Postpartum depression pill is safe and effective, new trial data shows

For Sahar McMahon, having her second baby was a completely different experience than having her first. Her postpartum negative mood, low energy and inability to focus were feelings that she had never felt before.

With her first daughter, Ophelia, McMahon downloaded an app to her phone to excitedly track the baby’s month-by-month development, and the pair often would go on playdates with friends.

But with her second daughter, Lenora, McMahon felt no motivation to leave their home. She didn’t even feel motivated to take a shower. She constantly felt tired, yet she couldn’t sleep. McMahon thought that her overwhelming fatigue was simply due to being a new mom.

“I did not realize that anything going on was postpartum depression,” said McMahon, 39, of Queens, New York.

“I never wanted to hurt myself. I just was existing. There were points where my kids would be screaming. I would leave them screaming in the living room. I’d go in my room, close the door, scream into a pillow, and then I’d think, ‘What are we doing this for?’ ” she said. “My whole thought process was very pessimistic, and that’s not who I am at all.”

Late one night in 2021, when McMahon had put her daughters to bed but couldn’t fall asleep, she searched the Internet for some help. She Googled her symptoms: loss of energy, crying spells, inability to sleep.

“I scrolled online, and that’s when I found the trial,” she said.

McMahon, who was by then four months postpartum, immediately signed up to participate in a phase three trial of zuranolone, a postpartum depression medication.

“When I started the drug, the next day, I woke up and I’m like, ‘OK.’ I immediately just started feeling more like me,” McMahon said. Because the trial was a double-blind study, she didn’t know at the time whether she was given the medication or a placebo – but she says she saw benefits overnight with her mood, energy and motivation to engage with her children.

In the weeks that followed, McMahon says, her life changed for the better.

‘It saved my life. It saved my marriage. It saved my kids.’

Zuranolone, given as a daily pill over the course of two weeks, is in clinical development and has been granted “priority review” by the US Food and Drug Administration as it considers the pill for approval, according to the makers of the drug, Sage Therapeutics and Biogen.

A “priority review” designation means the FDA “will direct overall attention and resources to the evaluation of applications for drugs that, if approved, would be significant improvements in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions when compared to standard applications,” according to the agency.

The FDA is expected to make a decision and take action on approval by August 5.

Results from the phase three trial were published Wednesday in the American Journal of Psychiatry. The study of 196 women with severe postpartum depression found that those who took a daily 50-milligram dose of zuranolone in a pill for 14 days showed “significant improvements in depressive symptoms” compared with those who were given a placebo.

These improvements were still reported 28 and 45 days later, according to the study, which was funded by Sage Therapeutics and Biogen. The findings are part of a collection of data that will probably be reviewed by the FDA.

“This was the key second trial that could support FDA approval. We published the first clinical study in 2021,” said Dr. Kristina Deligiannidis, a professor at the Institute of Behavioral Science at the Feinstein Institutes for Medical Research in New York, who was lead author of both studies.

That previous study of zuranolone, the results of which were published in 2021 in the journal JAMA Psychiatry, found that among 151 women with postpartum depression, those taking 30 milligrams of zuranolone daily for two weeks reported greater reductions in their depressive symptoms than those taking a placebo. Those reductions in symptoms were seen within three days and lasted through at least 45 days, according to the study, which was conducted in 2017 and 2018 at 27 sites.

“In the first study, we tested 30 milligrams, which was associated with good safety and tolerability, good efficacy,” Deligiannidis said. “Then we replicated these findings in the second trial in the larger sample at the 50 milligrams, and we found very similar efficacy and safety at that dose.”

In the latest trial, researchers from the Feinstein Institutes for Medical Research at Northwell Health and other US institutions examined the efficacy and safety of a 50-milligram dose of zuranolone among the 196 women, who were between the ages of 18 and 45. Within the group, 21.9% of the women were Black, and 38.3% were Hispanic.

Among the women who took zuranolone, the researchers noticed rapid responses to the treatment as early as day three.

The day after the women completed the 14-day treatment course, the researchers found that 57% reported a 50% or higher improvement in their depressive symptoms, compared with 38% of those on a placebo.

