Hello and welcome. I'm Dr. Rob Kotez, Director of the Clinical and Research Program for Psychosis at Gritty Health System and Associate Professor at Emory University School of Medicine. I'm so pleased that you're joining us for today's SMI Advisor webinar, Management of Psychiatric Disorders During and After Pregnancy. Next slide, please. SMI Advisor, also known as the Clinical Support System for Serious Mental Illness, is an APA and SAMHSA initiative devoted to helping clinicians implement evidence-based care for those living with serious mental illness. Working with experts from across the SMI clinician community, our interdisciplinary effort has been designed to help you get the answers you need to care for your patients. Next slide. Today's webinar has been designated for one AMA PRA Category 1 credit for Physicians, one Nursing Continuing Professional Development Contact Hour, one Continuing Pharmacy Education Hour, and credit for participating in today's webinar will be available until November 21, 2023. Slides from the presentation today are available to download in the webinar chat. Select the link to view. Captioning for today's presentation is also available. Click the 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. Please feel free to submit your questions throughout the presentation by typing them into the question area found at the lower portion of your control panel. We'll reserve 10 to 15 minutes at the end of the presentation for Q&A. Now I'd like to introduce you to the faculty for today's webinar, Dr. Jennifer L. Payne. Dr. Payne is Professor and Vice Chair of Research in the Department of Psychiatry and Neurobehavioral Sciences at the University of Virginia and directs the Reproductive Psychiatry Research Program, which studies psychiatric disorders triggered by times of hormonal change in women. Dr. Payne is a reproductive psychiatrist and her research has identified two epigenetic biomarkers of postpartum depression that are approximately 80% accurate in determining which women are at elevated risk. She and her colleagues are actively working on identifying the underlying biological basis of postpartum depression and other reproductive mood disorders. Her research interests include best management practices for psychiatric disorders in pregnancy, premenstrual dysphoric disorder, and perimenopausal depression. She is the current president of both the Marseilles of North America and International Marseilles Perinatal Mental Health Societies and serves on the Committee on Women's Mental Health for the American Psychiatric Association. Dr. Payne, thank you so much for leading today's webinar and I'll turn it over to you. Great. Thank you for having me. I really appreciate it. Well, welcome today and I'm looking forward to talking to you about management of psychiatric disorders in pregnancy. These are my disclosures. I'll pause for a sec. These are our learning objectives. I'm hoping that today, after listening to this lecture, that you'll be able to identify two risks of untreated depression during pregnancy, define the term confounding by indication, name two psychiatric medications that should not be used during pregnancy, and describe why they shouldn't be used. Then finally, explain the mechanism of action of the new FDA-approved medications for postpartum depression, including brixanilone and xeranilone. Here's an outline of what we'll be covering today. First, we're going to address why it's actually quite important to treat psychiatric illness during the perinatal time period and how it's important to both mother and the baby. Then we'll describe a general approach to designing a treatment strategy for pregnancy and lactation. We'll talk about safety data of psychiatric medication use and how many studies have been confounded by indication and we need to conduct more well-controlled studies. Then at the end, we'll talk about the new treatments for postpartum depression, brixanilone and xeranilone. First and foremost, why treat perinatal psychiatric illness? This is data really taken from the CDC as well as other countries that shows that the United States really has the highest maternal mortality rate amongst our peer nations. In the U.S., there are 17.4 maternal deaths per 100,000 live births in 2018 compared, for example, to 1.8 in Norway. Really, this is a pretty shocking statistic when you look at it in comparison to other countries around the world. This includes more recent data, including in 2021. What it shows is that the U.S. maternal mortality rate is increasing over time. It's increasing more so in the non-Hispanic black population compared to the white population. In general, the maternity mortality continues to increase in the United States. What most people don't realize is that the leading cause of maternal mortality is psychiatric in nature. It is either suicide or overdose deaths. You can see here that when we list out the conditions leading to maternal mortality, mental health conditions account for 22.7 percent of maternal mortality in the United States. This is a very important topic and really is a strong indication as to why we need to treat psychiatric conditions during and after pregnancy. We'll talk specifically about maternal suicide. It's actually a major cause of maternal death in pregnancy and accounts for up to 20 percent of all postpartum deaths. Now, I don't want you to get the wrong idea. Suicide is a rare event during pregnancy and, in general, is lower than in the general population. In general, psychiatric disorders are the leading cause of indirect maternal deaths in the perinatal period. There's, in general, a myth out there that women should really tolerate being depressed during pregnancy and postpartum for the sake of the baby. In order to have a pristine and clean pregnancy, women should stop their medications for pregnancy when the truth is that depression during and after pregnancy leads to poor outcomes not just for the mother but for the baby and the pregnancy itself. When mothers are depressed during pregnancy, there's a strong association with preterm birth, low birth weight, gestational diabetes, preeclampsia, and c-section. All of these pregnancy outcomes are associated with adverse long-term health outcomes for the exposed infants. If a baby is born with low birth weight or preterm birth, they have higher rates of, for