Welcome, and thank you for attending our workshop on Clinical Approaches for Reproductive Psychiatry. I am proud to introduce the Johns Hopkins Women's Mood Disorder Center and our faculty who are all going to talk to you today about different aspects of reproductive psychiatry. These are our learning objectives for the overall workshop. We're hoping that you'll be able to identify two treatments of premenstrual dysphoric disorder, describe a general approach to designing a psychiatric medication plan for pregnancy, name two mood-stabilizing medications that can be used during lactation, and define the terms perimenopause as well as menopause. All the speakers today are faculty members in the Johns Hopkins Women's Mood Disorder Center. Our first speaker is Dr. Lisa Hanzo, who will be talking about premenstrual dysphoric disorder. She is a clinical psychologist and assistant professor in the Department of Psychiatry at Johns Hopkins. Lisa's research focuses on premenstrual dysphoric disorder with a special interest in the role of neuroactive steroids and hormones in stress. Her K23 focuses on treatment of premenstrual dysphoric disorder using low doses of selective serotonin reuptake inhibitors. Because today's recording is recorded, I'm going to introduce all of the speakers at once. I will go next. I will be talking about designing a psychiatric treatment plan for pregnancy. I'm an associate professor of psychiatry as well as of gynecology and obstetrics at Johns Hopkins. I'm the founder and the director of the Women's Mood Disorder Center, and I'm an expert in the management of psychiatric disorders during and after pregnancy as well as during other times of reproductive change. My research focuses on the genetic basis of postpartum depression, and we've identified two epigenetic biomarkers that are predictive of postpartum depression with an accuracy of about 70 to 80 percent. Our next speaker is Dr. Lauren Osborne, who will be talking about treating postpartum depression as well as other psychiatric disorders during lactation. Dr. Osborne is an associate professor of psychiatry as well as of gynecology and obstetrics at Johns Hopkins. She directs our postdoctoral fellowship program in reproductive psychiatry. As a reproductive psychiatrist, she conducts research on the biological mechanisms of perinatal mental illness with a focus on neurosteroids and the immune system. In addition, she's the chair of a national task force working to create standards for education in reproductive psychiatry. Last but not least, Dr. Lindsay Standeven will be talking about perimenopausal depression. Dr. Standeven joined our faculty this past summer, and she's an assistant professor in the Department of Psychiatry. She's also the assistant director of the Women's Mood Disorder Center Clinic. Her clinical and research interests are in perinatal mood disorders, infertility, and polycystic ovary syndrome. I hope you will enjoy today's talks, and we'll look forward to your questions. Take care. Hi, I'm Lisa Hanso. I am an assistant professor and psychologist in the Women's Mood Disorder Center at Johns Hopkins, and today I'm going to be talking about identifying and treating premenstrual dysphoric disorder, or PMDD. So this talk covers three main parts. The first is identifying PMDD and talking about some of its clinical features. The second part is focused on PMDD diagnosis, and the third part focuses on PMDD treatment. So a few key points about PMDD. The first point about PMDD is that it is tied to the menstrual cycle. So the menstrual cycle is, as you can see in this slide, typically around 28 days, starting with day one being the onset of bleeding, and then going up to around day 28 before the next cycle starts. You can roughly divide the menstrual cycle into two halves. The earlier half is called the follicular phase, and the latter half is called the luteal phase, and it's divided kind of in the middle by ovulation. You can see in the luteal phase, there's a lot of hormonal activity going on, and this is also when women with PMDD are experiencing symptoms. So they typically are having symptoms around day 22 to 28 of the cycle, so the last week or so of the luteal phase. So the second point about PMDD is that it is a mood disorder, and so I pulled some quotes from a recent paper that looked at the subjective experience of women with PMDD. I thought this really nicely captured the idea that PMDD is not just major depression that happens to be tied to the menstrual cycle. It's a bit more nuanced than that. There tends to be a component of irritability or anxiety, and so some of these quotes from the women with PMDD, they say, my family would say to me, it's like, you're not yourself. I feel like it's an altered ego. I'm a completely different person. I'm talking about being in the luteal phase. I was feeling very low, very hopeless, tearful, getting angry as well, so you notice that sort of anger, irritability component, and it would swing all over the place, so again, there's this component of moodlability that can occur as well, and then the third person saying it was depressing, it was miserable, but it wasn't just that, meaning it wasn't just depression. It was something more than that, and then the next point about PMDD is that it's fairly common, so the prevalence is around 3% to 8%, which is similar to PTSD or panic disorder, so here I've plotted data from the U.S. National Comorbidity Survey study. This study actually didn't include PMDD, so I popped it in there so that you can see, and the prevalence, again, it's pretty similar to PTSD or panic disorder. It's much less prevalent than major depression, but it's more prevalent than things like OCD or bipolar disorder, so it's actually more common than I think a lot of people think that it is. All right, so let's go ahead and jump into PMDD evaluation and diagnosis, so I'm going to start right off with the DSM-5 diagnostic criteria for PMDD, so criterion A is that you need to have at least five symptoms present in the luteal week. They remit after menses, and this has to be in the majority of cycles in the past year. Criterion B, you have to have at least one core mood symptom. Again, it's a mood disorder, so you need to have a mood symptom there. These include affective lability, so this can look like tearfulness or a sensitivity to rejection, irritability or anger. This can look like interpersonal conflicts, low mood. We can see things like hopelessness or self-deprecating thoughts, and then anxiety or tension. Criterion C, you have to have at least one of these, and these are the more classic kind of major depression-type symptoms, so decreased interest, trouble concentrating, low energy, changes in appetite, sleep disturbances, feeling overwhelmed, and then unique to PMDD, we have physical symptoms, so