Hello and welcome. I'm Dr. Megan Ehret, Professor of Pharmacy Sciences and Health Outcomes Research at the University of Maryland School of Pharmacy. I'm pleased you're joining us today for today's SMI Advisor webinar, Psychiatric Medications in 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, please. Today's webinar has been designated for one AMA PRA Category 1 credit for Physicians and one Nursing Continuing Professional Development Psychopharmacology Hour. Credit for today's webinar and participating in the webinar will be available until March 28th, 2023. Next slide, please. Slides from the presentation today are available now in the handout area found in the lower portion of your control plan. Please select the link to download the PDF of the slides. Next slide, please. Please feel free to submit your questions throughout the presentation by typing them into the question area found in the lower portion of the control panel. We'll reserve 10 to 15 minutes at the end of the presentation for any questions and answers that should come up. Next slide. Now I'd like to introduce you to today's faculty for the webinar, Dr. Tawni Smith. Tawni is a board-certified psychiatric pharmacist who serves as an associate professor in the Department of Psychiatry and Behavioral Sciences at Dell Medical School and has an additional appointment in the University of Texas at Austin College of Pharmacy. She has outpatient practices at UT Health, Austin Women's Reproductive Mental Health Clinic, and she serves as a psychopharmacology consultant at the Mulva Clinic in Neurosciences. She also practices at Ascension-Seton Shoal Creek Hospital in Austin, where she is the director of the Psychopharmacology Consult Service. We are so pleased to have Dr. Smith with us today to present this webinar. Thank you, Dr. Smith, for leading the webinar, and I will now turn the slides over to you. Thank you for that kind introduction, Dr. Ehret. I am so excited to be here today to talk to you about the use of psychiatric medications in pregnancy. I have no financial conflicts of interest to report, but will be discussing off-label use of medications since there are no current psychotropic medications that have an FDA indication for use in pregnancy. Here are the learning objectives for the talk today. In the first part of the session, I'm going to briefly discuss the risks of serious mental illness during pregnancy, and then I'm going to move into the risks of psychotropic medication use. Specifically today, I'll focus on antidepressants, mood stabilizers, and antipsychotics. I'm going to try to emphasize newly available data versus rehashing some older data, unless it's appropriate. For the last section, I'm going to shift gears a little bit, and we're going to talk about the physiologic changes that women experience during pregnancy and how some of these changes may impact the pharmacokinetics of our psychotropic medications. When I'm first talking to my patients about the use of psychotropics in pregnancy, this discussion often starts along the lines of, no decision is risk-free. There are risks that are associated with untreated illness, and then there's risks associated with the medication use in pregnancy. Really, what my job is, is to walk through a discussion about what is known or even uncertain about each of these risks to help women make an informed choice for themselves. There's no one-size-fits-all approach, and it's really important to individualize the discussion to specific characteristics of the woman. The last thing is also to make sure that there's coordination with the care team. This is really important that the entire care team is on the same page. These are decisions that can be challenging, sometimes stressful for the mom-to-be. Because of this, we really want to try to avoid mixed messaging about treatment decisions or choices. When weighing the risks, I often hear this approached as a risk-benefit analysis, but I think of it more as a risk-risk analysis. What are the risks of untreated illness, not only to mom and how this may impact the child and the family? In a couple slides, I'll talk about what untreated illness looks like from an epidemiologic lens, but we also have to look at the patient's own history as we're making these decisions. Patients with frequent episodes of psychiatric illness, declining course, maybe they're coming to you and not stable currently, or if they have a previous history of perinatal illness, these are individuals that are going to be much more likely to become ill during the current perinatal period. Now, we're weighing that against the risks of in utero exposure to the medications. We're going to look at things like tritogenicity risk, obstetric complications, fetal and neonatal complications, and what the long-term effects that may be associated with that in utero exposure. When I begin this risk discussion with women, many do not appreciate that that baseline risk is actually not zero. In fact, the rate for birth defects in the United States is collectively between 2% to 4%. You will now find this fact in the labeling of all medications with the newish FDA pregnancy labeling rule. It's been around for a little while, I guess, at this point. We have to be aware that things like smoking, alcohol use, obesity, and controlled diabetes, they will elevate these risks. I highlight these things specifically because these may be factors that are more commonly seen in our SMI population. Our preterm birth rate for the United States is a little over 10%, but you'll see a lot of variability depending on the state that a woman lives in, or even a county within that state. Lastly, the rate of miscarriage for detective pregnancies, meaning a woman knows she's pregnant, is roughly 15% to 20%, with some estimating up to 50% if we include those pregnancies where fertilization has occurred, but hasn't been detected. Roughly one in five women experience mental illness in pregnancy collectively, making them one of the more common issues facing pregnant women. This is more common than gestational diabetes or preeclampsia, but yet these