Welcome to the webinar. I'm Dr. Jennifer Payne. I'm a professor and vice chair of research in the Department of Psychiatry at the University of Virginia. I'll be talking today about the frontier of reproductive psychiatry. We'll get started with some housekeeping slides. This webinar does qualify for CME credit, and the APA has designated this live event for a maximum of 1.5 AMA PRA category one credits. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Today's presentation is available. Just click show captions at the bottom of your screen to enable. Click the arrow and select view full transcript to open captions in a side window. You can also participate by sending in your questions in the Q&A button. Please feel free to submit your questions throughout the presentation by typing them into the question area found in the lower portion of your control panel. We will reserve 10 to 15 minutes at the end of the presentation for Q&A. We'll be collecting them throughout the presentation, but we'll answer them at the end of the presentation. These are my disclosures. The most pertinent disclosures is that I'm a writer and editor for UpToDate. I have two patents, one for epigenetic biomarkers of postpartum depression, and I'll be talking about those biomarkers today. And in addition, I have served as a consultant for a number of different companies, including Sage, Breed Biologics, Pure Tech, Mark, Flow Health, and perhaps most importantly Dionysus Health, which is a startup company that is working to bring the biomarkers to market. Here are our learning objectives for today. First of all, I'd like you to be able to define the term reproductive depression and understand what that means and why we think it's an important term. In addition, we'd like you to identify the primary mechanism of action of the new FDA-approved medications for postpartum depression, brixanilone and ziranilone. I'd also like you to be able to discuss how the new GABA positive allosteric modulator drugs, sometimes we refer to them as PAMs, alter the treatment approach for postpartum depression. And then I'd also like you to be able to define the term epigenetics and discuss how identification of women at elevated risk for postpartum depression in the third trimester before onset of symptoms might alter the treatment approach for postpartum depression. So let's get started. First, we'll talk about reproductive depression. As many of you know, women have twice the rate of depression than men, but really only during the reproductive years. And if you look at this slide here, you can see that the rates of depression in boys and girls are about the same until really the age of menarche. And then women have twice the rate of depression throughout the reproductive years. And then around the time of menopause, the rates return to about the same in men and women. And in fact, in older ages, greater than 60, men may have higher rates of depression compared to women. And this really nicely correlates with the cycles of hormonal change that women go through on a monthly basis and then during and after pregnancy. So it's only during the reproductive years that women have twice the rate of depression compared to men. So what exactly is reproductive depression? Well, it's depressive episodes or symptoms that occur in conjunction with times of hormonal change in women. And we can see a bunch of different reproductive depressions, which really can range. There's a spectrum from symptoms to actual syndromes. So for example, many women have premenstrual mood symptoms, but far fewer qualify for a diagnosis of premenstrual dysphoric disorder. In addition, in women with preexisting mood disorders like major depression and bipolar disorder, we can see that about a third of them will have premenstrual mood exacerbation, meaning that their mood disorder either returns or gets worse in the luteal phase of the menstrual cycle. Similarly, most women after they deliver a baby will experience something called postpartum blues, which is a mild syndrome of emotional instability that really resolves over the course of a few days and doesn't cause functional impairment. In contrast, postpartum depression is a major depressive episode that occurs in the postpartum time period. And postpartum psychosis, for the most part, is an episode of bipolar disorder that occurs in the postpartum time period. We can also see perimenopausal mood instability in most women. However, a subset of them will develop perimenopausal depression. We've also seen lots of instances of mood disorders being induced by various hormonal contraceptive pills, and even the Mirena IUD can induce mood disorders and mood symptoms in susceptible women. And it's really during times of hormonal change that we see the triggering of mood symptoms or mood disorders. So during the luteal phase of the menstrual cycle, it's when progesterone and estrogen levels are dropping precipitously prior to the onset of menses that most women will experience mood symptoms or the onset of a mood disorder. And similarly, in the postpartum time period, it's during the time right after delivery that estrogen and progesterone are dropping precipitously that triggered mood symptoms in susceptible women. So the big idea is that times of hormonal fluctuation can trigger mood symptoms in women and increase the risk for mood disorders and, in particular, depression. Let's turn now to postpartum depression. The definition of postpartum depression is essentially a major depressive episode that is occurring during the postpartum time period. Now, about 50% of cases of postpartum depression actually start during pregnancy and typically in that third actually start during pregnancy and typically in that third trimester right before delivery. In the DSM-IV, we actually had the term postpartum, and the requirement was that symptoms had to begin within one month postpartum. The DSM-V now uses the term peripartum, which recognizes the fact that many cases of postpartum depression begin during pregnancy and then continue postpartum. How common is postpartum depression? Well, it really depends on the population. As noted, many postpartum depressions begin during pregnancy, and so rates are not always completely clear. In the general population of women, about 13 to 17% of women will develop postpartum depression when it's assessed just during the postpartum time period, so it probably includes cases that began during pregnancy. Women who experience postpartum depression are very likely to go on to develop depressive episodes that occur outside of the postpartum time period. In women with pre-existing mood disorders, like major depression and bipolar disorder, the rate is much higher, so about 20 to 30% will develop postpartum depression with symptom onset in the immediate postpartum time period, and if you include women that become ill during