Rethinking Postpartum Depression: Biology, Biomarkers, and New Treatments with Jennifer L. Payne, MD

Journal of Clinical Psychiatry: https://www.psychiatrist.com/jcp/

Publisher of peer-reviewed research discussed in this episode.

National Pregnancy Registry for Antidepressants: https://womensmentalhealth.org/research/pregnancyregistry/antidepressants/

Biomarkers:

• DNA methylation biomarkers prospectively predict both antenatal and postpartum depression: https://pubmed.ncbi.nlm.nih.gov/31843207/
• Seeing the Future: Epigenetic Biomarkers of Postpartum Depression: https://pmc.ncbi.nlm.nih.gov/articles/PMC3857665/
• Biomarker or pathophysiology? The role of DNA methylation in postpartum depression: https://pubmed.ncbi.nlm.nih.gov/24059792/

DOD Work in Segment II:

• Metabolites of Progesterone in Pregnancy: Associations with Perinatal Anxiety: https://pmc.ncbi.nlm.nih.gov/articles/PMC10530426/
• Neuroactive steroid biosynthesis during pregnancy predicts future postpartum depression: a role for the 3α and/or 3β-HSD neurosteroidogenic enzymes? https://pubmed.ncbi.nlm.nih.gov/39885361/

Dr. Jennifer L. Payne is Professor of Psychiatry and Neurobehavioral Sciences and Vice Chair of Research at the University of Virginia, where she directs the Reproductive Psychiatry Research Program and holds a joint appointment in obstetrics and gynecology. She completed her medical training at Washington University, residency and chief residency at Johns Hopkins, and a mood disorders fellowship at the National Institute of Mental Health. Dr. Payne is a past president of both the International Marcé Society for Perinatal Mental Health and the Marcé Society of North America, and serves on the editorial board of the Journal of Clinical Psychiatry.

Ben Everett, PhD, is the creator and host of The JCP Podcast, a series that brings together leading voices in psychiatry to explore the latest research and its clinical implications. Everett earned his PhD in Biochemistry with an emphasis in Neuroscience from the University of Tennessee Health Science Center. Over a two-decade career spanning academia, publishing, and the pharmaceutical industry, he has helped launch more than a dozen new treatments across psychiatry, neurology, and cardiometabolic medicine. His current work focuses on translating complex scientific advances into accessible, evidence-based insights that inform clinical practice and foster meaningful dialogue among mental health professionals.

This transcript has been auto-generated and may contain errors. Please refer to the original recording for full accuracy.

00:00 – Introduction and Guest Overview

Dr. Ben Everett: Hello, and welcome to the JCP Podcast, where we explore the science and stories shaping mental health care today. I’m your host, Ben Everett, Senior Scientific Director with Physicians Postgraduate Press, publisher of the Journal of Clinical Psychiatry. On this podcast, we speak with clinicians, researchers, and thought leaders advancing the field of psychiatry with a focus not just on what’s new, but what’s meaningful for our listeners in clinical practice.

Dr. Ben Everett: Postpartum depression affects roughly one in eight women following childbirth and is one of the most underdiagnosed and undertreated conditions in all of medicine.

Dr. Ben Everett: For decades, treatment has largely defaulted to antidepressants developed for major depression, agents designed around serotonin and norepinephrine, not around the biology of the postpartum period itself. But a paradigm shift has been underway. We now understand that the dramatic hormonal changes surrounding childbirth, particularly the sharp drop in progesterone metabolites known as neuroactive steroids, may be central to why some women develop postpartum depression and why a new class of GABAergic therapeutics appears to work so rapidly and so specifically in this population.

Dr. Ben Everett: My guest today is at the forefront of this work. Dr. Jennifer Payne is Professor of Psychiatry and Neurobehavioral Sciences and Vice Chair of Research at the University of Virginia, where she directs the Reproductive Psychiatry Research Program. She holds a joint appointment in obstetrics and gynecology, completed her medical training at Washington University, and residency and chief residency at Johns Hopkins.