receive a lot of focus and screening and intervention. When we're talking about the risks associated with SMI in pregnancy, we have more information about the impact of depression than what we have for mania or psychosis. Even though depression is better studied, the obstetric and neonatal risks are ever evolving. There's not always a consistency in what's reported, and so sometimes it's hard to parse through some of that information. Part of that difficulty is that it's challenging to disentangle the effects of illness and confounding variables from the effects of treatment. In the left-hand side of the slide, we talk about the cohort studies, and importantly, this includes both treated and untreated women with SMI. What studies have shown in this case is that there are reported higher rates of preterm delivery, low birth weight, miscarriages, and intrauterine growth restriction. Additionally, women with bipolar disorder and schizophrenia are more likely to have C-section deliveries, and these two diagnoses have also been associated with congenital malformations. Specifically, in schizophrenia, there are reports of higher rates of congenital malformations, specifically cardiac malformations, and it's interesting in that that risk is reported even when the diagnosis of schizophrenia comes after the birth, suggesting that it's related to the disease itself. Additionally, when we dig into the literature looking at antipsychotic use for the indication of nausea in pregnancy, we don't see that increased risk of congenital malformations, so again, suggesting that it's an illness effect and not necessarily a medication effect. We have some concerns for the mother with untreated or undertreated illness in regards to self-care and adherence to obstetric care, so things like attending their prenatal visits or taking prenatal vitamins. We also worry about the increased use of substances, and this can be tobacco, alcohol, or illicit substances. Mental health is one of the leading causes of pregnancy-related death, and I think it's something that's not always appreciated. There was a recent CDC committee that concluded that 100% of mental health deaths are preventable. Now, there was a point in time where pregnancy was seen as this protective period in regards to mental illness, but there really has been no evidence to indicate that pregnancy offers this protection. It's also not necessarily seen as being this higher-risk period per se, but there is considerable evidence that the postpartum period entails a heightened vulnerability, so sometimes even if a medication is discontinued prior to pregnancy or in the first trimester, it is really important to discuss the risks of untreated illness in the postpartum and have a discussion about when it might be appropriate to reintroduce the medication. In an ideal world, we're having these risk discussions with women as a part of a pre-pregnancy consultation or even at the time that the medication is prescribed. However, because greater than 50% of pregnancies are unplanned, a rate that's thought to be even higher in our patients with schizophrenia, we're often faced with the question of what happens if I stop the medication. When it comes to depression, we have studies reporting findings on both sides, so some with worse outcomes and some showing no difference, but notably, the FDA Pregnancy Labeling for Antidepressants discusses the 2007 VIGERA study, which demonstrated an elevated risk of depression recurrence in women who discontinued their antidepressant. What is a more consistent finding, so regardless of the study, is that those with more severe illness and recurrent illness are going to be at higher risk of recurrence during pregnancy. This is where knowing the mom's history can be really helpful in thinking about the particular risk of recurrence for that individual mom, and so when we're trying to make that decision about whether or not to continue medications. In regards to risks of discontinuing mood-stabilizing medications, there's less data in general, but what we have suggests a two-fold increase in risk of recurrence, most frequently depression, especially if the medication is stopped suddenly or tapered off over a period of less than two weeks, and when recurrence does occur, it happens sooner, and women will spend more time ill during pregnancy, and also that higher risk of postpartum relapse that we talked about before. I will say that one limitation to this data is that it's primarily based on the use of lithium as a mood stabilizer during pregnancy, and so those, it's not known if those risks are the same with other mood-stabilizing medications. Again, we have less information about the risk of discontinuing antipsychotic medications during pregnancy, but if we're assuming that pregnancy is not protective of a relapse, we know that discontinuing antipsychotics is a significant risk factor for relapse and schizophrenia. We have data that suggests that women with schizophrenia who become pregnant discontinue their medication at high rates, especially in the first trimester, and this has been linked with an almost two-fold increase in risk for relapse. Because the risk of recurrence in our SMI population, if I have a mom who chooses to stop or taper off her medication, we will discuss their contingency plan, should the illness return during pregnancy, because that risk is likely elevated. This plan can always be adjusted, and they aren't committed to following this plan, but I frame it in a way that it's better to have these conversations during times of stability than when in the middle of an exacerbation and possibly in crisis. In this next section, we're going to transition to talking about risks associated with medications. While this is a vastly growing body of evidence, there are a lot of limitations and challenges that we run into when we're trying to study reproductive safety of psychotropics. This is just something that I want you to keep in mind as we discuss each of the classes of medications. First, we rely almost exclusively on observational trials, and this is due to the ethical