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Perinatal Depression and Precision Psychiatry

A new pharmaceutical specifically for postpartum depression is approved and a large, ongoing study may yield insight into depression generally.

March 29, 2019

From The Staff Medicine Psychology Physiology

When physician-scientist Samantha Meltzer-Brody began collaborating with a small biotech startup, Sage Pharmaceuticals, it was with modest expectations. She was curious if the pharmaceutical the biotech company was developing would have any effect at all on perinatal depression.

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"I don’t think any of us thought we would see the robust response that we did. That was, you know, quite an amazing surprise," says Meltzer-Brody, a perinatal psychiatrist who studies postpartum depression at the University of North Carolina at Chapel Hill. She served as the academic principal investigator for the study of the pharmaceutical through its phase 3 clinical trials. Recently, the U.S. Food and Drug Administration approved the drug, called brexanolone, which is administered over the course of 60 hours at a certified medical center. It is expected to be on the market starting this June.

Meltzer-Brody gave a talk earlier this week at the Research Triangle Park chapter of Sigma Xi (American Scientist is published by Sigma Xi) and we spoke after her talk about both the newly approved drug—a subject of much media coverage, including the On Point radio panel she had been a part of just prior to her talk—and her ongoing study to apply the tools of precision medicine to tailor future treatment.

“Until you understand the biology, you're really just throwing jello at the wall.” —Samantha Meltzer-Brody

When that precision-medicine study began it was also widely reported in part for its use of an app to collect data. In our interview—from which I made a podcast (transcribed below)—Meltzer-Brody says the hope is that those results will be coming in the next year or so and provide new insights into what causes depression generally and so how better to treat it.

Image credit: Syane Luntungan - USAID EMAS


Transcript

Robert Frederick

Childbirth is a profound time for women—
[music starts]
—biologically, socially, and psychologically.

Samantha Meltzer-Brody

And all women that give birth experience that. But for the 10-15% that develop postpartum depression there is something else going on.

Frederick

On this episode of the American Scientist podcast, a new pharmaceutical treatment for postpartum depression and using the tools of precision medicine to develop tailored treatments for the future. I’m Robert Frederick.
[music ends]
When physician-scientist Samantha Meltzer-Brody began collaborating with a small biotech startup, it was with modest expectations. She was curious if the pharmaceutical the biotech company was developing would have any effect at all on perinatal depression.

Meltzer-Brody

I don’t think any of us thought we would see the robust response that we did. That was, you know, quite an amazing surprise.

Frederick

Meltzer-Brody is a perinatal psychiatrist who studies postpartum depression at the University of North Carolina–Chapel Hill. She served as the academic principal investigator for the study of the pharmaceutical through its phase 3 clinical trials. Recently, the U.S. Food and Drug Administration approved the drug, called brexanolone, which is administered over the course of 60 hours at a certified medical center. It is expected to be on the market starting this June, 2019.

Meltzer-Brody

So it’s been a real step forward, I think, for our understanding of the pathophysiology of depression, and is the first drug specifically for postpartum depression. It’s, I think, great progress forward for women’s mental health.

Frederick

And it may also be a way forward for treating depression more broadly. That’s still to be determined by the wider research and medical community now that the drug has FDA approval. Meltzer-Brody will be focused on an ongoing genome wide association study about post-partum depression.

Meltzer-Brody

So these are women that suffered considerably. This is doing a lifetime assessment because you’re looking at DNA. And you’re really able to examine women that it was really profound time in their lives.

Frederick

Meltzer-Brody spoke with me after a talk she gave on applying the tools of precision medicine—tools like genome-wide association studies—to understanding perinatal depression. Here’s our interview, which I began by asking whether all forms of postpartum depression are the same

Meltzer-Brody

Postpartum depression is not a “one size fits all” kind of label. What's really important and our work has shown is understanding the timing of onset. So for many women the post-partum period is a time they come in high contact with health care providers or certainly all of pregnancy, too. And when we screen someone for postpartum depression at four-to-six weeks postpartum we really need to understand ‘do the symptoms start then—do they start in pregnancy —is this someone that's been depressed 20 years.’ These are really important issues to understand because it's critical for developing the most effective treatment plan.

