Bipolar Disorder in Pregnancy and Postpartum with Crystal T. Clark, MD, MSc

Journal of Clinical Psychiatry

Publisher of peer-reviewed research discussed in this episode.

Dr. Crystal T. Clark – LinkedIn

https://www.linkedin.com/in/crystalclarkmd/

Rates of Major Depressive Disorder and Bipolar Disorder in Black and White Postpartum Women (JCP, 2024)

https://www.psychiatrist.com/jcp/rates-major-depressive-bipolar-disorder-black-white-postpartum-women/

The 2024 study discussed at length in this episode’s chapter on racial disparities in perinatal bipolar diagnosis.

A Comparison of Symptoms of Bipolar and Unipolar Depression in Postpartum Women (J Affect Disord, 2022)

https://pubmed.ncbi.nlm.nih.gov/35041868/

The MDQ-based screening study Dr. Clark walks through when discussing how to distinguish bipolar from unipolar postpartum depression.

Dr. Crystal T. Clark is Associate Professor of Psychiatry at the University of Toronto and Canadian Research Chair in Reproductive Mental Health, set to become incoming head of the Department of Psychiatry at Women’s College Hospital. Trained at Johns Hopkins, she spent a decade at Northwestern before returning to Toronto in 2022, where she leads clinical care for perinatal bipolar disorder and Black maternal mental health. She has over 60 peer-reviewed publications and an H-index of 20.

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

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

00:00 – Introduction: A Career Built on Closing the Evidence Gap in Perinatal Bipolar Disorder

Dr. Ben Everett: Hello and welcome to the JCP podcast. I’m your host, Dr. Ben Everett. In each episode, we sit down with leading clinicians, researchers, and educators to explore the science shaping mental health care today, with a focus on the insights that matter most to you in clinical practice. conversation addresses what I think is one of the most consequential and still underappreciated problems in psychiatry: bipolar disorder through pregnancy and the postpartum period. For most of the history of modern psychiatry, the default was to do less. medication, less monitoring, and frankly, less counsel about even having a family. of women were told they simply needed to discontinue all their medications and hope for the best. we have now suggests that many of those approaches, while well-intentioned, were not as effective as hoped, in some cases, may have caused some unintentional harm. My guest today has spent her career generating the evidence that makes individualized, proactive, evidence-based management of perinatal bipolar disorder possible. Crystal Clark is Associate Professor of Psychiatry at the University of Toronto, Canadian Research Chair in Reproductive Mental Health, and as of July, so just a few days, uh, from now, I think she’ll be taking over as the incoming head of the Department of Psychiatry at Women’s College Hospital following a comprehensive international search. appointment marks a milestone worth pausing on. It reflects both the strength of her research program and a recognition that the kind of scientifically rigorous, equity-focused leadership she has built in reproductive mental health is exactly what the department, like the Women’s College, needs at this moment. Crystal Clark, trained at Johns Hopkins, completed a VA Advanced Fellowship in Mental Illness Research, Education, and Clinical Center Fellowship at Baylor in Pittsburgh, and spent a decade at Northwestern before moving back to Toronto in two thousand twenty-two, where she has served as clinical lead for perinatal bipolar disorder and Black maternal mental health. Her research has focused on exactly what the field needed most. longitudinal pharmacokinetic data on lithium, lamotrigine, qui– uh, quetiapine, and risperidone across pregnancy and postpartum in women with bipolar disorder. She was also an author on the 2024 CANMAT Clinical Practice Guideline for Perinatal Mood and Anxiety Disorders, leading its bipolar s- disorder section. She has over 60 peer-reviewed publications, an H-index of 20, and I should mention, as we always like to plug our board members, she is a member of our own Journal of Clinical Psychiatry Editorial board. So with that, Dr. Clark, welcome to the podcast.

Dr. Crystal T. Clark: Thank you, Dr. Everett. It’s a pleasure to be here.

02:30 – The Discontinuation Era and the Stigma of Childbearing with Bipolar Disorder

Dr. Ben Everett: All right. Now look, let’s, let’s get into this. I, I want to start with history because I think it’s important to map the, the arc of this discussion how this field is thought about perinatal bipolar disorder is generally, I think, really important context for what you’ve spent your career addressing. So there was a period, and it really persisted surprisingly long into the modern era when I really started looking into this, where there was a clinical assumption that pregnancy was somehow protective against psychiatric relapse in, in women with bipolar disorder. And that assumption was really consequential because women were counseled to discontinuize their, their current, you know, psychotropic medications that were helping control their, their bipolar disorder. And, you know, the basis of this, I-I’ll call it a hypothesis because there wasn’t really any evidence to suggest this. So where did that idea come from? And, you know, can you unpack some of that history for us?

Dr. Crystal T. Clark: Yeah. I, I always find this history quite fascinating actually, because, know, i- in modern day and in my career, I can’t say that I have seen this, this, um, the same. There– Most of my patients abso-absolutely have a recurrence if they’re not taking medication, and, and have a history of bipolar disorder, um, while pregnant and postpartum. with that said, I will say that, you know, some of the ear-early studies I think really captured maybe a few patients. I do have an occasional patient that for whatever reason they do fine in pregnancy and then everything falls apart postpartum. But I would say it’s a few. I don’t know if they overestimated that few or, or what the, the issue was that led them to believe it was a entire population with bipolar disorder who did well in pregnancy, ’cause this is definitely not like, you know, some conditions like multiple sclerosis where there is this remission that we see in pregnancy. That is not, a phenomenon we’ve experienced, um, broadly or, or even for the majority of patients with bipolar disorder in the perinatal period. but they held onto that for a long time. Definitely the nineteen seventies, eighties, that was the, that was the standard. Stop all the medications. Women are fulfilled and doing much better in pregnancy and feeling well and happy, and I’m wondering who they were talking to.

Dr. Ben Everett: Um, you know, and the other thing that happened on top of, you know, women, you know, being, being counseled to just discontinue their medication, they’d be fine without it. but sometimes women would have been counseled just like, “You know, you have bipolar disorder. It’s probably not a good idea for you to get pregnant because you’re gonna have to come off all this medication.” And, that, that is painful for me to listen to as a husband and a father that, you know, a woman would, would get that kind of counsel. Um, y- you know, again, is that just, know, kind of a, a knee-jerk hypothesis or was there any data to actually suggest that, that women should just maybe just not have children?

