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A novel postpartum depression treatment, with lingering questions

A novel postpartum depression treatment, with lingering questions

Dr. Lee S. Cohen, Director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital, recently shared his insights on zuranolone for postpartum depression with Ob.Gyn News on August 15th.

Postpartum depression (PPD) remains the most common complication in modern obstetrics, and a leading cause of postpartum mortality in the first year of life. The last 15 years have brought considerable progress with respect to adoption of systematic screening for PPD across America. Screening for PPD, most often using the Edinburgh Postnatal Depression Scale (EPDS), has become part of routine obstetrical care, and is also widely used in pediatric settings.

That is the good news. But the flip side of the identification of those women whose scores on the EPDS suggest significant depressive symptoms is that the number of these patients who, following identification, receive referrals for adequate treatment that gets them well is unfortunately low. This “perinatal treatment cascade” refers to the majority of women who, on the other side of identification of PPD, fail to receive adequate treatment and continue to have persistent depression (Cox E. et al. J Clin Psychiatry. 2016 Sep;77[9]:1189-1200). This is perhaps the greatest challenge to the field and to clinicians – how do we, on the other side of screening, see that these women get access to care and get well with the available treatments at hand?

Recently, a widely read and circulated article was published in The Wall Street Journal about the challenges associated with navigating care resources for women suffering from PPD. In that article, it was made clear, based on clinical vignette after clinical vignette from postpartum women across America, that neither obstetricians, mental health professionals, nor pediatricians are the “clinical home” for women suffering from postpartum mood and anxiety disorders. The article painfully highlights the system-wide failure to coordinate mental health care for women suffering from postpartum psychiatric illness.

Within a day of the publication of The Wall Street Journal article, the Food and Drug Administration approved zuranolone (Zurzuvae; Sage Therapeutics; Cambridge, Mass.) for the treatment of PPD following the review of two studies demonstrating the superiority of the new medicine over placebo. Women who were enrolled met criteria for major depressive disorder based on Diagnostic and Statistical Manual of Mental Disorders criteria beginning in no earlier than the third trimester of pregnancy or later than 4 weeks of delivery. The two studies included a combined sample size of approximately 350 patients suffering from severe PPD. In the studies, women received either 50 mg or 40 mg of zuranolone, or placebo for 14 days. Treatment was associated with a significant change in the Hamilton Depression Rating Scale at day 15, and treatment response was maintained at day 42, which was 4 weeks after the last dose of study medication.

Zuranolone is a neuroactive steroid, which is taken orally, unlike brexanolone (Zulresso; Sage Therapeutics; Cambridge, Mass.), which requires intravenous administration. Zuranolone will be commercially available based on estimates around the fourth quarter of 2023. The most common side effects are drowsiness, dizziness, and sedation, and the FDA label will have a boxed warning about zuranolone’s potential to impact a person’s driving ability, and performance of potentially hazardous activities.

It is noteworthy that while this new medication received FDA approval for the PPD indication, it did not receive FDA approval for the treatment of major depressive disorder (MDD), and the agency issued a Complete Response Letter to the manufacturers noting their application did not provide substantial evidence of effectiveness in MDD. The FDA said in the Complete Response Letter that an additional study or studies will be needed; the manufacturers are currently evaluating next steps.

Where Zuranolone Fits Into the Treatment Algorithm for Severe PPD

Many clinicians who support women with PPD will wonder, upon hearing this news, where zuranolone fits into the treatment algorithm for severe postpartum major depression. Some relevant issues that may determine the answer are the following:

Cost. The cost of brexanolone was substantial, at $34,000 per year, and was viewed by some as a limiting factor in terms of its very limited uptake. As of this column’s publication, zuranolone’s manufacturer has not stated how much the medication will cost.

Breastfeeding. Unlike selective serotonin reuptake inhibitors, which have been demonstrated to be effective for the treatment of PPD and safe during pregnancy and lactation, we have sparse data on the safety of zuranolone for women who wish to breastfeed. It is also unclear whether women eligible for zuranolone would, based on the limited data on safety in lactation, choose deferral of breastfeeding for 14 days in exchange for treatment.

Duration of treatment. While zuranolone was studied in the context of 14 days of acute treatment, then out to day 42, we have no published data on what happens on the other side of this brief interval. As a simple example, in a patient with a history of recurrent major depression previously treated with antidepressants, but where antidepressants were perhaps deferred during pregnancy, is PPD to be treated with zuranolone for 14 days? Or, hypothetically, should it be followed by empiric antidepressant treatment at day 14? Alternatively, are patient and clinician supposed to wait until recurrence occurs before pursuing adjunctive antidepressant therapy whether it is pharmacologic, nonpharmacologic, or both?

Treatment in patients with bipolar disorder. It is also unclear whether treatment with zuranolone applies to other populations of postpartum women. Certainly, for women with bipolar depression, which is common in postpartum women given the vulnerability of bipolar women to new onset of depression or postpartum depressive relapse of underlying disorder, we simply have no data regarding where zuranolone might fit in with respect to this group of patients.

The answers to these questions may help to determine whether zuranolone, a new antidepressant with efficacy, quick time to onset, and a novel mechanism of action is a “game changer.” The article in The Wall Street Journal provided me with some optimism, as it gave PPD and the issues surrounding PPD the attention it deserves in a major periodical. As a new treatment, it may help alleviate suffering at a critical time for patients and their families. We are inching closer to mitigation of stigma associated with this common illness.

Thinking back across the last 3 decades of my treating women suffering from PPD, I have reflected on what has gotten these patients well. I concluded that successful treatment of PPD is not a “one-stop shop,” but rather typically includes a combination of pharmacologic and nonpharmacologic interventions, along with family and community-based support groups, as well as a culture that reduces stigma and by so doing lessens the toll of this important and too frequently incompletely-treated illness.

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital (MGH) in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. The Center for Women’s Mental Health at MGH was a non-enrolling site for the pivotal phase 3 SKYLARK trial evaluating zuranolone. Full disclosure information for Dr. Cohen is available at womensmentalhealth.org. Email Dr. Cohen at [email protected].

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