By: Giavanna Carr, PharmD Candidate c/o 2025

Postpartum depression, also known as PPD, is classified as perinatal depression, which is experienced by those who have recently given birth. PPD is the leading complication following childbirth, affecting 1 in 7 women worldwide.¹ Oftentimes, this is the first time the mother suffers from any type of depression, and it is likely to occur in future pregnancies.¹

Pathogenesis of PPD

Although the pathogenesis of PPD is not yet known, studies show that a combination of the hypothalamic-pituitary-adrenal (HPA) axis, lactogenic hormones, and immunological system are involved in the disease.² The HPA axis is involved in the release of cortisol, a stress hormone. Thus, lack of HPA axis function may lead to a poor stress response. The cortisol release is heavily increased during pregnancy and the weeks following childbirth, which may be responsible in part for the disease process of PPD.² In addition, during pregnancy, there are rapid changes in estradiol and progesterone which have the potential to lead to depressive episodes in women. The lactogenic hormones, oxytocin and prolactin, are responsible for the synthesis of breast milk as well as the milk let-down reflex.² In addition to its lactogenic properties, oxytocin is also nicknamed the “love hormone” due to its release in response to sensory nerve activation, especially during labor, breastfeeding, and skin-on-skin contact between mother and baby.³ It was noted that low levels of oxytocin simultaneously indicated failure to lactate and onset of PPD.² Oxytocin can be related to failure to lactate because this hormone is responsible for lactogenesis, the secretion of milk, and thus without the proper functioning of this hormone, the mother will be incapable of breastfeeding. Additionally, low levels of oxytocin would inhibit the warm interaction typically felt between mother and child shortly after birth. Such setbacks with low oxytocin could result in PPD because inability to breastfeed may accentuate the mother’s feeling of worthlessness and guilt, hindering the development of the maternal-fetal bond.²

Diagnosis of PPD

It is important to be able to differentiate PPD from the “baby blues.” Typically, “baby blues” subside within the first two weeks of giving birth whereas symptoms lasting over 2 weeks could signify PPD. According to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), PPD is considered in patients with a major depressive episode peripartum onset, meaning the period during or shortly after childbirth, in addition to the following symptoms: depressed mood, loss of interest, insomnia, psychomotor retardation, worthlessness or guilt, fatigue, suicidal ideation, impaired concentration, and change in weight and appetite for up to four weeks.²

PPD screening is routine during infant wellness checkups. The most common questionnaire to diagnose PPD in the healthcare setting is the Edinburgh Postnatal Depression Scale (EPDS). The EPDS consists of 10 questions regarding mood and thoughts surrounding the mother and their child.⁴

In addition to diagnosis through the DSM-5 and EPDS, depression may be caused as a side effect of another disease state, such as hyperthyroidism or hypothyroidism. Such disease states can be diagnosed through blood tests taken inpatient.

Treatment of PPD

The treatment options for PPD differ depending on the severity of the symptoms experienced by each individual patient. Options include antidepressant medicines such as selective serotonin reuptake inhibits (SSRIs) , serotonin and norepinephrine reuptake inhibitors (SNRIs), or tricyclic antidepressants (TCAs).⁵ Antidepressants were found to take 3 to 4 weeks to show effects, and symptoms may return if the medication was stopped too soon. When stopping antidepressant treatment for PPD, providers recommend reducing the dose slowly rather than discontinuing the medication all at once. In addition to medications, psychotherapy as well as participating in a support group are recommended in cases of PPD.⁵

In 2019, Sage Therapeutics received Food and Drug Administration (FDA) approval for an intravenous (IV) drug, Zulresso (brexanolone), for the treatment of PPD, making it the first drug to be approved for this indication by the FDA. ⁶ If PPD is detected early, a provider may recommend giving IV brexanolone in the hospital. Since the medication is only available through a risk evaluation and mitigation strategy (REMS) program and the infusion time takes 60 hours, Sage Therapeutics worked to develop a drug with a novel mechanism of action that eliminated such complications.⁶

On August 4, 2023, the FDA approved Zurzuvae (zuranolone), the first and only oral treatment approved for the treatment of PPD.⁷ Zuranolone is a rapid acting neuroactive steroid that targets the GABA-A receptor. The GABA system is responsible for regulating brain function, and Zuranolone is thought to rebalance the dysregulated neurons to restore brain functions including mood, arousal, behavior, and cognition.⁷ Zuranolone was developed by Sage Therapeutics and Biogen and will be available as a once-daily tablet, scheduled as a controlled substance by the Drug Enforcement Administration.⁸ 

Unlike brexanolone and existing antidepressant therapies for  PPD, zuranolone has a rapid onset of action and was seen to reduce depressive symptoms as early as three days after beginning treatment.⁶ Additionally, this medication is only taken for a 2-week span, so it may be preferred by patients who do not want to be placed on a long-term therapy.