pregnancy, it's about 50%, so a very large percentage of women with pre-existing mood disorders will become ill during the peripartum time period. So why is this important? Well, I think it's important for the mother, but it's also important because there are significant effects on the exposed infant. Postpartum depression is actually the most common complication of having a baby, and depression during pregnancy increases the risk. It's one of the strongest predictors of being depressed during the postpartum time period, and we know that when mothers are depressed in the postpartum time period, the exposed infants actually are at risk for lower IQ, slower language development, increased rates of ADHD and behavioral problems, and the later development of psychiatric illness, and we think this is because mothers are not interacting with their infants in the way they would normally, so they're not playing with them as much, they're not talking to them constantly in the high-pitched voice, they're not in their face, and that really has significant effects on brain development. So it's actually quite important that we get mothers identified and treated for postpartum depression. In addition, mothers with postpartum depression are prone to a whole host of other behaviors that really increase the risks for their children. So mothers who are depressed are more likely to smoke and use other substances, they're more likely to use the emergency room for health care, they're less likely to talk to their babies or give their kids vitamins or put them in car seats, and they're less likely to get their kids vaccinated or go to well-baby checkups, and these behaviors put their children at risk for a lifetime history of various health issues and problems. So the big idea is that it's really important to rapidly and effectively treat postpartum depression for both mother and child. Now let's talk about the underlying biology of postpartum depression and moving towards more targeted treatments. So I'm going to talk and focus today on the GABAergic hypothesis of depression and postpartum depression. And the idea here is that depressive disorders are actually stress disorders, and GABA is the major inhibitory neurotransmitter in the brain and it mediates the effects of stress on the brain. So GABA balances and fine-tunes excitatory neurotransmission of various neuronal systems, including the monomergic and cholinergic projections to the forebrain. And there's been accumulating evidence in both humans and animal models, which implicates alterations in the GABAergic system, including at the GABA receptor level and underlying depression and anxiety disorders. So the idea here is that GABA actually controls the brain's response, the HPA axis response to stress. The GABA receptors act on corticotropin-releasing hormone neurons in the paraventricular nucleus of the hypothalamus and thus help control the stress response of the HPA axis. Acute stress decreases GABAergic control, leading to release of CRH and cortisol. Levels of inhibitory neuroactive steroids rise in that setting, which increases GABA A receptor activity and then resets the system. In chronic stress, the GABAergic function decreases, but with longer-term changes, including decreased GABA levels and changed GABA A receptor subunits and inhibitory neuroactive steroid levels actually decrease over time. So the HPA axis remains active in chronic stress. Here's a picture of the GABA A receptor. It's a heteromer composed of five subunits, usually composed of two alpha subunits, two beta subunits, and one delta. It's ligand-gated and multiple agents act on the GABA receptor. So there are actually receptor binding sites for benzodiazepines, alcohol, and neurosteroids, and all of those binding sites are separate from each other. When a ligand binds the GABA receptor, it increases its affinity for the GABA neurotransmitter. GABA is inhibitory and it leads to sedation, calmness, and anti-seizure activity. And neuroactive steroids like allopregnanolone are positive allosteric modulators of the GABA receptor. And you can see here that neurosteroids have their own ligand binding site that's separate from alcohol, barbiturates, and benzodiazepines. This is a drawing of the neuroactive steroid pathway and how it's metabolized. And what you can see here, if you focus in on progesterone, progesterone is metabolized to a middle metabolite and then ultimately is metabolized to allopregnanolone and pregnanolone. Allopregnanolone and pregnanolone are positive allosteric modulators of the GABA-A receptor. Progesterone is also metabolized to negative allosteric modulators of isoallopregnanolone and epipregnanolone. And these act in the opposite direction from the positive allosteric modulators. So when they bind to the GABA receptor, they actually decrease its affinity for GABA and thus increase the excitatory activity in the central nervous system. We think it's the balance between these positive allosteric modulators and the negative allosteric modulators that really, really programs the brain's response to stress and its ability to rebound from stress. Postpartum depression appears to be related to sensitivity to the normal rapid drop from extremely high levels of estrogen, progesterone, and its metabolite allopregnanolone during pregnancy to pre-pregnancy levels. So here, this is showing levels of progesterone and allopregnanolone that slowly rise during pregnancy and then postpartum drop back to pre-pregnancy levels. Sensitivity to times of hormonal change, such as during the postpartum time period, is often associated with a prior history of other reproductive-related mood disorders, such as premenstrual symptoms or premenstrual dysphoric disorder. And one idea is that the GABA A receptors, which are down-regulated during this increase in neuroactive steroids like allopregnanolone during pregnancy, can take some time to recover and up-regulate in the postpartum time period in women who are susceptible to postpartum depression. Progesterone and allopregnanolone rise steadily through pregnancy before a sudden drop in the postpartum time period. Neurosteroids are potent modulators of the GABA A receptor, and the rising levels of allopregnanolone in pregnancy are thought to down-regulate the GABA A receptors in the brain and change what subunits of the receptor are prominent, which also changes how it responds to the GABA neurotransmitter. After delivery, hormones rapidly return to pre-pregnancy levels, but GABA A receptors may take time to recover in women who are susceptible to postpartum depression. Stress also plays a role in postpartum depression and can result in changes in allopregnanolone levels and in the GABA A receptor. Pregnancy is accompanied by significant changes in gonadal steroid and allopregnanolone, I'm sorry, and neuroactive steroid levels that then precipitously decrease