FDA Approves New Postpartum Depression Treatment

A first-of-its-kind medication has been approved to treat postpartum depression, the U.S. Food and Drug Administration (FDA) recently announced. The fast-acting antidepressant, called zuranolone, comes in a pill that would be taken once a day for two weeks.

“The 14-day treatment, marketed as Zurzuvae, significantly improves depressive symptoms as early as day three,” says Dr. Lauren Osborne, a reproductive psychiatrist at NewYork-Presbyterian/Weill Cornell Medical Center. “Having depression or anxiety in the postpartum period is a medical complication of pregnancy just like any other, and it should be treated. The approval of zuranolone is a major advance in a population for whom it is important to have a rapid effect.”

Postpartum depression is a serious but common condition, affecting about 1 in 8 women, according to the Centers for Disease Control and Prevention. Symptoms can include crying more often than usual, feeling angry, withdrawing from loved ones, or feeling numb or disconnected from their newborn. The condition is associated with lower breastfeeding initiation and poor bonding between the mother and baby, and research suggests that it can have adverse effects on infant behavioral, emotional, and cognitive development. In severe postpartum depression cases, women may experience suicidal thoughts, and mental health conditions are the leading cause of pregnancy-related death.

Health Matters spoke with Dr. Osborne, who is also associate professor of obstetrics and gynecology and of psychiatry at Weill Cornell Medicine, to learn more about how zuranolone works, its side effects, and next steps now that it has been approved by the FDA.

How effective is zuranolone?
With postpartum depression, there are psychosocial contributors (such as sleep deprivation and role transitions) and biological ones. All women undergo a drastic drop in reproductive hormones (estrogen and progesterone) after childbirth, and research shows that women who are particularly vulnerable to hormonal shifts are at high risk for postpartum depression. For patients with postpartum depression experiencing these psychosocial and biological contributors, drugs like zuranolone may help.

Results of two Phase 3 clinical trials — the last testing phase before a drug is submitted for regulatory approval and released in the market — were published in the American Journal of Psychiatry in July 2023 and in JAMA Psychology in June 2021.

In the most recent 45-day trial, 196 women with severe postpartum depression were given either 50 milligrams per day of zuranolone or a placebo for 14 days. The Hamilton Rating Scale for Depression, a 17-item scale to measure depression in people before, during, and after medication, was used. At day 15, the patients on zuranolone had greater than a 15-degree drop in their Hamilton score. Those who were on placebo had over an 11-point drop. This represents a significant placebo effect, but there was still a statistically significant difference between the drug and placebo at that time point.

The previous trial consisted of 151 women with postpartum depression, who received 30 milligrams of zuranolone or placebo for 14 days. Results found significant reductions in depressive symptoms, also assessed by the Hamilton Rating Scale for Depression, compared with placebo at day 15.

Now, what happens at the end of 45 days, the length of the trials? We do not have data on that yet. At this point, it looks like the effects of the two-week treatment at 42 days are still sustained, but we do not know what is going to happen six months out. Are people going to need another course? Are they going to need to go on another medication to maintain that effect? More research will help us know.

What are its side effects?
The most common were drowsiness, dizziness, diarrhea, and fatigue. There was also no loss of consciousness, withdrawal symptoms, or increased suicidal ideation or behavior among the participants on the treatment.

Why does postpartum depression occur? How does zuranolone work to treat it?
Zuranolone is a synthetic form of allopregnanolone, a metabolite of progesterone, that rises greatly across pregnancy and has a calming effect on the brain.

Allopregnanolone modulates the GABA-A receptor, which is the receptor that controls the action of the major inhibitory (calming) neurotransmitter in the brain. Numerous studies have identified that dysregulation in this system — both shifts in the levels of allopregnanolone and changes in the conformation of the receptor — may play an important role in postpartum depression. While zuranolone itself is a new medication, it mimics a hormone that is natural in the body and works through a mechanism that we know to be implicated in postpartum depression from many years of basic scientific research.

Is this the first drug approved to treat postpartum depression?
Brexanolone, also a form of allopregnanolone, was the first drug approved by the FDA for postpartum depression. But uptake for brexanolone, which was approved in 2019, has been hard: it is administered intravenously over 60 hours and its side effects include sudden loss of consciousness and excessive sleepiness, requiring continuous monitoring in a healthcare setting. Zuranolone, by contrast, is an oral, two-week treatment, and participants in the clinical trial did not experience sudden loss of consciousness. For these reasons, this new option will likely increase access to treatment for people with postpartum depression.

Are there other treatments for postpartum depression?
Selective serotonin reuptake inhibitors (SSRIs), other antidepressants, and psychotherapy can be used effectively. But when we start somebody on an SSRI, it can take up to 4 to 6 weeks at a therapeutic dose to have a response, and we then continue the medication for nine months to a year. Zuranolone works quickly and is taken for two weeks only — though we don’t know yet how long the effect will be sustained.

Can women breastfeed while on zuranolone?
We do not have data yet on whether zuranolone can be used during breastfeeding since breastfeeding patients were not included in this study. Data on breastfeeding safety are being collected, however, and will be published eventually.

Data on compatibility with breastfeeding for brexanolone have been recently published and are reassuring on relative infant dose and show the rapid elimination of allopregnanolone from breast milk, and in many programs using brexanolone, breastfeeding patients are now included.

Without data for zuranolone specifically, however, we can’t yet advise breastfeeding patients on the risks.

Now that zuranolone has been approved, what can people expect next?
The next step is going to be for the insurance companies to decide whether they are going to pay for it. As with most new drugs, some companies will decide to pay for it and others will not.

Is there more to learn about this drug?
The other thing we will have to be careful about, at least initially, is that we do not know if the drug is safe in patients with other mental health conditions, such as bipolar disorder. So it is important to screen for other mental health conditions.

There is tremendous excitement about the possibility of zuranolone because it is working off this mechanism that is so specific to the postpartum period and to this distinct condition. It has a lot of potential as a treatment that could, if it continues to prove to be effective, transform the way we practice and treat patients in this postpartum period.

Lauren M. Osborne, M.D., is a reproductive psychiatrist at NewYork-Presbyterian/Weill Cornell Medical Center and serves as the vice chair of clinical research in the Department of Obstetrics and Gynecology at Weill Cornell Medicine. She is also associate professor of obstetrics and gynecology and of psychiatry at Weill Cornell Medicine. Dr. Osborne recently launched the Perinatal Wellness Program, a pilot program to screen patients across pregnancy and after childbirth for mental health conditions and connect them to mental healthcare within the OB-GYN setting. Dr. Osborne is an expert on the diagnosis and treatment of mood and anxiety disorders during pregnancy, the postpartum, the premenstrual period, and perimenopause and conducts research on the biological mechanisms of perinatal mental illness.