A Fast-Acting Pill Received Approval for Postpartum Depression—Is It a Game Changer? | Clinical Pharmacy and Pharmacology | JAMA

Treatments have consisted mainly of talk therapy, sometimes combined with standard antidepressants such as selective serotonin reuptake inhibitors (SSRIs), which can take up to 12 weeks to provide relief.

“Having access to an oral medication will be a beneficial option for many of these women coping with extreme, and sometimes life-threatening, feelings,” Tiffany Farchione, MD, director of the Division of Psychiatry in the FDA’s Center for Drug Evaluation and Research, said in a statement.

A fast-acting pill is expected to play a vital role for birthing patients who might be considering harming themselves or their infants, but zuranolone’s long-term efficacy isn’t known, and for many people, medication alone won’t be enough to alleviate postpartum depression.

“Most women, to be honest, have a really good idea of when depression came on,” Kristina Deligiannidis, MD, the first author on both studies, noted in an interview.

The participants in this study, more than half of whom were Black women or Hispanic or Latina women, were randomly assigned to receive 50 mg of zuranolone or placebo pills for 2 weeks. About 15% of the participants entered the trials taking a stable dose of an antidepressant, “but they were still severely depressed,” Deligiannidis said. They were not taken off their antidepressant for the trials, and the FDA ultimately approved zuranolone for use alone or with an antidepressant.

There was also a high placebo response in the study, which Deligiannidis and her coauthors speculated was influenced by the high number of clinic visits during the study—8 in 45 days, which is more than people in real-world settings would usually have in that time frame.

“The placebo is a pretty potent treatment for depression,” psychiatrist Katherine Wisner, MD, director of the Asher Center for the Study and Treatment of Depressive Disorders at the Northwestern University Feinberg School of Medicine, noted in an interview. Wisner was not involved in the zuranolone trials.

According to its label, a 50-mg dose of zuranolone is to be taken in the evening with fatty foods to enhance drug absorption. (The recommended daily dose for people with severe liver impairment or moderate to severe kidney impairment is 30 mg; zuranolone will be sold in 20-, 25-, and 30-mg capsules.)

Despite the nighttime dosing, the driving prohibition could be a deal-breaker for some patients, Wisner noted. For example, she said, what if someone was prescribed zuranolone after they returned to work and had to drive to their job fewer than 12 hours after taking the drug?

That would be especially problematic for people who couldn’t afford a rideshare service, she pointed out. “If they don’t go to work, they don’t buy food or diapers,” Wisner explained. “I do think it’s something that has to be considered.”

The label also warns that the drug can cause central nervous system (CNS) depressant effects such as somnolence, dizziness, and confusion. If patients develop CNS depression, prescribers can reduce the dose to 40 mg or consider discontinuing the drug. Besides sleepiness or drowsiness and dizziness, the label states that zuranolone’s most common adverse effects are colds, diarrhea, fatigue, and urinary tract infections.

In her experience, Deligiannidis said, zuranolone’s adverse effects have not interfered with patients’ ability to care for their infants. “They got up when the baby cried,” she said. “They did not feel they couldn’t do what they needed to do in the middle of the night.”

Like other antidepressants, zuranolone may increase the risk of suicidal thoughts or actions in people 24 years of age or younger, the label warns.

The FDA-required Medication Guide for the drug also notes that zuranolone is a federally controlled substance because it can be abused or lead to dependence.

Zuranolone will become commercially available under the brand name Zurzuvae in the fourth quarter of this year, according to Sage and Biogen.

Considering that some people with postpartum depression can’t even afford generic SSRIs, “what I worry about is how difficult it’s going to be for insurance to approve” zuranalone, Wisner said, adding that she’s concerned it might become a “novel exciting drug for the advantaged few.”

Sage set brexanolone’s price at $7450 per vial, for a total of $34 000 for the required 60-hour-long infusion. (Sage did not respond to an inquiry from JAMA about how many people have received brexanolone since the FDA approved it or whether it plans to continue marketing it now that zuranolone has been approved.) As of mid-August, the company had not yet revealed zuranolone’s list price.

In an interview, psychiatrist Alan Schatzberg, MD, director of the Stanford Mood Disorders Center and a consultant for Sage, said he suspects that it will be difficult for payors to refuse to cover zuranolone since it’s the only FDA-approved oral treatment for postpartum depression.

But if history is any indication, Schatzberg predicted, zuranolone’s approval could spur improved screening and diagnosis of postpartum depression.

But on the same day that the FDA approved zuranolone for postpartum depression, the agency informed Sage and Biogen that their application to market the drug for the treatment of adults with major depressive disorder, a much more common condition than postpartum depression, “did not provide substantial evidence of effectiveness to support the approval,” according to the joint press release from the companies.

One reason zuranolone has appeared to be more efficacious in postpartum depression than in major depressive disorder could be that people with the former are a more homogeneous group than those with the latter, Schatzberg said.

Major depressive disorder has numerous subtypes, he pointed out. For example, he said, half of patients with major depressive disorder also have anxiety and have a much lower response rate to typical antidepressants. “It’s an unmet need but a common disorder.”

Zuranolone, however, is both an antidepressant and an anxiolytic, Schatzberg noted. “I think there are paths forward for ultimately getting approval” for major depressive disorder.

The long-term effects of zuranolone aren’t yet known. After all, the clinical trials tracked participants for only a month after their 2-week course of treatment ended.

“I would be interested in conducting a longitudinal study with those women who took zuranolone…to follow them for 12 months and see how they’re doing,” Judite Blanc, PhD, an assistant professor of psychiatry and behavioral sciences at the University of Miami Miller School of Medicine, who was not involved with the trials, said in an interview.

Although zuranolone is faster-acting than SSRIs, research suggests that by the end of 8 weeks or so after starting treatment, the response rate for both drugs is about 60%, Wisner said. However, she pointed out, zuranolone has never been compared head-to-head with an SSRI such as sertraline, her choice for treating postpartum depression because of good evidence of its safety during breastfeeding. (The zuranolone trials prohibited participants from breastfeeding while taking their pills and for a week afterward.)

“We really need to know what happens beyond 45 days to be able to judge the difference between the 2 drugs,” Wisner said. She said she expects a patient eventually will ask her to prescribe zuranolone for postpartum depression, and when that happens, “I intend to keep a pretty careful record because it’s a new drug, and we have to figure how best to use it.”

Deligiannidis said she anticipates that some of her patients with severe postpartum depression won’t need further treatment after a course of zuranolone, except perhaps counseling. Others might still have depression after finishing their 2 weeks of zuranolone, so they would be candidates for longer-term treatment with a standard antidepressant and psychotherapy.

As she and her coauthors of the more recent study noted, zuranolone has been tested only in people with severe postpartum depression. Its usefulness for new mothers with moderate postpartum depression isn’t known, although once a drug is approved for any indication, clinicians can prescribe it as they see fit.

Blanc called zuranolone “a game changer,” but said it’s not a panacea for what is often a multifactorial condition.

“When are we going to start addressing the social determinants of postpartum depression and maternal mortality?” she asked. “It’s about environmental stress.”

Social factors such as intimate partner violence and a lack of partner or family support, as well as biological factors, contribute to postpartum depression, Blanc explained in her interview with JAMA.

Medications, she said, even those as promising as zuranolone, are “just one layer.”