FDA Approves First Drug to Treat Postpartum Depression

The new treatment could alleviate symptoms of depression in under three days.

Posted Mar 20, 2019

Anneka/Shutterstock
Source: Anneka/Shutterstock

Postpartum depression strikes 400,000 American women every year, and one in nine will experience the disorder in their lifetime. These new mothers experience sadness, hopelessness, low energy, and suicidal thoughts, all of which can disrupt the pivotal process of bonding. Yet standard antidepressants can take several weeks to work—or to reveal that they’ve failed.

A new medication, approved yesterday by the FDA, can alleviate symptoms of postpartum depression far more quickly, in just a two and a half days. The benefits can last for at least a month, research suggests.

“Newborns obviously require an enormous amount of care. If mom is really suffering, it very quickly becomes a family crisis,” says Samantha Meltzer-Brody, who conducted clinical trials of the drug and directs the Perinatal Psychiatry Program at the University of North Carolina School of Medicine. “A drug that acts rapidly can make a huge difference.”

The new drug, brexanolone, was developed by Sage Therapeutics and will be marketed as Zulresso. The drug is delivered intravenously over 60 hours in a hospital or medical center. Priced around $34,000, the new treatment should be available in June, according to Sage Therapeutics. The company is currently developing a similar treatment as a pill.

The treatment represents a completely new route into the brain, working on GABA receptors rather than on monoamine pathways, the typical target for antidepressants. (The newly approved depression drug esketamine also acts on glutamate and GABA.) Brexanolone is a synthetic version of allopregnanolone, which acts on GABA receptors. Levels of allopregnanolone steadily rise during pregnancy but abruptly drop once the baby is born, which is linked to changes in mood that may lead to postpartum depression. An infusion of brexanolone boosts allopregnanolone back to its third-trimester peak and then lowers it more gradually.

“One of the main regulatory systems in the brain that quiets down brain activity is the GABA system,” says Steve Kanes, Chief Medical Officer at Sage Therapeutics. “Zulresso isn’t turning the GABA system on or off—it’s adjusting the volume, which allows the brain to achieve a more normal system of functioning.”

Sage Therapeutics funded and submitted three clinical trials demonstrating brexanolone’s effectiveness in women with moderate to severe postpartum depression. A phase 2 clinical trial assessed how the medication influenced 21 women’s scores on a 52-point measure of depression called the Hamilton Rating Scale for Depression. Sixty hours after treatment with a placebo, their scores fell by about nine points, on average. With brexanolone, their scores dropped by 21 points.

“With other antidepressants we see two or three point differences between the drug and the placebo. A difference of 12 points is huge,” says Walter Dunn, a University of California Los Angeles psychiatrist and a member of the committee that reviewed brexanolone for the FDA. The medication is so promising because it acts quickly, powerfully, and the benefits are sustainable, Dunn says.

Meltzer-Brody would agree. The first patient treated with brexanolone was severely depressed, she recalls. The woman was withdrawn, didn’t want to interact with her baby, and contemplated suicide. But just 24 hours after the infusion began, she brightened, regained her appetite, and wanted to engage with her child. “It was a dramatic change unlike anything I had seen before in my career,” Meltzer-Brody says.

Two phase 3 clinical trials of nearly 250 women provided further evidence that brexanolone led to greater improvement than a placebo, although the placebo effect wa stronger in these trials (as is typical of phase 3 trials). Importantly, the improvements were long-lasting. Of the 70 percent of women who responded to the drug, 94 percent continued to experience benefits at the end of the 30-day follow up period.

The advisory committee convened to review the evidence for brexanolone in November 2018. The panel voted that the drug was effective (18 to 0), that the drug was safe (16 to 2), and that the benefits outweighed the risks (17 to 1).

The most common side effects were sleepiness, dizziness, and headaches. But six patients experienced a more serious safety concern: fainting. A few committee members were particularly alarmed, including Jess Fiedorowicz, director of the Mood Disorders Center at the University of Iowa Carver College of Medicine. They worried that the number of women who lost consciousness could multiply once thousands of women began taking the drug. And the consequences could be deadly; a woman could hit her head and severely injure herself. She could drop her child if she fell, or suffocate the baby if she was breastfeeding. For these reasons, Fiedorowicz voted yes on efficacy but no on safety.

Due to these concerns, the FDA required that the drug be administered at certified health care facilities so that patients would be monitored closely throughout the infusion. The FDA’s mitigation plan ultimately led Fiedorowicz to vote yes on the final question—whether the benefits of the drug outweighed its risks.

The mode of delivery, though, may reduce access to the treatment for many women, Fiedorowicz says. Women who can’t afford the treatment, lack the support for a three-day hospital stay, or live in a rural area may struggle to obtain brexanolone.

Despite these hurdles, the approval is a promising step forward. “Now we have an entirely new mechanism that we can pursue and refine,” Fiedorowicz says. “This opens up a number of new doors for treating postpartum depression.”