Dr. Ben Everett: She subsequently completed a mood disorders fellowship at the National Institute of Mental Health. Over her career, Dr. Payne has become one of the leading figures in the biological underpinnings of perinatal depression. With her collaborator, Zachary Kaminsky, she identified and has since replicated epigenetic markers that prospectively predict postpartum depression, work that is now moving toward FDA review through a startup company, Dionysus Health. Her lab has been at the forefront of understanding the role of neuroactive steroids, such as allopregnanolone, and dynamic GABA-A receptor reconfiguration in the pathophysiology of postpartum depression and premenstrual dysphoric disorder, with multiple active DoD and NIH-funded trials exploring these mechanisms.

Dr. Ben Everett: Dr. Payne has also been deeply involved in the clinical development of GABA-A receptor modulators. She served as the brexanolone service line leader at both Johns Hopkins and UVA, and she has been active in evaluating zuranolone, the first oral neuroactive steroid approved for postpartum depression. She currently serves on the editorial board of the Journal of Clinical Psychiatry, and she has been president of both the International Marcé Society for Perinatal Mental Health, as well as the Marcé Society of North America for Perinatal Mental Health. Dr. Payne, welcome to the podcast.

Dr. Jennifer L. Payne: Thanks for having me.

02:45 – Scientific Origins: From Alzheimer’s Disease to Postpartum Depression

Dr. Ben Everett: All right. Well, before we get into the science, I always take a few minutes, do some icebreakers, try and get to know our guest a little bit better as a person, as a scientist. So you completed a Howard Hughes Medical Institute fellowship at the NIH during medical school at Washington University. It’s a remarkable opportunity for a medical student. What were you working on, and what do you think that experience taught you and set you on your way in your career?

Dr. Jennifer L. Payne: So that was a great opportunity. We actually lived on NIH campus and identified a lab that we worked in for the entire year. Back then, I was really interested in Alzheimer’s disease, and I was doing single cell experiments and working a little bit with rodents. And I think what I took from that experience was the idea that in Alzheimer’s disease, we were very focused on understanding familial Alzheimer’s disease, with an idea that that would then allow us to understand more sporadic cases. And in my subsequent research, I identified postpartum depression as what I wanted to study for my career. It’s really an example of a depressive disorder that’s more homogeneous and can help us shed light on major depression more generally, kind of like what I was doing with Alzheimer’s disease back then.

06:30 – Why Postpartum Depression Is a Natural Model for Studying Depression Biology

Dr. Ben Everett: You went on to do a residency and chief residency at Johns Hopkins before completing your mood disorders fellowship at the National Institute of Mental Health. Was there a particular patient or a case or a moment during that training that really crystallized this focus on perinatal mental health specifically?

Dr. Jennifer L. Payne: Great question, and I think most people who know me think I just like to work with pregnant women and get to see their babies at the end of the pregnancy. But honestly, I backed into postpartum depression from a scientific perspective. When I was doing my NIMH fellowship, we used to have these brainstorming sessions every week or two, and we were really trying to think about how do we get to understand the underlying biology of major depression and bipolar disorder. And I always say I had one good idea in my entire career, and that was that it came to me that we could study postpartum depression because we could predict the timing of when postpartum depression is going to occur. So if you take a hundred pregnant women and follow them through pregnancy, about thirteen to fifteen of them will get depressed in the postpartum time period. And if you take a hundred pregnant women with preexisting mood disorders, about thirty to fifty will get sick in the postpartum time period. And so you can actually measure biological changes prior to the onset of the depressive illness and then afterwards so that you can understand the biology. And that’s actually why I started studying postpartum depression. If you take a hundred men and follow them for a year, none of them might develop a depressive episode. So it’s a kind of a natural model.

Dr. Ben Everett: Makes it a little bit easier to do the prospective trial when you understand your patient population. It’s not just who shows up at the clinic or in the emergency department. So you spent your career working at the intersection of biology and clinical care. Basic mechanisms on one side, women sitting in front of you in the clinic on the other. How do you bring these two together?