Dr. Crystal T. Clark: No, there’s no data. This is all stigma. Um, a- and it’s one of the things that continues to, uh, just– I, I don’t know. I, I don’t understand it. I, uh, and I still hear th- some of this today, families, doctors, um, patients believing that they should not have children. And, And, I know that it’s stigma because we don’t counsel anyone else with an illness, uh, particularly a physical illness, not to have kids, um, in most cases, you know, very rare circumstances, some severe terminal illness, something like that. But, but not, this type of condition where there’s effective treatments, and it can remain managed, and people can still live very fulfilled, capable lives. Um, we, we don’t typically do that. You know, diabetes, seizure disorder, I mean, even HIV, where, like, we have treatments, they’re effective. We can, um, these days protect mom and baby. So we don’t counsel women not to have the child or expand their family in any way that they choose to. I, I find it so disturbing that that was the message, um, and very disturbing that that continues to be the message, depending on who the treating, uh, doctor is. had patients come to me, um, as recent as the last, in the past, like, five years who have said, “Well, you know, my, my family doesn’t think I should have a, a, a baby. I’ve been told by my OB not to have any children.” They’ve never had any children. They just have a diagnosis of bipolar disorder. And yes, they may have had a severe episode, um, in the past that everyone is terrified that they will have again, but they desperately want to have a child and, and grow their family in that way. And, and I’m thankful to say that, you know, I’ve been able to help with treatments and close monitoring, um, them to expand their family, and their– and the family is like, “Wow, I didn’t know that was possible. didn’t know that she could stay well, stay out of the hospital, um, and still have a healthy baby.” And, and I’m, I’m glad we’re there, but we need to make that universal, uh, a universal practice and understanding, and, and that part, we’re not there yet.

Dr. Ben Everett: Yeah, and I, I couldn’t agree more. And I tell you, you know, I can only imagine the impact that, you know, that type of counsel would have on a patient’s, you know, sense of identity, their agency. So many women, you know, they, they grow up as, as girls and they just can’t wait to get married and start a family. And, you know, it seems like you would really be taking away something that could be part of your core identity, um, you know, if that was a dream of yours.

Dr. Crystal T. Clark: absolutely. I feel it’s a lot of shame. People end up feeling very ashamed, um, feeling less than, you know, or even alien some way. Like I’m, you know, I, I’m just not like everyone else and, and the stigma that haunts them, um, in the, in this context is, is awful. yeah, it, it’s just awful to see, and I, I’m glad, I’m glad we are, are doing better these days and, and changing this narrati- narrative and that the paradigm is definitely shifting because, because it’s just not true. We just don’t have evidence to support that. We never have.

08:30 – Reweighing the Risk-Benefit Calculus: Untreated Illness as Its Own Danger

Dr. Ben Everett: Yeah. Well, that’s great. I, I think the third thing that clinicians would have engaged with is the question of, you know, in, in medicine, everything is, is, you know, risk-benefit when we’re talking about treatments and, and things like that. it, it seemed a lot of this was just, you know, even if they didn’t have data, um, they were like, “Well, you know, we need to protect fetal, you know, fe-fetal growth and development, and so maybe we just discontinue all your medications.” but, you know, it, it seemed like they were thinking about, okay, that’s potential harm to the fetus, but, you know, what about the potential harm to the mother of not having the productive medication? And can you kinda help this, this risk-benefit as, as people are thinking about, all right, well, you know, there’s a risk to the fetus, but there’s a risk to the, to the mother as well. H-how do you grapple with that? And then, you know, how have we, you generated, uh, data or what data has, has come about now to help, educate that, you know, there’s an appropriate way to have this risk-benefit discussion?

Dr. Crystal T. Clark: Yeah. Go back in time a little bit, just kind of what we were discussing, where we started out where there was this idea that women were well in pregnancy if they had a mental illness, especially bipolar disorder. Um, and that evolved to… I’m not sure at what point that evolved to, well, it’s the medications that are very risky, but I know somewhere in the 1970s, ’80s, the focus was on medication, um, and the risk of medication in pregnancy, particularly for, mental illness and especially bipolar disorder. And then thankfully, we got, you know, after thirty years of that, we got to like the early 2000s and, researchers started showing that, actually there is a recurrence of illness. Matter of fact, for those who are stopping mood stabilizers that are used to treat bipolar disorder, seventy-one percent will have a recurrence. Um, so they will have a, a, an episode, and often that episode is depression. And, and so then there was that focus, like, “Okay, well, actually they’re not well, it recurs, um, when they stop their medication, so they should keep taking the medication.” But there was still this narrative that the medication is bad. And so there was still a lot of variability in practice because you have some people worried about liability. gonna– Anytime you tell a, um, a mother that, you know, there’s this chance that baby is gonna have a fatal heart condition or be malformed or, um, you know, have any type of complication,” that is scary. No one wants to take that risk unless it’s absolutely justifiable. and so, you know, then there’s that, you know, people are gonna opt out. The physician definitely doesn’t wanna be sued for something bad happening or even have to witness that. Thankfully, as we got further into the 2000s, start, um, seeing in like 2010 on, which is not that long ago, we’re talking like fifteen, sixteen years, where we started to see that there was a lot more evidence coming out that shows that actually untreated illness, untreated bipolar disorder illness in pregnancy is a risk to the pregnancy itself as well as the fetus. Because for a while there, there was also the, “Okay, well, who cares what happens to mom? As long as the baby’s okay.” You know, she can relapse, have all the symptoms, all the behaviors, not be doing well, but as long as we protect the baby. And a lot of mothers felt like that was their duty to do. Like, “I’ve just gotta struggle through this no matter what, not be treated until I can deliver.” But we’ve shown, the research has shown, um, in the field that actually untreated illness is quite risky to the m- the pregnancy and to the mom. So we’re seeing things like, babies being born low birth weight, small for gestational age. Um, moms, of course, their, their behavior might change. They might be n- malnutrition. They might not be going to prenatal visits. Um, they might u- use substances to self-medicate to make it through, thinking that those are less risky or just unable to control that craving. so there’s a host of complications that come along with untreated illness. And thankfully, we’re finally at the point where we can have a more balanced discussion with the patient and, and partnership with the patient about, “Well, these are the risks of, of known risks of these medications, and these are the known risks of the illness if it’s active and untreated in pregnancy.” And most often, the benefits of treatments justify any small risk that comes along with the, uh, medication.