concerns about enrolling a pregnant woman in a randomized controlled trial. Often while a potential risk for a specific congenital malformation may be elevated, that absolute risk can still be low. We're going to see that pretty universally, although not with all of them, but we're going to see that pattern with the medications that we're discussing today. What this means is that you need really large databases in order to detect these effects, so the ends in these studies of exposure have to be really high in order to detect any kind of congenital malformation. For many of the U.S. registry trials, we're really looking at pretty small numbers, often less than 1,000 exposures, and so we have to be cautious about overselling safety data if it's something that isn't detected. The use of the databases has limitations as well, and mostly this is in the form of not being able to control for known confounding variables. As we begin to examine the potential for a medication to be teratogenic or to cause complications, there are a lot of different factors that can influence outcomes, such as the dose of the medication or how long it's been taken. Of course, the physical properties of the drug determine how much crosses the blood placenta barrier. General rule of thumb is those physical and chemical properties that allow the drug to transfer across the blood-brain barrier are the same ones that allow the blood placenta transfer, so we can assume that psychotropics that cross the blood-brain barrier are going to cross the blood placenta barrier, although they do so in varying amounts. And then lastly, of course, the timing of exposure is going to determine different risks. Often women aren't aware that they are pregnant until four to six weeks after conception, possibly even longer. This brings them halfway through their first trimester, which we think of as the greatest period of vulnerability as far as the developing fetus. For instance, if one of our concerns is in regards to cardiac malformation, the highest risk period for this is through week six. That risk does extend to week nine, but up to week six being the highest risk period. If we are already past week nine, we are past that risk window, so exposure has already happened if a woman is on a medication, and that has to go into our decision-making. If cardiac defects are one of the things that we're worried about and we're already past that window, then we have to talk about what are those things that we might be worried about with continued use or discontinuing. In general, we have much less information about those behavioral and functional outcomes that occur with those later exposures. In our current healthcare system in the US, it's incredibly challenging to follow women and children over time to track these specific areas. Also, the mental health, both of the mother and the father, as well as home environment after birth, can be confounding factors when we're trying to interpret some of those long-term data. Now, the SSRIs are by far the most studied psychotropic medication. There's a plethora of data with the SSRIs, but even with that, you'll see varying reports with that. But at this point in time, we do not consider them to be major teratogens with first-trimester exposure. But as I alluded to, depending on the city that you review, you can see varying reports of risk for congenital malformations, but I think importantly, there's not been a consistent pattern with specific agents, which, for me, provides a little bit of reassurance. As you're likely aware, with the older pregnancy labeling, paroxetine was given a Category D as far as its pregnancy classification, and this was due to the risk of cardiac defects. However, there have been several studies since those earlier reports that have not found the same association, so it's really still up for debate as to whether paroxetine is linked to a higher risk of cardiac defects. The labeling of SSRIs does discuss the persistent pulmonary hypertension of the newborn with third trimester exposure. This is a risk I will discuss with patients, but this too has not been reported in all studies. With those studies, not finding an association after correcting for confounding variables like c-section delivery or smoking status, which are both known risk factors for PPHN. And so some of those other studies are criticized for not correcting for those confounding variables. If the risk does exist, that absolute risk is very small, so less than 1%. And this is in comparison to 0.1 to 0.2% in the general population. One of the things that has been a little bit more consistent of a finding is the risk of poor neonatal adaptation with roughly a quarter to a third of infants exposed to SSRIs experiencing this. The symptoms are typically transient and self-limited and generally not dangerous. However, if you put yourself in the shoes of mom and families that might be going through this with their newborn, and especially if this results in a NICU stay, even if it's just being precautionary, this can be scary for them. So it's important that we discuss this risk with women so that they are aware that this is a possibility. Older publications recommended tapering the SSRI in the third trimester to reduce this risk, but when this practice was actually studied, what was discovered is that the risk of PNAS did not change and only left women at an elevated risk of postpartum illness because now their depression was no longer being treated. So this is not something that we do in our practice and is not generally recommended in the community at large. Regarding neurobehavioral outcomes, again, as I had talked about earlier, this is a more challenging part to study, but the data that we do have are encouraging any developmental delays that are seen early on in some studies show a catching up, which is reassuring. And then regarding the behavioral issues, children of moms with depression show an elevated behavior, show elevated behavioral issues, so it may have to do more with genetics and environment versus in utero exposure. And then of late, I'm sure that many of you have