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A Fast-Acting Pill Received Approval for Postpartum Depression—Is It a
Game Changer?
Rita Rubin, MAAlthough approximately 1 in 8 people
with a recent live birth experience
postpartum depression symptoms, treatments for the condition havebeen limited.
Treatments have consisted mainly oftalk therapy, sometimes combined withstandard antidepressants such as selective
serotonin reuptake inhibitors (SSRIs), which
can take up to 12 weeks to provide relief.
In 2019, the US Food and Drug Administration (FDA) approved brexanolone, an
intravenous injection marketed as Zulresso,
the first treatment specifically for postpartumdepression.
Brexanolone is fastacting but requires
Medical News websitethat patients be
hospitalized for a 60-hour-long infusion, during which they must be monitored for excessive sedation and loss of consciousness.
On August 4, though, the FDA approved
the first pill for treating postpartum depression. Zuranolone, which the agency had
designated for priority review, is an oral version of brexanolone. Like the infusion, zuranolone is fast-acting, but, taken once a day,it’s far more convenient.
“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.
Untreated, postpartum depression has
negative consequences for both mothers
and their children, a 2019 systematic review
concluded. It affects mothers’ psychological health, quality of life, and interactions
with their infant, partner, and other family
members. Severe maternal postpartum depression seems to have a greater impact onchildren’s development than mild postpartum depression, and the risks are greater forchildren in lower socioeconomic populations, the systematic review authors noted.
A fast-acting pill is expected to play a vital role for birthing patients who might bejama.com

iStock.com/SDI Productions

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.

How the Drug Was Studied
The FDA approved zuranolone on the basisof 2 phase 3 clinical trials that enrolled postpartum women whose severe depression
started in their last trimester or within thefirst 4 weeks after delivery. (Because the onset of depression can occur before delivery
as well as after, the American Psychiatric Association’s Diagnostic and Statistical Manualof Mental Disorders, Fifth Edition, began referring to it as “peripartum depression.”)“Most women, to be honest, have areally good idea of when depression cameon,” Kristina Deligiannidis, MD, the first author on both studies, noted in an interview.
The first study, published in 2021 in
JAMA Psychiatry, randomly assigned women
up to 6 months after delivery to receive
30 mg of zuranolone or placebo pills oncea day for 2 weeks, at which point 148 out of
150 had completed treatment.
The second study, published in theAmerican Journal of Psychiatry a week before the FDA approved the drug for postpartum depression, included 196 women up
to 12 months after delivery. Frequently,“women do not get diagnosed and do notpresent for treatment until many months after they deliver,” explained Deligiannidis, professor at the Institute of Behavioral Scienceat the Feinstein Institutes for Medical Research in Manhasset, New York.
The participants in this study, more thanhalf 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 doseof an antidepressant, “but they were still severely depressed,” Deligiannidis said. They
were not taken off their antidepressantfor the trials, and the FDA ultimately approved zuranolone for use alone or withan antidepressant.

(Reprinted) JAMA Published online August 23, 2023

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Both studies met their primary end
point—a significant reduction on average
from baseline in the Hamilton Rating Scalefor Depression total score at day 15 compared with placebo. The more recent study,
which used the 50-mg dose, also met all its
key secondary end points, with a significant reduction in depressive symptoms seen
as early as day 3 and sustained through theend of the study at day 45, a month after participants had finished their 14-day courseof pills.
There was also a high placebo responsein the study, which Deligiannidis and her coauthors speculated was influenced by
the high number of clinic visits during thestudy—8 in 45 days, which is more thanpeople 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 Centerfor 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.

A Potential Deal-Breaker?
The FDA is requiring a “black box warning,”
its strongest possible caution, on zuranolone’s label. It states that the drug can impair a person’s ability to drive and perform
other potentially hazardous activities. Patients might not be able to tell they’re impaired, so they should not drive or operate
heavy machinery within 12 hours of taking
zuranolone.
According to its label, a 50-mg dose ofzuranolone is to be taken in the evening withfatty foods to enhance drug absorption. (Therecommended 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 forsome patients, Wisner noted. For example,
she said, what if someone was prescribedzuranolone after they returned to work andhad to drive to their job fewer than 12 hours
after taking the drug?
That would be especially problematic forpeople who couldn’t afford a rideshare service, she pointed out. “If they don’t go towork, they don’t buy food or diapers,” Wisnerexplained. “I do think it’s something that has
to be considered.”
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The label also warns that the drug cancause central nervous system (CNS)
depressant effects such as somnolence,dizziness, and confusion. If patientsdevelop CNS depression, prescribers can
reduce the dose to 40 mg or consider discontinuing the drug. Besides sleepiness ordrowsiness and dizziness, the label statesthat 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 theirinfants. “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 ofthe 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 forthe drug also notes that zuranolone is a federally controlled substance because it can beabused or lead to dependence.
In addition, people who could become
pregnant should use effective contraception while taking zuranolone and for a week
after. The National Pregnancy Registry for
Antidepressants at Massachusetts General
Hospital already has been gathering information about the safety of brexanolone
during pregnancy and will be adding zuranolone to the list of antidepressants it isevaluating, according to a news releasefrom Sage Therapeutics and Biogen, which
jointly developed zuranolone.