Clinical Trial of Zuranolone

On June 30, 2021, a randomized clinical trial was published that assessed the efficacy and safety of zuranolone in individuals who suffered from PPD. This was a phase 3, double blind, randomized, placebo-controlled trial which consisted of 153 adult women with PPD.⁹ The study focused on female patients, aged 18 to 45 years old, revealing at most 6 months postpartum. All patients had exhibited a major depressive episode diagnosed by the DSM-5. Patients must agree to either cease breastfeeding completely or stop lactating prior and for 7 days after the last dose for a total of 21 days.⁹ A total of 275 patients were screened, however 122 were screen failures, thus only 153 patients were randomized. Of the 153 patients who were recruited and enrolled in the trial, 77 were randomized to receive the intervention, 30 mg of zuranolone orally every evening for 2 weeks. The remaining 76 were randomized to receive the placebo capsule for 2 weeks.⁹

The effect of the medication was tested using a 17-item Hamilton Rating Scale for Depression (HAMD-17).⁸ At baseline, a score of 26 or higher was necessary to partake in the study, and the primary efficacy endpoint was measured by the change from baseline in HAMD-17 score at day 15. Zuranolone demonstrated significant day 15 HAMD-17 score improvements from baseline vs placebo [−17.8 vs −13.6; difference, −4.2; 95% confidence interval (CI), −6.9 to −1.5; P = .003].⁸ This difference was deemed statistically significant being that the 95% confidence interval did not cross 0 and the P value was below 0.05.  Secondary endpoints looked at the change from baseline in HAMD-17 score at other time points such as day 3, 8, 21, and 45. Sustained differences in HAMD-17 scores favoring zuranolone were observed from day 3 (difference, −2.7; 95% CI, −5.1 to −0.3; P = .03) through day 45 (difference, −4.1; 95% CI, −6.7 to −1.4; P = .003).⁸ Similarly, this difference was deemed statistically significant, being that the 95% CI did not cross 0 and the P-value was below 0.05.

Adverse Reactions

At the end of the study, it was concluded that zuranolone was generally well tolerated being that of the 78 participants in the zuranolone group, only 3 reported having a severe adverse event (4% of the group), and only 2 reported having a serious adverse event (1% of the group).⁷ It is of importance to mention that there was the same percentage of participants reporting severe and serious adverse events in the control group as well, 4% and 1%, respectively. The most commonly reported treatment-associated adverse events were somnolence which was reported in 15% of the participants, headache reported in 9%, dizziness and upper respiratory tract infection reported in 8%, diarrhea reported in 6%, and the rest of the adverse events were reported in less than 5% of participants.⁹

Conclusion

Zuranolone demonstrated a statistically significant change from baseline in HAMD-17 score as compared to placebo at every time point tested for both the primary and secondary endpoints tested in the study mentioned above. Zuranolone exhibited both rapid and sustained improvements through its ability to show an effect on day 3 and sustain this effect through day 45.⁹ Limitations of this study existed in the areas of follow-up. The patients taking part in the study were only observed up until day 45, therefore any additional effects experienced by patients beyond this window were not recorded. For these reasons, an ongoing open-label study investigating the sustainability of effects as well as any need for retreatment of depressive episodes.⁹ A safety precaution required in the study was to cease breastfeeding during the study and for 1 week following the study, a total of 21 days. The safety of zuranolone in breastfeeding women is still unknown and is of interest in future studies.⁸  Despite these areas of further research, zuranolone has the potential to be a successful new treatment for patients suffering from PPD looking for an oral treatment option.

References

1. Postpartum depression. March of Dimes. Last Reviewed March 2019. Accessed August 14, 2023. https://www.marchofdimes.org/find-support/topics/postpartum/postpartum-depression
2. Schiller CE, Meltzer-Brody S, Rubinow DR. The role of reproductive hormones in postpartum depression. CNS Spectr. 2015;20(1):48-59. doi:10.1017/S1092852914000480
3. Uvnäs-Moberg K, Handlin L, Petersson M. Self-soothing behaviors with particular reference to oxytocin release induced by non-noxious sensory stimulation. Front Psychol. 2015;5(1529). doi:10.3389/fpsyg.2014.01529
4. Sit DK, Wisner KL. Identification of postpartum depression. Clin Obstet Gynecol. 2009;52(3):456-468. doi:10.1097/GRF.0b013e3181b5a57c
5. Postpartum depression. OASH Office on Women’s Health. Last Updated October 17, 2023. Accessed October 20, 2023. https://www.womenshealth.gov/mental-health/mental-health-conditions/postpartum-depression
6. Global Healthcare. Zuranolone approved for postpartum depression but misses out on bigger MDD indication. Clinical Trials Arena. Published August 9, 2023. Accessed August 21, 2023. https://www.clinicaltrialsarena.com/comment/zuranolone-postpartum-depression-misses-out-mdd-indication/
7. FDA Approves Oral Treatment for Postpartum Depression. Formulary Watch. Published August 6, 2023. Accessed August 21, 2023. https://www.formularywatch.com/view/fda-approves-oral-treatment-for-postpartum-depression
8. Zurzuvae (zuranolone) [package insert]. Cambridge, MA; Sage Therapeutics, Inc; Issued August 2023.
9. 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(9):951-959. doi:10.1001/jamapsychiatry.2021.1559

Published by Rho Chi Post