As the researchers continued to follow the women through 45 days, 61.9% of participants who received zuranolone, compared with 54.1% of those taking a placebo, reported a 50% or higher improvement in their depressive symptoms.

Some of the women given zuranolone reported drowsiness, dizziness or sedation. Among the 98 who were given zuranolone, 16 reduced their dosage from 50 to 40 milligrams due to those side effects.

“Since zuranolone is an acute, 14-day treatment course, the medication is not taken chronically, any side effects should be confined to the short treatment course,” Deligiannidis said.

In the trial, 26.5% of the women taking zuranolone reported drowsiness, 13.3% had dizziness, and 11.2% had sedation. A smaller share of participants had headache, diarrhea and nausea. The researchers noted that none of the people taking zuranolone had side effects so severe that they lost consciousness, experienced withdrawal symptoms or reported increased suicidal ideation or behavior. No patient deaths were reported.

“The greatest benefits of zuranolone are its rapid antidepressant effects, short at-home treatment course and generally well-tolerated side effect profile,” Deligiannidis said. “For many patients, they may only need a short, acute treatment course followed by close monitoring.”

McMahon said that she did not experience any side effects with zuranolone and that she hopes the FDA approves the drug.

“It saved my life. It saved my marriage. It saved my kids,” said McMahon, who is now doing well along with her husband, 4-year-old Ophelia and 2-year-old Lenora.

“Just, the ricochet effect of sitting around, gaining weight, watching TV, going to sleep on the couch, not interacting with my kids, letting them figure it out, letting them stay up on iPads and tablets,” she said. “I can’t imagine how much further I could have fallen into a depression.”

Hopes of expanding access

Current treatment options for postpartum depression include standard-of-care antidepressants, but it can take up to 12 weeks to get responses to such treatments. Another treatment option is Zulresso, the first FDA-approved drug in the United States specifically for the treatment of postpartum depression.

Zulresso is given as a 60-hour intravenous infusion of the drug brexanolone, and as such, it must be used within a health care setting – not at home.

Both brexanolone and zuranolone are versions of a naturally occurring substance in the body called allopregnanolone, a neuroactive steroid that is a metabolite of the hormone progesterone. Levels of allopregnanolone can rise dramatically during pregnancy and then abruptly drop after childbirth, potentially contributing to postpartum depression.

“Neuroactive steroids are naturally made in the brain and are breakdown products of progesterone that protect brain networks from the damaging effects of stress and maintain healthy brain network functioning,” Deligiannidis said.

So restoring allopregnanolone with medications structurally similar to it, like brexanolone or zuranolone, can help provide some relief to people with postpartum depression. Both drugs work in a similar way; they are just administered differently.

“The main difference is that Zulresso is given as a single 60-hour infusion, which requires an in-hospital stay, versus zuranolone, which is taken daily by mouth for 14 days at home in the evening,” Deligiannidis said.

“There’s so many of us in the field that are just waiting to have additional options and faster-acting treatments for women. Brexanolone truly is a life-saving medication; however, we’ve had many challenges with access, to get it to patients,” she said. “My hope is that with an oral option, an at-home option, that we’re able to provide similar benefit to more patients rapidly.”

More needed to tackle maternal mental health crisis

The new phase three trial suggests that zuranolone might offer a quick and effective oral treatment for postpartum depression across diverse groups of women, Judite Blanc, assistant professor of psychiatry and behavioral sciences at the University of Miami Miller School of Medicine, wrote in an email.

Blanc, who was not involved with the new study, praised the diversity of participants, emphasizing that the inclusion of Black and brown women suggests that the findings can be more generalizable.

“This could be particularly beneficial for women who face barriers to accessing long-term treatments, such as low-income women or those with limited healthcare access. However, from a scientific, social, and ethical standpoint, this clinical trial is not the panacea to tackle the maternal health crisis in the U.S. and globally,” Blanc wrote.

“Medications shouldn’t be the first or only line of treatment for mental health conditions, particularly among women, children, and historically oppressed populations,” she said.

And as the effect of zuranolone reported in the trial was followed only for 45 days among postpartum women who don’t breastfeed, Blanc added that “we need further studies to assess the long-term impact of Zuranolone, including among breastfeeding mothers, as well as the patient-child interaction.”

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