seen either in the lay press or even in published articles about a potential link with autism and SSRI exposure, and there was an earlier study that found this association, but when you look at studies that take sibling analyses or include sibling analyses or paternal mental health into consideration, there does not seem to be an association. And so while I may talk with patients about this being a potential risk, it's not something that I'm as concerned about with more recent data. We have a lot less data with SNRIs with really only data available with venlafaxine and duloxetine. The limited data that we do have are reassuring. Neither agent is thought to be a major teratogen. We have some of the same concerns that we have with SSRIs regarding the PPHN and PNAS, since there's that shared mechanism of action of serotonin reuptake inhibition. But one of the things that's unique to the SNRIs is the concern about an elevated risk of gestational hypertension, and specifically when it's used in the second half of pregnancy. Now, the report is with venlafaxine specifically, but it's kind of extrapolated, I guess, across the the class of SNRIs. And not surprisingly, in the study that showed this with venlafaxine, the higher doses elevated that risk. So as you increase the dose, the risk of gestational hypertension increased. So not dissimilar to what we see as far as risk within the dose relationship in non-pregnant patients. We know even less regarding the rest of the antidepressants. Here, I've kind of classified them as the atypical antidepressants, bupropion, mirtazapine, trazodone, nifazodone, don't appear to be major teratogens. But again, the data are pretty limited. We do not have any data for the newest agents of bilazodone and borteoxetine. So before moving on to the next section, I wanted to kind of summarize a little bit. So continued use of an antidepressant may be required during pregnancy, especially in women who have recurrent depression or a history of more severe depression. And so in these women, we may be more strongly considering the use of antidepressants in pregnancy. With the currently available data, even with all its limitations, the SSRIs, the SNRIs, and the atypical antidepressants don't appear to be major teratogens. There is some concern about that PPHN with third trimester exposure, but that absolute risk is pretty small. And then we do worry about the PNAS with roughly a quarter to a third of infants that are exposed to antidepressants in utero experiencing this phenomenon. So next, I'm going to move into discussing our traditional mood stabilizers. I'll start off with our gold standard, lithium. I'm guessing you are probably familiar with the concerns about cardiac malformation, specifically Epstein's anomaly with first trimester exposure. I do want to highlight that that absolute risk is much smaller than was once thought with those earlier registry studies, and that the risk is probably closer to like a 1 in 1,000. It is recommended to get a high-resolution ultrasound and fetal echo between weeks 18 and 20 to assess for those potential cardiac defects. As far as other adverse outcomes, we actually have pretty limited data, even though lithium has been around for a really long time. And most of the information that we have is derived from case reports, and so the exact prevalence of these things is not known. But you will see things like floppy baby, tremor, transient hypothyroidism, diabetes insipidus, that have all been reported with lithium exposure in utero. And lamotrigine is considered one of the preferred agents both for bipolar and epilepsy during pregnancy because of its low risk for major malformations. There was one early study that reported an increased rate of cleft palate, but we've had five subsequent ones that have not found the same association. And so it appears that this is probably something that we're likely not having to worry about. Regarding neurodevelopmental outcomes, there have been several recent studies published that provide us with reassuring data and also kind of add to that the reasons that we might consider the use of lamotrigine, continued use of lamotrigine in pregnancy. Now on the other side of the spectrum, we have our friend valproic acid, which is the most hereditary medication in psychiatry. And because of the significance of the risks, it's really a medication we should be avoiding in women of childbearing age, if at all possible. And really thinking of it more as a medication of last resort, so meaning we've exhausted other options. We're not only concerned about cardiac and neural tube defects with first trimester exposure, but also with its association with adverse neurodevelopmental outcomes. And this includes a reduction in IQ, developmental delays, and also an increased risk of autism and ADHD. Because of these risks, we do recommend high-dose folic acid supplementation during pregnancy, if the VPA may be used, must be used, and if at all possible, using doses less than one gram. Like VPA, we're also concerned about neural tube defects with carbamazepine, although to a lesser extent. On the other hand, oxcarbamazepine does not appear to be associated with major malformations, but the data are fairly limited. There was a recently published study that found an association with the use of both of these medications and increased risk of intellectual disability. And there was another study that had looked only at carbamazepine, and they reported that in utero exposure was associated with poor academic performance. So carbamazepine is probably another one of those medications that we should be avoiding during pregnancy, or even in women of childbearing age, if possible. If we do need to use either of these agents in pregnancy, again, the high-dose folic acid is recommended. The last group of medications that I'll talk about today are the antipsychotics. Overall, our first-generation antipsychotics, and then quetiapine, olanzapine, risperidone, and aripiprazole do not appear to be major teratogens. You will see a recent study with risperidone and then one olanzapine that have