example, cardiovascular disease when they're at age 40 and 50. These are not benign conditions that should be easily dismissed. Treating pregnancy-related depression is important for the pregnancy outcomes as well. In addition, postpartum depression is really the most common complication of childbirth. Depression during pregnancy increases the risk that the mother will be depressed during the postpartum time period. Large and robust studies have shown that postpartum depression has significant effects on the development of the exposed infant. Babies who are exposed to significant maternal depression in the postpartum time period have lower IQ and slower language development than infants who are not exposed to postpartum depression. In addition, they have higher rates of ADHD, more behavioral problems, and the later development of psychiatric illness. We think this is because the mother is not interacting normally with her infant. As you know, infancy is a period of rapid brain development and skill development. If an infant isn't stimulated in the right way, they are at a disadvantage to their peers who are stimulated in the right way. We think this is how the lower IQ and slower language development is associated with postpartum depression. In addition, when moms are depressed, they have a whole host of other behaviors that put their children at risk. They are more likely to smoke and use substances. They're more likely to use the emergency room for health care and less likely to talk to their babies, less likely to give their children vitamins or use car seats, and they're also less likely to get their kids vaccinated or go to checkups. The prevention of and treatment of postpartum depression is actually incredibly important for that exposed child. How do we think about designing a psychiatric medication management plan during pregnancy? This is kind of a general approach that I use when I see a woman who's either planning for pregnancy or is early in pregnancy, and we try to decide what medications to continue and what not to continue during pregnancy. First of all, there's a discussion, and preferably this discussion happens before a woman is pregnant, but it can take place early in pregnancy. A lot of people like to think about a risk-benefit discussion, and this is not a risk-benefit discussion. It is a risk-risk discussion. There's the risk associated with medication exposure and then the risks associated with untreated psychiatric illness, both for the mother as well as for the child, and so that's really what you want to compare in this discussion. Yes, taking Prozac during pregnancy is an exposure for the child, but being depressed during pregnancy is also an exposure for the child, and there may be greater risks associated with that in particular cases. This leads me to rule number one. You should assume that all women of reproductive age will get pregnant, and I actually talk about whether a medication I'm prescribing for a woman of childbearing age can be taken during pregnancy from the moment I prescribe it, unless a woman is really unable to comprehend that kind of conversation early in the course of her treatment. I do not recommend prescribing medication early in the course of her treatment. I think it's important to have those discussions because even today, 50% of pregnancies are unplanned in the United States. In addition, just because a woman is taking precautions and is using some form of birth control, women still get pregnant. One year of my clinical practice, I had a woman get pregnant another one get pregnant using birth control pills, and a third one get pregnant after her husband underwent a vasectomy, and it did not fully work. So just because a woman is using contraception, do not assume that she will not get pregnant. I think it's best to discuss potential complications for any pregnancy and what a woman would do if she accidentally got pregnant from the beginning and make it a part of regular psychiatric care. I also like to emphasize to my patients that the preference is to have a planned pregnancy regarding psychiatric medications, and that if we were going to make psychiatric medication changes, we would prefer to do that prior to the pregnancy. Rule number two is that you have to consider exposure to psychiatric illness in utero as an exposure for the baby, which leads us to rule number three, which is to limit the number of exposures for the baby, and that exposure to psychiatric illness counts. So the goal is really to keep mom well during pregnancy in order to eliminate that exposure. In addition, we try to maintain the mother on as few medications as possible, and we try to make medication changes before pregnancy and make sure that mom is stable before getting pregnant. Rule number four is to try to use medications that we have more data on, and in general, this may mean that older medications have more data. In addition, the epilepsy literature increases the sample sizes for the anti-seizure medications that we use commonly in psychiatry. In addition, a lot of people refer to the FDA categories, but they are actually being phased out because they are not as useful as they may seem on the surface of it. There is a nice source online called Reprotox that can give you up-to-date information on psychiatric medication use during pregnancy. These are the FDA categories, and I talk about them because they're still floating around out there, and you can Google them, and patients will often come in asking about category C versus B categories, and I think it's important to understand what the problems are with the FDA categories. So they range from A to X, with A meaning that they're well-controlled studies in pregnant women and that there's no increased risk of fetal abnormalities, to X, where there have been studies that show that there are fetal abnormalities with exposure to a particular medication or the use of the product is contraindicated in women who are or may become pregnant. The categories B, C, and D have increasing risk associated with them in human studies. However, part of what really confused people was category B, and I'll go to the next slide to show you this. Category B means that either animal studies have revealed no evidence of harm to the fetus, but there's no human data at all, or animal studies did show an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus. And