with delivery. Thus, levels of allopregnanolone are dramatically lower postpartum compared to pregnancy. Women who develop postpartum depression may have specific vulnerabilities in the GABAergic system, such as lower levels of allopregnanolone during pregnancy or GABA A receptor subunit differences that make them particularly vulnerable to developing depression in the perinatal period in the setting of low allopregnanolone levels. We can think of postpartum depression as a special case of vulnerability in the GABAergic system that gets triggered, likely due to the stress surrounding of becoming a parent and the hormonal changes that occur during pregnancy and delivery that expose vulnerabilities in the GABAergic system. So now let's turn to neuroactive steroid treatments for postpartum depression. In 2019, the FDA approved the first drug for postpartum depression. Now for those psychiatrists in the audience, we all know that antidepressants of all kinds can be used to treat postpartum depression. In general, up until these last few years, the frontline treatment for postpartum depression were selective serotonin reuptake inhibitors. They had the best evidence for the best evidence for working for postpartum depression. And particularly for women who had not previously had major depressive episodes outside of the perinatal time period, SSRIs were really considered the first choice. In women who had major depression outside of the perinatal period, the recommendation was to go back to whatever antidepressant or class of antidepressants she had previously responded to. But in 2019, the FDA approved the first drug for postpartum depression, which is known as Brexanilone. In 2023, the FDA approved the first oral agent for postpartum depression known as Ziranilone. And these two drugs have really been a paradigm shift in treatment. In general, they require just a short course of active treatment, and I'll compare the two here in just a minute. They have a very rapid onset of efficacy on the order of hours to days, and a long duration of effect. So these are medications that can be administered for a short period of time. They have a very rapid and significant onset of efficacy. And then even in the absence of continuing the drug, there's a long duration of effect. This is in stark contrast to all other antidepressants, except for perhaps ketamine, which does have a short course of treatment and a rapid onset of efficacy, but does not have a long duration of effect. Brexanilone is a natural allopregnanolone which is formulated for solubility. It is administered as an IV. There's a continuous IV infusion over 60 hours followed by 12 hours of observation. Brexanilone really requires admission for monitoring with pulsometry and for every two hours during the infusion and another caregiver must accompany the patient if a child is present. You can use antidepressants concurrently with it but that antidepressants that are sedating might increase the risk of an adverse event with sedation with this IV formulation. There is a boxed warning for excessive sedation and sudden loss of consciousness. A small number of patients lost consciousness while receiving Brexanilone. This was reversed by stopping the infusion and it was reversed immediately. There is a REMS program because of this potential for loss of consciousness and the patient needs to be registered and outcomes need to be recorded. So Ranilone is a synthetic allopregnanolone analog and it was approved in late 2023. It has once a day dosing which we generally recommend is in the evening and you take it for only 14 days. It can be used at home in contrast to Brexanilone which really requires a significant nursing care. There is a concern for ability to drive less than 12 hours after the dose and there's no REMS program for it. For Brexanilone, there were four studies that that led to FDA approval. The first was reported in 2017 with an open label proof of concept study. They had planned to enroll 10 people. They enrolled four and the results were so significant that they stopped the study early and moved to double-blind placebo-controlled trial. The second study was also published in 2017. It was a small double-blind placebo-controlled study in 21 research participants. And then finally in 2018, they published two multi-site double-blind placebo-controlled trials with 246 participants. They published both of those trials in one publication. So the total number of participants in the research were 271. FDA approval came in March of 2019 and notably Brexanilone was designated a breakthrough therapy and granted fast-track approval because its results were so startling and significant. For all the Brexanilone studies, postpartum depression was defined as beginning no earlier than the third trimester and no later than 12 weeks after delivery. They used the Hamilton Depression Rating Scale or the HAMD to determine inclusion. And then the primary outcome measure was the change in HAMD from the start of the infusion to 60 hours after start of infusion. So literally the primary outcome measure was change over the course of three days and a Hamilton Depression Rating Scale. Participants could be on a stable dose of an antidepressant, but they had to be on that antidepressant for two weeks or longer. And there was a mixture of participants taking antidepressants and not taking antidepressants who participated in the studies. The manufacturer required no breastfeeding either at all or until after day 12 of the study, and there were 30 days of follow-up data. This is the infusion plan. And in general, there's a step up from really 30 milligrams up to 60 or 90 milligrams depending on the study, and then a step down during day three. This is a combined results for study one and study two. And what you can see here is a very significant and quick reduction in the HAMD score. In the top graph, it's talking about the Brexanilone 90 and the Brexanilone 60 milligram groups. In the Brex 90 group, there was a 14.6 point drop on the HAMD from the beginning of the infusion to 60 hours of the infusion. And in the placebo group, it was 12.1. This was statistically different. The proportion of participants achieving remission was higher in the Brexanilone group than in the placebo group. And I'll show you that data here in just a minute. What you can see here is that it's a rapid and sustained response to Brexanilone. So the placebo and the active study groups separated by 24 hours after the start of the infusion, and that's the purple arrow here. And they remained statistically significantly different at 30 days post the start of the infusion. And so we see a very rapid response to Brexanilone, a separation from placebo very quickly, really within hours, and a sustained response through at least 30 days after the start of the infusion. Notably, that's 27 days off of study medication. And