An investigational medicine called zuranolone has generated significant, rapid, and enduring symptom reduction in women with postpartum depression. The drug was compared with placebo in a phase 3 trial conducted at 27 sites in the U.S.

Postpartum depression (PPD) affects about 13% of American women and is among the most common medical complications during and after pregnancy, according to the research team that conducted the trial. Reporting in the journal JAMA Psychiatry and led by Kristina Deligiannidis, M.D., of Zucker Hillside Hospital and Feinstein Institutes for Medical Research, the team included Handan Gunduz-Bruce, M.D., a 2007, 2005 and 2003 BBRF Young Investigator.

PPD "is underdiagnosed and undertreated and can persist for years," the researchers noted. "Complications of untreated PPD include maternal suicide, lasting negative effects on infant and child development, and depression in partners."

Zuranolone has a mechanism of action similar to that of brexanolone, a fast-acting (within 3 days) drug for PPD approved by the FDA in 2019. Significantly, however, zuranolone is delivered orally, in contrast with brexanolone which is delivered via infusion. Zuranolone's pharmacology profile makes it suitable for once-daily dosing, the investigators said. In the phase 3 trial, nearly all patients self-administered the drug as outpatients.

Brexanolone, the first medicine ever approved specifically to treat PPD, was developed over a 25-year period, through basic research that included important contributions by Cynthia Neill Epperson, M.D., whose early work on PPD was supported in part by 1995 and 1997 BBRF Young Investigator grants and later by a 2005 BBRF independent Investigator award.

PPD has been linked to disruptions of signaling by the inhibitory neurotransmitter GABA. These disruptions are thought to be related to dramatic changes in the period just before and after childbirth of circulating levels of the hormone allopregnanolone, which modulates neural receptors for GABA. In her pioneering research, Dr. Epperson mapped changes in cortical GABA levels across the menstrual cycle and in postpartum women.

In brain regions involved in emotion and self-perception, neural connectivity supported by GABA signaling correlates with allopregnanolone levels in a way that distinguishes women who develop PPD from those who do not. GABA has also been linked in animal models with the stress pathway called the hypothalmic-pituitary axis, which is implicated in PPD.

A total of 153 women, average age 28, were recruited for the randomized, double-blind outpatient trial of zuranolone. Half received 30mg of zuranolone orally each evening for 2 weeks. The other half received placebo. Participants were diagnosed with PPD 6 months or less postpartum, with major depression beginning in the third trimester of pregnancy up to 4 weeks postdelivery. To qualify for the study, participants must have ceased lactating at screening or agreed to stop breastfeeding from just prior to receiving zuranolone until 7 days after taking the last dose.

The researchers reported that women receiving zuranolone demonstrated "rapid (within 3 days), clinically meaningful, and sustained antidepressant effects," measured through the 45th day of the trial. They also demonstrated "rapid and sustained improvements in anxiety and improved global and maternal functioning compared with placebo."

Noting that "a high proportion of patients" remained in remission over the 45 days, the authors said zuranolone's "sustained effect is clinically meaningful and similar to effects observed in brexanolone infusion studies." While the drug's effect past 45 days is unknown, the trial made a convincing case for zuranolone's "short-term outpatient utility in PPD," the researchers concluded.

"The need for rapid and effective resolution of PPD symptoms cannot be overstated," they added, "given the prevalence of PPD and the negative effect untreated PPD can have on mothers, children and parents."

Several team members including Dr. Gunduz-Bruce are employees of Sage Therapeutics, the developer of zuranolone. Dr. Deligiannidis and others on the team reported consulting and/or funding relationships with the company.