because this, particularly category B, is kind of a combination of two different types of data, it's frequently misunderstood as being safer than category C or D. However, most new medications, when they first come out, have been tested in animals and there's no data in humans, and so they will frequently be classified as category B. And because we don't have data on them, we don't actually know if they're safer than category C or D. And this was really confusing, and this is the reason why they're being phased out. In addition, category X includes medications that a woman just wouldn't take during pregnancy, such as contraception. And I've had a couple of patients call me saying that they had gotten pregnant taking birth control pills, and they were concerned they needed to abort the pregnancy because the baby would be malformed. However, there's no evidence that birth control pills contribute to fetal abnormalities, and they're simply in category X because you would not take them during pregnancy. So as you can see, the FDA categories are quite confusing and really shouldn't be used to judge risk in a particular case. Instead, the FDA labeling system now is supposed to include a summary of the current literature on the safety of the use of that medication during the reproductive years. This brings me to rule number five, which is that every case is different, and in other words, there really are no rules. And by this I mean you have to really think carefully about each case as you're considering what to do during pregnancy. So a woman who's taking fluoxetine, for example, for premenstrual mood symptoms, it's a very different case than a woman taking fluoxetine because she was hospitalized several times and had two suicide attempts. And so you need to consider all the nuances of that particular case in front of you when you design a treatment plan. Rule number six is to make voluntary medication changes prior to pregnancy and make changes during pregnancy only if needed. In other words, if the woman becomes ill or there's a change in blood levels. And then finally, don't undertreat. There's a tendency for patients and their physicians alike to undertreat psychiatric illness in pregnancy. There's a sense of, oh, well, I won't increase my antidepressant because even though I'm having symptoms of depression, because I can just get through the pregnancy and that will decrease the exposure to the baby. In reality, you're increasing the exposure to the baby because the baby's being exposed to the medication that is inadequately dosed. And therefore, the baby's being exposed and therefore the baby's being exposed to active psychiatric illness in the mother. So that's two exposures instead of one. So it's important to treat to wellness during pregnancy. In addition, another common scenario is for a woman to become pregnant, maybe planned, maybe accidentally, and be on a newer medication. And the instinct in that setting is to switch the woman to an older medication that we have more data on. And that is the wrong instinct as well, unless she's on a medication that we know causes fetal malformations. Most psychiatric medications are not associated with major fetal abnormalities. And so switching to an older medication once a woman is pregnant increases the number of exposures for the baby. So the baby's exposed to the newer medication that mom was already on, is then exposed to the older medication that the woman is switched to, and is potentially exposed to psychiatric illness if mom fails the older medication and develops symptoms. So that's up to three exposures instead of one. So only make medication changes if you need to during pregnancy. And rule number seven, if there are blood levels available for a particular medication, monitor them. One of the studies that I've been working on and haven't finished yet, but one of the things that I often do in pregnancy, if a woman's taking Lamotrigine, I will get a blood level, preferably outside of pregnancy when she's doing well, so that we know that the blood level that keeps her mentally stable. And then I'll monitor that blood level during pregnancy. One of the things that happens with lamotrigine is that estrogen increases the metabolism of lamictal. So lamictal levels tend to decrease across the course of pregnancy. By monitoring that level, you can prophylactically increase lamotrigine if the blood level drops below the level that usually keeps the mother well. This is actually done in neurology for women with epilepsy. And I think we should be considering doing it for our patients who are taking lamotrigine for psychiatric reason. If you do increase a medication during pregnancy, you should consider decreasing it postpartum to limit the number of side effects that a woman might develop in the postpartum time period when her metabolism and blood volume return to normal. Rule number eight, it's a team sport. And I think of the psychiatrist as the quarterback. It's important as the mental health provider to talk to the other members of the team. Women with psychiatric disorders who are pregnant will often get very conflicting information from the different doctors and members of their team, whether that includes their partner, their mother-in-law, their sister, et cetera. I make an effort to talk to a woman's OB-GYN and explain what I'm doing during pregnancy, why I'm continuing certain medications, and why that's important. I also think it's helpful to meet with the patient and her family, with as many people who can be there, and explain the thinking of what we're doing medication-wise during pregnancy. That seems to really avoid a lot of drama and a lot of conflict. And what about unplanned pregnancies? Well, first of all, it's really important to not panic. And this is, again, a good reason to start having these conversations prior to pregnancy. If there are medications that the woman is on that you want to discontinue, you should taper those medications, preferably the way you would outside of pregnancy, to take her off of those medications. One example, I got a call from a woman one day that had been on six milligrams of Xanax, and she got unexpectedly pregnant, and her doctor would no longer prescribe any Xanax, even though she was out of the medication. And so I had her come in, and we planned a taper of the Xanax that was appropriate and safe for