this is the remission rates based on a HAMD score of less than or equal to seven. And what you see here is really phenomenal. It's about 70% of patients that received Brexanilone achieved remission. And this was as early as 24 hours after the start of the infusion, and this is in stark contrast to the placebo group. And even though the placebo response was significant, it clearly did not respond in a way that achieved remission for those who received placebo. And to just put this in context, the remission rate to SSRIs, for example, is about 30% in clinical trials. We have about a 50% response rate to SSRIs and about a 30% remission rate in good standardized double-blind placebo-controlled trials. So this was really very significantly different from our standard antidepressant treatments. So what about safety? Well, in general, Brexanilone is pretty well tolerated, and the most frequent adverse events were headache, which is one of the most frequent adverse events for any medication, but also dizziness and being overly sleepy or somnolent. The package insert cites most frequent adverse event as sleepiness, dry mouth, passing out, and flushing of the skin or face. About 5% of participants who received Brexanilone had excessive sedation, including loss of consciousness, which was relieved by stopping the infusion immediately. And in that setting, the infusion can be started once again at a lower dose. And this is really why this requires an inpatient setting or a very special setting with very attentive nursing care, because if a patient becomes overly sedated and passes out, that infusion needs to be stopped immediately. And so you really need constant pulse ox monitoring and constant attention to if the patient is appropriately conscious and arousable. There is participation in a risk evaluation and mitigation strategy that's required. The label has a black box warning about excessive sedation and sudden loss of consciousness, and Brexanilone is classified as a class four controlled substance. Here's the box warning and the notice that there's a REMS safety program that requires registration of the patient in the program. Issues to overcome for use on a psychiatry unit, the biggest one is the constant pulse ox monitoring and immediate nursing response. I will tell you that I was able to get a Brexanilone unit started at Johns Hopkins. Johns Hopkins has standard psychiatric units with complicated medical issues. So it was fairly straightforward for us to start a Brexanilone unit on psychiatry. Most of the other units that are using Brexanilone are using them in the setting of OB-GYN, because the nursing availability is there, the nursing experience is there, and the pulse ometry is also there. Nursing also has to do assessments, which can include using the Richmond agitation and sedation scale or RAS scale for excessive sedation every two hours during waking hours and every four during sleeping hours. And this really requires increased nursing staffing. So summary, Brexanilone is rapidly effective in the treatment of postpartum depression. It's generally well-tolerated, and the most common side effect is sedation. Both response and remission rates were higher in the Brexanilone-treated groups based on the mean reduction of the HAM-D score from baseline to 60 hours after the start of the infusion. And Brexanilone's new mechanism of action targeting GABA-A receptors is exciting and opens a new avenue to explore in the treatment of major depression in general and postpartum depression specifically. And Brexanilone is not only rapidly acting, it has a sustained response for at least 30 days after the infusion. So now let's turn to Zoranilone. This was formerly known as Stage 217, and so you may see a reference in the literature to Stage 217, and it's talking about Zoranilone. It has a similar mechanism of action to Brexanilone and is a positive allosteric modulator of the GABA-A receptor. However, it's an oral agent, and it's suitable for once-daily dosing. It has been studied in major depression and postpartum depression, and studies are using either 30 milligrams or 50 milligrams of Zoranilone. There have been two studies in postpartum depression, one with 30 milligrams and one with 50. And in all studies to date, Zoranilone was given once-daily for 14 days and then stopped. The FDA approved its use for postpartum depression only in late 2023. Its approval for the use in major depression is pending. This is the ROBIN study, which is a double-blind placebo-controlled trial of 30 milligrams of Zoranilone compared to placebo. They had women with a significant HAMD score of greater than or equal to 26. This was double-blinded and placebo-controlled. Participants received a one-to-one randomization of 153 subjects, and they received either Zoranilone, 30 milligrams, or placebo once a day orally for 14 days. And day 15 was the primary endpoint, and then they conducted a naturalistic follow-up through day 45 after the initiation of either the placebo or the Zoranilone. They again used the least square mean change from baseline and the HAMD from baseline to day 15, and safety and tolerability were assessed by adverse event reporting and standard clinical assessments. And here you can see that there was, again, a very significant response rate that was rapid, so that you could start to see separation from placebo by day three. And certainly at the primary endpoint, there was a statistically significant difference in the placebo group versus Zoranilone, 30 milligrams. And then interestingly, what you can see is that even though patients were not taking the oral medication from day 15 onwards, that separation continued through 45 days after the start of the study. The primary endpoint at day 15 was met with a 17.8-point reduction in the HAMD score in the Zoranilone group versus a 13.6-point drop in the placebo group. Sustained differences in the two groups were observable and statistically significant by day three. One patient per group experienced a serious adverse event. There was a confusional state in the Zoranilone group and pancreatitis in the placebo group. And one participant in the Zoranilone group discontinued treatment versus none in the placebo group. This is the second study that was done. It was known as Skylark, and it was studying Zoranilone, 50 milligrams compared to placebo. Essentially had the exact same setup as the Robin study, with the primary endpoint being at day 15 with the least square mean change from baseline in the HAMD. They also looked at secondary endpoints at days 3, 28, and 45. They enrolled women with a major depressive episode beginning between the start of the third trimester and up to four weeks postpartum. And they could be on a stable dose of an antidepressant. They enrolled 196 women and randomized 98 to each of the placebo and the Zoranilone groups. And I'm sorry, that's a repeat