13:30 – From Residency to Research: Uncovering the Pharmacokinetic Evidence Gap

Dr. Ben Everett: I appreciate that context. So your research career has really been built on, on fulfilling this fundamental evidentiary gap, right? We simply don’t know how these medications behave pharmacokinetically during pregnancy in, in these women with bipolar disorder. So can you– con just– can you, you know, tell us about what that gap looked like, like when you started, what motivated you to, to really think that this was where you wanted to s- you know, be passionate about in your career?

Dr. Crystal T. Clark: Yeah. I– this starts back in residency. Um, a resident, I remember having patients I w-um, that were taking lamotrigine and, and other s-um, psychotropics for bipolar disorder. I have always been very intrigued by the overlap of psychiatry and obstetrics, um, to the point where I, I really battle with, okay, which one, which one do I do, uh, for my career? I, I chose psychiatry, obviously, but I found that even in, I was so drawn to that patient population, and I remember having patients who were taking lamotrigine, for example, you know, they were well when they first started coming to me. Might have been following them well before they were pregnant, and then they became pregnant, and then we were seeing this relapse. And, um, I remember there being concerns about, well, is the patient taking the medication? Maybe they’re just not being adherent, and, and that’s why we’re seeing this relapse. And, and I, I remember having patients and thinking, “No, some of these people I really believe are taking this medication,” but we are, we’re not sure why they’re relapsing. So time, the practice was to add the medication. Okay, well, that one’s not working anymore. They’re having a relapse. Now we add another medication. But as I progressed through my career, my concern became, well, if we’re trying to reduce exposures to just multiple medications, and we’re trying to keep people well who choose to remain in treatment during pregnancy, is there something going on that’s keeping them from staying well? um, when– as a fellow, I started looking at data on lamotrigine s-appreciating what neurologists had appreciated in, in the context of women with epilepsy while pregnant, that the lamotrigine, uh, elimination clearance really increases during pregnancy as much as two hundred to three hundred percent, which is quite significant, which means then the concentration of the drug is dropping as much as seventy percent. And I’m like, “Well, if there’s no drug in the bloodstream, then how can there be a much drug at the receptors than what they’re retreating?” Uh, so that led me to to better appreciate, well, how do things change pharmacokinetically, and how do we adjust our practice to deal with those pharmacokinetic changes like our neurology colleagues have done for women with epilepsy and, and their management during pregnancy for seizures? It’s a little more complicated, though, for bipolar disorder because seizures are– you seize or you don’t. There’s not this, like, sprinkling of symptoms that lead up to the full seizure necessarily, um- Whereas with bipolar disorder, there, you know, you can start to see a little more anxiety, you know, some sadness creep in, a little more irritability, you know, and then before you know it, they’re in a full-blown episode. so trying to tease out, um, the best way to monitor the lamotrigine concentration, the best way to be proactive and prevent relapse, um, has been of the, the, the ongoing, uh, research of my career. How do we develop an algorithm or a standard of care? But what I learned over the course of my career is that, yeah, lamotrigine absolutely plummeting in terms of its, uh, concentration and increasing drastically in terms of its clearance in pregnancy c-can lead to therapeutic failure of the drug, and therefore can increase the risk of relapse or recurrence. And, that is something that I, I think we sh-should not be happening. We should be able to be more proactive and more preventative for our patients, which requires some personalization to each individual. But, um, I believe we can develop some standards, that, that help most.

18:00 – The Pharmacology of Pregnancy: How Lamotrigine, Lithium, and Antipsychotics Are Metabolized Differently

Dr. Ben Everett: Really good. So let, let’s get a little deeper into the science here, ’cause I think this is where your work has really had its most direct clinical impact and where the gaps in clinical practice are probably still most consequential. So you mentioned with lamotrigine, um, some of the PK changes. So you walk us through the physiological changes of pregnancy that make standard dosing, you know, unreliable? Is it, is it, you know, uh, um, you know, e-EGFR, uh, increases, you know, your hepatic, uh, you know, CYP or UGT enzyme, you know, induction ramps. You’ve got inducers, you’ve got, you know, uh, inhibitors, all these types of things. So what have you found in terms of, you know, how these things change during pregnancy? And, you know, how do you, how do you think we should be addressing those changes?

Dr. Crystal T. Clark: Uh, so it definitely changes depending on… I- it’s all about how the m- the drug is metabolized and what, and by what substrate, and what substrate it, it’s, you know, um what metabolic pathway leads to its metabolism. You know, that’s gonna vary for lamotrigine versus lithium versus some of the antipsychotics that we use to treat bipolar disorder and, and conti-and continue to prescribe during pregnancy. With lamotrigine, it is, it is the glucuronidation metabolic pathway, and so the main enzyme is UGT1A4, and that enzyme is absolutely upregulated in response to the rising levels of estradiol in pregnancy. So we know that estradiol levels rise significantly, um, throughout pregnancy until far into the third trimester and then, um, and then, you know, fall off a cliff, as we say, at delivery. Well, similarly, we see that pattern. There’s like a one-to-one relationship between estradiol increasing and the, the activity of the UGT1A4 enzyme increasing. And the more it increases, of course, the more it– the quicker it metabolizes or it eliminates lamotrigine from the system. so it breaks it down into its metabolite which is further metabolized by another enzyme that is not upregulated, and then it’s, uh, renally excreted. And that is quite significant because then not only does the lamotrigine clear a lot quicker, much more rapidly, as early as five weeks gestation, um, so really early in pregnancy, reaching kind of a plateau at some point in the third trimester, and then too falls off a cliff when, um, at delivery. So at that point, um, everything goes back to baseline and, and now we’re, you know, dealing with other things we have to, um, worry about if the drug has been adjusted in pregnancy. that’s pretty much the trajectory. We see different things, though, f-with lithium, for example, um, where we’re looking at the cardiac output and how it increases fifty percent in pregnancy, and as a result of that increased cardiac output, we’re getting more glomerular filtration through the kidney, um, which is how lithium is excreted. It’s e-exclusively excreted through the kidneys, so the more filtration, the quicker you’re gonna eliminate lithium. whereas with other drugs, like the antipsychotics, more cytochrome P450, uh, enzyme activity, and that varies depending on which cytochrome P450 enzyme, whether we’re talking about 2D6 or 3A4. And, and sadly, we have not actually studied enough of the cytochrome P450 enzymes and how they are impacted, um, in pregnancy enough to have really good guidelines. We do for CYP2D6, but not for 3A4 and, 2D6 and some of the other ones. Yeah.

