Zuranolone Offers An Innovative Treatment for Postpartum Depression

Postpartum depression (PPD) is defined as a major depressive disorder developing within 12 months after childbirth.¹ Patients with PPD present with persistent symptoms of depressed mood, lack of pleasure, fatigue, insomnia or hypersomnia, changes in appetite/weight, and suicidal ideation, among other symptoms.¹ Recent US data suggest that approximately 1 in 8 women report postpartum depressive symptoms, and globally the prevalence of PPD is estimated to be approximately 17.2%.^2,3 Given the widespread occurrence of PPD, early detection and treatment is critical.

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Treatment of PPD is dependent on the severity of the disorder and patient-specific factors. The 2023 American College of Obstetricians and Gynecologists (ACOG) guideline recommends psychotherapy as first-line treatment of mild-to-moderate PPD.⁴ If this fails or pharmacotherapy with selective serotonin reuptake inhibitors is recommended (based on patient history or preference), serotonin-norepinephrine reuptake inhibitors are considered reasonable alternatives. For moderate-to-severe PPD with onset in the third trimester or within 4 weeks postpartum, ACOG recommends consideration of brexanolone (Zulresso; Sage Therapeutics), the first FDA-approved medication specifically for PPD administered as a 60-hour continuous intravenous (IV) infusion.⁴ A major advantage of this agent versus conventional antidepressants is its rapid onset of effect. However, it has several drawbacks including a lack of efficacy data beyond 30 days and restricted access. Patients must be enrolled in the brexanolone risk evaluation and mitigation strategy (REMS) program that requires inpatient monitoring during infusion at certified treatment centers due to excessive sedation and potential loss of consciousness.⁴ As such, the decision to use brexanolone should balance the benefits over the risks.

In August 2023, the FDA approved zuranolone (Zurzuvae; Biogen), the first oral medication indicated to treat PPD in adults. Subsequently, ACOG updated its recommendations to also include consideration of zuranolone for patients with moderate-to-severe PPD developing in the third trimester or within 4 weeks postpartum, weighing the risks versus benefits of treatment.⁵ Like brexanolone, zuranolone isan analog of allopregnanolone. Allopregnanolone, derived from progesterone, peaks during the third trimester of pregnancy and drops sharply post-delivery; this decline has been associated with PPD.⁶ Zuranolone acts as a positive allosteric modulator of γ-aminobutyric acid type A (GABAA) receptors, decreasing the effect of diminished endogenous allopregnanolone levels.^7,8

Clinical Studies

The FDA approval of zuranolone was based on the results of 2 phase 3, double-blind, randomized, placebo-controlled trials designed to assess the efficacy and safety of zuranolone in women with PPD.^9,10 The ROBIN study (NCT02978326) enrolled females between the ages of 18 and 45 who were within 6 months postpartum and had experienced a major depressive episode no earlier than the third trimester and no later than 4 weeks following delivery. Eligible participants had a baseline 17-item Hamilton Rating Scale for Depression (HAMD-17) score of 26 or greater. Concomitant use of antidepressants was allowed if patients were on a stable dose for at least 30 days before baseline. Patients received zuranolone 30 mg (n=76) or matching placebo (n=74) orally once daily every evening with food for 2 weeks.⁹

TheSKYLARKstudy (NCT04442503) followed a similar protocol as the ROBIN study with the exception that patients were within 12 months postpartum and they received zuranolone 50 mg (n=98) or matching placebo (n=98), orally once every evening with fat-containing food for 14 days.¹⁰ In both studies, the primary efficacy end point was the change from baseline in the HAMD-17 total score at day 15. This score was also assessed on days 3, 28, and 45 as were several other secondary efficacy end points. Safety was evaluated through monitoring of adverse events, clinical assessments, and assessment of suicidality and withdrawal symptoms.^9,10

The primary end point was met in both studies. Zuranolone-treated patients had a greater reduction in depressive symptoms at day 15 compared with the placebo group. In ROBIN, the HAMD-17 total score decreased by 17.8 points with zuranolone versus 13.6 points with placebo (least-squares mean difference, -4.2; 95% CI, -6.9 to -1.5; P = .003) and in SKYLARK the reduction was 15.6 versus 11.6, respectively (least-squares mean difference, -4.0; 95% CI, -6.3 to -1.7; P = .001).9,10 Notably, the effects of zuranolone were rapid (noticed by day 3) and sustained through day 45.

Overall, zuranolone was well tolerated. The most common adverse reaction was somnolence/sedation, reported by 19% of patients in the ROBIN study and 36% of patients in SKYLARK.^7,9,10 Other adverse events, reported by at least 5% of zuranolone-treated patients and at a rate higher than that reported by the placebo group, included dizziness, nasopharyngitis, diarrhea, fatigue, and urinary tract infection. No patient experienced suicidality or withdrawal symptoms.^7,9,10

Safety

Zuranolone is classified as a schedule IV-controlled substance due to its potential for abuse and physical dependence.⁷ As a result of central nervous system (CNS) depressant effects, the prescribing information includes a black box warning regarding the impaired ability to drive or engage in activities requiring mental alertness; patients should avoid these tasks for at least 12 hours after taking zuranolone.⁷ A dosage reduction should be considered for patients who develop CNS depression, those unable to avoid concomitant use of zuranolone with other CNS depressants, and those concurrently taking strong cytochrome P-450 (CYP) 3A4 inhibitors. Although suicidality was not reported by zuranolone-treated patients in clinical trials, antidepressants are associated with ahigherincidenceof suicidal thoughts and behaviors in patients 24 years of age or younger. Therefore, zuranolone should be discontinued if patients experience suicidal thoughts, behaviors, or worsening depression.⁷

