By Ahizechukwu C. Eke, MD, PhD, MPH
Associate Professor in Maternal Fetal Medicine, Division of Maternal Fetal Medicine, Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, Baltimore
SYNOPSIS: Zuranolone was well tolerated and resulted in substantial improvement of depressive symptoms in the postpartum period, suggesting that it may be a promising new oral therapy for postpartum depression.
SOURCE: Deligiannidis KM, Meltzer-Brody S, Maximos B, et al. Zuranolone for the treatment of postpartum depression. Am J Psychiatry 2023;180:668-675.
Depression is one of the most prevalent mental health conditions during pregnancy and the postpartum period, with an estimated prevalence of 10% to 15% of all pregnancies in the United States.1 Although the prevalence of depression during pregnancy is on the rise, the reported figures may underestimate the true extent of the problem because of the tendency to underreport and the negative perception around mental health problems.2 Multiple factors contribute to the onset of depression in pregnant and postpartum women, including a history of previous depressive episodes, psychosocial stressors, hormonal fluctuations, and insufficient social support.2 Women who have a personal or family history of mental disorders also are more likely to be at a higher risk for postpartum depression.3
Untreated depression during pregnancy can have significant consequences for the mother, such as long-lasting effects on her emotional and psychological well-being. This may lead to postpartum depression and its associated adverse outcomes.3,4 Maternal depression also has been linked to fetal and neonatal complications, including a higher likelihood of preterm birth, low birth weight, and neurodevelopmental problems during childhood.3,4 Hence, it is crucial to find safe and effective therapies to treat postpartum depression.
Various antidepressants, specifically selective serotonin reuptake inhibitors (SSRIs), have been used for managing depression during pregnancy and the postpartum period. However, it is important to note that the use of SSRIs during pregnancy has been associated with increased risks of prematurity, persistent pulmonary hypertension, respiratory distress syndrome, feeding difficulties, jaundice, endocrine and metabolic disorders, and hypoglycemia in newborns.5,6 Consequently, this has sparked significant interest in newer pharmaceuticals. Zuranolone, a neuroactive steroid that acts as a positive allosteric modulator of the gamma-aminobutyric acid type A (GABA-A) receptor, was approved by the U.S. Food and Drug Administration (FDA) in 2023 for the treatment of postpartum depression.7 Although zuranolone has shown favorable outcomes in studies involving nonpregnant adults for the treatment of depression, its use during pregnancy and the postpartum period has been limited because of insufficient efficacy and safety data.7,8 In light of the positive outcomes observed in alleviating depression symptoms in nonpregnant individuals with major depressive disorders using a 50 mg/day dosage of zuranolone, Deligiannidis and colleagues hypothesized that it would be beneficial to explore the effects of zuranolone at the same dosage in women with postpartum depression.9 Consequently, they designed this study to assess the efficacy and safety of administering zuranolone at 50 mg/day compared to a placebo in postpartum women with depression.
This randomized clinical trial included women between the ages of 18 and 45 years who met the following criteria: a baseline score of 26 or higher on the 17-item Hamilton Depression Rating Scale (HAM-D), experiencing a major depressive episode during the third trimester of pregnancy or within four weeks after giving birth, and being within 12 months postpartum. Patients who previously had been diagnosed with bipolar or psychotic disorders or had a history of attempted suicide, as well as those who were at risk of suicide during the current episode of postpartum depression, were excluded.9
Participants were randomly assigned in a 1:1 ratio and given either zuranolone at a dose of 50 mg per day or placebo. The trial consisted of a screening phase, a treatment period lasting 14 days, and follow-up observations until day 45 from start of therapy.9 The difference in HAM-D total score from the start of therapy to day 15 of treatment was the primary efficacy endpoint. Differences in HAM-D scores at days 3, 28, and 45, and Clinical Global Impressions-Severity (CGI-S) ratings at day 15 were the key secondary outcome measures. Additional secondary outcome measures included HAM-D response, defined as a ≥ 50% reduction in the score from the first assessment, and remission, defined as a total score of 7 or less on days 15 and 45; the Clinical Global Impressions improvement response on day 15; a change in the Hamilton Anxiety Rating Scale; and Montgomery-Åsberg Depression Rating Scale total scores from baseline at day 15.9 The Edinburgh Postnatal Depression Scale total score and the nine-item Patient Health Questionnaire were used to measure patient-reported outcomes compared to baseline. Safety and tolerability were assessed by analyzing vital signs, drug-associated adverse events, clinical laboratory data, and electrocardiogram readings. Suicidal thoughts and acts were assessed using the Columbia-Suicide Severity Rating Scale, and withdrawal symptoms were evaluated using the 20-item Physician Withdrawal Checklist.9
To achieve a statistical power of > 90%, assuming a type-1 error rate of 5% (two-sided), and a drop-out rate of 10%, a sample size of at least 192 women (86 evaluable patients per group) was required to allow for the detection of a treatment difference on the primary endpoint, assuming a true difference of four points and a standard deviation of eight points. The primary analysis was by intention-to-treat.