of the same slide, so we will skip that. And this is, these are the results. And again, you can see a significant difference between placebo and Zoranilone by day three. And they met their primary endpoint at day 15, and the two groups continue to be statistically significantly different at day 45. These are the response and the remission rates. And you can see that the response rates are again quite significant with about 70% of women receiving Zoranilone having a response rate. The remission rates were not as good as Brexanilone, but still were quite significant, and on the order of between 50 and 60%, which again is better than our standard antidepressant treatments. And importantly, they did a separate analysis for anxiety symptoms. And what they found was that, this was in the Robbins study using the 30 milligrams of Zoranilone, that there was a very significant change again by day three in anxiety symptoms, looking at the HAM-A, or the Hamilton Anxiety Scale, that continued to be significantly different through day 45. So Zoranilone has evidence for efficacy in both postpartum depression and postpartum anxiety. The oral noractive steroid Zoranilone is also rapidly effective in the treatment of postpartum depression. It's generally well tolerated with the most common side effect being sedation. And for that reason, we recommend giving it at the evening, preferably at the evening meal, in greater than 12 hours before driving. Both the response and remission rates were higher in the Zoranilone groups based on the mean reduction in HAM-D score from baseline to day 15. Brexanilone and Zoranilone's new mechanisms of action targeting the GABA-A receptor, again, is quite exciting and opens a new avenue to explore in the treatment of major depression and postpartum depression. Zoranilone is not only rapidly acting by day three after starting the oral agent, but it also has a sustained response for at least 45 days after initiation of treatment. And it was approved for the treatment of postpartum depression at the end of 2023, and is available, though generally specialty pharmacies are the ones that are obtaining it. So what does this mean for treatment recommendations? I told you earlier that prior to the last few years, the general treatment recommendation for postpartum depression were selective serotonin reuptake inhibitors. So how are we thinking about using Zoranilone and Brexanilone at this time? Well, these are kind of my thoughts on this, but I have talked a lot about this with other reproductive psychiatrists, and I think this is a pretty standard thought process for those of us in the field. For Brexanilone, you really want to use it for patients who are requiring an inpatient setting, have severe depression, suicidality, or really want rapid relief or need rapid relief, so pretty serious symptoms. Having said that, and having started a Brexanilone unit, slightly less severe cases of patients who did not necessarily require an inpatient setting except for the use of Brexanilone, Brexanilone can be considered for them as well. What's wonderful about Brexanilone is that it acts rapidly, people feel better within the first day, and it really only requires a three-day inpatient stay, and then a woman is done. And so if she really wants to breastfeed and does not feel comfortable breastfeeding on these agents, Brexanilone can be a very rapid and quick way to get a woman better and back to breastfeeding in a fairly quick manner. We tend to use classic antidepressants when there's a history of a previous response, a significant history of recurrent major depression, and therefore there's evidence that a woman is probably going to need ongoing treatment. Classic antidepressants can be used in pregnancy and during lactation, although they're not specifically approved for postpartum depression. Right now we do not recommend the use of Brexanilone or Xeranilone during pregnancy, so for women who become depressed during pregnancy, classic antidepressants still need to be used. For Xeranilone, we're thinking about using Xeranilone for that first episode of postpartum depression when there's not a history of significant recurrent major depression, and when there's an inadequate or only a partial response to a more standard antidepressant during pregnancy or after delivery. So in other words, if a woman's having her first postpartum depression, I would certainly think of using seranolone in that setting. The main reason being that you're not committing that woman to a long-term treatment with a medication. You can do 14 days and stop the medication. And if she's had a response, that can be it, at least for now. When there is a history of recurrent major depression, and a need for ongoing antidepressant medication, that's when I would think about using more standard antidepressants. Now insurance coverage and costs likely play a role in clinical decision making. Both of these agents are quite expensive. That being said, many insurance companies are seeing the usefulness of using these medications and limiting either an inpatient stay or limiting the need for ongoing medication management. Economic modeling suggests that seranolone is more cost effective compared to SSRIs for treating postpartum depression, and insurance companies are hearing that. In addition, the company Sage and Biogen have a number of different programs that can help potential patients with covering the cost for these drugs. So here are some best practice recommendations for both of these drugs. For rexanolone, you really have to have a hospitalized setting for 72 hours with monitoring for excessive sedation or loss of consciousness. And because of that, there will need to be support for caring for the baby. And there's also a REMS program that the patient will need to participate in. So there were a number of cases that I have seen where we've not been able to administer rexanolone because there was not child care support outside of the hospital for a particular woman's children. So that can be a consideration at play when you're thinking about using these medications. In general, we recommend pausing breastfeeding. And again, that can be for a brief period if you use rexanolone. But we know that exposure in breast milk is low. So very little of the drug actually gets into breast milk. You can lower the dose from 90 micrograms per kilogram per day to 60 micrograms per kilogram per day if a woman becomes overly sedated. And for rexanolone, we see a statistically significant separation from placebo by 24 hours, which is sustained for at least 30 days in trials. So for xanolone, we recommend evening dosing with a fatty meal to really increase the absorption of the medication. So taking the dose at dinnertime is generally recommended. We recommend starting with 50 milligrams and can lower to 30 milligrams if there's excessive sedation. We also