Dr. Jennifer L. Payne: Well, I think they come together on an almost daily basis. Right now in my current role, I’m seeing patients less often. But I’ve really been inspired taking care of women during pregnancy and in the postpartum time period who have psychiatric illness. Psychiatric illness is really poorly understood in terms of how to manage it during pregnancy. There’s a lot of rumors and myths about how to do that, and I’ve kind of spent my career trying to dispel those. And then taking care of those patients has really inspired my research work, including trying to bring this biomarker blood test to market. It’s not that I want to or expect to make any money out of this, but I would really like to change standard of care so that we’re predicting who’s at risk for postpartum depression and then preventing postpartum depression rather than waiting for people to get sick.

08:00 – Screening, Underdiagnosis, and the Stigma Gap

Dr. Ben Everett: Prevention versus a pound of cure. So prevention is something I believe very much in. All right, well, let’s set the stage with some context on postpartum depression itself. I think the biology really makes sense if we understand clinically what’s at stake. You just went through some of the incidence and prevalence of pregnant women who can go on to develop postpartum depression. How do you think that is accurately captured in the clinical setting outside of the research setting?

Dr. Jennifer L. Payne: I think it’s not. We know that less than fifty percent of cases are identified, even fewer are actually treated. Lots of states and clinics have mandated routine screening, and these are generally done by self-rated scales, and they are not always instituted. So not every patient that comes to a clinic actually gets the screen. And if they do, they don’t have to be honest. And many women feel ashamed that they’ve developed what is the most common complication of childbirth, and cannot admit to others, and sometimes even to themselves, that they’re really struggling with a depressive episode.

09:30 – A Personal Account of Postpartum Depression and Advocacy

Dr. Ben Everett: Resonates with me personally, and I’ll share. I think people know I’m an open book. My wife had severe postpartum depression after our first child was born — this is two thousand and five. I think we’ve done a lot better here in the last twenty years. But what I remember most is kind of exactly what you’re saying — it took a long time to understand what was going on. We heard so much about “Oh, it’s normal. You can expect some baby blues,” in air quotes, these types of things. And so it probably took us four to five months to really understand that what she was going through was — if that was normal, I can’t imagine that that should be normal. And honestly, I walked into the kitchen one day, and she was on the kitchen floor just bawling her eyes out. And I was like, “Okay, there’s no way this is normal.” And we got an SSRI, which was the best thing we had then. It certainly helped, but I think not as good as what is available now. When our second child was born in two thousand and eight, we really went in as strong advocates for her personal health, and we had a treatment plan established so that when she was discharged from the hospital, she was on an SSRI. So it was much better, and she had a better experience as a second-time new mom. The bonding and all that was much better and much more natural. So all that said, do you think this kind of proactive planned approach — which we sort of had to construct ourselves — is that becoming standard of care, or are we still leaving too much to chance?

Dr. Jennifer L. Payne: We are leaving too much to chance. And good for you that you guys were able to advocate for yourselves and get the appropriate preventive strategy the second time around. Many women don’t have the support or resources or knowledge to do that. And this is why I am so inspired by a blood test. First of all, I think a blood test reduces stigma, and it circumvents the need for self-report. And it identifies early in pregnancy who’s at elevated risk so that the doctor and the patient and her support system can make a preventive plan. And that can look different for different people — it might be a referral to a mental health provider, it might be starting an antidepressant, it might be making sure that her partner takes leave and is more supportive during that initial postpartum time period. But we can do better, and we should be doing better in this day and age than what we’re doing.

12:00 – Epigenetic Biomarkers: Predicting Risk Before Delivery

Dr. Ben Everett: I’m going to pivot to biomarkers because it just feels more natural right now. One of the most distinctive aspects of your research — and something you’ve brought up a couple of times already — is this biomarker work. It runs in parallel with the neuroactive steroid research, which we’ll get to in a minute. But you and Zach Kaminsky have identified epigenetic biomarkers that prospectively predict postpartum depression. Can you give us an accessible overview of how these work? Is it just a simple blood-based biomarker? Tell us about your test.

