By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
The FDA has approved a second upsilon amino butyrate A receptor positive allosteric modulator (i.e., allopregnanolone agonist), the first oral treatment of postpartum depression.1 Zuranolone is a synthetic heterocyclic analog of allopregnanolone. It received a fast-track designation and priority review. Zuranolone will be marketed as Zurzuvae.
INDICATIONS
Zuranolone can be prescribed to treat postpartum depression in women.2
DOSAGE
Patients should take 50 mg once daily in the evening for 14 days.2 They should take the medication with fat-containing food. Physicians can lower the dose to
40 mg once daily if patients report central nervous system (CNS) depressant effects. Physicians can lower the dose to 30 mg if patients are taking this medication concomitantly with a strong CYP3A4 inhibitor or are managing severe hepatic impairment or moderate to severe renal impairment. Zuranolone can be purchased as 20-mg, 25-mg, and 30-mg capsules.
POTENTIAL ADVANTAGES
Zuranolone is orally bioavailable and has a longer elimination half-life compared to brexanolone, the first FDA-approved solution for postpartum depression. In contrast to brexanolone, which requires hospitalization and intravenous administration over 60 hours, zuranolone can be taken orally once a day for 14 days. Zuranolone does not require obtaining the drug through a risk evaluation and mitigation strategy program.
POTENTIAL DISADVANTAGES
Zuranolone carries a boxed warning, cautioning patients about impaired driving or engaging in other potentially hazardous activities.2 Zuranolone may cause CNS depression and embryo-fetal toxicity. There is potential for abuse and misuse, similar to alprazolam, and may produce physical dependence.2 Zuranolone is a substrate for CYP3A4; therefore, patients should avoid concomitant use with a strong inducer. The most frequently occurring adverse reactions are somnolence and dizziness. It is unknown whether depression could relapse after the 14-day treatment course.
COMMENTS
A decline in allopregnanolone levels in the postpartum period may be responsible for depression and anxiety symptoms. Brexanolone, a synthetic allopregnanolone, has demonstrated efficacy; however, it must be administered by continuous intravenous infusion over 60 hours in a hospital. An improved oral version, zuranolone, underwent an evaluation in two randomized, placebo-controlled studies.2-4
Study participants met the diagnosis for a major depressive episode with onset of symptoms in the third trimester or within four weeks of delivery. Eighteen to 21% of study participants were on stable doses of antidepressants.2-4 Study participants mainly were white or Black (54%-70% in study 1, 18%-42% in study 2).
Participants were randomized to zuranolone (50 mg in study 1 and 40 mg in study 2; n = 98 in study 1 and n = 76 in study 2) or placebo (n = 92 in study 1 and n = 74 in study 2). The efficacy endpoint was the change in the 17-item Hamilton Depression Rating Scale (HAMD-17) total score from baseline to day 15. The baseline mean score was 28.6 (severe depression).
Zuranolone produced a 55% (study 1) to 63% (study 2) reduction vs. a 40% to 47% reduction, respectively, for placebo. The placebo-subtracted difference (95% CI) was -4.0 for study 1 (-6.3 to -1.7) and -4.2 for study 2 (-6.9 to -1.5). Response (≥ 50 reduction in HAMD-17 score) rates were 72% (zuranolone) vs. 48% (placebo) in study 1 and 57% vs. 38.9% in study 2. The median time to first HAMD-17 response was nine days for zuranolone and 43 days for placebo, with the change from baseline favoring the zuranolone as early as day 3.3,4 Remission rates at day 45 were 53% (zuranolone) vs. 30% (placebo) in study 1 and 44% vs. 29.4% in study 2. A dose of 30 mg of zuranolone also has been reported to improve anxiety symptoms, insomnia symptoms, and patient-perceived functional health vs. placebo.5
CLINICAL IMPLICATIONS
Approximately one in eight surveyed women with a recent live birth reported depressive symptoms during the postpartum period.1,6 This condition can adversely affect maternal-infant bond and may even lead to suicidal ideation. There are no comparative studies of zuranolone vs. brexanolone, although the magnitude of placebo-subtracted differences in the clinical studies appeared similar.7 Zuranolone is expected to be available the fourth quarter this year and still needs a Drug Enforcement Administration schedule as a controlled substance. The manufacturers of zuranolone also applied for the indication of treating major depressive disorder, but the FDA denied the application, an outcome that might affect pricing because the target patient population might be smaller without that extra indication.
REFERENCES
1. U.S. Food & Drug Administration. FDA approves first oral treatment for postpartum depression. Aug. 4, 2023.
2. Sage Therapeutics. Zurzuvae prescribing information. August 2023.
3. 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;78:951-959.
4. Deligiannidis KM, Meltzer-Brody S, Maximos B, et al. Zuranolone for the treatment of postpartum depression. Am J Psychiatry 2023; Jul 26: appiajp20220785. doi: 10.1176/appi.ajp.20220785.
5. Deligiannidis KM, Citrome L, Huang MY, et al. Effect of zuranolone on concurrent anxiety and insomnia symptoms in women with postpartum depression. J Clin Psychiatry 2023;84:22m14475.
6. Bauman BL, Ko JY, Cox S, et al. Postpartum depressive symptoms and provider discussions about perinatal depression — United States, 2018. MMWR Morb Mortal Wkly Rep 2020;69:575-581.
7. Sage Therapeutics. Zulresso prescribing information.
Zuranolone can be prescribed to treat postpartum depression.
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