recommend driving only more than 12 hours after the nighttime dose until you know how sedating the medication is in a particular patient. For both of these medications, we do not recommend using them during pregnancy. There's no evidence or study for that yet. But it can be started after delivery if a woman is not responding to a standard antidepressant or is having new onset symptoms. Again, we suggest pausing breastfeeding during xanolone treatment, but exposure and lactation is low. And for xanolone, it separates from placebo after two doses by day three. And there are sustained effects through six weeks. And there's even some evidence that about 50% have a sustained improvement for a year after one 14-day course of 50 milligrams in major depression. This is repeating some of the same information on the previous slide. For brixanolone, generally people up titrate from 30 micrograms to 60 micrograms to 90 micrograms. Both 60 and 90 have been shown to be effective, with 90 being a little bit more effective. And then you step down the dose. You titrate the dose down, again, over that last 24 hours of the infusion. In xanolone, we also recommend abstaining from sex or using effective contraception during the course of drug administration, simply because we do not have any data on a woman becoming pregnant while taking xanolone. So up to date, I mentioned that I'm an editor at UpToDate. And most people are very familiar with UpToDate. They tend to make current standard recommendations of how to approach various illnesses, including psychiatric illnesses. And they often develop protocols for how to think about a treatment approach in particular situations. There are now new recommendations on UpToDate for severe postpartum depression or unipolar major depression in the postpartum time period. And they have an algorithm that nicely outlines this. But in general, they are recommending that in patients with no history of antidepressant treatment, that xanolone or brixanolone be used as the first line of antidepressant treatment, and that in non-responders, then move to SSRIs. And in addition, in patients with a history of successful treatment with an antidepressant prior to pregnancy, they recommend resuming that antidepressant. And then if there is no response or only a partial response, to give a trial of xanolone or brixanolone. And then finally, in patients with a history of antidepressant use during pregnancy, and then with a relapse of symptoms in the postpartum time period, they also recommend moving immediately to xanolone or brixanolone in that setting. So this is a really new approach to the treatment of postpartum depression. And UpToDate is suggesting that we should be thinking about xanolone and brixanolone early in the course of a treatment approach for postpartum depression. So I'm going to move now to my research work on epigenetic biomarkers of postpartum depression. I will not bore you with a ton of slides here, but I do think this is a frontier of reproductive psychiatry. And I am hopeful that this research will actually change standard of care in our approach to managing perinatal depression. So let's talk about what epigenetics exactly, what does that mean? So epigenetic changes are heritable changes in gene activity, which are not caused by changes in DNA sequences. So every cell in your body has the same DNA in it. And yet, different cell types produce different DNA products or messenger RNAs, different enzymes, et cetera. And so a cell that's in your brain has very different DNA activity compared to a cell that's in your liver. And it's the epigenetic changes that really turn genes on and off and make cell types individualized. So DNA methylation and histone modification alter how genes are expressed in individual cells. And this is why differentiated cells in a multicellular organism only express the genes that they need to carry out their function as a neuron or a liver cell, for example. And what's really interesting is that environmental exposures can induce epigenetic changes and change gene expression. And if you think about psychiatric illness, I think it's highly likely that epigenetic changes are what underlie many of our psychiatric disorders. I've always thought of psychiatric disorders as a biological vulnerability that in the setting of certain environmental influences develops what we call a psychiatric illness. So people with major depression likely have a genetic vulnerability. But only in the setting of significant stress or substance use, for example, does that vulnerability become expressed. And one of the ideas is that hormonal changes really are a change in one's environment and can induce epigenetic changes that result in psychiatric illness. So there are numerous animal studies that have demonstrated that estrogen has anxiolytic and antidepressant effects specifically within the hippocampus. Estrogen administration, for example, results in increased synaptic plasticity and dendritic spine density in the hippocampus. And estrogen withdrawal results in decreased hippocampus BDNF expression. And so there's been a hypothesis out there that the increased levels of estrogen during pregnancy can lead to epigenetic changes in the hippocampus that result in decreased synaptic plasticity, or what we essentially clinically call depression in the setting of estrogen withdrawal. So it's that fluctuation in estrogen that can lead to epigenetic changes that then result in decreased synaptic plasticity in the hippocampus, which is essentially a clinical depressive episode. So my basic science partner, Zach Kaminsky, and I initially started with a mouse model. So we took mice. We exposed them to estrogen to simulate about the same levels that we see in pregnancy. And then we screened for genetic loci that were responsive to estrogen in the mouse hippocampus. So we looked at genes specifically in the mouse hippocampus that had extra methylation or decreased methylation in response to estrogen exposure. We then took a sample of women that I had very carefully characterized as to whether or not they develop postpartum depression or did not develop postpartum depression. So I had followed them through pregnancy and into the postpartum time period. And we cross-referenced those genes that were changed by estrogen exposure and looked at samples, looked at the same genes and blood from women who did and did not develop postpartum depression, but who were clinically well during pregnancy. And this original study was done with a sample of women that I had collected as part of my K award. This was a long time ago. And I had followed 93 women with mood disorders, either major depression or bipolar disorder through pregnancy and into the postpartum time period. This observational study is ongoing. We've now enrolled over 500 pregnant women and followed them through pregnancy and into the postpartum