Dr. Jennifer L. Payne: So Zach Kaminsky and I worked together at Johns Hopkins about thirteen, fourteen years ago. And we had a really great conversation where we were talking about what was new then, which were epigenetics. And epigenetics are changes at the level of the gene that essentially allow that gene to be expressed or suppress that gene’s expression. And epigenetics are really why cells from different organs are expressing different genes. A cell in your brain has different genes being expressed compared to a cell in your liver, and it’s epigenetic changes that really determine what genes are turned on and turned off. In this case, we’re talking about methylation changes at the level of the gene. And so we had this idea that the hormonal changes associated with pregnancy and childbirth might turn on or turn off epigenetic changes that then predispose to the development of postpartum depression. We started off with a mouse model and exposed mice to estrogen, and then specifically looked at genes in the hippocampus that were differentially methylated by estrogen exposure. Zach then used what’s called a greedy algorithm — meaning he used machine learning — to identify the smallest number of genes that were epigenetically modified in a particular way when someone was going to develop postpartum depression. That list of genes from the mouse model was then applied to blood samples from women I had very carefully clinically characterized. And we were able to pull out two genes that were epigenetically modified in a particular way when someone was going to develop postpartum depression. I did not initially talk about these biomarkers back then because I thought, “This will never replicate.” And it has actually replicated. We replicated it in six different samples, and there’s an outside group at VCU that replicated our work and has published a preprint on that replication. So it continues to hold, which is great. We now have Department of Defense funding to validate the biomarkers and hopefully take the data to the FDA for approval to develop a blood test for postpartum depression. The original test had just two genes. We eventually added a third, which measured inflammatory markers, because we wanted the test to work whether someone was depressed during pregnancy or not. Zach is currently working on expanding the number of genes in the algorithm, but the current algorithm includes those original two genes. I think it’s likely that our epigenetic biomarkers are representative of larger, more global epigenetic changes that predispose to depressive disorders. Regardless, what we can do now is take blood in the third trimester and say whether a woman is at high risk of developing postpartum depression by three months postpartum or at low risk. And I’d like to emphasize that low risk does not mean no risk — some of those women who do not have the biomarkers still develop depression in the year following delivery. But what I think the biomarkers are really representing is central nervous system sensitivity to reproductive hormonal change.

17:15 – Ethics, Autonomy, and the Case for a Predictive Blood Test

Dr. Ben Everett: Really exciting work. Anytime we talk about biomarkers in the context of psychiatric illness, there’s an ethical dilemma. Do people want to opt into knowing that they’re at high risk? How do you manage or think through the ethics of that?

Dr. Jennifer L. Payne: First of all, we’re already screening for postpartum depression, so we’re already having conversations in the clinic that this is the most common complication of childbirth, and we’re going to screen you and ask you potentially uncomfortable questions about this. So some women will feel anxious if they have a positive biomarker test. But what I like about it is that it really puts women in control of knowing that they’re at high risk, and then they can actually develop a prevention plan. We test for gestational diabetes, and we don’t think twice about it, and I’m positive that some women get anxious about that test. But we do it because it improves outcomes for the mother and for the baby. And we know that postpartum depression has significant effects on the development of the exposed child. Babies whose mothers are depressed for long periods of time and have significant symptoms have lower IQ, slower language development, and more behavioral and psychological problems. And that’s because the bonding process is not totally normal. The interaction between mom and baby that really develops the central nervous system is not normal. So women can feel more in control of making sure that they’re at their best for their developing child. I understand that people worry about this, but I think some of that worry has to do with the stigma of mental illness, rather than really understanding that we have some science here that can improve outcomes.

Dr. Ben Everett: I agree. There’s the stigma side of it. I always opt in — my 23andMe, every time there’s a new one, I always opt in, but I’m a scientist. I think it’s really a gift you could give a new mom if you say, “Hey, we want to set you up to be in the best position to bond with your new child and really set both of you up for a great future together.” I think that’s a wonderful gift.

Dr. Jennifer L. Payne: I agree. And we have not published this finding yet, but in our studies, the women who have a positive biomarker test and don’t go on to develop postpartum depression, a majority of them are taking antidepressants. So we know that we can prevent the onset of postpartum depression by intervening in women with the biomarkers.

