First Oral Postpartum Depression Medication Receives FDA Approval
Abstract
While zuranolone may be a significant advance in maternal mental health care, the medication’s failure to also receive backing for major depression may signal that this medication will be a pricey option.
In August, the Food and Drug Administration (FDA) approved Zurzuvae (zuranolone) to treat postpartum depression in adults. Postpartum depression is estimated to affect 1 in 8 women. The medication—which was jointly developed by Sage Therapeutics and Biogen—is a neurosteroid that acts on similar receptors in the brain (GABA receptors) as Zulresso (brexanolone), which was the first postpartum depression medication to receive FDA approval. Both medications offer rapid relief of depression symptoms, but while brexanolone requires hospitalization for a 60-hour intravenous infusion, zuranolone is a pill that patients can take daily at home for 14 days.
The recommended daily dose for Zurzuvae is 50 mg, which is based in part on results from a phase 3 clinical trial whose findings were reported July 26 in The American Journal of Psychiatry. In that trial, 196 women aged 18 to 45 with severe postpartum depression were assigned to take either 50 mg zuranolone or a placebo pill each evening for 14 days. Those in the zuranolone group experienced significantly greater improvements in their depressive symptoms than those taking placebo by day 15.
“Patients receiving zuranolone demonstrated robust, clinically meaningful, and rapid improvements in depressive symptoms, as assessed by change from baseline [Hamilton Depression Rating Scale] score, which were evident as early as day 3 and were maintained through day 45,” Kristina M. Deligiannidis, M.D., and colleagues wrote. Deligiannidis is a professor at the Institute of Behavioral Science at the Feinstein Institutes and was the principal investigator on the clinical trial.
The medication was generally well tolerated, with somnolence, sedation, and dizziness being the most common side effects. There were no reported events of loss of consciousness, which can occur during a brexanolone infusion.
The Zurzuvae label includes a warning noting that the drug can impact a person’s ability to drive and recommends that patients wait at least 12 hours after taking the medication before driving or engaging in other potentially hazardous activities.
Jennifer Payne, M.D., believes the limited, two-week treatment course of zuranolone will be welcomed by many mothers, but said its important to identify if zuranolone lasts longer than 45 days, which is how long the clinical trials tested.
“This approval could be huge for psychiatry,” said Jennifer Payne, M.D., vice chair for research and a professor of psychiatry and neurobehavioral science at the University of Virginia School of Medicine. Payne, who is an expert in women’s mood disorders, has consulted for Sage in the past but was not involved in the clinical development of zuranolone. “I’ve had to tell many new mothers that they may need to stay on an antidepressant for the rest of their life; now it may just be two weeks.”
The zuranolone trials conducted by Sage followed participants for only 45 days, so how long a single course of the medication may last is not yet known, Payne explained. However, she noted the company has conducted yearlong open-label studies of zuranolone in adults with major depression, and in those trials, most adults who responded to zuranolone needed only one or two treatment courses over a year.
Sage and Biogen applied for FDA approval of zuranolone for the treatment of both postpartum depression and major depression, but the FDA stated there was not enough clinical evidence to support the approval of zuranolone for the latter. According to a Sage press release, the FDA said an additional study or studies evaluating the medication for people with major depressive disorder are needed.
Payne was not surprised that placebo-controlled studies of zuranolone for major depression did not show as clear a signal of benefit since major depression is more heterogenous and affects a broader population than postpartum depression.
“I do think many people see the value of this new paradigm to treat depressive episodes as needed, so I imagine the medication will get over the finish line eventually,” she said.
Many Questions Remain
While the addition of an oral treatment option for patients with postpartum depression is exciting, Katherine Wisner, M.D., cautioned that much about the drug remains to be determined. Wisner is the Norman and Helen Asher Professor of Psychiatry and Behavioral Sciences and Obstetrics and Gynecology at Northwestern University; she was not involved with the development of zuranolone.
For one, while zuranolone is fast acting—an important consideration for new mothers who are depressed—it may not be more effective overall than current options such as selective serotonin reuptake inhibitors (SSRIs), she said. She said that there have been no head-to-head studies, but based on available trials that have used similar outcomes, an SSRI such as sertraline provides the same level of symptom improvement and chance of response (about 60%) as zuranolone, just over an eight-week versus two-week time frame.
The sedative side effects of the medication may also be a tough sell for new mothers concerned they may not hear their baby in the night or be able to drive to morning appointments, Wisner continued.
Ryan Van Lieshout, M.D., is also hopeful that zuranolone will improve perinatal depression care, but cautioned that efficacy was demonstrated within a narrow window of depression onset (third trimester to four weeks postpartum).
As noted in the AJP report in July, about 9% of the participants taking zuranolone had to lower their dose due to side effects. As a result, Wisner said that she thinks many physicians are likely to start patients on lower doses than the recommended 50 mg, which may reduce effectiveness.
The clinical trials of zuranolone also used a strict definition of postpartum depression, noted Ryan Van Lieshout, M.D., Ph.D., the Canada Research Chair in the Perinatal Programming of Mental Disorders and the Albert Einstein/Irving Zucker Chair in Neuroscience at McMaster University in Hamilton, Ontario. All participants had to have severe depression symptoms that arose sometime between the third trimester of pregnancy and four weeks after birth.
“That is a pretty narrow window,” he told Psychiatric News. “It will be interesting to see if the medication works for women who became depressed outside of this time, or if this clinical population reflects a unique type of depression that is particularly influenced by postpartum hormonal changes.” (Zuranolone is a synthetic derivative of the brain hormone allopregnalone.)
What Will It Cost?
While many unanswered questions remain about zuranolone’s clinical benefits and risks, perhaps an important question in the short term is how much this medication will cost.
Sage and Biogen have not yet disclosed a price for zuranolone, but analysts quoted in an article by CNN suggested that a two-week supply may be almost as expensive as a three-day brexanolone infusion, which costs about $35,000. This price is higher than what Sage had indicated Zurzuvae might cost if approved for major depressive disorder, the analysts added.
“It’s the same story over again; the cost of this new medication will be substantial, and the insurance coverage will be variable,” said Wisner. Given the expected costs, Wisner could envision a scenario in which insurers cover zuranolone only for women in the specific time frame used in clinical trials (depression between third trimester and 4 weeks postpartum). Even then, she said, the companies may reimburse only after a patient tries and fails to respond to a conventional antidepressant.
Van Lieshout said he expects that pricing and insurance coverage could limit zuranolone’s reach, both in the United States and Canada (which has yet to approve the medication for use). He thinks psychiatrists and other health professionals should emphasize the long-term familial benefits of maternal mental health care. Some of his latest research, for example, found that the infants of mothers who received group CBT showed significantly healthier brain activity related to emotion regulation (as measured by EEG) after 9 weeks compared with infants of mothers placed on a CBT waitlist.
“That’s a good argument for coverage; one therapy could promote the well-being of two generations,” he said.
Whether patients can afford Zurzuve or not is secondary to the fact that many patients with postpartum depression are being overlooked entirely, Wisner noted.
“The majority of women with postpartum depression aren’t even being diagnosed, and as a result are receiving zero care; this approval will not change that disparity.” The Policy Center for Maternal Mental Health released state-by-state report cards, based on such factors as provider availability, depression screening rates, and insurance coverage. Forty states and D.C. received a D or F, while California came out on top with a B- grade.
“It’s imperative that we use this opportunity when postpartum depression is in the news to advocate for better screening and access to care,” Payne said. “This is not a rare disorder.” ■