22:00 – From Algorithm to Practice: Applying and Titrating Lamotrigine Across Pregnancy and Postpartum

Dr. Ben Everett: And so you, you mentioned, you know, you’ve talked about lamotrigine, lithium, and then your atypicals. Let’s go back into, into lamotrigine a little bit more because you’ve actually published an algorithm uses a prepregnancy reference concentration as the target. did I get that right? That, that’s, that’s how it works?

Dr. Crystal T. Clark: Yes.

Dr. Ben Everett: Yeah. Okay. You know, are you finding that, uh, you know, uh, are a lot of clinicians, uh, whether it’s– and, you know, they’re, they’re obstetrician or, or a psychiatrist, do you find that people are actually, you know, pulling these, these levels, the metabolite levels and using the, reference points to help manage, you know, lamotrigine levels to ensure that you’ve got a, you know, a– what I’ll call a protective dose, at least what they want at baseline prior to pregnancy? I think it’s a pretty big deal that we’ve got this research now and you’ve, you’ve got this kind of figured out. But, you know, are, are we finding an uptick? Are people actually applying this in the clinic?

Dr. Crystal T. Clark: Yes. So great question. is– So I wouldn’t say it’s an algorithm in the true sense quite yet, but there are some, some basic, framework for algorithm, um, in terms of checking the baseline or pre-pregnancy concentration, uh, for lamotrigine and using that as a target throughout pregnancy. I would love to see that universally, uh, used. I would say that, um, my colleagues, probably, I don’t even know if majority are, but I, I would at least venture to say that at least fifty percent, um, approach it that way. Of course, you know, they have to have seen the patient before the patient is pregnant or, or, um, you know, the patients come in for care or with pregnancy planning, which is not always the case. So sometimes it’s just not an, an option, and it’s not standard of care enough that when women have been well and in treatment and are taking lamotrigine, that whoever their doctor is that’s prescribing has said, “Okay, let me get that, therapeutic level because you’re doing well. We may need to refer to this sometime in the future if you ever choose to have children.” would love to see that happen. But often people might come in with an unplanned pregnancy or, um, and they’re well into pregnancy before anyone has thought to check that level just by the nature of, uh, how things work. and that’s, um, yeah, that makes it a little more complicated and a little more difficult. But we as a field, there are definitely some thoughts that maybe that’s not necessary. Um, you know, do we– we wait until people have more symptoms? And when they have more symptoms, do we just kinda blindly increase the dose? Do we need to know the level adequately treat them or increase the dose? Um, once we, we check the level, what’s a good level? There’s no thresholds, no exact therapeutic range for lamotrigine. Um, so a lot of people question that. And of course, my response to that is, use the baseline if you have it, you know. And if you don’t have it, yes, we’re kinda shooting in the dark. But there is so often that we miss the opportunity to check a pre-pregnancy level when a person is in remission, doing well, adhering to their medication, uh, we just miss that opportunity. And I, I wish, um, and hope for the future that that will become more standard practice. the meantime, yes, I’m still working on a, well, what do you do if, um, the level has dropped? You have that pre-pregnancy level, it drops, um, two points. you, you know, do you go up two hundred milligrams, one hundred milligrams? How quick? And, and so there are definitely still some questions to be answered to, um, better formalize that algorithm.

Dr. Ben Everett: Yeah. But it sounds like you’re on your way, so that’s really exciting. I think the, the flip side of that is, right, so you’ve had a, um, a woman who’s, you know, let’s say, had an unremarkable pregnancy, hopefully. Say they’ve been able to stay on their, their medication, everything’s good, and then they deliver. you know, now you– the, the PK resets pretty quickly, right? For, for the mom, you know, post, uh, post-delivery. You know, what, what do you see? So let’s say you’ve had a patient, you’ve increased their dose, you know, a couple hundred milligrams over the pregnancy. How do you manage the, the titration back down to, to what they were on, uh, baseline? Based on, you know, now you’re on this higher dose than you were on baseline. Again, this risk-benefit. How, how quickly do you find you need to taper and, and what’s that look like?

Dr. Crystal T. Clark: Yeah. I, I have, I have seen many things in the course of studying this, and unfortunately, only took me to see one patient become toxic to make me very, um, cautious about not reducing that medication dose immediately postpartum. So immediately after delivery, I’m reducing, uh, the dose by twenty-five percent, and this is, of course, assuming the dose has been increased as for many patients it, uh, needs to be. Um, and then after that first reduction of twenty-five percent after delivery, I’m going down by twenty-five percent every three to four days to get them back to whatever their pre-pregnancy dose was. and I, I have found that that works pretty well in terms of preventing toxicity or any adverse side effects and yeah, my patients have done well. But I did have a patient who did not reduce that, I wanna say it was a week and a half postpartum. She had not reduced her dose yet and, it had been increased by two hundred in pregnancy and, and often I have to go up double, um, or more, um, to maintain wellness for some patients. yeah, she became toxic, um, ataxic, had to be hospitalized. It was, a scary thing. She’s doing well today, but, um, but yeah, it was, it was very scary at the time.

Dr. Ben Everett: I can imagine, especially, you know, Yeah. when you’ve got a new mom, you know, everybody wants to be at home, you know, hoping everything goes okay. So it’s, it’s never a good outcome to have to have a, a patient, um, you know, hospitalized for that. But I’m happy to hear that She is well now. I think that’s the most important thing.

Dr. Crystal T. Clark: is well. They’re thriving.

Dr. Ben Everett: That’s, great.

Dr. Crystal T. Clark: Yes.

28:30 – Lithium in Pregnancy: Monitoring Levels and Revisiting the Ebstein’s Anomaly Risk

Dr. Ben Everett: great. All right. Well, you mentioned lithium. Um, so let’s get a little bit more into lithium now. Lithium does have a neurotherapeutic index. It’s also renally cleared. Um, so this increase in GFR, you know, definitely has an impact there as well. You know, how do you manage lithium? You mentioned it a little bit earlier, but kind of the same type of thing. You’re gonna follow the levels, titrate up, and then titrate down as necessary.