been associated with a small elevated risk of malformations in one study each. They were different studies. But this has not been reported in other studies. So at least at this point in time, we are not considering them major teratogens. We do have concerns about elevating the risk of gestational diabetes with our more metabolically concerning medications. So this here, we're talking about olanzapine, quetiapine, clozapine. But this being said, there's not been a consistent finding in the data, but it's certainly something we want to be cognizant of and monitor appropriately. All antipsychotics have a warning in the labeling about concern for EPS and withdrawal symptoms. There was a study that was published in the last few months that reported rates of a poor neonatal adaptation of around 30% with the SGAs, or second-generation antipsychotics, which if you remember was a rate that was very similar to that of our SSRIs. And even from a symptom standpoint, it looked very similar. In general, when we look at the long-term studies, which is quite limited with the antipsychotics, but with the information that we have, and there was a study that came out recently, another recent study, and that did not see an association with neurodevelopmental disorders. The exception to that being one of those recent studies did see a very small but statistically significant increased risk with aripiprazole that wasn't seen with the other SGAs that were included in the study. I will say though, the authors do warn that these findings need to be replicated before we abandon the use of aripiprazole in pregnancy. So there's likely more to come here, but this is, and this has not really shifted how we use aripiprazole in our pregnant patients. But again, this will be something to watch for in in future studies. Lastly, I'm often asked about the use of LAIs in pregnancy. In general, it's not recommended for all patients, but we have certainly had patients that we've used them in. It's typically been in patients who have a strong pattern of being non-adherent with medications that has led them to a psychiatric hospitalization during pregnancy, and that's generally when we're considering the LAI. So in summary, for many of our SMI population, discontinuing medications or having unstable illness during pregnancy is going to come with risks of relapse or recurrence, and we are wanting, often wanting symptoms to remain stable during pregnancy to reduce that risk of instability throughout pregnancy or in that high-risk postpartum period. This means for many of our patients, we have to think about starting or the continued use of medications throughout pregnancy. Of course, if this is a new onset mental illness, we're going to go with a medication that has the most safety data, but in women with recurrent illness, the medication we want to use is the one that works. This means that we may be continuing a medication with little to no data about its safety in pregnancy, and really what we're trying to do is avoid multiple medication trials because if we switch to the quote-unquote safer option that turns out to not be effective and have to return to their original agent, we are now looking at two medication exposures as well as an exposure to an undertreated illness. We should probably always be optimizing non-pharmacologic interventions regardless of pregnancy status, but we want to especially do this in pregnancy, and this means encouraging therapy if they're not already engaged in it. I want to take a second to highlight that women with schizophrenia are more likely to be the victim of violence, including domestic abuse, and so they may benefit from more wraparound services and support throughout that perinatal period. In general, we want to use the lowest effective dose, and so if we're implementing those non-pharmacologic interventions, that hopefully allows us to be more successful at doing that as a goal, and then also avoiding polypharmacy if we can, and most importantly, we really need to take that patient-centered approach. It's a collaborative decision. My job is to help guide those decisions, and I will tell patients that specifically that ultimately this is their choice, that using the medications in pregnancy is voluntary, and women can choose to change their mind about medications at any time. Now, of course, the complication of using psychotropics in pregnancy doesn't just stop with the risk-risk discussion, and as you may be aware, and as you can see in this table, there are a lot, a lot of physiologic changes that occur during pregnancy, and these changes could impact pharmacokinetic parameters of medications. While many of these physiologic changes are fairly well established, the impact these changes have on specific medication disposition during pregnancy is not as well studied. As you can imagine, though, if we change how we absorb, distribute, metabolize, or excrete medications, that's going to impact things like area under the curve, and the maximum concentration, or even a half-life of a medication, so that right drug dose for a woman prior to conception may not necessarily be the right dosing strategy during pregnancy. I think this picture is really helpful to visually highlight the physiologic changes that we can see in pregnancy and how it changes by trimester. One of the big changes we see here in the lower left-hand corner is that change in kidney function, with both an increase in blood flow to the kidneys as well as the GFR. You can see here that it peaks in the second trimester and then dips back down a little bit in the third trimester. This becomes important for a medication like lithium that goes exclusively through the kidneys. This was a study conducted by a West Saloon colleagues. It was looking at lithium levels and serum creatinine throughout pregnancy and how much of a change in the levels that we can see. You can see that as the serum creatinine decreases, so does the expected lithium levels. Now, lithium has what we call a narrow therapeutic window. If we're looking at a decrease of a level by 36%, that certainly could result in a