There are insufficient data regarding the risk of birth defects, miscarriage, or other adverse maternal/fetal outcomes from clinical studies. However, based on animal studies, zuranolone may cause embryo-fetal toxicity. As such, prior to initiating therapy with zuranolone during pregnancy, patients must be informed of the potential risks and should consider enrolling in the National Pregnancy Registry for Antidepressants. Patients with childbearing potential should use effective contraception during and for 1 week after treatment with zuranolone. Moreover, because zuranolone is present in breast milk at low levels, the benefits of breastfeeding and treatment with zuranolone should be weighed against the potential adverse effects on the nursing infant and lack of maternal treatment.⁷ There are no data on the effects of zuranolone on the nursing infant and limited data on the effects on milk production.⁷

Drug Interactions

Concomitant use of zuranolone with CNS depressants, including alcohol, may result in increased impaired psychomotor performance and CNS depressant effects. If unavoidable, dose reduction of zuranolone is advised. Because zuranolone is metabolized by CYP3A4, use with a strong CYP3A4 inhibitor increases the risk of adverse effects and a dosage reduction is warranted. Concurrent use with CYP3A4 inducers should be avoided because the efficacy of zuranolone is reduced.⁷

Dosing and Administration

Zuranolone is available through participating specialty pharmacies and formulated in capsule strengths of 20 mg, 25 mg, and 30 mg.^7,11 The recommended dose is 50 mg orally once daily in the evening for 14 days.The medication can be used as monotherapy or as an adjunct to antidepressant therapy. Administration with a fat-containing meal, typically ranging from 400 to 1000 calories with a fat content of 25% to 50%, is recommended as it enhances absorption in the gastrointestinal tract.⁷ A dose reduction to 30 mg orally once daily is required when zuranolone is used with strong CYP3A4 inhibitors and for patients with severe hepatic impairment (Child-Pugh C) or moderate to severe renal impairment (eGFR<60mL/min/1.73m²). If CNS depressant effects occur, the dosage may be reduced to 40 mg orally once daily. Thesafety and effectiveness of zuranolone beyond a 14-day single treatment course is currently unknown.⁷

Conclusion

Zuranolone marks a significant advancement as the first oral medication FDA-approved for the treatment of PPD, demonstrating improvement in depressive symptoms in as soon as 3 days. For many patients, zuranolone may be the preferred choice of therapy. Unlike brexanolone, patients can access the medication without enrolling in a REMS program, and it does not require inpatient IV administration. Nevertheless, despite costing less than brexanolone, the approximate $16,000 cost of treatment with zuranolone may limit access for some patients.¹² Additionally, questions about the optimal duration of therapy persist, suggesting a need for further research and clinical experience to fully understand zuranolone's place in the management of PPD. Regardless, zuranolone enhances health care providers’ ability to address the complex needs of patients with PPD, offering new hope for rapid and sustained relief from depressive symptoms.

References

1. Screening and Diagnosis of Mental Health Conditions During Pregnancy and Postpartum: ACOG Clinical Practice Guideline No. 4. Obstet Gynecol. 2023;141(6):1232-1261. doi:10.1097/AOG.0000000000005200

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. Published 2020 May 15. doi:10.15585/mmwr.mm6919a2

3. Wang Z, Liu J, Shuai H, et al. Mapping global prevalence of depression among postpartum women [published correction appears in Transl Psychiatry. 2021 Dec 20;11(1):640. doi: 10.1038/s41398-021-01692-1]. Transl Psychiatry. 2021;11(1):543. Published 2021 Oct 20. doi:10.1038/s41398-021-01663-6

4. Treatment and Management of Mental Health Conditions During Pregnancy and Postpartum: ACOG Clinical Practice Guideline No. 5. Obstet Gynecol. 2023;141(6):1262-1288. doi:10.1097/AOG.0000000000005202

5. Zuranolone for the treatment of postpartum depression. The American College of Obstetrics and Gynecology. August 2023. Updated January 30, 2024. Accessed July 29, 2024. https://www.acog.org/clinical/clinical-guidance/practice-advisory/articles/2023/08/zuranolone-for-the-treatment-of-postpartum-depression

6. Brexanolone. Clinical Pharmacology. Updated March 28, 2024. Accessed July 29, 2024. https://www.clinicalkey.com/pharmacology/

7. Zurzuvae. Prescribing information. Sage Therapeutics; 2023. Accessed July 29, 2024. https://documents.sage-biogen.com/us/zurzuvae/pi.pdf

8. Zuranolone. Clinical Pharmacology. Updated May 24, 2024. Accessed July 29, 2024. https://www.clinicalkey.com/pharmacology/

9. Deligiannidis KM, Meltzer-Brody S, Gunduz-Bruce H, et al. Effect of Zuranolone vs Placebo in Postpartum Depression: A Randomized Clinical Trial [published correction appears in JAMA Psychiatry. 2022 Jul 1;79(7):740. doi: 10.1001/jamapsychiatry.2022.1274] [published correction appears in JAMA Psychiatry. 2023 Feb 1;80(2):191. doi: 10.1001/jamapsychiatry.2022.4181]. JAMA Psychiatry. 2021;78(9):951-959. doi:10.1001/jamapsychiatry.2021.1559

10. 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

11. Sage-Biogen. Starting Zurzuvae. Zurzuvae for Healthcare Professionals. Accessed June 1, 2024. www.zurzuvaehcp.com/en-us/home/access-and-resources/getting-patients-started.html

12. Dunleavy K. After scoring limited FDA nod, Sage and Biogen call an audible on pricing strategy for Zurzuvae. Fierce Pharma. November 7, 2023. Accessed July 29, 2024. https://www.fiercepharma.com/pharma/sage-biogen-will-charge-15900-postpartum-depression-drug-zurzuvae