Dr. Crystal T. Clark: Yeah. Um, so lithium is exactly the model I, I wish we were using for lamotrigine, of course, with the absence of a, um, clearly defined therapeutic range. with lithium, we thankfully have that, so it makes it, it easier. But I will tell you, people still don’t, still don’t, uh, do it consistently, unfortunately. And we still have cases where people are taken off of lithium during pregnancy. Um, so there’s that. But I– But in terms of monitoring, yes, um, ideally, there has been someone who has captured the lithium level pre-pregnancy, and it, and it’s more standard of practice to do so. So in most cases, um, there is that data to refer to for where have you done best, what level, um, were you at your best? And, And, we use that level to monitor throughout the trimesters of pregnancy, checking it at least, um, from my practice, I check it once each trimester. we see the changes as early as, you know, first trimester, mid-first trimester because you’re seeing changes in the heart rate and cardiac output– not heart rate, but the cardiac output As early as the first trimester. So that increase in cardiac output by fifty percent then increases the, uh, glomerular filtration rate. Therefore, I’m checking, you know, by the mid to late, uh, first trimester to see, okay, is this, know, are we still at point seven if that’s their pre-pregnancy level, or is it now something different? And I, I remember having a patient who came in, and her level was, uh, point eight you by beginning of second trimester, she was symptomatic, and her level was point four. You know, like a fifty percent reduction.

Dr. Ben Everett: reduction, yes.

Dr. Crystal T. Clark: so, yeah, that was pretty significant. Now, it– thankfully, unlike lamotrigine, it do- it kind of, for many people will have a dip, and it won’t continue to be such a rapid change throughout pregnancy. so that’s the reason I’m not checking it more than once, uh, each trimester. in my experience for individual patients, it does not, um, increase in the third trimester. There’s some data that suggests it could increase, and, and so go in reverse. We go from it declining to increasing in the third trimester. I haven’t seen that. I see a steady decline with individual patients unless there’s something going on with the kidney. So we always have to be worried about gestational hypertension, preeclampsia, other conditions that affect, uh, the kidney, which could therefore, of course, increase the lithium levels during pregnancy. But in a patient with no complications, healthy, we see a steady decline. We want to increase the drug by, like, a hundred and fifty milligrams when we see those declines happening and recheck and make sure that they’re in the therapeutic range or at their pre-pregnancy level. have, um– I do recommend checking third trimester, um, maybe even a couple of times if, if not more, for someone who’s at risk of preeclampsia, gestational hypertension or, or other complications, or you become aware of a complication. Sometimes the lithium level is our first indicator that actually there’s something going on with the kidney that needs to be investigated by their OB team. Um, so, so it also, um, is helpful in that regard, but also keeps– checking it keeps them from becoming toxic.

Dr. Ben Everett: Yeah. Well, that’s good. Um, and, and speaking of, you know, toxicity with lithium was, you know, historically we think about it as having some, uh, teratogenic effects, uh, the Ebstein’s anomaly. but it seems that that was dramatically overstated in the early data. Maybe not dramatically. I might, I might be, uh, speaking a little bit too poetically here. Um, but can you walk us through this reassessment and, and how it’s been revised and, you know, how do you counsel patients about, you know, if they’re on lithium and doing well on it? It-it’s really you– it-it’s working for you. Let’s not rock the boat. We should probably stay on lithium.

Dr. Crystal T. Clark: Yeah. Well, I’m thankful for the patients, uh, that, you know, the data that led us to being very scared of, uh, lithium exposure during pregnancy, and especially during the first trimester, which came out from the International Registry of– or Register of Lithium Babies back, I believe, the nineteen seventies, a four hundredfold increase of Ebstein’s anomaly. So again, quite scary. Who wants to take it with that type of uh, towards their baby? but thankfully over time, more rigorous systematic studies have– mean, every time someone does a study, it seems like the, the risk gets lower. Um, the more we tease out confounders, um, more lithium is, I think, managed more carefully these days too, ’cause some of the reports back in the day, the doses were really high also. And I’m like, don’t use those doses most times these days.” So I’m not sure what the difference was or how lithium may have been formulated, um, back then, but, but that has changed as well. today, thankfully, what we’re seeing is that there’s a very small absolute, um, risk increase for Ebstein’s anomaly or any cardiovascular malformation. But Ebstein’s anomaly specifically, we’re seeing like a– the difference between one to five cases per two hundred thousand in the general population to two to eight cases for those who are exposed to lithium. So two to eight cases out of two hundred thousand, people having babies in the population. So it’s not– it’s a very small, um, increase. And, thankfully I will say I’ve never seen a case in my practice, and I am definitely one of the people who don’t, who is not afraid to prescribe or maintain lithium during pregnancy and counsel my patients to do so if that’s been the most effective treatment for them. Um, so I’m thankful to not have seen the case. I’m gonna knock on wood, hope to not see any. Um, but I– even amongst my colleagues, I rarely hear of a case. Every now and then, um, I hear of one, but it’s, it’s very rare.

35:00 – Atypical Antipsychotics: Quetiapine and Risperidone Pharmacokinetics

Dr. Ben Everett: That’s really good. I think that’s encouraging and, you know, should give people, um, you know, some confidence if they’re having a, you know, this conversation with a pregnant woman and, and like, you know, now we have some data that can really address this and, you know, that sounds like, Yeah if you’re from one, one in five in the general population to two to eight in the pregnant, you know, population, that’s like these are pretty similar numbers. Yes, a small increase, but very similar. All right, well let, let’s move on to, to atypical antipsychotics. You know, it’s, it’s great that there are now so many tools in the, in the tool belt when it comes to the, the atypical classes. but a couple that, that come to mind for which we have, you know, data, um, uh, were quetiapine and, and risperidone. So when we look at the PK of these in, um, you know, in, in, in the literature, in your research, um, you know, what have you found there?