her. Again, also don't switch to an older medication, because the baby is already exposed to the newer medication, and that horse has left the barn. Don't close the door at that point. What about breastfeeding? Well, almost all psychiatric medications can be used during breastfeeding. Even those that should not be used during pregnancy can be used during breastfeeding. There are two exceptions to that rule, and the first is clozapine. I think clozapine is absolutely contraindicated during breastfeeding, because it really would require weekly blood draws from the infant, and I just don't think that's fair. Lithium has a bad reputation for use, both during pregnancy and breastfeeding, but babies are exposed to lithium if their mother is taking lithium during breastfeeding. But the blood levels in the infant are usually either non-detectable or extremely low. The main concern about breastfeeding while on lithium is that if a baby develops a dehydrating illness, the lithium level can creep up and become toxic fairly quickly in a small child. You do not want to allow women who are disorganized and not doing well from a psychiatric perspective to breastfeed on lithium. But if you have a mother who's organized and would have a low threshold for taking her baby to the emergency room in the setting of, say, a GI illness, I think it's appropriate to consider breastfeeding while using lithium. I've had a number of patients successfully breastfeed while using lithium, and I think in the appropriate patient population, it can be done quite well. Now, a lot of people get slightly obsessive about what medication to use during lactation, and they will look up which medications have a lower rate of getting into the breast milk. And that's fine if you're starting an antidepressant or another medication during lactation. However, if a mother has been taking a medication during pregnancy, I would not recommend switching to a lactant just for lactation. And the reason for that is that it increases the number of exposures for the baby, and the baby had a higher exposure in utero than they will get through the breast milk. So don't obsess about that. If you need to start a medication during pregnancy, it's reasonable to consider which ones have a lower rate of getting into breast milk. But don't do that as a matter of course. LactMed is a drugs and lactation database that's available online that has very helpful information along these same lines. So are psychiatric medications safe during pregnancy and lactation? And I'm going to focus on antidepressants here, because the most studies that we have have been done with antidepressants. I will summarize at the end kind of general recommendations for all different types of psychiatric medications in pregnancy. But I think the literature on the safety of antidepressant use in pregnancy is a very useful discussion in understanding how to design studies to determine if a medication is safe during pregnancy or not. So there are a number of problems with this literature, particularly the early literature. So a lot of studies don't control for the underlying psychiatric illness. And so babies whose mothers take a psychiatric medication during pregnancy may not just be exposed to that medication. They may be also exposed to the psychiatric illness symptoms themselves. And that exposure can cause problems for the pregnancy and for the baby. In addition, they don't tend to control for severity of psychiatric illness, and in particular risk factors that are found in a higher rate in the psychiatric population. So for example, the psychiatric population has higher rates of diabetes, smoking, substance use, obesity, and all of those other risk factors can influence pregnancy and infant outcomes. In addition, most studies don't control for whether the mother was psychiatrically ill and for the use of multiple medications. And women who take a psychiatric medication during pregnancy are more likely to take other types of medications during pregnancy. So this is confounding by indication. The idea behind this is that those who receive a particular medication or therapy are placed on the medication because it's clinically indicated, and therefore are more or less likely to develop an outcome on that basis alone. So for example, if you have a history of angina or chest pain, you're more likely to be put on a calcium channel blocker. And then it becomes somewhat unclear if you have a myocardial infarction, whether that was related to the original history of chest pain or related to the exposure of the calcium channel blockers. And this is really one of the most important limitations of evaluating treatments used in cohort studies. Now I put this other slide up because I think it's slightly funnier. So in the summer, there's an increased risk of shark attacks, and that has been associated with ice cream sales. But it's unlikely that those shark attacks are provoked by people eating ice cream. It's really more likely a confounding variable of there being a heat wave or it being summertime that those two things are associated. So I'd like you to think about the use of psychiatric medications during pregnancy is really a marker for a population of women who are different from the general population of women with attendant risk factors and behaviors that can affect birth outcomes. So studies which compare pregnant women with depression who are taking medications with pregnant women with depression who are not taking medications are controlling for the underlying confounding by indication psychiatric illness. And they are far less likely to find associations between antidepressant exposure, heart defects, persistent pulmonary hypertension, although there's one recent exception to that, and autism, for example. So I took a number of studies, this was several years ago, that looked at the risk of various outcomes with antidepressant exposures and had unadjusted odds ratios, and then went on to adjust for psychiatric illness, and some of which adjusted for severity of illness and other confounding behaviors. What you can see here is that in the unadjusted odds ratio, it looks like antidepressant and utero exposures associated with cardiac defects, preterm birth, persistent pulmonary hypertension, and autism. But when you adjust for the psychiatric illness, all of them except for preterm birth and persistent