sub-therapeutic level. Again, you can see that little increase in the third trimester and then importantly, a return to normal in the postpartum. This leads us to the recommendation that we monitor lithium levels more closely in pregnancy. Outside of pregnancy, we're typically getting levels every three to six months, but it is recommended to get them monthly during pregnancy. At week 36, begin to get them every week. Because of the volume loss and risk of dehydration during labor and delivery, there are some experts that recommend holding the lithium 24 to 48 hours before a scheduled C-section or induction, or to hold it at the onset of labor. Then, get a level 24 hours after delivery and restart the lithium once a level falls below the therapeutic range. Part of this recommendation came from a 2004 study that reported worse neonatal outcomes with higher lithium levels at delivery. I will say though, this is not a consistent recommendation across experts. I'll present a study on the next slide that provides some different recommendations. One of the other things I want to highlight from this slide is that even though we will frequently do once a daily dosing with lithium in a non-pregnant patient, it is recommended to split the dose to two to three times daily dosing. I think two times a day is more reasonable. Then, also to use extender release lithium. If you had someone who was previously on the immediate release, consider switching them over to the extender release product to minimize those high peaks. This is the more recent study that suggests that we don't need to hold during labor and delivery. Basically, in this study, holding it didn't change maternal or neonatal outcomes. They also recommended starting that weekly monitoring at 34 weeks and not waiting till 36 weeks. But so how this is handled like whether holding or when you're whether you're getting weekly levels at 34 weeks or 36 weeks it's probably gonna be different depending on your facility. In our group our practice is to recommend holding but with the caveat that it's important to get lithium restarted because of that high risk of relapse in the postpartum period for our women with bipolar disorder. The authors in this study actually recommended targeting those anti-manic or I guess the mania levels that we typically acute mania levels that will typically target like that 0.8 to 1 immediately after delivery and for the first month postpartum and really with the whole idea of trying to to prevent a relapse. One of the other things that we worry about especially with our psychiatric medications is the changes in drug metabolism that can be seen in pregnancy and it's thought that these changes impact psychotropic drugs more than probably any of the other physiologic changes that occur in pregnancy. Specifically we can see increased expression of CYP2D6 and CYP3A4 as well as the phase 2 UGT enzymes or glucuronidation. What this means is that if there is a particular drug that's a substrate of one of these enzyme pathways we would expect the level to decrease in response to the increased enzyme activity. On the other hand, CYP1A2, 2C19 and 2B6 activity actually decrease and throughout pregnancy so substrates of these enzymes may result in an increase in the level. Let's take a look at how these how these changes impacted antidepressants in one study. This is one of the larger published studies on changes in antidepressant disposition in pregnancy. Weston and colleagues they evaluated SSRIs as well as vanilla vaccine data from two routine therapeutic drug monitoring services in Norway. Their Norwegian healthcare system has a they more regularly get therapeutic drug monitoring of psychotropic medications. This was information that was readily available to them and what they did was compared a woman's own baseline so her non-pregnant values to the values throughout pregnancy. Importantly, there were not statistically significant changes in the vanilla vaccine. Excuse me, sorry, acetalapram and fluoxetine and so dose alterations would not be expected for these medications. However, serum concentrations were significantly lower from baseline for acetalapram, peroxetine and fluoxetine. The 24% drop that we see here in the blue with acetalapram levels was it replicated what's been reported in other studies so this was similar. However, the authors didn't actually recommend changing acetalapram doses despite the statistically significant decline. The reason for this is that acetalapram, you may remember, is a racemic mixture and the R enantiomer, which is the inactive metabolite, is primarily metabolized through CYP2D6, which as a reminder is increased in pregnancy, versus the S enantiomer, also known as acetalapram, is primarily metabolized via CYP2C19, whose activity is decreased during pregnancy. So they felt that it was appropriate just to keep the dose stable throughout pregnancy, just like what is recommended for acetalapram. Now, the data with fluvoxamine was a little unexpected. Fluvoxamine is metabolized through CYP2D6 and 1A2. Again, CYP2D6 increases, 1A2 decreases in pregnancy, and so there was some thought that these changes would actually result in like a minimal net change in the levels, but obviously the study did not indicate that. But what the study suggests, at least in the three patients, the three pregnancies that were included as a part of this, is that during pregnancy, the CYP2D6 metabolism may be the dominant enzyme pathway for fluvoxamine. But again, this is just measurements from three pregnancies and really needs to be replicated. Now, sertraline, on the other hand, which you can see here with the increase, we saw this sharp increase. And while sertraline is metabolized through a variety of enzymes, the CYP2C19 is thought to be the predominant one, and its decreased activity in pregnancy may explain this finding. It's interesting, though, when you look at sertraline data in other studies, there's a lot more variability. So there's some studies reporting an increase, some with a decrease, some with no change, and there has been some speculation that CYP2C19 polymorphism