The new postpartum depression drug and the turmoil of new parenthood

What the approval of zuranolone and the science behind the drug mean for our understanding of the parental brain and the future of treatment.

Photo by Solen Feyissa on Unsplash

You may have heard: The U.S. Food and Drug Administration has just approved a first-of-its-kind pill for postpartum depression. Zuranolone is an important advancement for treating new parents in crisis.

What it is not: a cure-all. It is not the big medical breakthrough that will make postpartum depression a condition for the history books. We have not solved it.

Why? Because mental health is complicated. Because the U.S. health care system offers no guarantee that effective medications will be made available to the people who need them. And because postpartum depression is not actually a single disorder that affects people with a specific, identifiable predisposition to it.

In fact, “postpartum depression” is a catch-all phrase generally used to describe the onset of depression during pregnancy or afterward that may occur through a wide range of mechanisms related to genes, medical history, social conditions, major hormonal changes, brain circuitry, or immune response. Researchers are working to untangle its many causes and find ways to better treat it.

Zuranolone, developed by Sage Therapeutics, is one. A promising one. The science behind this medication is fascinating and has a lot to tell us about the neurobiology of new parenthood.

A whole new approach

The most remarkable thing about this drug is that it works so fast. Selective serotonin reuptake inhibitors, or SSRIs, might not take full effect for several weeks, and the course of treatment may be indefinite. Zuranolone is meant to be taken for just 14 days. As

Emily Oster

put it, “short-term use with fast results.”

Oster does a good job of explaining in detail the effectiveness of the drug, according to the most recent trial in which one group of new mothers took zuranalone and the other took a placebo (the whole post is worth reading):

First, both groups improved a lot, which I think is heartening. Even the placebo group depression scores improve almost immediately, which is what we call the “placebo effect.” Second, the group taking the medication improve more, and that happens almost at once. By day 3 they are lower on their scores, and that is true all the way through day 45, long after the medication has stopped. 

For those taking zuranolone, scores fell faster and stayed lower, for the duration of the study. Those patients also saw improvements in anxiety symptoms and insomnia.

The study included women close to birth—in their third trimester or within four weeks postpartum. That’s important, the researchers note, because not all postpartum depressions are the same. Different timing of onset could indicate different causes.

And this drug targets a mechanism that is especially important right around delivery—a finding researchers stumbled upon a bit by chance. It’s generally referred to as GABA signalling, involving the neurotransmitter Gamma-aminobutyric acid and its receptors.

GABA is the primary inhibitory neurotransmitter in the nervous system, meaning it can tamp down activity. GABA receptors are widespread in the brain and a specific subset of them are especially present in brain regions involved in stress and emotion regulation.

Pregnancy disrupts those GABA receptors, in a big way. Progesterone skyrockets during pregnancy, and with it the metabolite allopregnanolone, which influences the inhibitory actions of those GABA receptors.

During pregnancy, allopregnanolone increases so much that, on its own, it would have a sedative effect, neuroscientist Jamie Maguire told me while I was reporting Mother Brain. Maguire directs a lab at Tufts Graduate School of Biomedical Sciences. Her work was foundational to the development of zuranolone. I checked in with her again this week.

She and her colleagues have pointed to a counter-effect to all that inhibition, a balancing of the scales. In pregnant mice, GABA receptors are downregulated, essentially taken off line. After delivery, allopregnanolone declines rapidly and those receptors recover.

Here’s the thing: so much about the physiology of pregnancy operates on a “just right” model—not too much, not too little. If those receptors don’t recover, and activity at the ones online is low, that introduces a vulnerability for mood dysregulation, Maguire said.

The story of how she and her colleagues came to recognize that vulnerability is one of a discovery made where no one was looking for one.

In the early 2000s, Maguire and her colleagues were researching the role of neurosteroids in catamenial epilepsy, or seizures linked to the menstrual cycle. They were studying a line of laboratory mice bred to lack certain GABA receptors.

Lab technician Reyes Main Lazaro came to Maguire frustrated. He was struggling with breeding the mice. The females would get pregnant and have pups, but they wouldn’t care for them. Some pups were eaten by their mothers soon after birth. Some died from neglect. Lazaro began documenting the incidents.

“We looked at their maternal care, and we looked at a bunch of different behaviors and said these animals are exhibiting abnormal behaviors during this postpartum period, and this is very unusual,” Maguire said. “I credit him with being the person that made the observation and really launched all of this.”