20:45 – Allopregnanolone and the Neuroactive Steroid System

Dr. Ben Everett: Well, this is really fascinating. So we’ve talked the biomarker side, and in doing so we’ve touched on some of the underlying neurobiology and the neuroactive steroids and the GABA-A system. That’s really what’s going to be at the heart of today’s episode. I want to make sure everybody’s on the same page — most of our listeners are clinicians, not neuroscientists per se, but I want them to come away with a real intuition for this biology and how it’s so important in the perinatal period. Let’s start with allopregnanolone. What is it? Where does it come from? What’s its normal role in the brain?

Dr. Jennifer L. Payne: Everybody knows about allopregnanolone now. It’s a neuroactive steroid — a derivative of progesterone. Progesterone is metabolized to several different neuroactive steroids. And there are basically two different types of neuroactive steroids we want to talk about here. There are the positive allosteric modulators of the GABA-A receptor and the negative allosteric modulators of the GABA-A receptor. The GABA system is the major inhibitory neurotransmitter system in the brain. It acts in several different ways, but one of its jobs is to help modulate the HPA axis. So when the HPA axis gets stressed, the GABAergic system eventually kicks in and calms the HPA axis down. The GABA system also helps set the inhibitory tone across the entire central nervous system. So the positive allosteric modulators of the GABA-A receptor basically increase GABAergic tone, and the negative allosteric modulators decrease GABAergic tone — they have these opposite directions. And allopregnanolone is a positive allosteric modulator of the GABAergic system. It’s of interest because we know that progesterone increases across the course of pregnancy, and with that, allopregnanolone increases across the course of pregnancy. And then after delivery, both progesterone and allopregnanolone precipitously drop. And we think that there are some alterations in the neuroactive steroid pathway or at the level of the GABA receptor that predispose women to developing a depressive episode in the setting of that precipitous drop of allopregnanolone.

23:30 – GABA-A Receptor Subtypes: Why Neuroactive Steroids Are Not Benzodiazepines

Dr. Ben Everett: All right. Well, GABA is the brain’s primary inhibitory neurotransmitter, as you covered, but these neuroactive steroids interact with the GABA-A receptor differently than, say, benzodiazepines. Would you explain that distinction to a clinician? Why does it matter?

Dr. Jennifer L. Payne: So it’s interesting. The GABA-A receptor has binding sites on it, and benzodiazepines have a binding site on the GABA-A receptor, as do alcohol and barbiturates. And then it also has these neuroactive steroid binding sites. There are two types of GABA-A receptors. There are synaptic GABA-A receptors and extrasynaptic GABA receptors. The synaptic ones are involved in quick neurotransmission, and those are where the benzodiazepines can bind. But the extrasynaptic GABA receptors are really setting the overall inhibitory tone across the central nervous system. And the neuroactive steroids, while they also act on the synaptic GABA receptors, really act on the extrasynaptic GABA receptors to set the overall inhibitory tone within the central nervous system. The benzodiazepines don’t act on those extrasynaptic GABA receptors. So sometimes people have said to me that allopregnanolone and the new FDA-approved treatments for postpartum depression are really just a benzodiazepine, and that’s not true because they actually act very differently within the central nervous system.

Dr. Ben Everett: I think that’s an important differentiation, because to reset the entire tone and maintain the entire tone, you can’t just be working synaptically. It’s so much more complex than that. So that’s really an important distinction that our listeners need to understand today. Very distinct from benzos in terms of mechanism of action.

25:30 – DoD-Funded Research: Neuroactive Steroid Shunting and GABA-A Reconfiguration

Dr. Ben Everett: All right. So your recent DoD-funded work is directly examining neuroactive steroid biosynthesis and dynamic GABA-A receptor reconfiguration in women who go on to develop postpartum depression. Without getting too far into this, what’s sort of the central hypothesis you’re trying to get to here?

