First oral treatment zuranolone’s FDA approval and its impact on postpartum depression: a new hope – a correspondence

Postpartum depression (PPD) is a type of mood disorder that affects some individuals after they give birth. It is characterized by a range of emotional and physical symptoms that can significantly impact a new parent’s well-being, their ability to care for their baby, and their overall quality of life. PPD typically occurs within the first few weeks or months after childbirth, but it can develop anytime during the first year. New parents with PPD often experience intense feelings of sadness, hopelessness, and emptiness. Irritability, mood swings, and excessive crying are also common. PPD can manifest with physical symptoms such as fatigue, changes in appetite (either overeating or loss of appetite), and disruptions in sleep patterns (difficulty falling asleep, staying asleep, or sleeping too much). Individuals with PPD might have trouble concentrating, making decisions, or focusing on tasks1. PPD affects a significant number of new parents in the United States. It is estimated that around one in seven women (or about 14–20%) experience PPD after giving birth. Women who have previously experienced PPD are at a higher risk of experiencing it again with subsequent pregnancies. The recurrence rate for PPD is estimated to be around 30–50%. Many cases of PPD go undiagnosed and untreated. Only about 15% of individuals with PPD receive professional help2. In 2017, a research study revealed that suicide constituted ~5% of perinatal fatalities among Canadian women, predominantly happening within the initial 3 months following childbirth due to PPD3. Current treatment of PPD includes selective serotonin reuptake inhibitors (SSRIs) like sertraline and fluoxetine are commonly prescribed for PPD (Table 1). Table 1 - Pharmacological treatment. Selective serotonin reuptake inhibitors (SSRIs) Medications such as fluoxetine (Prozac), sertraline (Zoloft), and escitalopram (Lexapro) are often considered first-line treatments for postpartum depression (PPD). They work by increasing the levels of serotonin in the brain, which can help alleviate depressive symptoms. Serotonin and norepinephrine reuptake inhibitors (SNRIs) SNRIs like venlafaxine (Effexor) and duloxetine (Cymbalta) also affect serotonin levels, but they additionally impact norepinephrine. These medications can be effective for PPD in some cases. Tricyclic antidepressants (TCAs) While less commonly prescribed due to potential side effects, TCAs like amitriptyline and nortriptyline may be considered when other options are not effective or well-tolerated. Atypical antidepressants Bupropion (Wellbutrin) is an example of an atypical antidepressant that affects both dopamine and norepinephrine. It can be used as an alternative for individuals who have not responded to SSRIs or SNRIs. Monoamine oxidase inhibitors (MAOIs) MAOIs like phenelzine (Nardil) are usually reserved for cases where other treatments have failed due to their potential interactions with certain foods and medications. Yet, these medications can take weeks to work and may lead to side effects. Concerns about breastfeeding can also impact treatment decisions. Estrogen therapy stabilizes hormone levels linked to PPD, but it is still being studied, and its risks and side effects need more investigation. Cognitive behavioral therapy helps manage PPD symptoms by changing negative thought patterns. However, access to qualified therapists can be limited, and attending regular sessions might be challenging for new mothers. Recently FDA approved first oral treatment of zuranolone to treat PPD4. Zuranolone belongs to a class of drugs known as positive allosteric modulators of gamma-aminobutyric acid type A (GABA-A) receptors. GABA-A receptors are critical components of the central nervous system that play a crucial role in regulating mood, anxiety, and other emotional states. Zuranolone’s mechanism of action involves enhancing the activity of GABA-A receptors. GABA-A receptors are inhibitory neurotransmitter receptors, and their activation leads to a reduction in neuronal excitability, thereby promoting relaxation and calming effects. By acting as a positive allosteric modulator, zuranolone amplifies the response of GABA-A receptors to the neurotransmitter GABA, resulting in anxiolytic and antidepressant effects4. For treating PPD, the efficacy of Zurzuvae in adults was assessed by conducting two randomized, placebo-controlled, double-blind and multicenter studies5. During this phase 3 trial with a double-blind design, women experiencing severe PPD were randomly assigned in a 1:1 ratio to receive either a daily dosage of 50 mg zuranolone or a placebo for a period