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The FDA approved zuranolone for postpartum depression in August, and the drug recently hit the market for patients this month. Experts are celebrating its delivery of care and rapid response rate.
There are few more paradoxical conditions known in medicine than postpartum depression—a disease that which changes what could be the happiest days of a new mother’s life into a series of cognitive impairment, lowered energy, or even suicidal ideation. And despite these dire circumstances that a new mother may encounter, few treatment options have ever been made available for clinicians to prescribe. Understandably, investigators have prioritized advances to postpartum depression treatment for years; in 2023, they reached a breakthrough.
Zuranolone, a GABA-positive allosteric modulator, is an oral medication taken for 14 straight days. In one study, participants on zuranolone had reduced depressive symptoms on day 3 and the symptoms continued reducing throughout the 45-day study period. The US Food and Drug Administration (FDA) approved zuranolone on August 4, marking it as the first oral drug to treat postpartum depression.2,3
The breakthrough just reached the market this month, when Biogen Inc. and Sage Therapeutics announced zuranolone (ZURZUVAE) became available for patients on December 14.3
But zuranolone is not the first treatment approved for postpartum depression—brexanolone (ZULRESSO), an intravenous (IV) injection, arrived 4 years ago after its FDA approval in March 2019. But to receive this treatment, patients must enter a restricted program called Zulresso REMS Program, requiring a health care provider in a certified facility to administer the drug through an IV. Patients must register in the program prior to receiving the IV, and the infusion lasts 60 hours.
After the IV infusion, health care providers must monitor their patients for sedation and sudden loss of consciousness, as well as monitor the oxygen levels in their blood. After the treatment, patients are told not to drive, operate machinery, or do any dangerous activities until drowsiness from the treatment is completely gone. Adverse events with brexanolone include sleepiness, dry mouth, loss of consciousness, and flushing.
With zuranolone, some adverse events in the clinical trials included drowsiness, dizziness, diarrhea, fatigue, nasopharyngitis, and urinary tract infection. When tested for just major depressive disorder—not postpartum depression—other events included fatigue, somnolence, headache, dizziness, diarrhea, sedation, and nausea, but they were mild. People who are on zuranolone are also advised not to drive until 12 hours after taking the medication. While both zuranolone and brexanolone have adverse events, zuranolone can be more favorable with it being an oral treatment versus an IV treatment.
“[Zuranolone] could potentially replace brexanolone,” Anita Clayton, MD, of the University of Virginia School of Medicine, told HCPLive. “[For brexanolone] you have to be in the hospital for 72 hours. It’s much more preferable to be able to take a pill every night for 14 days.”
Both brexanolone and zuranolone are pricey, but zuranolone actually costs a lot less in comparison. While brexanolone sits at around $34,000 for treatment, not including hospitalization costs, zuranolone costs about half that at $15,900 for the 14-day course.5
“For a single course, that price was set based on utilization for health care, whether you had an ER visit, whether you saw your psychiatrist repeatedly, the cost of medicines, hospitalizations, if you didn't respond to medicines—things like that from an established cohort,” Clayton said. “Using currently available standard of care—antidepressants—it presumably will be covered mostly by insurance for women with postpartum depression.”
Despite the cost, Clayton believes zuranolone provides enough benefits since patients would not have to chronically take antidepressants daily.
“And so, you wouldn't have kinds of side effects that interfere with quality of life, sexual dysfunction, cognitive impairment, sleep disturbance, weight gain, emotional blunting, etc,” Clayton said, “and I think that could be really exciting for people and definitely feel that it’s worth it.”
Along with avoiding driving behind the wheel after taking zuranolone, the FDA recommends for people to take 50 mg of Zuranolone with a fatty meal and to be aware of the sedation side effect.
“The sedating effects are significant enough that persons should be guided to take it in the evening,” Tiffany A. Moore Simas, MD, of UMass Memorial Health and co-chair of American Congress of Obstetricians and Gynecologists’ Maternal Mental Health Expert Work Group, told HCPLive.