Dr. Jennifer L. Payne: We’ve recently published a paper on a fairly small sample size that demonstrated that in women who were clinically well during pregnancy but went on to develop postpartum depression, they had, A, elevated levels of progesterone, and B, a shunting of that neuroactive steroid pathway away from positive allosteric modulators towards the negative allosteric modulators — which is a very interesting finding. It’s showing that the GABAergic system is vulnerable to stress prior to the onset of symptoms of postpartum depression. And when we got that finding, we wanted to, A, look in a larger sample size, and B, start to look at things like neurosteroidogenic enzyme expression and GABA-A subunit expression so that we could really understand the entire picture. And that’s what that DoD grant is funding. We’re going to recruit a larger sample and be able to look at the neuroactive steroid metabolic pathway, both at the level of the neuroactive steroids themselves but also looking at activity of the neurosteroidogenic enzymes, and look at the GABA receptor subunits to see if we can understand why a woman develops postpartum depression.

Dr. Ben Everett: Can you imagine this being sufficient to explain postpartum depression, or do you think it’s going to be so much more complex — HPA axis dysregulation, neuroinflammation, the epigenetics? There are so many different things that can go on.

Dr. Jennifer L. Payne: I think it’s likely that for different people there are different vulnerabilities, and we’re going to have to account for that. I’m hopeful that we’ll replicate our previous work in this larger sample. What I’m particularly interested in is the enzyme activity. Do people have a difference in the enzyme activity that is driving the shunting towards a negative allosteric modulator of the GABA system, which therefore decreases the activity of the GABAergic system and the central nervous system? I don’t know. We might find that there’s no difference in enzyme activity and there are other things that we need to look at. But it’s a comprehensive look at the entire system, and that’s what I’m excited about.

Dr. Ben Everett: It’s been a really exciting section for me because I like the science. I think you’ve done a really good job of breaking it down in a way that I hope our listeners can use clinically, even though a lot of this is still under development. But I think it can change the way people can talk to their patients and think a little bit more about some of the underlying issues that may be going on.

29:30 – Brexanolone: Clinical Proof of Concept and Why It’s No Longer Available

Dr. Ben Everett: Well, let’s transition over to brexanolone. This was really the clinical proof of concept that this biology matters. You’ve been involved with it clinically at both Hopkins and UVA. Can you briefly explain the mechanism and what made brexanolone so conceptually exciting when it first came to market?

Dr. Jennifer L. Payne: Absolutely. So brexanolone is essentially a synthetic version of allopregnanolone. And it was studied in postpartum depression, starting off with my colleague Samantha Meltzer-Brody at UNC, and it just had phenomenal results. It’s an IV infusion given over the course of sixty hours. And what is remarkable is that patients with postpartum depression have a response within the first twenty-four hours. And then there’s a higher response and remission rate to brexanolone than what we see with standard antidepressant treatments, and there’s a sustained response. So you have a sixty-hour infusion — you go on to be clinically well if you respond to it, and thirty days later you’re still well. So it’s a little bit different — you’re not having to stay on a medication that has side effects for a year afterward, or wait eight to twelve weeks for it to kick in. Brexanolone was a great breakthrough. It was phenomenal to see the responses that we could get. But it is no longer available clinically, because the company decided to pivot towards an oral version called zuranolone. Zuranolone is a little bit different from brexanolone in that it’s not exactly allopregnanolone — it’s an allopregnanolone analog, so it has some chemistry added to it. But it acts on the GABA-A receptor as a positive allosteric modulator in the same way that allopregnanolone does. The oral agent you take for fourteen days, and you see response rates within three days, which again is groundbreaking in terms of treating a depressive episode.

Dr. Ben Everett: I remember following brexanolone when it came out. I actually had some friends at Sage Therapeutics who worked on that team, and it was very difficult to get patients to go in and do the infusion. I would imagine that as a clinician, this is so much easier — you can take it at home, you don’t have to come in for the infusion. So hopefully the uptake has been a lot higher with zuranolone and it’s helping a lot of women.

Dr. Jennifer L. Payne: Yeah, I completely agree. Having started a unit at Hopkins, it was difficult to talk women into coming in and being away from their babies. We do not have mother-baby units here in the United States. And try as I did to find a way around that, I could not find a way that women could bring their babies in with them. So women were very reluctant to do the infusion. And fourteen days at home — it’s like a course of antibiotics. Doesn’t sound so bad.