Dr. Crystal T. Clark: Yes. Um, the antipsychotics is a whole ‘nother, whole ‘nother bag in terms of, uh, when we think about Uh, reproductive safety as well as thinking about the pharmacokinetic profile. Uh, thankfully, you know, early data is showing that many of these medications are, not a teratogen during pregnancy. We’re not seeing an increased risk of congenital malformations above the general population or, or any other pattern of, severe adverse outcomes. What we are seeing, unfortunately, is, um, gestational diabetes in some cases or, um, delayed movements, um, after exposure where the babies do catch up by the time they’re, um, school age, uh, with their peers. even more so when we start to think about the pharmacokinetics, okay, well, if you’re taking this medication and it’s been determined that that’s the best treatment and, um, what’s gonna be best to reduce the risk of the illness exposure, then what we’re dealing with in some cases is what’s the optimal dosing during pregnancy as well as during breastfeeding and, and postpartum. Uh, quetiapine, for example, I see lots of patients don’t wanna take it postpartum because whatever happens, even though they might have been tolerating the, uh, sedative profile of it, uh, during pregnancy, by the time they’re postpartum, they, they can’t get up to attend to their baby, and they’re not comfortable with that, and so they’re less likely to adhere to it, for example. but when we think about, well, okay, this person who’s taking the quetiapine is also having, uh, more mood symptoms creep in, um, during pregnancy. Is that because they’re a rapid metabolizer of quetiapine? They have a, a, um, you know, more act– 3A4 or, or what’s happening? And so I’ve done a little bit of that research. There does seem to be, for example, with quetiapine, some increased CYP3A4 activity that suggests that, okay, if you’re seeing a patient who is starting to have symptoms creep in, they’re taking quetiapine as one of their drugs or as their– or as monotherapy, then you might wanna increase that first before adding another medication, which is typically what I do with most of these drugs because I see this so often, often due to the pharmacokinetic changes during pregnancy. similarly, something like risperidone, which is metabolized by the cytochrome P450 system as well, that being CYP2D6, we know that there’s an induction, um, a greater metabolism, greater activity specifically with that drug, with that enzyme and therefore that drug in, in pregnancy. I do have patients where risperidone is not as effective because they need to go up in dose because there is an increased, um, You know, met-metabolism of it, of the risperidone due to CYP2D6. And we thankfully have great guidelines. That one has been well studied. The CPIC guidelines are– detailed that very well in terms of what we ex-expect to see with the, you know, rapid-acting, um, CYP2D6. So there’s that one. But then it gets more complicated when you start to look at olanzapine or some of the other antipsychotics where there’s multiple pathways working together, and it’s not clear if you’re g-you’re gonna see a increased, um, activity or a decreased activity of that enzyme, um, and or the several enzymes that are acting on that particular drug. And therefore, you don’t know if you’re gonna have increased clearance or decreased clearance of that drug or increased, um, activity of that drug. That, that gets a little more tricky, but my rule of thumb has been more often than not, if I see relapse or symptoms setting in to increase the drugs that they’re, uh, taking before adding something else and adding a unnecessary exposure.

40:00 – Distinguishing Bipolar from Unipolar Postpartum Depression with the MDQ

Dr. Ben Everett: All right. So let’s move on from, you know, drug metabolism. You, you’ve covered, you know, five or six different agents that are commonly used to treat, uh, you know, uh, bipolar disorder, uh, mood stabilizers and the like. Um, but part of what can make perinatal bipolar disorder so, you know, difficult to, to, to manage is it, it could be misidentified, right? It could either be missed entirely or it could be misdiagnosed as unipolar depression. most patients with bipolar, they, they, you know, trend, uh, to the depressive, um, pole instead of the manic pole. But you had a, a paper come out in twenty twenty-two in Journal of Affective Disorders, and you actually directly compared depress– uh, depressive symptom profiles in postpartum women with bipolar versus unipolar depression. um, can you walk us through your findings from that, from that study? I found this pretty interesting.

Dr. Crystal T. Clark: Yes, I, um, I found that study pretty interesting too because, we, we’re challenged with trying to determine who has bipolar disorder who doesn’t, particularly in the postpartum period when people are presenting mostly with postpartum depression, but some of that might be bipolar depression. it’s hard to tell because people are also not always the best historians or they don’t remember that hypomanic episode. this is– maybe the birth itself or the pregnancy itself was that seminal event to, onset this disorder. so so there’s a lot of things we don’t know to really, you know, nail the diagnosis, so to speak. Um, I’ll be happy when we have a biomarker for that, but I digress. but what this study showed was that when we looked at the Mood Disorder Questionnaire, otherwise known as the MDQ, and we stopped, counting certain, um, certain qualifiers such as, uh, does the person, you know, do they feel like this caused some problems, the symptoms that they endorsed, did they feel like it caused some problems? When we took out that criterion, um, we found that we capture w-way more of the, the patient population who have bipolar disorder, which, which I found really fascinating because it helped me to appreciate in my career that actually, you know, everyone doesn’t feel that this is a problem. And that has rang true in patients who don’t– who aren’t pregnant or postpartum, um, who have bipolar disorder. It depends on how severe their symptoms have been and what ways it’s impacted their life, but they may or may not feel like it’s all a problem. Have they had severe depressive episodes, or have they had a lot of, um, manias that they actually enjoyed, you know? Um, so that, that was a, know, a, a eye-opening, uh, and something that I’ve consid-continued to consider throughout my career. but also we found that, you know, scoring positive on the MDQ, seven positive, um, questions or seven answers that are endorsed symptoms Was enough to identify these patients taking out those other qualifiers. And what we were noticing was that those who scored positive on the EPDS, the MDQ was actually able to distinguish, okay, you’re positive on the EPDS, but is that depression or is that bipolar depression? The MDQ was able to let us know that if it was positive with those seven symptoms scored positive, that this is actually bipolar disorder. What was great was that we were able to follow that up with a standardized assessment. So it wasn’t just like, we, we noticed that they had the positive EPDS and the positive MDQ, but actually, when we went to look at the mini-diagnostic assessment, they actually had bipolar disorder. Um, so it, it matched up well with what we were seeing in terms of the MDQ, um, positive screens. And since then, the recommendation been, okay, if you see someone postpartum in for depression, let’s not have a knee-jerk reaction to q-quickly give them a antidepressant without screening for bipolar disorder. And that can be done in our, you know, OB’s office, the family practitioner’s office, the pediatrician’s office for that matter. But definitely our psychiatrist should be screening, uh, for bipolar disorder, and the MDQ is not the perfect, uh, screener. We, we could still, uh, fine-tune, fine-tune our approach to really capturing this illness, but, but it’s one of the best assessments we have. Um, and it definitely can help to reduce the risk of treating someone for bipolar depression inappropriately with an antidepressant.