The Cost of Treatment
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 thatshe’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.
Cost isn’t the only potential obstacle totreatment, though. In a 2018 survey ofpeople who’d recently delivered an infant,
1 in 8 said that their clinician hadn’t asked
about depression in postpartum visits; 1 in
5 said they weren’t asked about depression
in prenatal visits.
Butifhistoryisanyindication,Schatzberg
predicted, zuranolone’s approval could spur
improved screening and diagnosis of postpartum depression.
“What happens is proven efficacy of aparticular drug will drive diagnoses,” he explained. For example, he said, after the FDA
approved lithium in 1974 as the first treatment for bipolar disorder, physicians became more likely to properly diagnose patients who had bipolar disorder.

A “No” for Major Depressive Disorder
Both zuranolone and brexanolone areneurosteroids and analogues of the hormone allopregnanolone. Allopregnanolone is derived from progesterone, whichrises during pregnancy but then begins tofall in the third trimester and plummets
after delivery. However, “[e]vidence relating perinatal mood and anxiety symptoms
with absolute levels of allopregnanolone
has been equivocal, especially in larger
population studies,” a 2020 review article
noted.
Like barbiturates and benzodiazepines, zuranolone and brexanolone arepositive allosteric modulators of the neuroactive steroid γ-aminobutyric acid type A(GABA-A) receptor. GABA signaling appears
to play a role in postpartum depression as
well as in major depressive disorder.
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 drugfor the treatment of adults with major
depressive disorder, a much more common condition than postpartum depression, “did not provide substantial evidenceof effectiveness to support the approval,”

JAMA Published online August 23, 2023 (Reprinted)© 2023 American Medical Association. All rights reserved.

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according to the joint press release fromthe companies.
“We’re extremely disappointed forpatients, and we don’t agree with the
FDA’s view,” Sage Chief Executive Officer
Barry Greene said in an August 7 investor
call. That day, his company’s stock dropped
49% in response to the FDA’s denial for
major depressive disorder. “We really can’t
speculate on the FDA’s thinking,” Greene
said. He would say only that Sage is “evaluating the next step” and would describe
what that is “as soon as we can provide
more clarity.”
Meanwhile, Sage is currently recruiting
for a clinical trial of zuranolone in treating pediatric patients with major depressive disorder, according to ClinicalTrials.gov.
One reason zuranolone has appeared tobe more efficacious in postpartum depression than in major depressive disorder could
be that people with the former are a morehomogeneous 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 amuch 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.

Unanswered Questions
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 alongitudinal study with those women who
took zuranolone…to follow them for 12

jama.commonths 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 theend of 8 weeks or so after starting treatment, the response rate for both drugs isabout 60%, Wisner said. However, shepointed out, zuranolone has never been
compared head-to-head with an SSRI suchas 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 thatsome of her patients with severe postpartum depression won’t need further treatment after a course of zuranolone, except
perhaps counseling. Others might still havedepression after finishing their 2 weeks ofzuranolone, so they would be candidates forlonger-term treatment with a standard antidepressant and psychotherapy.
As she and her coauthors of the more recent study noted, zuranolone has beentested 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.

More to It
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?” sheasked. “It’s about environmental stress.”
InanopinionpiecepublishedinMedPage
Today after zuranolone’s approval, Blanc
noted that postpartum depression “is notjust a biological or an individual issue but aculmination of complex interactions between gender roles, societal expectations,and systemic inequalities.”
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.”
Published Online: August 23, 2023.
doi:10.1001/jama.2023.16499
Conflict of Interest Disclosures: Dr Deligiannidis
reported consulting for Brii Biosciences, Gerbera
Therapeutics, GH Research, Neuroscience
Software, Reunion Neurosciene, andSage Therapeutics; receiving grants from Sage
Therapeutics awarded to Zucker Hillside
Hospital/Feinstein Institutes for Medical Research
related to clinical trials of brexanolone andzuranolone and from the National Institutes of
Health and Vorso Corporation; and receiving
royalties from an NIH employee invention.
Dr Schatzberg reported consulting for Sage
Therapeutics, Neurawell, ANeurotech, Magnus,
Alto Neurosciences, Parexel, and Signant andholding equity in Corcept, XHale, Titan, Merck,
Delpor, Epiodyne, and Owl Insights. Dr Blanc
reported serving as coprincipal investigatorof a study on the use of virtual reality technology
to improve the mental health of pregnant people
and new mothers that was a collaboration
between the University of Miami Miller School of
Medicine and BehaVR. No other disclosures werereported.
Note: Source references are available throughembedded hyperlinks in the article text online.

(Reprinted) JAMA Published online August 23, 2023

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