Frederick

What is the newest treatment plan available?

Meltzer-Brody

Over the last week, there has been a lot of excitement about the approval of brexanolone / Zulresso, which is a new intravenous medication for the treatment of postpartum depression. I've served as the academic P.I. and our team at UNC participated in the initial open label study through the phase 3 clinical trials. So this is a new mechanism of action. It’s a positive allosteric modulator of GABAA. And it is a proprietary formulation of allopregnanolone.

So it's been a real step forward, I think, for our understanding of the pathophysiology of depression and is the first drug specifically for postpartum depression -- it's a, I think, great progress for women's mental health.

Frederick

When you started this study was your goal creating a new drug?

Meltzer-Brody

When we had the opportunity to do an open label study with a proprietary formulation of allopregnanolone, we went into it wondering if we would see any kind of signal. And so I think we had very modest expectations. We were collaborating with a small biotech startup -- Sage Therapeutics -- who had a handful of people working at that time. They'd been studying this drug in treatment refractory status epilepticus. But because of the hormone hypothesis of postpartum depression and allopregnanolone being known in preclinical work for really having a potentially significant role—both as a positive allosteric modulator of GABAA but in preclinical studies showing that increasing ALLO decreased depressive symptoms—we were curious. And I think we went into it with curiosity and wondering if we would see a signal. I don't think any of us thought we would see the robust response that we did that was, you know, quite an amazing surprise.

Frederick

The hormone hypothesis being...

Meltzer-Brody

Well the hormone hypothesis has been that the rising and falling hormones—estrogen, progesterone—during pregnancy and then that fall very quickly postpartum happens in all women that give birth. That's normal physiology, but there's been work over the years, including by David Rubinow and colleagues initially at the NIH, which showed that in vulnerable women—you know, the question is ‘Why are they vulnerable women?—but in vulnerable women this rise and fall can precipitate depression for reasons that have been unclear. You know, what exactly is about that makes someone vulnerable or more sensitive to the hormonal fluctuations? And is it genetic underpinnings, which has been a source of our research? Is it just regular version of the HPA (Hypothalmic Pituitary Adrenal) Axis, which can be impacted by early life trauma and adversity? Is it, you know, disregulation of GABAA. So it's something that there's been a lot of work around. But until now and with this drug I think it really has sort of opened up a whole new line of research in probing this and I think it will spawn some really interesting new work that will increase our understanding of not just postpartum depression but depression more broadly.

Frederick

So a kind of precision medicine being applied to something that is typically applied to a mental health disorder—the domain of psychiatry. What is it about postpartum depression that makes applying the tools of precision medicine—precision psychiatry—a good choice?

Meltzer-Brody

I think that postpartum depression in the perinatal period is such a rich time. There is enormous amount of bio/psycho/social things going on for all women. So you have all the biologic changes the hormonal change the immune the logic change along with the transformation in people's lives of becoming a parent, the physical demands of birthing, the re-arrangement in family dynamics—so it's just a profound time. And all women that give birth experience that. But for the 10 to 15% that develop postpartum depression there is something else going on. And to the extent that for some women—we know one of the greatest risk factors is previous history of depression—so why people are more vulnerable to that. We know that people who have early life trauma and perhaps deregulation of the HPA access that is persistent for people that have deregulation perhaps of GABAA—for people that are particularly sensitive to hormonal fluctuations. So I think that it is a really rich area for understanding the heterogeneity and really trying to develop tailored treatments. It also, I think, is a very impactful time and one reason I've loved working in this area is that you're not just treating mom, you are also treating mom baby and family, so it's something that has multigenerational effects and has always felt particularly meaningful.