may explain some of these differences. And we don't have actually data to support this theory, but we do have one study looking at CYP2D6 polymorphisms and its impact in paroxetine in pregnancy. So this was a study with paroxetine, and it included the genotype data. What they found was that changes in paroxetine metabolism in pregnancy depended not only on the gestation week, but also on the CYP2D6 genotype. And so while there was an expected decrease in those with ultra-rapid or normal metabolizers, so that revving up of the CYP2D6 even more, like we saw in the previous slide, there was an actual increase in paroxetine plasma concentration in those who were intermediate or poor metabolizers. And so this is just kind of an indication that it's not always as straightforward as we might think, and that metabolizer status may give us kind of different results in pregnancy. Because CYP2D6 and 3A4 are involved in the metabolism of many antidepressants or other psychotropic medications, clinically what I see providers do is wanting to kind of preemptively increase antidepressant doses as the pregnancy progresses. But it's important to understand that the dosing is not straightforward, as we have seen here the last two slides, and that there may be factors that are kind of influencing what those drug levels are. And in fact, most experts in perinatal psychiatry will discourage arbitrarily adjusting doses and really encourage more kind of close monitoring for worsening of symptoms and only making adjustments based on clinical need and not just arbitrarily increasing them. As I previously mentioned, we can see an increase in glucuronidation. This can be significantly, this can significantly impact lamotrigine levels, which is how lamotrigine is primarily broken down. And we can see this effect as early as week five, so it starts to rev up pretty quickly. The lowest concentrations are seen in that second and third trimester, which you can see on the in the graph on the right hand side of the slide. If any dose adjustments are done in pregnancy, the dose will likely need to be readjusted to the preconception dose pretty quickly in the postpartum as glucuronidation returns to normal within two to three weeks postpartum. And you'll see there, several authors have made suggestions on how to do these postpartum dose adjustments, and I've provided one of those here. Now guidance for how to manage lamotrigine dosing during pregnancy was initially drawn from our neurology colleagues and based on epilepsy management, where there's a greater correlation between the level and seizure response. However, you are likely aware that there has not been a level associated with its use in bipolar, a correlation between level and its effect as a mood stabilizer. And so many perinatal mental health experts approach the lamotrigine dosing similar to antidepressants, so meaning that they closely monitor for symptoms and adjust only if there's a clinical need. And again, with that rationale being that there's not a defined therapeutic range for lamotrigine in bipolar disorder. So in conclusion, in women of childbearing age, we always have to think about the possibility of pregnancy. And these risk discussions really should come at the time the medication is initially being prescribed and revisited throughout their care. Part of the education includes not only the potential risks of medication, but also of the illness itself. It's also important to discuss risks of abruptly stopping a medication in response to learning that they're pregnant. And if you think about something like lamotrigine, that if they stop it and they're off of it for more than six to seven days, we're having to do that re-titration all over again. Oftentimes, we've already passed that risk window for teratogenicity when the pregnancy is detected. And that's also something that we have to keep in mind in our decision-making. In our SMI population, it's not uncommon for us to conclude that the risks of medication exceed that of staying on the medication. They're off the medication, exceed that of staying on the medication. But we want to try to do that at the lowest effective dose, minimize the number of medications that the fetus is exposed to. So this means that it may be best to continue medication even in the absence of data versus switching medications. Although I'd not recommend arbitrarily increasing doses of medication due to changes in metabolism, it may require closer follow-up as the pregnancy progresses and adjusting doses in response to either worsening symptoms or even possibly experiencing an increase in side effects if there's a decrease in how the medication is being metabolized. And if the dose adjustments in pregnancy do occur, we may have to do those dose adjustments in the postpartum to their pre-pregnancy dose. And so that's always something to to be aware of. The next couple slides are some resources that I've put together that I think are helpful to have. And as I mentioned, the use of psychotropics in pregnancy is ever-evolving. And I recognize it can be incredibly challenging to keep up with the most recent data. The Mass General Hospital Center for Women's Mental Health is a fantastic resource. They provide up-to-date information through blog posts on their website. You can also subscribe to their weekly newsletter that'll alert you to new literature, as well as their blogs. And they also provide weekly virtual rounds where you can bring your cases to discuss with Drs. Freeman and Cohen, who weigh in with their expert opinion. I attend those rounds myself and find it incredibly helpful. Mother to Baby is also a great resource. We regularly, in our clinic, use their medication fact sheets to give to our patients. And so that's a helpful resource. You can also text perinatal-related questions to them on the fly and get a response back that way if there's something that you'd like a quick answer to. Another really fantastic resource is the Postpartum Support International. Here, volunteer perinatal psychiatrists across the country provide a one-time clinician to clinician consult. They