Stephanie Hathaway knows the agony of postpartum depression all too well, having been tormented by intrusive suicidal thoughts after each of her two daughters were born. Both bouts were excruciating, but the second, in 2017, was unremitting.
Hathaway took an antidepressant that had worked for her before, spent five days in a hospital near her home in South Windsor, Conn., and underwent intensive outpatient therapy. Despite all that, a loop kept playing in her head: “My husband deserves a better wife, my children deserve a better mom, and the world would be better off without me.”
Desperate after suffering for more than five months, Hathaway volunteered for a clinical trial of an experimental antidepressant from Cambridge-based Sage Therapeutics, given intravenously over 60 hours. Eight hours into the infusion, which made her sleepy, she awoke from a nap. The fog had lifted. She was thinking of meatloaf recipes for her family instead of suicide.
“I called my husband, and I’ll never forget what he said,” Hathaway recalled. “He said, ‘Stephanie, I have not heard the you in your voice in so long.’”
The one-time treatment, called Zulresso, was approved by the Food and Drug Administration in 2019 as the first medicine specifically for postpartum depression. But the $34,000 antidepressant was a commercial flop, partly because few hospitals offered the 2½-day infusion. Sage chief executive Barry Greene said that only “hundreds” of people received it, “not the thousands of moms we hoped to help.”
That could soon change. Sage scientists have devised a new medicine, dubbed zuranolone, that works in the brain the same way as Zulresso but can be taken as a once-a-day pill for two weeks. Zuranolone was one of two drugs that prompted Cambridge-based Biogen to strike a partnership in 2020 that paid Sage $1.5 billion.
After years of inattention from the pharmaceutical industry, the focus on postpartum depression is a welcome development for doctors and patients. Even though few women have received Zulresso, its FDA approval and effectiveness galvanized researchers, said Dr. Kristina Deligiannidis, an associate professor at the Feinstein Institutes for Medical Research in Manhasset, N.Y.
“It really jump-started the field to think about patients with postpartum depression,” said Deligiannidis, a psychiatrist who worked on the clinical trials for Zulresso and zuranolone, both of which work on different parts of the brain than commonly prescribed antidepressants.
Last month’s tragedy in Duxbury thrust postpartum depression into the spotlight. Lindsay Clancy, a 32-year-old nurse at Massachusetts General Hospital, has been charged with killing two of her children and strangling a third who later died. Clancy, who jumped out of an upstairs window at her home after the alleged Jan. 24 attacks, had said on social media beforehand that she was suffering from postpartum depression.
Although intrusive and suicidal thoughts are common features of the condition, it’s rare for mothers to act on them and harm a baby or themselves. But postpartum depression is far more prevalent than many people suspect. Up to 1 in 8 new mothers — about 500,000 in the US each year — develop symptoms, although many cases go undiagnosed, according to the Centers for Disease Control and Prevention.
“Our goal is to help as many of those women as we can,” Greene said. Although psychotherapy and traditional antidepressants are often recommended, getting an appointment with a therapist can take months. And the most commonly prescribed antidepressants, selective serotonin reuptake inhibitors, or SSRIs, typically take four to six weeks to work, if they do at all.
Sage believes that zuranolone will offer faster relief. In one advanced clinical study of nearly 200 women with the condition, depression dropped significantly after just three days in 26.5 percent of those who received zuranolone compared with 12.5 percent of those who got a placebo. Those figures rose to 57 percent for zuranolone and 38.9 percent for placebo after the full two weeks of treatment. The benefits continued for at least one more month — the duration of the study. “Moms got better, and stayed better,” Greene said.
“A medication that works in three days is really exciting, and that’s one of the reasons this is getting so much attention,” said Dr. Nancy Byatt, a psychiatrist who studies postpartum mental health at the UMass Chan Medical School.
Dizziness, drowsiness, and sedation were common side effects of zuranolone, as they are for Zulresso. As with other antidepressants, the drug didn’t work for everyone, and many people who got the placebo got better too. But Byatt said that it was at least, “if not more,” effective than other antidepressants.
The drug is based on the natural molecule allopregnanolone, a byproduct of the hormone progesterone that rises during the third trimester of pregnancy and falls precipitously after the baby is born, said Sage’s chief medical officer, Dr. Laura Gault.
Zulresso, the company’s infusion drug, is made from synthetic allopregnanolone, while zuranolone contains a version of the molecule that was chemically tweaked to help it work as a once-a-day pill. Yet Sage says that its drugs are not merely replacing something that is missing.
During depression, communications between brain regions become disrupted. Much like allopregnanolone, both of Sage’s medicines target brain receptors that use the neurochemical called GABA to reduce and slow communication between brain cells. “That really changes the way that brain regions are communicating with each other,” Gault said.
Dr. Greg Mattingly, a psychiatrist and associate clinical professor at Washington University who tested zuranolone in clinical trials, compared GABA to the brakes in a car, and its counterpart brain chemical ― glutamate ― to the gas pedal. The two molecules become imbalanced in people with depression, he said. “If either gets stuck, you’re not going to get where you need to be,” he explained. The medicine makes the brain receptor more sensitive to GABA.
The dramatic effects of Sage’s medicines have spurred a few other biotechs to launch early-stage efforts to make depression drugs, all based on new formulations of allopregnanolone. Boston-based PureTech Health and Salt Lake City-based Lipocine have devised pills containing the natural molecule. Brii Biosciences, which is based in China, California, and North Carolina, is making an injectable and possibly long-lasting version of the drug.
Considering how many people postpartum depression afflicts, it’s surprising that there’s not more competition. But Lipocine chief executive Mahesh V. Patel said the condition is considered a “niche market” compared with major depressive disorder, which afflicts 21 million Americans.
Sage and Biogen have also tested zuranolone on men and women with major depression unrelated to pregnancy and gotten encouraging results, prompting the companies to seek FDA approval for that condition as well. Such an approval would have far greater impact on the firms’ bottom lines than selling the drug solely as a treatment for postpartum depression.
In fact, Biogen’s new chief executive, Christopher Viehbacher, recently said he considers zuranolone and Leqembi, the firm’s recently approved drug for Alzheimer’s disease, potential blockbusters.
Sage expects to soon hear from the FDA on the regulator’s timeline for reviewing zuranolone for both forms of depression. Priya Singhal, Biogen’s head of development, said she hopes the FDA will approve it late this year or early next year.
For some Sage employees, the effort is deeply personal. Charlotte Heiney, who works in the firm’s clinical business operations, said she joined the company in 2021 partly because of her memories of postpartum depression following the birth of her first son five years earlier. She and her husband only decided to have a second son, in 2019, when they learned that Zulresso had been approved.
“It quite literally changed our lives,” Heiney, of Annapolis, Md., said of the medication.
Stephanie Hathaway, whose suicidal thoughts were vanquished by Zulresso in the 2017 clinical trial, believes the drug saved her life. Nonetheless, she and her husband didn’t want to take a chance that she might have another bout of postpartum depression when they decided to have a third child. The couple, who now live in Houston, adopted a baby boy, Tucker, in 2021.
She said the thoughts that tormented her after the birth of her daughters, Hadley and Brenley, make her feel empathy for Lindsay Clancy.
“I have a level of compassion for her that the general public can’t understand,” said Hathaway, 37. “I’m so thankful that with all I went through, I never had the thought of harming my own children.”
Ryan Cross can be reached at firstname.lastname@example.org. Follow him on Twitter @RLCscienceboss. Jonathan Saltzman can be reached at email@example.com.