Frederick

Precision medicine—precision psychiatry—seems like it would be something that would require a lot of data. Where would all that data come from? Just one hospital that you work in, or...?

Meltzer-Brody

So we have realized that you need to have really large sample sizes to understand genetic signature, for example, and a lot of ,you know, big data team science has been required to move the field forward our understanding of many things. In postpartum depression we've been working with a team including Dr. Patrick Sullivan—an internationally known psychiatric geneticist at UNC—and Jerry Guintivano and others to understand the genetic signature of postpartum depression. And we were able to partner with Apple using their research kit to study postpartum depression by recruiting women via an app-based study and then to ask women who had a positive clinical history to contribute a DNA sample using a spit kit. And we were overwhelmed when we launched this in 2016 with the iOS version of having 10,000 people respond in a month. And then have subsequently expanded to an Android version, a Spanish-speaking version in the US, and then other countries have joined in. But it's resulted in us having thousands of DNA samples that are now being genotyped to allow us to work together with colleagues around the world for a large scale GWAS—Genome Wide Association Study—of postpartum depression that we really needed the app-based samples to hopefully be in a place where we can investigate this. And we won't know, you know, until the analysis is completed. But I think it has been an exciting way to really do a population-based outreach. And we've had women participate from all 50 states for the study in ways that if you were just recruiting locally you would never be able to do.

Frederick

Any concerns about self selection bias?

Meltzer-Brody

Well certainly women who desire to participate—what we know is that they had more severe symptoms than you see if you just do, you know, a typical rating scale used is the Edinburgh postpartum depression scale and scores of greater than 12 are consistent with major depressive episode: the mean EPDS score of women that participate in the app was 23. So I think you're getting women with more severe symptoms. That's actually convenient if you're trying to do a genetic study.

So these are women that suffered considerably. This is doing a lifetime assessment because you're looking at DNA. And you're really able to examine women that it was really profound time in their lives. I mean birth is profound. Women remember if they had postpartum depression. And you're getting people who it was significant enough—and I think the suffering was significant—that they felt it was worth their time and effort to participate in an app-based study.

Frederick

In marrying these two avenues of research, the idea is then to suggests to women who are about to give birth that they might be at higher risk for postpartum depression and to proactively suggested a treatment for them?

Meltzer-Brody

Well, I think the goal of the genetic study is to understand the genetic signature, which can allow you to do lots of things: it helps you understand the pathophysiology difference; it may lead to what we would call prospective identification—so understanding who may be genetically at risk, which then could alter the way you approach monitoring and treatment during pregnancy and postpartum period; it may open up new ways of treating the disorder. So I think it just—until you understand the biology, you're really just throwing jello at the wall. And, I think that—I like to use the breast cancer example because our understanding of different receptor subtypes has led to enormous advances in how breast cancer is treated and survival rates. So offering the same treatment to every one that comes in did not work out so well. And I think we have to apply that paradigm to how we think about psychiatry in general and to postpartum depression.

Frederick

When can we expect results from...?

Meltzer-Brody

Well, the large scale GWAS is sort of happening now so I think the results would probably be in the next year—is the hope. So we're excited about that and again it's a team: Patrick Sullivan, Jerry Guintivano, and colleagues around the world collaborating on this large-scale effort. It's exciting though to be at a place where we can take this next step.

Frederick

Samatha Meltzer-Brody thank you very much.

Meltzer-Brody

Thanks so much for the opportunity to talk.

[music]
Frederick

Samantha Meltzer-Brody is a perinatal psychiatrist who studies postpartum depression at the University of North Carolina - Chapel Hill. Online at American Scientist dot org, find an accompanying blog post to this podcast and a transcript.

You’ve been listening to a podcast from American Scientist magazine, published by Sigma Xi, The Scientific Research Honor Society. I’m Robert Frederick. Thanks for joining us.
[music ends]

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