31:30 – Zuranolone: Mechanism, Practical Considerations, and Real-World Access

Dr. Ben Everett: Not at all. Is there a certain screening you’re using for when zuranolone might be better? We’ve talked about the rapid onset of action being amazing. Anything else we need to counsel patients about in terms of safety? Can you still breastfeed while you’re on zuranolone? What else needs to be part of that conversation?

Dr. Jennifer L. Payne: The major side effect — which can be very helpful, quite frankly — is that it makes people sleepy. And so women will sleep very soundly. And that of course can be a problem in the setting of being at home with a newborn. Women who don’t have other supports can be intimidated about taking zuranolone because they’re concerned that they won’t wake up when the baby wakes up. So that’s a consideration. There’s also a black box warning to not drive for twelve hours after taking zuranolone. So if you have other kids to get to school at seven AM, you have to think carefully about when you’re taking zuranolone so that you’re not too sedated when you’re trying to drive. In terms of breastfeeding, it is recommended by the manufacturer to not breastfeed while taking zuranolone. However, we know the relative infant dose is very small in breast milk. And many women clinically are choosing to go ahead and breastfeed while taking zuranolone. I have not had a case yet where a baby was too sleepy from exposure in breast milk.

Dr. Ben Everett: I’m curious — do you know if they’re doing a registry? It seems like this would be a great opportunity to follow that up if women do decide to get on this medication, to make sure the option is open to them. There’s a registry that could really help generate additional data.

Dr. Jennifer L. Payne: I have not looked into that specifically.

Dr. Ben Everett: I’ll follow up and see if we can throw something in the show notes. That would be a great opportunity for them to do that. Registries end up being very costly, so a lot of times manufacturers won’t do it unless FDA maybe mandates it. But the data we can get from those is just so beneficial. All right. Well, access and cost, as with so many medications, remain significant barriers. Are you finding this is getting easier to prescribe? Is there something about a note and a prior authorization that can help get this for a woman who really needs it?

Dr. Jennifer L. Payne: I’m finding that it’s gotten easier to prescribe, and more and more insurance companies are covering it. In general, you have to have some sort of rating scale — either the Edinburgh Postnatal Depression Scale or the Patient Health Questionnaire-9 will do — and you have to have a significant score on that. I have not heard of situations where insurance companies have covered it outside of the indication for postpartum depression. So occasionally we will have patients who are presenting primarily with anxiety, and I’m pretty sure that zuranolone will work for postpartum anxiety, but they’re not meeting criteria for postpartum depression, and we’ve had insurance companies turn us down for that indication.

Dr. Ben Everett: With that activity in the extrasynaptic space, I imagine it would — yeah, the hypothesis certainly fits. But it’s a no-brainer in the brain.

37:00 – PMDD as a Window into Shared Biology

Dr. Ben Everett: All right. Well, this has been a great conversation. Let’s transition and talk a little bit about PMDD. Is this really a window into the same biology? Our discussion today is mostly focused on postpartum depression, but is the underlying biology similar?

Dr. Jennifer L. Payne: We’d love to know, and we have an NIH-funded grant to study that, so stay tuned. My suspicion is it’s similar but not exactly the same. And I think there’s at least two different biological phenotypes, if you will, of PMDD. One of the things we’re about to publish on — but this is unpublished as of this recording — our biomarkers that are predictive of postpartum depression are also associated with premenstrual dysphoric disorder, but only if those individuals respond to selective serotonin reuptake inhibitors. So there are really two types of PMDD cases: those that respond to SSRIs and those that do not, and it’s about fifty-fifty. I think it’s likely the biology will be similar to that of postpartum depression in women who respond to SSRIs. So we have a whole protocol going on where we’re looking at the neuroactive steroids and the enzyme activity and the GABA-A subunits, and we’re dividing it by women who respond to SSRIs and those who don’t.