The plasticity of these GABA receptors and their role in postpartum depression became a major focus of the lab. Lazaro died in 2017, two years before the FDA first approved the use of a postpartum depression drug whose development stemmed from his observations. That was brexanolone, a synthetic allopregnanolone also developed by Sage and administered by IV. The two drugs are distinct but use similar mechanisms.

To be frank, researchers haven’t connected the dots here, from perinatal changes in GABA signalling that may lead to dysregulation, to exactly how these drugs confer an antidepressant effect influencing mood and behavior.

One working hypothesis is that the drugs alter the “network state” of brain regions involved in fear and emotion processing, changing the activity locally and altering how they synchronize or relate to one another. And that may be why the antidepressant effects remain well after the course of treatment ends.

One thing I love about Maguire’s work is how wonderfully incompatible it is with the idea that postpartum depression is a failure or an absence of a maternal instinct. So much change happens during this profound period of development. So many pieces are thrown into the air, and it takes time, support and sometimes medication for them to settle into place.

“The more we can provide evidence that this is just a biological phenomenon and it has nothing to do with your capability to be an excellent mother—that’s the best thing we can do to destigmatize postpartum depression,” Maguire told me.

A question of access and priorities

Only a few medical facilities have ever offered brexanolone since it launched in 2019, under the name Zulresso and with a price of $34,000. That didn’t include the cost of the three-day inpatient stay required for administration of the drug, another barrier to patients caring for a newborn.

Zuranolone, marketed as Zurzuvae, was expected to be dramatically less expensive and more accessible, taken by pill at home.

Then, Sage’s stock fell on Monday, despite the positive news of zuranolone’s postpartum approval. The company also had asked the FDA to approve zuranolone for use in patients with major depressive disorder, a much larger pool of patients. The agency said no, citing insufficient evidence of its effectiveness. (For a comprehensive look at what’s going on there, see Brittany Trang’s reporting in STAT, which is paywalled.)

The company indicated it was reconsidering pricing of the drug. From Jacqueline Howard at CNN:

Sage and Biogen are expected to price Zurzuvae as much as three times higher because of its failure to win approval for major depressive disorder, a condition that affects 15 million people in the US, compared with about 500,000 for postpartum depression, according to Salim Syed and Uy Ear, analysts for the Wall Street firm Mizuho.

The expectation is that “they push it closer to Zulresso pricing,” Syed wrote in an email Tuesday, referencing another Sage drug for PPD that’s given by IV infusion and costs about $35,000. The analysts noted that Sage had said it would keep the pricing of Zurzuvae below $10,000 if it were cleared in major depressive disorder as well, a threshold important for coverage through Medicare, Ear wrote.

Sage could try again, with new evidence from clinical trials on major depressive disorder, and that could level the postpartum pricing some. We don’t know when or if that will happen.

Now or later, we don’t know how many people might have access to zuranolone or, at a population level, how many people it can help.

We do know that the risk of postpartum depression increases with financial instability, a history of depression or abuse, an unplanned or unwanted pregnancy, or pregnancy complications, including prior pregnancy loss.

We know that providing people at higher risk with social supports and psychotherapy can help.

We know there’s a whole lot more we can do as a society to mitigate those risks, including improving clinical care and implementing paid leave for all.

Dr. Lucy Hutner, a psychiatrist who specializes in reproductive mental health, put it this way in an interview with

TWO TRUTHS

:

[O]ur culture is quick to embrace the idea that things can be fixed easily and quickly. It’s a lot harder—but equally as important—to dig into the multifaceted causes and solutions of postpartum depression: the severe degrees of social isolation in our country, the astounding lack of support for parents, as well as the severe impact on marginalized populations such as systemic racism and sexism, as noted in a 2023 United Nations analysis.

Those things are harder. They’re more complicated. The solutions require dedicated, long-term political will. There is no magic pill for those entrenched issues. Bottom line, we need human solutions for a human crisis. That’s harder. That doesn’t lend itself to a nice headline in the media, even though it’s every bit as important.

This drug may represent a substantial advance for many patients, and that’s very important. But it’s both/and. We still have an enormous amount of work to do politically, socially, and medically.

Both. And.

More research on the manifold causes and potential treatments of postpartum depression. Real action on support for young families.