also provide a variety of free online group therapies. I don't even know how many different kinds there are, but they range from like a postpartum psychosis to pre-pregnancy loss group therapy. And then lastly, on here, there are several states that also provide perinatal psychiatry access program to providers within their state. This includes Texas, where we just launched our peri-APN pilot this past August. And I actually serve as one of the consultants for this program. Here's some lactation resources. And the last thing I want to leave you with today is a reminder about the pregnancy registries. This registry information is available in each of the product package inserts. The patient does have to enroll herself in the registry, but it should take minimal effort on her part. My understanding is that it only involves one phone call during pregnancy and then one in the postpartum. And the plug that the more women we have that participate in these registries, the more data we have regarding the safety of psychotropic medications in pregnancy, and just the more informed we can be. The next five slides are my references. And with that, I will conclude. And thank you so much for attending the webinar today. And with that, we will start to take questions. Thank you for such a great presentation, Dr. Smith. Before we shift into question and answers, I'll just take a quick moment and let you know, as you are putting questions in the question box, that SMI Advisor is accessible from your mobile device. So you can use the SMI Advisor app to access resources, education, upcoming events, complete mental health rating scales, and even submit questions directly to our team of experts. So we'll make a plug to download the app at smiadvisor.org backslash app. So with that, we just have a few minutes that we could take some questions and answers. One of the things, Dr. Smith, that I'm always very interested in is we're seeing a lot with ADHD and stimulants. I know you didn't have an opportunity today, but you know, just thinking outside the box, you know, do you have any off-the-cuff recommendations thinking about stimulant efficacy and safety in pregnancy? Yeah, first I would, like I would say, you know, the decision to make or to use stimulants or any kind of medication for ADHD, I guess my threshold for with which I'll use medications for this indication, like that the illness has to be much more severe, so maybe a more severe ADHD that has some safety concerns. So like if they're having car accidents or, you know, that there's like a higher level of concern for the ADHD, then I may, then we're going to give stronger consideration to using the stimulants. In general, when we're talking about methylphenidate or the myxamphetamine salts, there doesn't appear to be an association with, as far as its trigenic risk. There is one large database study that suggested a link with cardiac defects with methylphenidate, but many others have not found this link. And one of the things that we do worry about, so like the SNRIs, there's also concern for gestational hypertension. So that same study that reported the Venlafaxine found that same relationship with the stimulant medication. So with that, you know, when we're using them, kind of in that second half of the pregnancy, maybe higher risk of that. And similarly, like the higher the dose, that the higher the risk with it. There is a new study that just came out on adamoxetine, actually this month, in the Journal of Clinical Psychiatry, so hot off the press. And their, the safety profile looks pretty good with that, as far as the low risk for trigenicity. There was only roughly a thousand I think included in that. And so again, if it's one of those things that's, you know, less than one in a thousand, then, you know, we may not have gotten that signal. But at least, you know, this was one of the first studies to include that, include that medication. And so it makes us feel a little bit more comfortable about its use. So next slide, please. The presentation will be recorded and will be sent out. But I also wanted to let everyone know, if there are topics that were covered in this webinar that you'd like more information from other colleagues or mental health professionals, you can always post a question or comment on the SMI Advisors webinar roundtable topics discussion board. It's an easy way to network and share ideas with other clinicians who participate. And we'll make sure that Dr. Smith is able to answer questions if they're posted there as well. If you have questions about this webinar or other related topics to evidence-based care from SMI, you can also get consults done within one business day from one of our SMI Advisor National Experts. So 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 with SMI. It's completely free and confidential service. And the information is here as well. SMI Advisor is just one of the many SAMHSA initiatives that are designed to help clinicians implement evidence-based care. We encourage you to explore the resources available on the Mental Health Addiction and Prevention TTCs, as well as the National Center for Excellence for Eating Disorders and Suicide Prevention Resource Center. These initiatives cover a broad range of topics from school-based mental health through the opioid epidemic. To claim credit for participating in today's webinar, you'll need to have met the prerequisite attendance threshold for your profession. Verification of attendance may take up to five minutes. Then you'll be able to select Next to advance and complete the program evaluation before claiming your credit. Please join us next week on Friday, February 2nd, as Jason Phillip presents Culturally Competent and Trauma-Informed Crisis Management. Again, this is a free webinar, February 2nd from 3 to 4 Eastern Time on Thursday. Thank you, everyone, and thank you, Dr. Smith, for your time today. Until next time, take care.

psychiatric medications

pregnancy

untreated illness

medication use

individual's history

severity of illness

antidepressants

mood stabilizers

antipsychotics

potential risks