Dr. Ben Everett: Yeah And it, it, it’s validated. It’s, it’s pretty simple to, to do. Yeah I think that’s a lot of the tools in psychiatry. It might not be perfect, but, you know, it’s, it’s probably– it’s b- it’s certainly better than not doing any assessment, right? And.

Dr. Crystal T. Clark: Absolutely.

Dr. Ben Everett: Yeah, Um, and, and so that’s the key.

Dr. Crystal T. Clark: yeah, and I, I, and I, and I share that it’s not perfect mainly because often people say, “Well, I get a lot of false positives,” and I go, you know, and they complain about the, uh, screener. But, but to your point, absolutely. It’s better than doing nothing and taking the chance that you treat someone inappropriately, which could have devastating consequences.

45:30 – Racial Disparities in Perinatal Bipolar Disorder Diagnosis

Dr. Ben Everett: Yeah. kind of along the same line, in 2024 you have a JCP paper where you actually looked at, uh, rates of, uh, MDD and bipolar in Black and white women in this postpartum, period, and the, the difference here I thought was really striking. Can you tell us what you found in that paper?

Dr. Crystal T. Clark: Yeah, so it was really interesting. This paper, um First, I’ll say really reflects the, the lack of data, um, in terms of, uh, racial data, uh, in the perinatal period, particularly in a study like this. Like, often, um, these studies, and they’re big studies, but there’s no racial breakdown. And why it matters in this context is that we know that maternal mortality rates, um, are high amongst Black women in the US, um, and in other high-income developed countries. mental health happens to be one of the leading causes of the mortality. And, and so that’s made me very interested in, well, you know, what, what are we seeing in terms of mental health? And most of the data in the field has, Let me back up. Has made me very interested in what we’re seeing in terms of mental health amongst Black women who are pregnant and postpartum, and how that may overlap with the data we’re seeing amongst, uh, those who are, um, among those that we’ve lost, um, post-birth or, uh, during pregnancy. And what I, what I have found interesting over the course of my career as I look at data for Black perinatal mental health is that too often we’re just talking about symptoms, symptom burden. And that, that’s important, of course. We, we definitely want to know who has symptoms. But we don’t talk enough about diagnosis. And, and that could be because people aren’t getting diagnosed. Um, they’re completing screens, but never, uh, either following up or being followed up or never, um, being referred or never being diagnosed or treated. It’s, you know, there, there are studies that really speak to all of that. And leaves us wondering, what, well, what’s the prevalence? What is the prevalence of mental illness in terms of diagnosis amongst this, uh, patient population? this study, um, is one of the few that has been able to actually speak to diagnosis beyond symptoms. and I found it very interesting that what we saw in this population was that those who had– those who were Black had lots of symptom burden higher than that of their white counterparts. But when you looked at diagnosis, the diagnosis was, um, almost equivalent for a major depressive disorder. However, when you looked at bipolar disorder, there was a higher prevalence amongst Black women. And that I found striking because first of all, we don’t know much about bipolar disorder in Black women, especially during the perinatal period, but not really at all. that has historical context too. Um, people being misdiagnosed with schizophrenia instead of bipolar disorder Uh, not being diagnosed at all, um, diagnosed with other psychotic disorders instead of bipolar disorder. So this is also one of the first papers to really say this, you know, there’s a, a prevalence, um, this is the prevalence in this population, um, which was higher, um, than expected actually. And to take a step further, there was, um, w-we couldn’t prove this in the study, but were able to at least start to think about, well, this population also had high trauma and, you know, what’s the link between trauma and, uh, bipolar disorder? And there’s, there’s definitely, uh, researchers out there looking at this, and there’s, uh, studies that show that there is a association, especially childhood trauma. um, so that, you know, is there a disproportionate amount of Black women who have endured trauma and therefore go on to have bipolar disorder? We don’t know, but th-that makes, those are some of the questions you start to ask with this, this type of data set and, um, these types of findings. that study, um, yeah, I was very excited just to see, start to unpack this a little bit in our field. And it, you know, there’s still plenty of gaps that we need to address, but it, it raises lots of questions for us to continue to explore so we can figure out, you know, how to get people the treatment they need.

50:00 – Designing a Postpartum Monitoring Plan for High-Risk Patients

Dr. Ben Everett: Great. Um, all right, so let, let’s, uh, move on from, from that and let’s focus in on the postpartum window for just a minute because we know, know, there is some data now that this is really the, the most critical point, we could say the most dangerous point for a woman with bipolar disorder. there was a twenty sixteen meta-analysis that found a thirty-seven percent overall postpartum relapse risk. But rates, uh, rates dropped dramatically, uh, when, you know, when this was thought about and, and there was some prophylactic care given. So with that said, you know, monitoring and follow-up also becomes like less intensive despite the fact that we’ve got this data. You know, what is a, a well-designed postpartum monitoring plan look like in, in your, you know, estimation?

Dr. Crystal T. Clark: So we know that there’s a double the risk of relapse for patients with bipolar disorder in the postpartum period, and that they’re a hundredfold more likely to develop postpartum psychosis compared to those, um, in the general population. so this is a very vulnerable time for those who have bipolar disorder or have a predisposition to develop it. And when I think about monitoring during the postpartum period, um, because we don’t always know You know, a lot of people don’t know their family history. They don’t know what the risks are. They may not know they have the diagnosis. Risk may– We might be aware that they have the diagnosis and, and are treating them accordingly, but because there can be many unknowns, I think we have to have a, um, similar monitoring, um, to reduce the risk of anyone being lost to follow-up or not getting the care that they need. I’m typically… I, I will admit that I, I have the privilege of being able to follow patients monthly or, or more frequently if I need it. I think monthly is the ideal because, um, you’re able to check in, see if anything’s changed, adjust doses, follow up on that adjustment. Um, you know, for someone who needs more frequent monitoring because you are adjusting doses even better. But I think when we start to not see people for three and six months after having a child, that’s when things get pretty risky. We definitely wanna be able to see them during that. I, I have my patients come back the third or fourth week postpartum Um, yes, sometimes they forget or, you know, they have to cancel appointments. They’re, they’re, you know, uh, managing other doctor’s appointments. But, um, but usually by that sixth week postpartum when they’re seeing their OB, they’re also have, have seen me or will be seeing me as well. And then from there, we kinda set our pace for a monthly visit check-in. Doesn’t have to even be long. Often we’re talking twenty minutes, and it’s just, um, a great– My patients tell me it’s a great support. It’s a great way for them to, you know, “Okay, is this normal? Do I– Am I, um, am I feeling o-okay? What I’m experiencing, is this too much anxiety?” Or, you know, they– we talk through those things. And sometimes it’s normal experiences. Other times I’m like, “Oh yeah, no, the anxiety is not normal.” “And, um, yes, you should be sleeping more,” and, “What can we do?” And we work through those, uh, different things to, um, optimize their wellness during that time. I feel like the more touch points possible, the more, more chance we have to, um, help women in the, the most way, uh, to stay well, to prevent relapse, to prevent and, and to intervene quickly and timely when they need it.