Out of the 196 participants who were randomized (98 in the zuranolone group and 98 in the placebo group), a total of 170 patients (86.7%) successfully completed therapy and follow-up on day 45. Demographic and baseline characteristics were balanced between both groups. Zuranolone therapy demonstrated a significant improvement in depressive symptoms compared to placebo at day 15, as indicated by the change in HAM-D score from baseline (least squares mean [LSM] change: -15.6 vs. -11.6; LSM difference: -4.0, 95% confidence interval [CI] -6.3, -1.7; P < 0.05). Similar significant improvements were observed on day 3 (LSM: -9.5 vs. -6.1; LSM difference: -3.4; 95% CI, -5.4, -1.4; P = 0.001); day 28 (LSM: -16.3 vs. -13.4; LSM difference: -2.9; 95% CI, -5.4, -0.5; P = 0.02; and day 45 (LSM: -17.9 vs. -14.4; LSM difference: -3.5; 95% CI, -6.0, -1.0; P = 0.007). The CGI-S score at day 15 showed a substantial improvement with zuranolone in comparison to placebo. The most frequent side effects that occurred as a result of treatment and were reported by patients were sleepiness (zuranolone, 26.5%; placebo, 5.1%), dizziness (zuranolone, 13.3%; placebo, 10.2%), and sedation (zuranolone, 11.2%; placebo, 1.0%). There were no instances of maternal death from suicide.
COMMENTARY
The results of this clinical trial indicate that zuranolone shows potential as an effective treatment for postpartum depression.9 This is evidenced by the significant and lasting reduction in depressed symptoms observed in women who received zuranolone compared to those who received placebo. The rapid onset of action of zuranolone is important, especially in the setting of postpartum depression, since early intervention is vital for the welfare of both the mother and the newborn.7,8 Although zuranolone shows tremendous potential for managing postpartum depression, additional studies are needed to evaluate its long-term safety, including potential effects on the fetus and newborn during pregnancy and breastfeeding, respectively.
Zuranolone is the first oral medication approved by the FDA exclusively for the treatment of postpartum depression in adults.10 Orally administered at a 50 mg daily dose for a duration of 14 days, zuranolone may cause adverse reactions such as dizziness, vertigo, exhaustion, somnolence, gastrointestinal disturbances, rhinorrhea, and urinary tract infections. Given its potential central nervous system adverse effects, it is imperative to inform patients and provide them with necessary precautions when performing activities that require alertness.11 Although zuranolone has great potential for rapid scale-up in the management of postpartum depression, there still are obstacles to overcome, such as the high cost of therapy, challenges with preauthorization, and concerns regarding the availability of zuranolone to women who need therapy.
Based on the promising results from studies involving the use of zuranolone for the treatment of depression during the postpartum period, the American College of Obstetricians and Gynecologists (ACOG) recommends considering zuranolone therapy during the postpartum period (within one year after giving birth), as well as for treating depression that begins in the third trimester of pregnancy or within four weeks after delivery.11 ACOG recommends that the use of zuranolone necessitates a careful consideration of the advantages, such as notable improvement of symptoms and prompt resolution, in conjunction with the associated risks, including the potential for suicidal ideation, potential teratogenicity requiring contraceptive protection, sedation that may hinder the performance of certain daily activities such as driving, and the absence of efficacy data beyond a 42-day period.11
REFERENCES
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- Hodgkinson S, Beers L, Southammakosane C, Lewin A. Addressing the mental health needs of pregnant and parenting adolescents. Pediatrics 2014;133:114-122.
- Howard LM, Khalifeh H. Perinatal mental health: A review of progress and challenges. World Psychiatry 2020;19:313-327.
- Dunkel Schetter C, Tanner L. Anxiety, depression and stress in pregnancy: Implications for mothers, children, research, and practice. Curr Opin Psychiatry 2012;25:141-148.
- Olivier JD, Akerud H, Kaihola H, et al. The effects of maternal depression and maternal selective serotonin reuptake inhibitor exposure on offspring. Front Cell Neurosci 2013;7:73.
- Gover A, Endrawes K, Molad M, et al. The effect of SSRI exposure in pregnancy on early respiratory and metabolic adaptation in infants born preterm. Children (Basel) 2023;10:508.
- Ali M, Ullah I, Diwan MN, et al. Zuranolone and its role in treating major depressive disorder: A narrative review. Horm Mol Biol Clin Investig 2023;44:229-236.
- Li Z, Wu Q, Peng P, et al. Efficacy and safety of zuranolone for the treatment of depression: A systematic review and meta-analysis. Psychiatry Res 2024;331:115640.
- Deligiannidis KM, Meltzer-Brody S, Maximos B, et al. Zuranolone for the treatment of postpartum sepression. Am J Psychiatry 2023;180:668-675.
- U.S. Food and Drug Administration. FDA approves first oral treatment for postpartum depression. Published Aug. 4, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-first-oral-treatment-postpartum-depression
- The American College of Obstetricians and Gynecologists. Zuranolone for the treatment of postpartum depression. Published August 2023. https://www.acog.org/clinical/clinical-guidance/practice-advisory/articles/2023/08/zuranolone-for-the-treatment-of-postpartum-depression
Zuranolone was well tolerated and resulted in substantial improvement of depressive symptoms in the postpartum period, suggesting that it may be a promising new oral therapy for postpartum depression.
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