Zuranolone: A Breakthrough in the Treatment of Postpartum Depression

On August 4, 2023, the U.S. Food and Drug Administration (FDA) approved zuranolone (Zurzuvae^®) for the treatment of severe postpartum depression (PPD). To date, zuranolone constitutes the first oral medication specifically targeted for PPD. An earlier alternative, brexanolone (Zulresso^®), developed as an intravenously (IV) formulated agent, was approved on March 19, 2019. Both agents function as neuroactive steroids that bind to γ-aminobutyric acid (GABA) receptors within the brain and stand out by dint of their novel mechanism of action and fast-acting effects.

As an oral agent, zuranolone is expected to address the unmet needs faced by women for whom the use of brexanolone is infeasible. Viewed in this light, zuranolone is being considered a “game changer” for the treatment of PPD. It is the objective of this Editorial to discuss the recent approval of zuranolone, explore its utility and potential shortcomings, and emphasize its significant promise for the treatment of an oft life-threatening condition.

PPD constitutes the most common complication of childbirth, affecting ∼13%–15% of pregnant women in the United States. ¹ This major depressive disorder is widely regarded as a contributor to suicide and to drug overdose. ² A leading cause of mortality among pregnant and postpartum mothers, PPD remains under-recognized and undertreated. ³ The importance of diagnosing and treating PPD is further underscored by the recognition that untreated PPD may adversely affect the cognitive and emotional development of children. From an economic standpoint, the societal burden of PPD is estimated at 14 billion U.S. dollars according to a study that followed a 2017 U.S. birth cohort for a total of 5 years. ⁴

The etiology of PPD is likely to be multifactorial, involving neurobiological mechanisms as well as psychological and sociopsychological factors. A distinguishing physiological feature of PPD, as compared with depression at other times in a woman's life, is the more central role of reproductive hormones. One such hormone is allopregnanolone, a metabolite of progesterone. As is the case for progesterone, allopregnanolone increases steadily throughout pregnancy, reaches peak levels in late pregnancy, and drops precipitously at childbirth.

In 1986, allopregnanolone was discovered to constitute a neuroactive steroid as well as a modulator of GABA-A receptors. ⁵ The GABA-A system has long been regarded as having a significant association with both anxiety and depression. ² It is hypothesized that there may exist a subgroup of women who are especially sensitive to hormonal fluctuations during reproductive events. ⁶ This hypothesis is supported by animal, correlational, and hormone manipulation studies. ⁶ For the women in question, the decline in allopregnanolone at childbirth may play a role in the development of PPD. ⁶ Hence, there have been extensive efforts to develop pharmacological treatments that address the impact of hormonal fluctuations in vulnerable women.

Until recently, the pharmacological treatments of PPD included a variety of established antidepressants, most commonly, the selective serotonin reuptake inhibitors (SSRIs). ² SSRIs are the most widely prescribed antidepressants for PPD in light of their reassuring safety profile in pregnancy and lactation studies. One drawback of the SSRIs is the typical 4-to-6-week lag that is required to achieve a therapeutic effect. ² Furthermore, SSRIs do not address the hormonal factors implicated in PPD. In March of 2019, the U.S. FDA approved brexanolone (Zulresso), an IV formulation of allopregnanolone, as the first pharmacological treatment that is specifically designed for PPD.

The FDA approval was based on data from an initial open-label study and three randomized placebo-controlled trials that demonstrated the efficacy of brexanolone in reducing depression in postpartum women over a 60-hour continuous IV infusion that was designed to restore allopregnanolone levels to third trimester pregnancy levels. ² The results were both clinically and statistically significant, demonstrating a positive response with brexanolone versus placebo by the end of the 60-hour infusion period and through 30 days postinfusion. ⁷

Although most study participants reported no adverse events, 5% experienced excessive sedation or a sudden loss of consciousness that led the FDA to implement a Risk Evaluation and Mitigation Strategy (REMS), that is, a drug safety program designed to ensure that the benefits of the medication outweigh its risks. Presently, brexanolone is available only through this restricted REMS protocol. ² In brief, the REMS protocol mandates close monitoring for potential central nervous system (CNS) and respiratory depression in an REMS-certified facility. The adverse reactions seen in some of the aforementioned studies gave rise to the added requirement that another caregiver must be at hand when and if the baby is present during the treatment. ²

Treatment with brexanolone in an REMS-certified facility entails several key requirements: designation of a Zulresso™ REMS-authorized representative; identification of the optimal treatment unit and admitting service, creation, and implementation of Zulresso REMS training for all providers likely to care for these patients; and compliance in completing the necessary REMS documentation. ² Owing to the challenges involved in implementing the REMS protocol in any medical facility, only a limited number of medical facilities presently offer this IV-based treatment.

Logistical and system-based factors contribute additional challenges to the treatment mode. These challenges include the development of policy and protocols for administering brexanolone, contracting with insurance companies, ensuring insurance preauthorization, and the high cost. ² Additional barriers involve psychosocial factors such as the lack of access to perinatal psychiatric services, lack of family support needed during the 60-hour IV infusion, and cultural biases/stigmas that might dissuade individuals of certain minority populations from seeking mental health treatment for fear of shame and/or mistrust in the medical community.

To address the above issues, the FDA has recently approved an oral formulation of allopregnanolone, zuranolone (Zurzuvae). The efficacy of zuranolone for the treatment of PPD in adults was demonstrated in two randomized double-blind placebo-controlled multicenter studies. ⁸ In both phase 3 clinical trials that compared oral zuranolone versus placebo, patients in the zuranolone-treated groups demonstrated a statistically significant improvement in depressive symptoms as measured by the Hamilton Depression Rating Scale (HAM-D) at day 15 as compared with the placebo groups. Significant improvement in depressive symptoms was observed as early as day 3 and was sustained at all measured timepoints through day 45 of the treatment. ⁸

Zuranolone was generally well tolerated. Most treatment-emergent adverse effects, including somnolence, dizziness, and sedation, proved mild or moderate in severity. ⁸ Zuranolone will carry a boxed warning stating that patients should not drive or operate heavy machinery for at least 12 hours after taking it due to its CNS depressant effects. However, unlike brexanolone, treatment with zuranolone will not be restricted for use through an REMS protocol that will make it possible for patients to receive this treatment at home.

The ability to prescribe zuranolone in an outpatient setting will provide wider access and convenience for all patients experiencing PPD. Patients who are wary of seeking mental health services may feel more comfortable accepting treatment with zuranolone in an obstetrical and/or primary care clinic. At this time, the cost of zuranolone is unknown, but it is expected to be well below the cost associated with brexanolone. Given the prevalence and substantial adverse maternal and child outcomes associated with PPD, and the elimination of several barriers in receiving this targeted treatment, zuranolone represents a major breakthrough for the treatment of PPD.