54:00 – Future Directions: Formalizing the Lamotrigine Algorithm and Black Maternal Mental Health Research

Dr. Ben Everett: All right. That is really good information today. Um, I’ve learned a lot. But as we sort of move to, to, to our close here, I’d like to, to finish up with like where do, where do you see the field going? What are you working on right now? you know, you’ve mentioned, uh, lamotrigine, like it’s not quite an algorithm yet. You’re still working on that. Where, where, where are we with lamotrigine and, and where are you going?

Dr. Crystal T. Clark: Yes. Yes. so lamotrigine, I feel like it’s my, my, career, like my whole career will be– some part of it will be spent on lamotrigine. But hopefully, we get there sooner than that. Um, I am still working on that. I definitely have some work that is, uh, overdue to be put out, so, um, uh, hopefully, you’ll see a publication very soon. but also starting to look at, okay, with all the data that I’ve collected over the years, how might we actually revisit this, uh, formalizing of a, a true algorithm that, um, that we can personalize to the patient? Uh, so that’s very much still front of mind and still something I’m actively working on. the other– and of course, I’m hoping that it becomes a standard of care and not something that, um, you know, people kind of pick and choose whether or not they want to check a lamotrigine level or check a baseline level, um, because I believe it truly can improve the care for this patient population who’s taking lamotrigine. But otherwise, I’m also doing more, uh, work with looking at, um… Now being in Toronto, I’ve had the opportunity to, um, really look at programming for patients of different populations uh, Um, one of them being the Black maternal, uh, population. And as I said, there’s just been a, a gap in data, and it is a, a huge gap, um, in the Toronto area. Um, but it’s also a huge opportunity to look at, this uh, understudied area that and, and also think about how it will be translatable across North America and maybe other, other countries as well. But it, it’s a, a pretty open field here in terms of being able to really think about, well, wh-why aren’t people coming in and getting help? What are the barriers, whether that’s systemic or cultural, or, or based on discrimination? How do we improve that? How do we get better estimates of, you know, the prevalence and the symptom burden for this patient population? And, um, yeah, and, and then, you know, how do we intervene in a way that is, uh, sustainable, uh, for the community? Uh, so that, that has been, um, a new frontier, so to speak, um, that I tend to, I tend to find things that apparently, uh, requires me to pioneer something. Um, and but I find– I have a good time with it, and I, I see bipolar disorder as well as Black maternal health as, uh, underserved, communities in the field of psychiatry and a major, major gap for us to continue to address until we get it right.

57:30 – Closing Reflections: The Path Toward Diagnostic Precision

Dr. Ben Everett: I agree. And, uh, it sounds like you can be a trailblazer in that area. So sometimes it’s, it’s easier just to blaze a trail than to try and, you know, get into the, the areas that a lot of other people are working on. All right. So in, in closing, I always try and think of like one kind of, you know, question that just puts it, uh, you know, if there’s one thing you could change. So right now, if there’s one thing that you could change about the way, you know, whether it’s psychiatry, family doctors, the OBs manage women with bipolar disorder and women of reproductive age or while they’re, you know, pregnant, practice shift, one habit change, one piece of knowledge, what would it be?

Dr. Crystal T. Clark: Oh gosh, that was, that’s a hard one. I would say, um, just more… My dream is more diagnostic accuracy, um, as well as, as well as, um, something, a blood test, a biomarker or something that lets us know what people are gonna respond to as well. If we could get that technology and scientific advance going, would be great because I, I, I, um, you know, I feel for my patients who have to go through several medication trials. Um, we have to go through lots of like, okay, is it bipolar disorder? Everyone’s not a classic presentation. Um, is this trauma? To what degree is this borderline personality disorder? And if we could universally nail the diagnosis more accurately quick- more quickly and then get them to the right treatments, um, immediately, that would be, that would be nice. That would be amazing.

Dr. Ben Everett: That would be very amazing. And look, we’re getting closer to, to precision medicine and individualized care. I think of the, the things that are state-of-the-art now when I was in grad school, you know, seemed like, like deep brain stimulation in Parkinson’s disease was something I followed. We didn’t do that in my lab. It was just considered like heresy almost, and nobody would do it. You couldn’t– And now it’s, you know, now it’s standard of care. So these things do change, and I think of just, you know, where we started talking about the history, and like you said, a lot of that history is, is actually, it’s pretty recent history, and it’s kind of like, wow. So it’s good that we’ve come this far, but we’ve got, we’ve got further to go to help protect these women. Look, this has been a, a, a fantastic conversation. This is exactly what I was hoping we would get into. We hadn’t done anything like this on the show before. like the, the evidence you, you’ve put into place, you’ve got so much more that you can do. Just the clinical foundation that you’ve provided for, for, for care in this, in this area of, you know, uh, women with, uh, with bipolar disorder and this perinatal, period is just amazing and just really, uh, thank you for coming on today. I would be remiss if I did not say congratulations on you taking over as the head of department at Women’s College. It’s a major milestone in your career, and I know they’ll be, uh, uh, happy to have you.

Dr. Crystal T. Clark: Yes. Well, thank you so much, and thanks for having me on today. This has been a lot of fun. This, is a passion of mine for sure, and, um, yeah, I look forward to, uh, coming back one day with some updates.

Dr. Ben Everett: That’d be great. Yeah, I love your passion. It comes through in your smile. All right. Well, this has been the JCP podcast. Insightful, evidence-based, human-centered.