pulmonary hypertension become non-significant. And then when you adjust for severity of illness and other confounds, all of them except for preterm birth become non-significant. I will mention that there's one recent study that remains showing that there may be an association with persistent pulmonary hypertension, but that it's extremely rare. And there's also a study that found that exposure to maternal depression and pregnancy alone without exposure to antidepressants is associated with preterm birth. So I think we are stuck with preterm birth, but I think it's very reassuring that when we do well-controlled studies, many of these associations fall away. The other thing to know when you look at these studies is that the devil's really in the details. And there are a number of studies who have advertised a relative increase in risk rather than the absolute increase in risk. So a number of years ago, there was a headline that antidepressant exposure in utero increased the risk of autism by 87%. And when you read the paper, it was an absolute increase in risk of, I believe it was 0.5%. So it was a very small increase in absolute risk. And the example here is that if you don't drink caffeine, your chance of a heart attack is 1%. But if you drink caffeine, then you double or have 100% increase in risk when you look at it from a relative increase in risk. But the absolute increase in risk is only 1%. It's important to keep those details in mind. So here are some questions you can ask when you're reading the literature. What were the comparison groups? And did the authors control for confounding factors associated with psychiatric illness? How were the outcomes measured or defined? There's a study out there that looked at the risk of autism, but defined it as an evaluation for autism and found an increased risk for an evaluation for autism. And when they limited the study to actual diagnoses of autism, there was no finding. So you have to read those details. Was severity of psychiatric illness considered? Is the difference in outcome clinically meaningful? What's the change in absolute risk? What was the overall sample size? What was the sample size of the children with the outcome of interest? And was the study statistically corrected for multiple comparisons? So keeping those things in mind, you can be a little skeptical when you read particularly the older literature. Now what about the other psychiatric medication categories? I've listed a bunch here. In general, we really want to avoid valproic acid and carbamazepine use during pregnancy. When I see a woman of childbearing age and she's on valproic acid or carbamazepine, I try very hard to get them on a different regimen because eventually they either might become accidentally pregnant or might want to plan a pregnancy. And so I really try to avoid using them. I do use them in women of childbearing age when they have failed other classes of medications and I feel that I don't have a choice. Lithium has a bad reputation, I think in general, but it has a bad reputation for its use during pregnancy. And this is because there was a study early on that showed that there was an increased risk of Epstein's anomaly, which is a cardiac anomaly. But subsequent work has found that that risk is actually less than 1%. And in contrast, women who have bipolar 1 disorder who stopped their lithium for pregnancy, one study showed an 85% relapse rate and another showed a 100% relapse rate. So you can all guarantee that a woman will relapse with her bipolar disorder during pregnancy if she stops lithium for pregnancy. And the risk of Epstein's anomaly is actually quite small. So I do use lithium in appropriate cases during pregnancy. Lamotrigine and gabapentin are generally considered safe. We have fairly large sample sizes for those medications because they are anti-seizure medications and therefore have been used in the epilepsy population. We try to avoid the use of large amounts of benzodiazepines. And this is mainly because it can affect, particularly during delivery, the safe delivery of the infant and the infant can be born addicted to the benzodiazepines. And so we really try to use them more on a PRN basis or on a very small dose basis during pregnancy. Atypical antipsychotics don't have as much data as the antidepressant literature. And there are a couple of studies that have showed that exposure to atypical antipsychotics is associated with a mild developmental delay at six months that appears to have resolved by one year after delivery. It's important to note, however, that those studies did not control for confounding by indication. And so it's unclear if it's the exposure to the medication or the mother's serious mental illness. I used to have this slide and say I try to discontinue stimulants during pregnancy. However, there's growing evidence that stimulants can be used safely during pregnancy and they don't appear to be associated with major organ malformations. That being said, stimulants are often given in the setting of other psychiatric medications and they can be one of those medications that you try to eliminate for pregnancy. I think it's important to feel like you can use them. However, in particular situations, such as if a mother's trying to finish her degree or she's in a job that really requires focus and it's very important, or if she has a history of getting into car accidents when she does not use stimulants, I think those are all appropriate reasons to continue a stimulant during pregnancy. Buspirone is Category B because we really don't have any human data on it. That being said, because it's Category B, it's been used a fair amount during pregnancy. We just don't have great data on it because it's often prescribed in the setting of another medication. So I still use it during pregnancy in cases where women have clearly responded to it and do best when they're on it. This is just a little bit of data from a junior faculty of mine. What it shows is that we're probably under treating perinatal depression. On the bottom there, you can see this is data taken at second trimester, third trimester, two weeks postpartum, and six weeks postpartum. The number depressed are in the darker blue and the number that got a medication change at that particular study visit is the lighter blue. So what we're seeing is that even though women are meeting criteria for