Zuranolone was tested in placebo-controlled trials, 2 of them submitted to the FDA in the New Drug Application (NDA) package. In the first study, patients received 50 mg of zuranolone—specifically the Zurzuvae brand—or placebo daily for 14 days.6 Then, in the second study, patients received another zuranolone product that was equal to 40 mg of Zurzuvae or placebo for 14 days. Investigators monitored participants for 4 weeks after the 14-day treatment.
In both studies, the primary endpoint was change in depressive symptoms using the total score from the 17-item Hamilton Depression (HAMD-17) Rating Scale. Patients on zuranolone showed significant improvements in their symptoms compared to patients taking placebo, and the improvements maintained at day 42, the 4-week mark after the treatment ended.
Zuranolone improves symptoms at a rapid rate, and as Clayton pointed out, the medication would benefit people who need a rapid response.
“If someone were severely ill and suicidal, I might want to use it because it works fast,” Clayton said. “You don’t have to repeat the doses, like some of the other rapidly acting medications like esketamine—you have to repeat those very frequently—and that isn’t required with zuranolone.”
While Clayton worked on a study testing zuranolone for participants with major depressive disorder, the FDA did not approve the company’s NDA for such an indication despite the significant data. Clayton worked on the MOUNTAIN trial and the WATERFALL trial, the former which did not reach statistical significance in zuranolone improving depressive symptoms more than the placebo, but it did show zuranolone’s rapid onset of action. In the WATERFALL trial, the findings demonstrated a change in total score on the HAMD-17 from baseline to end of trial. The trial found significant improvement on day 3, and improvements continued throughout the study. Again, zuranolone demonstrated rapid action.
Nevertheless, Clayton is enthusiastic about this breakthrough with zuranolone being approved for postpartum depression.
“I think it can be really exciting,” Clayton said. “People have to trust the idea that this could potentially work for a given patient, and they don’t have to be on another antidepressant at the same time. So [I] think all of that is very positive for rapid onset, significant efficacy, and not having chronic long term side effects.”
Still, women may face challenges to even initiating postpartum depression care, including barriers to mental health screening. Moore Simas said how pregnant and postpartum individuals should be screened for depression—if they screen positive, they should be further evaluated and have access to the adequate treatment. Treatment can be lone pharmacotherapy or pharmacotherapy paired with psychotherapy.
“Not all perinatal individuals experience this full mental health pathway and those marginalized by racism and socioeconomic disadvantage are less likely to be screened and have access to treatment,” Moore Simas said. “Many obstetric care clinicians are uncomfortable addressing perinatal mental health. This leads to gaps in detection and treatment that needs to be addressed, along with the role of stigma in care seeking.”
Common screenings include Patient Health Questionnaire-9 and the Edinburgh Postnatal Depression Scale. Anna Wheelan, MD, of the UMass Memorial Health, talked to HCPLive about some of the concerns people have regarding the risk of untreated disease and the risk of medication. Concerns stemmed from when the first selective serotonin reuptake inhibitors (SSRIs) came out in the 1990s. One study showed an increase in congenital heart defects among the medication paroxetine, but other studies did not find the same results. Another concern had been persistent pulmonary hypertension of the newborn, as well as neonatal adaptation syndrome.
“When I look at, the other hand, the risk to mom and baby of untreated perinatal depression, I see increased risk for preeclampsia, preterm birth, impaired bonding and attachment, increased risk for postpartum psychosis, increased risk for maternal suicide and drug use, and impaired family bonding,” Wheelan said. “And so those risks greatly outweigh any minor risk of the medication. I strongly encourage practitioners and physicians and patients to have this discussion where I really think this is…almost no risk for SSRIs, and there are significant risks of untreated depression.”
With zuranolone’s rapid response rate and being an oral, easy-to-take medication, the drug will serve as a new treatment option for women with postpartum depression, shifting the landscape of treatment for this long under-met phenomenon.