time period. We've enrolled women both with and without mood disorders. And we evaluate them during every trimester of pregnancy. They can come into the study at any time point. So we have far fewer data at the first trimester, for example, but we try to evaluate them during each trimester. And then we look at two weeks postpartum, six weeks postpartum, three months postpartum, and then up to six months postpartum. And we obtained blood samples and an Edinburgh postnatal depression scale every visit. This is an observational study. It's naturalistic. Women are able to continue psychiatric medication use during pregnancy and start psychiatric medications during and after pregnancy during the study. It's really been over 13 years of work here. And since identifying our original biomarkers in that sample of women from my K award, we've actually replicated this work in seven individual samples, some of which we've collected and some of which other people have collected. And basically we've identified two genes that are epigenetically modified in a particular pattern when a woman is going to be depressed in the immediate postpartum time period. So the two genes are HP1BP3 and TTC9B. And with a specific pattern at those two genes, we can predict with about 80% accuracy who's gonna be depressed in the postpartum time period. Now, my work more recently has started to look at biomarker positive postpartum depression versus biomarker negative postpartum depression. And what we're finding is that there are unique clinical phenotypes for those two types of postpartum depression. Interestingly, the biomarker positive postpartum depression cases are all extremely anxious. So they are that kind of classic anxious depression that we see for postpartum depression. The cases that are biomarker negative are much more likely to have a history of recurrent major depression outside of reproductive life events. And I'm thinking of them as kind of your garden variety major depression that happened to develop a depressive episode in the postpartum time period. And I'm thinking of the biomarker positive group as being sensitive to estrogen hormonal fluctuations. What's exciting is we now have the ability to identify the underlying biology of two distinct types of postpartum depression that we can easily distinguish by looking at the biomarkers. So stay tuned for that. I hope I'll be able to tease apart exactly what the broken parts are and these two types of postpartum depression. As I noted, we have replicated these biomarkers now in about seven different studies. And over the course of the years, the biomarkers were actually improving our algorithms so that now we're able to identify about 80% of cases of postpartum depression. So what do these genes do? Well, the honest truth is we don't exactly know. We know that for TTC9B, the family members of that gene are associated with anxiety and their expression is regulated by estrogen and other reproductive hormones, which makes sense because we identified these genes using an animal model with estrogen exposure. HP1BP3 is a heterochromatin binding protein that regulates the expression of tons of genes. It's associated with stress response, age-related cognitive decline, and synaptic plasticity. And increased methylation at this gene is also associated with adolescent victimization. Both markers can be detected in circulating immune cells with a simple blood test. And now we can actually, there's actually commercially available test kits that can be used. There's a company that is doing methylation work commercially and so we are now able to actually think about commercializing these biomarkers as a test for postpartum depression. This is a nice slide put together by Zach Kaminsky that really shows the years and years of work that have gone into this. We've gotten several grants. We're getting more. We've published several papers. And interestingly, an outside group actually replicated our findings. This was published in a pre-print from researchers at VCU. And that was a nicely validating study that in someone else's hands that the biomarkers were validated. This is showing you the different groups that we have validated our biomarkers in. Most recent group was a, I had a colleague in Israel who collected samples for me and we again validated in that sample. And we are pleased that it keeps validating. And so we are now starting to look at commercialization of these biomarkers. So I've talked about this a little bit. The HP1BB3 has been shown to associate with the beta estrogen receptor. And we know TTC9B has been responsive to gonadal hormones and is involved in synaptic plasticity. Interestingly, there was a knockout model of HP1BB3 in mice and new mother dams showed a real big disturbance in maternal behavior. So knockout mice did not retrieve their pups in a way that they would normally and the pups had excessive death because of this. So we know that HP1BB3 is involved in maternal behavior. The exact way that is involved, we're not sure, but it's clear that maternal behavior is associated with this gene. So impact, understanding the broken part or parts underlying postpartum depression will potentially lead to earlier identification and treatment for postpartum depression. So my goal with my research is to move towards really understanding the underlying biology and then also moving towards a preventative model for postpartum depression rather than a reactive model. If we can identify 80% of cases of postpartum depression during pregnancy, we can start the process clinically of getting those patients who are at risk referred for psychiatric care, getting them more support, starting psychiatric medications in the immediate postpartum time period rather than waiting for them to get sick and have effects on their developing child. I also think having a blood test for a future mental illness will hopefully help decrease the stigma associated with mental illness. I think a lot of people, including doctors today, dismiss psychiatric illness as something that's only in your head and having a biologically based blood test for a mental illness will help decrease that stigma and perhaps encourage people to get the treatment that they need. So here I brought you a picture of the frontier of reproductive psychiatry and I am happy to entertain questions. And thank you for attending and paying attention for all this time. And currently there are no open questions, but I am happy to take questions of any sort on any topic I touched on or really anything about reproductive psychiatry. Or is there another area that you'd like me to touch on in more detail such as my experience in starting a Brexanilone unit or using Xeranilone, etc.? Please don't be shy. All right, my first question. Thank you so much. What was the remission rate of postpartum depression using xeronalone? So it was greater