being depressed, they are not getting medication changes as often as you would expect. So these are the take-home points. Active psychiatric illness during pregnancy and postpartum is associated with poor outcomes for the infant. The literature on the safety of psychiatric medications during pregnancy is frequently poorly controlled and often confounded by indication. And you need to really look at the literature as a whole to determine the safety of medications during pregnancy and see what the patterns are. And at this point, I think the patterns are really showing us that most psychiatric medications can be used when appropriate during pregnancy and lactation. With a few exceptions, most psychiatric medications can be used safely during pregnancy. So keep in mind that we are probably undertreating psychiatric illness during pregnancy, which is really increasing the exposures for the unborn child. So I'll turn now to the last portion of the talk. I'll be talking about new treatments for postpartum depression, including brixaniline and xeraniline. So the FDA has approved two medications specifically for the indication of postpartum depression. The first was brixaniline in 2019, and the second one is xeraniline, which was literally just approved. Both of these drugs really act as synthetic allopregnanolone, which acts on the GABAergic system in the brain. And so why are we targeting the GABAergic system? Well, the GABAergic system controls the stress response. The GABAergic system is really the major inhibitory neurotransmitter system in the brain. And when the HPA axis gets activated and cortisol gets released, it's the neurotransmitter system that calms it down and decreases activation of the HPA axis. This is a nice picture of the GABAa receptor, which is where allopregnanolone and these drugs work. The GABAa receptor is a heteromer composed of five subunits. It's ligand gated, and there are multiple ligands that can act on the GABA receptor. So benzodiazepines and alcohol act on the GABA receptor, but at different sites than neuroactive steroids, including allopregnanolone. And ligand binding basically makes the receptor be more likely to respond to the GABA neurotransmitter, and GABA is inhibitory, leading to sedation calmness, and it's also anti-seizure. What happens during pregnancy is that there's an increase in progesterone and its metabolite, allopregnanolone, during the course of pregnancy, and then there's a precipitous drop at the time of delivery. And neurosteroids, including allopregnanolone, are potent modulators of the GABA A receptor. And so if, as allopregnanolone is increasing across the course of pregnancy, if the GABA A receptors were not downregulated, pregnant women would sleep through their entire pregnancy because they would be over-sedated from the increased dose of allopregnanolone that their body is producing. And so what happens is that there's a natural downregulation of the GABA A receptors in the brain. And then after delivery, hormones rapidly return to pre-pregnancy levels, but the GABA A receptors may take some time to recover in women susceptible to postpartum depression. I will tell you that this is a theory and has not been proven, but those of us in the field are working hard to see if we can prove it or if there's some other vulnerability. But we do think that whatever the vulnerability is, it's within the GABA system. And this is a nice picture of what I just described for you. You can see that progesterone and allopregnanolone levels rise during the course of pregnancy and then precipitously drop and return to pre-pregnancy levels. And here in pre-pregnancy, we have a lot of GABA A receptors. And then during pregnancy, they get downregulated and then they need to recover to pre-pregnancy levels for the whole system to work properly. And it may be that in some women who are susceptible to postpartum depression, those GABA A receptors don't fully recover back into the synapse. So this is a study of brexanolone. Brexanolone is a 60-hour or a three-day infusion. So it's given by IV, and it's a continuous infusion over the course of three days. And what you can see here is a very significant drop in those women who received different doses of brexanolone over the course of the first 24 hours. And by three days postpartum, there was a significant recovery and change from baseline Hamilton depression rating score. So the mean reduction in HamD score in the brexanolone group ranged from 12 to 14, which was significantly different. I'm sorry, it was 14 in the brexanolone group. And in the group that got placebo, it was 12, which was significantly different. And the proportion of participants receiving remission was much higher in the brexanolone group than in the placebo group. And what you can see here is that this significant difference was significant by 24 hours after starting the infusion. So it's a very rapidly acting drug. You give it for three days, and the effect lasts for at least 30 days and clinically longer. I wanted to show you this slide in particular because I think it's quite striking. There's about a 70% remission rate with the use of brexanolone compared to a 20% or less remission rate in those receiving placebo. In most regular antidepressant studies, such as the SSRIs, the remission rate is about 25 to 30%. So we're having a significantly higher rate of remission, a significantly higher rate of response. It acts very quickly and it lasts even when you're not taking the medication. What about safety and tolerability? Well, in general, brexanolone is pretty well tolerated. And the most frequent adverse events are really headache, dizziness, and being sleepy and sedated. But about 5% of the participants who got brexanolone had excessive sedation, including loss of consciousness. Now you can reverse that by immediately stopping the infusion. But because of this, the FDA required a risk evaluation and mitigation strategy program. And you have to really give brexanolone on a unit where there's nursing available 100% of the time. So these patients have to be on a pulse ox that is monitored and someone has to be available to stop the infusion if the patient becomes over sedated. So brexanolone has been classified as a class four controlled substance. So in general, with brexanolone, it's rapidly effective. It's generally well tolerated. And the most common side