of 14 days. The primary focus of the study was to assess the change in the total score on the 17-item Hamilton Depression Rating Scale (HAM-D) from their initial state on day 15. Noteworthy secondary objectives included measuring changes in HAM-D scores on days 3, 28, and 45, as well as evaluating the alteration in severity based on the Clinical Global Impressions scale (CGI-S) on day 15. Throughout the trial, adverse events were closely monitored and recorded. Among the 196 patients who were randomly assigned (zuranolone, N=98; placebo, N=98), a total of 170 participants (86.7%) successfully completed the 45-day study period. The utilization of zuranolone in comparison to the placebo yielded statistically notable enhancements in depressive symptoms by day 15. Moreover, significant amelioration in depressive symptoms was also noted5. Zuranolone can be more discreet and less stigmatizing compared to other forms of treatment, such as injections or hospital visits. This may encourage more individuals to seek help for their PPD symptoms. It will have higher rates of patient compliance since they are simple to take and integrate into daily routines. It can be distributed through a wider range of healthcare settings, potentially increasing accessibility to PPD treatment in both urban and rural areas. It can provide flexibility in dosing, allowing healthcare providers to tailor treatment plans to the individual needs of each patient. It can facilitate early intervention for PPD and has the potential to reduce hospitalization. Although zuranolone’s FDA approval for PPD is promising, there are still some challenges to consider for its use. Not all individuals may respond equally to zuranolone, leading to variations in its effectiveness. Some women might experience significant improvements, while others might not see the same results. Like any medication, zuranolone could potentially have side effects ranging from mild to severe. Balancing the benefits with the potential risks is essential. The long-term effects of using zuranolone, especially during the postpartum period, need further exploration. Monitoring its impact on both maternal health and infant development is crucial. The accessibility of zuranolone could be a concern, as new medications might initially have a higher cost and limited availability, potentially limiting access for some individuals. Zuranolone’s interactions with other medications or treatments that postpartum women might be taking should be thoroughly studied to avoid any adverse effects. PPD is a complex condition that can vary greatly between individuals. Finding the right dosage and treatment plan tailored to each woman’s needs might require careful consideration. While zuranolone offers a pharmacological approach, it is important not to overlook the benefits of psychosocial interventions, such as therapy and support groups, in the overall treatment plan. Overcoming the stigma associated with PPD and seeking help is a challenge. Some women might be hesitant to use medication due to concerns about judgment or societal perceptions. Healthcare providers need to be adequately educated about zuranolone and its potential benefits and limitations to make informed decisions and provide comprehensive care. Determining the appropriate duration of zuranolone treatment and ensuring a smooth transition to other forms of support after discontinuation are important aspects to address. There remains a need for comprehensive studies that delve deeper into its long-term effects, interactions with other medications, and its impact on diverse populations. Rigorous clinical trials and longitudinal studies can provide invaluable insights into the treatment’s efficacy, safety, and potential limitations. The approval of zuranolone could potentially have a broader impact beyond its application in PPD. As researchers and clinicians gain a deeper understanding of its mechanism of action and therapeutic effects, there is a possibility that zuranolone’s insights may extend to other mental health conditions. Ethical approval Not applicable. Sources of funding Not applicable. Author contribution All authors were involved in the conceptualization of ideas, critical reviews with comments, the final draft, and the approval of the final manuscript. Conflicts of interest disclosure There are no conflicts of interest. Research registration unique identifying number (UIN) Not applicable. Guarantor Abubakar Nazir; Oli Health Magazine Organization, Research and Education, Kigali, Rwanda; E-mail: [email protected]; ORCID ID: 0000-0002-6650-6982. Consent Not applicable. Provenance and peer review Not commissioned, externally peer-reviewed.

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