It has taken decades for the medical establishment to recognize the vast scope of postpartum depression, or PPD.
Conservative estimates say 11 percent of women become depressed at some point in their first year of motherhood; others put that figure at closer to 25 percent. And that’s just the women who seek help. Likely, the numbers are greatly undercounted — according to one study, fewer than 15 percent of moms who had symptoms of PPD actually got help.
Most mothers experience some form of the “baby blues,” a mix of sadness and fatigue that crops up in the first week or two after delivery and fades relatively quickly. But postpartum depression lingers longer and can develop later, often months after a baby is born.
“During pregnancy, both estrogen and progesterone, the two major female hormones, go sky high. That’s normal. At the time of delivery, they fall precipitously. That happens in all women,” explained Dr. Samantha Meltzer-Brody, a perinatal psychiatrist who runs the University of North Carolina’s Center for Women’s Mood Disorders. “There’s been a theory that some women are differentially sensitive to that rise and fall.”
Not a single drug on the market today specifically targets PPD — which certainly shares many of the hallmark symptoms of clinical depression, but also has that hormonal underpinning that makes it very much its own beast.
“What’s most difficult for me is when I see someone come in who’s really suffering and is quite sick ... it’s going to take four to six weeks to get better.”
Talk therapy can be helpful, particularly for women with more mild symptoms of depression. Standard antidepressants — namely SSRIs, which increase the amount of serotonin in the brain — can also help women get back on their feet.
But SSRIs take weeks to kick in, for reasons researchers don’t fully understand.
“In general, even outside the postpartum period, when we think about treating depression or anxiety, we think about medications being effective on the order of weeks or months,” explained Dr. Anna Glezer, an assistant clinical professor of psychiatry at the University of California, San Francisco.
And while that lag time does not mean long-term effects are inevitable, it can be incredibly hard on women and their doctors, particularly in the most severe cases, when women have all but stopped functioning.
“As a perinatal psychiatrist, what’s most difficult for me is when I see someone come in and see me who’s really suffering and is quite sick, is that even if I start standard antidepressants right away, it’s going to take four to six weeks to get better,” said Meltzer-Brody. “It’s a bad scene.”
A PPD-Specific Drug
So it was fortuitous that five years ago, a fledgling biotech firm approached Meltzer-Brody to get her take on a drug the company was developing. The drug was brexanolone, Sage Therapeutics’ first-of-its-kind formulation of a neurosteroid that the company hopes can target some of the hormonal changes fundamental to pregnancy and childbirth and ultimately transform treatment for PPD.
Meltzer-Brody agreed to an initial trial with the participation of four patients struggling with severe postpartum depression at her clinic at UNC, one of the country’s only in-patient perinatal psychiatry units. The trial was open-label, meaning that both patients and doctors knew exactly what they were getting: a 60-hour intravenous infusion of the experimental treatment. But they had no idea whether it would work.
“Within 24 hours, we were seeing dramatic responses that then were sustained over a 30-day follow-up period,” said Meltzer-Brody, who took on the role of academic principal investigator on the trial. She described seeing patients who’d been totally withdrawn from the world suddenly emerge from their hospital rooms to chat with their families and dote on their babies, coming back to life like wilted flowers after a good long soak.
“What’s really exciting to me is that there is no drug on the market that is a neurosteroid that acts in this way,” Meltzer-Brody said. “It’s going after an entirely different mechanism of action. It would be something that would potentially treat women for postpartum depression in days. And that, I think, would be an amazing, positive step forward.”
Glezer, who is not involved in the research, said the drug would address a “very unique” need beyond women with mild to moderate symptoms who benefit from existing medications. It’s an injection, she pointed out, and requires professional administration.
“This is a really important thing they’re trying to do, because at this point the drugs we have to treat postpartum depression are drugs that are used to treat general depression, Glezer said. “So there’s nothing that’s been specifically developed for postpartum depression.”
Uncovering A New Mechanism?
A primary challenge in treating PPD is that its full causes are still unknown, and the development of brexanolone does not mean that researchers have finally discovered why some women experience postpartum depression and others don’t. A variety of factors may be at play. There are hormonal changes, yes, but also intense fatigue, financial and emotional factors, as well as the sheer stress of having one’s life flipped upside down by a helpless infant. After all, men experience postpartum depression, too.
Regardless of whether the causes are fully known, Sage Therapeutics believes it has tapped into a novel way of treating the most severe cases of PPD by targeting the brain’s GABAA receptors with an infusion of brexanolone.
“We are exploring the role of GABAA, which is a different neurotransmitter — it hasn’t really been explored for treatment of depressive episodes broadly, or PPD in particular to date,” said Dr. Steve Kanes, Sage Therapeutics’ chief medical officer. “We think it’s important to PPD because that mechanism itself is thought to be part of the trigger of what causes the PPD in the first place.”
“Within 24 hours, we were seeing dramatic responses that then were sustained over a 30-day follow-up period.”
After the success of brexanolone’s open-label trial, a phase 2 trial quickly followed, and results from both found the primary side effects included relatively mild issues like dizziness and drowsiness. The financial world is certainly excited about a new drug and a new mechanism for targeting PPD, and Sage’s shares have surged as the company has released results from its various trials (though it did garner some negative press for ads it ran in Boston around the annual American College of Obstetricians and Gynecologists meeting that featured women crying with pacifiers in their mouths).
But — and this is the big but — results from the phase 3 trial have not yet been published in a peer-reviewed journal. The company has signaled its intention to file a new drug application with the Food and Drug Administration in 2018, but a lot hangs on that next study and way it’s received by the broader scientific community.
“The peer-review part is obviously the critical part,” Meltzer-Brody said. “You know, pharma says this; that’s great. But what about the scientific community?”
For now, she’s simply excited that there’s possibly a new option for her patients on the horizon.
“The first patient we infused was someone who was extremely depressed, had lost 20 pounds in a short period of time postpartum because she wasn’t eating at all, was very sad, didn’t want to interact with the baby — didn’t want to interact with anyone — and the family was extremely concerned,” Meltzer-Brody said. “Twenty four hours after the infusion, she came out of her room, was smiling, ate her whole lunch, was talking to everyone. It was dramatic.”