Dr. Ben Everett: It’s really nice when we can have different phenotypes and understand exactly what people are going to respond to instead of being like, “Well, I don’t know — we kind of have two options and we’ll flip a coin.” The more we can get to this personalized area of medicine, the faster patients can get to recovery and the better outcomes we can have as a society. That’s really exciting.

39:30 – The GABAergic Hypothesis and the Future of Depression Subtypes

Dr. Ben Everett: All right, so kind of pivoting into the last section here. The bigger picture — what does all this mean for psychiatry? The approval of brexanolone and zuranolone is sometimes described as validating the GABA hypothesis of depression more broadly and moving away from our monoaminergic model of depression and anxiety. Do you think these drugs are really telling us something fundamental about depression and anxiety that we’ve maybe thought was simpler than it is?

Dr. Jennifer L. Payne: Well, I’m glad that people are bringing back up the GABAergic hypothesis of depression, because I think it does play a big role in many cases. But I think, again, we’re pivoting to being oversimple. We know that not everybody responds to these drugs. Zuranolone was studied in major depressive disorder, and while it did work in some people, it did not work at all in others — which tells you that there’s different biology at play for different people. I think at the end of the day we’re going to find that major depressive disorder has multiple different biological pathways leading to the clinical diagnosis of a depressive episode. I think the GABAergic hypothesis is a big one. And it definitely plays a role in at least maybe close to a majority of cases in postpartum depression, because there’s a direct assault on the GABAergic system with delivery of a child. But I think in the long run we’re going to find that there are several other different pathways, and that’s why we have conditions like treatment-resistant depression, bipolar depression, seasonal depression, premenstrual dysphoric disorder. What’s really exciting right now is that we’re getting closer to understanding the underlying biology of some of these conditions, and that will open the door for others.

Dr. Ben Everett: There have been some really good reviews on this lately, and we’ll have show notes with links to some of those that look across all the different areas implicated in different parts of depression and treatment-resistant depression. We’re having a lot of these same conversations across different areas of mental health.

41:45 – Improving Screening and Educating OBGYNs

Dr. Ben Everett: Let’s get to a practical consideration. We talk about how you’re supposed to be screening pregnant women for postpartum depression. Is that done as widely as it should be? And what can we do to help increase the screening rates for women?

Dr. Jennifer L. Payne: I think it’s starting to be done more widely. And this is really at the level of OBGYN clinics. One of the things that has been nice to see is that postpartum depression is being talked about more widely — we see it in the newspapers and magazines, and people are interested in it. More and more women are educated that this is a really common complication of childbirth, and that they need to get treatment because it’s not just affecting themselves, it’s affecting their children. So I think it’s growing. But I continue to see a lot of stigma and shame surrounding having a postpartum depressive illness. So I think what we can do right now is continue the conversation, and make sure that our OBGYNs are really educated in identifying when someone is depressed. I can walk into a waiting room and tell you who’s depressed and who isn’t by how they look. And yes, it’s a clinical interview diagnosis, but we need to do more education and training of our OBGYNs and get them to be more comfortable with identifying postpartum depression and starting treatment, because there are not enough psychiatrists, and there are definitely not enough reproductive psychiatrists to treat all the cases out there.

43:30 – Closing Remarks

Dr. Ben Everett: Amazing insight, and just the clinical expertise coming into that — walking into a waiting room and you can really see who it is. But we need to do a better job of educating, and hopefully we can get this podcast out to a lot of the OBGYNs out there in practice and make some positive impact for their patients. Well, our time together is drawing to an end. I want to be cognizant of your time today. But in closing, I really want to thank you for coming on the JCP Podcast. This has been a delightful discussion, Dr. Payne. I’ve learned a lot. I know our listeners will as well. Truly an illuminating conversation. I hope it will reshape the way our listeners think about postpartum depression, its biology, its treatment. There are some exciting things hopefully coming in the next couple years from the biomarker standpoint. It’s been a real pleasure having you on.

Dr. Jennifer L. Payne: Thank you so much for having me and for doing this podcast. I think it’s really important.

Dr. Ben Everett: Awesome. This has been the JCP Podcast. Insightful, evidence-based, human-centered.