than 50%. It was depending at the time point that you looked at, it was between 50 and 60%. So still higher than your average rate than standard antidepressant treatments. Ah, someone's using the chat. Ah, please type your questions in the Q&A button. So, I'll ask you a question. Do you think you'll be using the new positive allosteric modulators of the GABA receptor in your practice? Insurance authorization and tips. Excellent question. So, yes, you have to get insurance authorization. It is possible. What you want to document is that the onset of symptomatology was generally they're accepting during the third trimester and generally within the first month postpartum. It's a little unclear if they'll accept later onset, so six weeks, eight weeks out of delivery. I think it's important to use an Edinburgh postnatal depression scale or a PHQ-9 to record the severity of the symptoms. And I think you just need to really emphasize that this is a case of postpartum depression. Insurance companies are reluctant to support this for what they would consider a non-postpartum depression, a major depressive episode at this time. And then the other thing that I would say is that it's important to, A, go for insurance authorization, but then also look at programs through SAGE and Biogen in terms of supporting for, say, a high deductible or a high copay. Those programs have been very instrumental in us being able to get patients the drug. Could you comment on dependence and seizure risk? An exposed canine had a seizure, as well as neurological risk in exposed animal fetuses with xeranolone specifically. I believe there were noted in Skylark. Is there a concern for dependence and discontinuation, including seizure in patients exposed for the two-week course of treatment? So to my knowledge, there's not been seizure disorders. There is not a concern for dependence. So as I pointed out, the GABA-A receptor has multiple ligand binding sites that are specific to a type of pharmacological agent, if you will. And so the benzodiazepine and barbiturate binding sites are completely separate from the binding site for allopregnanolone. Allopregnanolone is a naturally occurring hormone. It's a metabolite of progesterone. And although it has sedative properties, it does not appear to have dependence properties. I do not know about the neurological risk in exposed animal fetuses, I'm sorry to say. But again, allopregnanolone is in a woman's body at high levels during the course of pregnancy. So the likelihood is low that there's going to be a significant effect on developing fetuses, but again, not zero. In fact, allopregnanolone levels are so high in pregnancy that if the GABA-A receptor didn't downregulate, women would sleep through their pregnancy. They would be over sedated. So we know that women do not have seizures in the couple of days it takes for those allopregnanolone levels to drop postpartum. So I'm not concerned about a seizure risk or dependence to these medications. I will say that I just gave a talk to obstetricians on these drugs, and they're very interested in them. I think that in particular, they're interested in Zoranilone because that's a little easier to prescribe since it's an oral agent. But I think they like the idea of a 14-day course. It's almost like giving an antibiotic and then not worrying about follow-up. I think what is unclear, and what is unclear for obstetricians, is when should they be using Zoranilone versus a standard antidepressant treatment. I think my recommendations in the talk are probably where we are right now, and that recommendation may move over the next couple of years. Right now, we're talking about a new onset postpartum depression. Someone who was on an antidepressant and got worse postpartum or had a recurrence of depression while taking the antidepressant is an appropriate candidate. Someone who has a long history of major depression and multiple treatments probably should still be given standard antidepressant treatments. But I do wonder if we will move those patients to having a kickstart to their recovery by also using a medication like Zoranilone. The other thing that's not completely clear that I think needs to be studied is the length of time we're giving these medications. So we see a response to Brexanilone in 24 hours. The choice of doing the infusion for three days was really based on the seizure literature. It had been developed for use in status epilepticus, and for those studies, they infused for three days, so they decided to do the same thing for postpartum depression. It's unclear if we actually need to infuse for three days. It might be that we need to infuse for one or two days, and the same can be said for Zoranilone. They chose a 14-day course, but there's no clear reason why a 14-day course is the requirement, and I think some of the research that needs to be done is to look at whether shorter courses of the medication can be used, which would benefit the patients in terms of exposures, but also in terms of cost. The other place that I think will be interesting, if Zoranilone becomes indicated for the treatment of major depression, is the use of these medications in the emergency room. I know that our emergency room is often full of patients for days and days on end, and being able to treat someone for a major depressive episode with a rapid onset of action that doesn't require an IV infusion will be really attractive, but we'll have to stay tuned on that and see if the FDA approves Zoranilone for the treatment of major depression. Is there a difference in onset of action for anxiety versus depression? That's a great question, and a little hard to say, because they only looked at day three, and by then there was already a response to both depression and anxiety, and it certainly paralleled each other, but they did not measure, for example, at 24 hours or day two, and so it looks right now like they parallel each other, but for all we know, anxiety symptoms could have evaporated within hours, but they did not look that early. If there are no more questions, then I can wrap up this session, so if you have another question, please type it now. Well, I want to thank you for attending today. I hope the information I've given you will help you in your practice as we start to learn how to use these new drugs. I hope you have some understanding of the GABAergic system and its role in the stress response and depression, and please stay tuned on my research. I hope that someday we'll be changing the standard of care from reacting and identifying postpartum depression to preventing postpartum depression, so thank you for coming very much. Have a good day.

reproductive psychiatry

CME credit

reproductive depression

hormonal changes

premenstrual dysphoric disorder

postpartum depression

GABAergic hypothesis

allopregnanolone

Brixenalone

epigenetic biomarkers

HP1BP3