effect is being sedated. Both the response and remission rates were higher in brexanolone compared to placebo. And its new mechanism of action is exciting and opens a new avenue to explore in the treatment of both major depression and postpartum depression. And it has a sustained response for at least 30 days after infusion. Now let's talk about xeranolone. If you're looking for the literature, it's known in the literature as SAGE 217. It has a similar mechanism of action to brexanolone and is also a positive allosteric modulator of the GABA A receptor. But it's an oral agent and it's suitable for once a day dosing. It's being studied in major depression and the FDA has approved it for the treatment of postpartum depression. They've looked at both 30 and 50 milligrams. And in all studies to date, xeranolone is given once a day, generally in the evening for 14 days and then stopped. And here's the data showing that there's a significant difference by day three. There's a clear, stronger decrease in symptomatology by day three of the oral agent. They met their primary endpoint in this particular study, which was at day 15, which is the day they stopped taking the medication. And that there was a sustained recovery for up to 45 days after starting the agent. The primary endpoint was met with a 17-point reduction in the xeranolone treated group versus a 13-point drop in the placebo group. The sustained difference in the two groups was observable and statistically significant at day three. And one patient per group experienced a serious adverse event. It was a confusional state in xeranolone and pancreatitis in the placebo group. And then one participant in the xeranolone group discontinued treatment and there were none discontinuing in the placebo group. This is the response and remission rates. And again, you can see a very high response rate in the xeranolone group where close to 80% by the end of this study were responding. There's a slightly lower remission rate, but still quite a significant difference than what we tend to see in more typical antidepressant treatments. So in summary, it's rapidly effective in the treatment of postpartum depression and was generally well tolerated. Both the response and the remission rates were higher in the xeranolone treated groups. And they met their primary endpoint at day 15. Their new mechanism of action is quite exciting. And it's not only rapidly acting, but has a sustained response for at least 45 days after initiation of treatment. And we think it may be available in late November or December of 2023. So a lot of people have asked my opinion on this. You know, when should we use brexanolone? When should we use classic antidepressants? And when should we use xeranolone? And I think this will evolve over time. And the insurance coverage and cost will likely play a role in clinical decision making. SAGE has a history of working well with insurance companies, so I'm expecting that that will be the case with xeranolone. But it's still unclear when we should use it. But it's still unclear how expensive it will be. I think that we will use brexanolone for inpatients, the women who are severely depressed in the postpartum time period, or who really want rapid relief and really just have a few days to get better. So I still think that there's a place for brexanolone. I think that the use of xeranolone is most obvious for the first episode of postpartum depression or when there is not a history of significant recurrent major depression. If a woman has a history of recurrent major depression and has responded to classic antidepressants, though, I think there's still going to be a role for using those classic antidepressants. Some of the patients that participated in the studies used classic antidepressants and also had a trial of xeranolone. So I think we'll see a combination approach for a lot of women. And this is my bibliography. And I want to thank you for listening and I will look forward to your questions. Dr. Payne, thank you so much. That was really, really wonderful. I know I learned a lot from listening to your talk. Before we shift into the Q&A, I just wanted to take a moment to let you know, everyone in the audience, that SMI Advisor is available from your mobile device. Use the SMI Advisor app to access resources, education, and upcoming events, complete mental health rating scales, and even submit questions directly to our team of SMI experts. Download this app now at smiadvisor.org. All right. So let's go ahead and get into the Q&A. We've got a couple questions from the audience. One question I was curious about is, and we've gotten some of these questions in our consultation system, when you think about antipsychotic medications in pregnancy, how do you think about the risk of an oral agent versus the same thing that's a long-acting injectable antipsychotic medication? That's a great question. I think people have different levels of comfort. In general, the way I approach it is if a woman is stable on a long-acting injectable prior to pregnancy, I would continue that during pregnancy. But if I'm starting a woman on an atypical antipsychotic during pregnancy, I'm going to favor using an oral agent, probably through pregnancy, simply because we don't know what her response might be to a long-acting injectable. And you can have complications when you jump to that fairly quickly. So I also think women who are pregnant are a little bit more, mental health providers will often keep a closer eye on them. And so it's a time where you can continue to use an oral agent a little bit easier during pregnancy. Great. Thank you. That's very helpful. Another question that kind of came up, I really appreciated one of the suggestions that you made about if a medication, you can get a level for it, consider getting a level for it for individuals that are pregnant. I'm wondering if you could talk a little bit more about sort of the psychopharmacology psychopharmacology and kinetics, that kinetic changes that one might expect during pregnancy. I thought the Lamotrigine example was very helpful, but are the other sort of in general pharmacokinetic changes come up or sort of specific medications we should be thinking about that might have a significantly changed level? So they really come up for all medications. So during pregnancy, there can be changes in how women metabolize