gynecologists. Updated January 30, 2024. Accessed April 17, 2025. https://www.acog.org/clinical/clinical-guidance/practice-advisory/articles/2023/08/zuranolone-for-the-treatment-ofpostpartum-depression

9. Marecki R, Kałuska J, Kolanek A, Hakało D, Waszkiewicz N. Zuranolone - synthetic neurosteroid in treatment of mental disorders: narrative review. Front Psychiatry. 2023;14:1298359. doi:10.3389/fpsyt.2023.1298359

10. Bains N, Abdijadid S. Major depressive disorder. In: StatPearls. StatPearls Publishing; 2023. Accessed April 17, 2025. https://www.ncbi.nlm.nih.gov/books/NBK559078/

11. Clayton AH, Lasser R, Parikh SV, et al. Zuranolone for the treatment of adults with major depressive disorder: a randomized, placebo-controlled phase 3 trial. Am J Psychiatry.2023;180(9):676-684. doi:10.1176/appi.ajp.20220459