Zuranolone: A Milestone in Postpartum Depression Treatment
Postpartum depression (PPD) is a mental health condition that affects women after childbirth, often leading to feelings of sadness, guilt, and worthlessness. Its consequences extend beyond the individual and can impact the maternal-infant bond along with child development.1 While existing treatments for PPD involve intravenous (IV) formulations, a groundbreaking shift occurred on August 4th, 2023, with the recent FDA approval of Zurzuvae (zuranolone), the first oral medication for PPD. It is important to note that Zulresso (brexanolone), a parenteral medication, was the first FDA approved medication for PDD, and received its initial approval in 2019. Brexanolone is available exclusively through a Risk Evaluation and Mitigation Strategy (REMS) program. This REMS program mandates that Brexanolone is administered by a certified healthcare provider and within a healthcare facility to ensure patient safety. The drug is administered as a continuous IV infusion over the course of 60 hours, during which patients are vigilantly monitored for potential sedation and sudden loss of consciousness. This regimen requires patients to remain within a healthcare facility throughout the entire infusion period, requiring them to set aside an extended amount of time and may cause disruptions to their daily lives. This level of commitment, along with the necessity for vigilant monitoring, can place a considerable strain on individuals and their support systems. As the first oral medication indicated for PPD, Zuranolone’s new approval marks an extraordinary leap forward in addressing the challenges of PPD and has the potential to drastically enhance the quality of life for mothers battling PPD.
Zuranolone acts as a neuroactive steroid gamma-aminobutyric acid (GABA) A receptor positive modulator. Its mechanism of action, while not completely understood, is believed to revolve around its positive allosteric modulation of GABA A receptors, which contributes to its potential efficacy in alleviating PPD symptoms.
The safety and efficacy of zuranolone was assessed in two phase 3, randomized, double-blind, placebo-controlled clinical trials. The Zuranolone Phase 3 trial (NCT#02978326) assessed the efficacy and safety of zuranolone in reducing depressive symptoms in women with PPD.6 Patients were randomized 1:1 to receive either placebo or zuranolone (30 mg) orally every evening for 2 weeks. The primary endpoint was the change from baseline in HAMD-17 scores for zuranolone vs. placebo at day 15. Among the randomized patients, 148 (98.7%) completed treatment. Zuranolone demonstrated significant improvements in HAMD-17 scores compared to placebo at day 15 (−17.8 vs −13.6; difference, −4.2; 95% CI, −6.9 to −1.5; p= 0.003). These differences in favor of zuranolone were sustained from day 3 through day 45. This sustained effect highlights the potential of zuranolone as a viable long-term option for addressing the challenges of PPD.
In the Zuranolone Phase 3 parallel-group trial (NCT# 04442503), women with severe PPD were randomly assigned to receive either zuranolone 50 mg/day or placebo for 14 days. The primary endpoint was the change from baseline in HAMD-17 scores at day 15. Out of 196 enrolled patients, 170 (86.7%) successfully completed the 45-day study period. Zuranolone-treated patients exhibited statistically significant improvement in depressive symptoms at day 15 (least squares mean [LSM] change from baseline in HAMD-17 score: −15.6 vs. −11.6; LSM difference: −4, 95% CI=−6.3, −1.7). The most common adverse events associated with zuranolone were somnolence, dizziness, and sedation, each reported in ≥ 10% of patients. Importantly, no instances of loss of consciousness, withdrawal symptoms, or heightened suicidal ideation or behavior were identified.
The recommended dosing regimen for zuranolone is 50 mg once a day for 14 days taken in the evening with a fatty meal. In cases of severe hepatic impairment, the recommended dose is 30 mg once daily for 14 days. Similarly, the recommended dose for individuals with moderate or severe renal impairment is also 30 mg once daily. In cases where patients experience central nervous system (CNS) depressant effects, the dose may be reduced to 40 mg once daily. zuranolone can be utilized as a standalone treatment for PPD or as an adjunct to oral antidepressant therapy, offering flexibility in its clinical application.
While the approval of zuranolone represents a step forward in addressing PPD, it’s essential to acknowledge the potential risks and adverse effects associated with its use. Healthcare providers should be aware of the potential adverse effects associated with zuranolone, including drowsiness, dizziness, diarrhea, fatigue, nasopharyngitis, and urinary tract infections. A boxed warning accompanies the medication, highlighting its potential to impair activities such as driving. A critical aspect of patient education is emphasizing the importance of refraining from driving or engaging in any potentially hazardous tasks for at least 12 hours after taking zuranolone. Caution is also needed when considering concomitant use of zuranolone with other medications due to potential interactions. Co-administration with CNS depressants could heighten psychomotor impairment. If combination with another CNS depressant is essential, adjusting the dose might be necessary. It is also essential to counsel individuals of childbearing age about the potential fetal risks associated with zuranolone and advise them on using effective contraception during treatment and for one week following its completion. Additionally, healthcare providers should closely monitor patients on zuranolone for potential suicidal thoughts and behaviors and consider adjustments to treatment if worsening depression or emergent suicidal tendencies occur.
Despite these potential risks and considerations associated with zuranolone use, the approval of this oral formulation signifies a breakthrough in the treatment of PPD for several compelling reasons. The transition from IV to oral administration brings about multiple benefits, making it a more patient-friendly and accessible option. Oral medications offer enhanced convenience and compliance for patients. This shift can enhance patient autonomy and lead to improved patient adherence to the treatment regimen, which ultimately contributes to better therapeutic outcomes.8 Lastly, brexanolone is subject to a REMS program, necessitating certified healthcare providers to administer the medication and closely monitor patients during their treatment. In contrast, zuranolone may present a more straightforward approach to treatment without the need for such intensive monitoring or specialized administration settings. While both medications may have potential side effects, the accessibility and ease of administration associated with zuranolone could make it a more feasible option for individuals seeking treatment for PPD.
Overall, the FDA’s approval of zuranolone as the first oral medication for PPD is a remarkable accomplishment in the field of women’s mental health. This breakthrough carries far-reaching significance, not just for offering a more convenient treatment avenue, but also for providing a renewed spark of hope among mothers grappling with PPD.
1. Mughal S, Azhar Y, Siddiqui W. Postpartum Depression. In: StatPearls. Treasure Island (FL): StatPearls Publishing; October 7, 2022.
2. U.S. Food and Drug Administration (FDA). FDA Approves first oral treatment for postpartum depression. August 4, 2023. Accessed August 26, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-first-oral-treatment-postpartum-depression.
3. U.S. Food and Drug Administration (FDA). FDA Approves first treatment for postpartum depression. March 19, 2019. Accessed August 29, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-post-partum-depression
4. ZULRESSO®(brexanolone). Prescribing information. Sage Therapeutics, Inc.; 2022
5. ZURZUVAETM (zuranolone). Prescribing information. Biogen Inc.; 2023
6. 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
7. Deligiannidis KM, Meltzer-Brody S, Maximos B, et al. Zuranolone for the Treatment of Postpartum Depression [published online ahead of print, 2023 Jul 26]. Am J Psychiatry. 2023;appiajp20220785. doi:10.1176/appi.ajp.20220785
8. Alqahtani MS, Kazi M, Alsenaidy MA, Ahmad MZ. Advances in Oral Drug Delivery. Front Pharmacol. 2021;12:618411. Published 2021 Feb 19. doi:10.3389/fphar.2021.618411