medications and the liver becomes kind of revved up, the kidneys become revved up and clear medications a bit faster. In addition, a woman's blood actually doubles during the course of pregnancy. And so a particular level in the first trimester is probably going to be lower in the third trimester. So I always counsel people to keep an eye on pregnant patients in that third trimester because some of them will relapse even though they're continuing their medication. So about a third of women will relapse during pregnancy, even if they continue their psychiatric medications. And that is probably because they're either metabolizing that drug differently or because their blood level has dropped. And so I think it's important to keep that in mind that the dynamic changes that happen during pregnancy are probably affecting how that woman is metabolizing her medication or the blood level itself. And you should have a low threshold for saying, you know, you're getting depressed again, let's go ahead and increase your antidepressant. But then in the postpartum time period, you want to consider decreasing it back down. Okay, excellent. Thank you. Another question I have is, you know, from sort of a public health standpoint, what is the best way to engage women in the postpartum period to kind of ensure that we're even able to kind of screen effectively for postpartum depression? And then sort of as a follow up to that, are there sort of specific questions that you like to ask in terms of screening for postpartum depression? So were you asking from like a policy perspective or from like a clinical practical perspective? Both. I think that the first question is really about like how as a system can we engage women in the postpartum period to make sure that people kind of if they do experience depression, how do we reach them? How do we make sure they don't fall through the cracks? And then number two, clinically, how do we best really screen for postpartum depression when we're seeing someone? So I'll give you three different answers for those two different questions. So from a policy perspective, extending Medicaid coverage through a year postpartum is the best way we can identify women who are depressed and get them treated. So making sure that mom has insurance when she walks out of the hospital with a new baby is a policy that I, you know, I wish all states would engage in. In terms of screening, we typically recommend kind of a standardized screening questionnaire. So there's the Edinburgh postnatal depression scale that's used both during pregnancy and postpartum that's pretty specific to this population that doesn't count certain things that change with pregnancy. So changes in weight, for example, are not heavily weighed in the Edinburgh. There's also the patient health questionnaire, PHQ-9 is often used in healthcare systems. The problem with those screening scales is that A, they have to be done and B, mom has to be honest. And a lot of women with perinatal depression are highly ashamed of how they are feeling and will not be honest. In addition, if they're from a minoritized population, they may be even more concerned about revealing what's going on with them to the doctors. So I think screening scales absolutely have their place. From a research perspective, I'm working on a blood test that can be done during pregnancy and is predictive of who's at elevated risk and who likely isn't. It's not 100%, but it's about 80% accurate. And I think that will take the screening scales out of the problem that many women face about being honest about what's happening with them. So stay tuned for that. That may be the future. But for right now, I think our screening scales are probably the best. From a clinical perspective, though, asking about a personal or family history of mood disorders, and that includes major depression, postpartum depression, and bipolar disorder is probably the single best question you can ask to see if a woman's at elevated risk. Thank you, Dr. Payne. Very, very interesting. Really looking forward to hearing more about the blood-based biomarkers. And unfortunately, we don't have any more time for questions. I had a lot more questions for you about ketamine and escetamine and ECT and clozapine and stuff, but we probably have to finish up now. So why don't we go to the outro? So if you have additional questions that weren't covered in this webinar and you'd like to discuss them with colleagues in the mental health field, post a question or comment on SMI Advisors Discussion Board. This is an easy way to network and share ideas with other clinicians who also participate in this webinar. If you have questions about this webinar or any other topic related to evidence-based care for SMI, you can get an answer within one business day from one of our SMI Advisors National Experts on SMI. This service is available to all mental health clinicians, peer support specialists, administrators, and anyone else in the mental health field who works with individuals who have SMI. It's completely free and confidential. All right, next slide. SMI Advisor offers more evidence-based guidance on prescribing antipsychotic medications to pregnant women, such as on long-acting injectable antipsychotic used during pregnancy. This resource goes over different considerations to think of when prescribing an LAI to someone who is pregnant. Access this resource by clicking on the link in the chat or by downloading the slides. To claim credit for participating in today's webinar, you need to have met the requisite attendance threshold for your profession. After the webinar ends, please click continue to complete the program evaluation. The system then verifies your attendance for credit claim. This might take up to about an hour and can vary based on your local, regional, and national web traffic and the use of the Zoom platform. And finally, we'd love to see you next week on September 28th as Dr. Deb Pinos presents Supporting Justice-Involved Individuals with SMI from Arrest to Recovery. Again, this free webinar will be September 28th from 3 to 4 p.m. on Thursday. Thanks so much again for joining us and until next time, take care everybody.

psychiatric disorders

pregnancy

perinatal period

depression

treatment strategy

medication exposure

safety data

postpartum depression

FDA-approved medications

individualized treatment plans