these can be things like menstrual cramps, headaches, or breast tenderness, that kind of thing. Criterion D is the usual distress or impairment. Criterion E, not an exacerbation of another disorder. Criterion F, and again, this is unique to PMDD, requires prospective daily ratings for at least two symptomatic cycles, and Criterion G, not due to substances or a medical condition. So, I want to highlight Criterion F. This is the prospective daily rating of symptoms. So, the gold standard for diagnosing PMDD is not just doing a clinical interview, but also having the patient daily rate their symptoms across at least two menstrual cycles. So, this can take different forms. The DSM actually doesn't specify what tool or instrument you should use for the daily rating. There are a range of tools available. The one with the best evidence, and it's actually often used in research settings, is called the Daily Record of Severity of Problems, or DRSP, and it's nice because it captures the key DSM-defined PMDD symptoms, and it asks the patient to rate them across the menstrual cycle. It's relatively easy to see it relatively easy to see it visually as well when the patient returns it to you. So, I'm going to talk about a few of the challenges with PMDD diagnosis. I think the, you know, key part here is that patients often report difficulty getting an accurate diagnosis. So, you can see, again, quotes from the study, patients saying, I felt like everybody thought I was making it up. My mental health team was saying, we don't believe in this kind of thing. We've never heard of it. The general practitioner kept knocking me back and saying, you're depressed. And so, you know, this point that women are feeling pretty invalidated about their experience of premenstrual mood symptoms, and this is consistent with some data that we collected recently. So, in conjunction with the International Association of Premenstrual Mood Disorders, IAPMD, I worked on analyzing some data from their 2018 global surveys. This was women worldwide and included over 2,500 women who are seeking care for PMDD. And we asked them to rate providers in three key areas. So, these were interpersonal factors, knowledge about PMDD, and diagnostic expertise for PMDD. And this data suggested some gaps in expertise. The thing that we were most surprised about was that in terms of diagnostic expertise, and this was namely asking patients to do the prospective daily rating, gynecologists actually rated the highest compared to psychiatrists or psychologists. And this was interesting because, you know, PMDD is a mood disorder. So, it's, you know, defined by the DSM. And so, we were expecting that psychiatrists and psychologists would actually be pretty well versed in diagnostics. It turned out, according to patient perception, that wasn't quite the case. So, a few challenges you might run into. The first is that PMDD symptoms can fit different patterns. So, we see here patient A, this is a pretty typical looking PMDD symptom pattern. This is what we usually expect, where you have some symptoms toward the end of the luteal phase, and then they drop off once menses begins. Pretty cut and dry. But sometimes you have patients like patient B, where you have a little spike in symptoms around ovulation, they go away, and then they come back again in the luteal phase. Or you might have patient C, where their symptoms start shortly after ovulation, and then last the full two weeks or so of the luteal phase. Or you can have people like patient D, where their symptoms actually go into the follicular phase for a couple of days. So, this can make PMDD a little bit difficult to ascertain in certain patients. The other challenge is to rule out other cyclic disorders. So, things like bipolar disorder or cyclothymia. Often patients come to me with PMDD, and they say that they've been misdiagnosed in the past with things like bipolar disorder. And I think on the positive side, the provider noticed that there was some cyclicity to the mood issues, but then they didn't quite put two and two together and realized that the cyclicity was tied to the menstrual cycle. So, that's a really important feature to look for. And so, you know, there are some similarities between bipolar disorder and PMDD. You have cyclicity, you have periods of euthymia, you can have irritability, but there are some important differences. So, again, PMDD is tied to the menstrual cycle. PMDD can also include those physical premenstrual symptoms that I mentioned, and PMDD also does not include hypomanic or manic symptoms. Another important thing to rule out is premenstrual syndrome or PMS. So, PMS is actually not a psychiatric disorder, and it can include only physical symptoms. So, it's not a mood disorder. It's defined by the American College of Obstetrics and Gynecology, ACOG. They define it as at least one symptom, could be mood, could be physical, that causes interference. It's present in five days prior to menses. It remits within four days of menses onset, and it has to be for at least three menstrual cycles in a row. You also want to rule out premenstrual exacerbation of another psychiatric disorder. So, these can be things like major depression, generalized anxiety disorder that worsen in the luteal phase. So, for instance, around two-thirds of women with major depression experience premenstrual worsening. If you have premenstrual worsening, the key differentiation is that you have the symptoms of, say, major depression across both phases, the follicular and luteal phase of the cycle, but the symptoms worsen in the luteal phase. So, that's something important to keep an eye out for. All right, let's go ahead and wrap up with treatment. So, I'm going to run through the key treatments for PMDD, and I'm going to focus on a few of them, which I'll highlight in blue on the next slide. So, the treatment approach, typically you want to start with non-pharmacologic. So, these are things like lifestyle modifications, sleep, exercise, diet. Calcium carbonate, also known as TUMS, has actually been shown effective in clinical trials for milder, more PMS-like symptoms, and cognitive behavioral therapy has shown some promising results as well. If you try the non-pharmacologic approaches and aren't seeing much of an improvement, you then want to move on either to a selective serotonin reuptake inhibitor or a monophasic oral contraceptive. I'll talk more about that. And then, the sort of last line treatments are a GnRH medication or oophorectomy. So, I'm going to go ahead and focus on some specific research on CBT, SSRIs, oral contraceptives, and GnRH medications. So, being a psychologist, I have to give a little shout out to CBT. So, CBT hasn't been studied extensively in PMDD, but there are some good studies on it. It has been shown to be superior to control conditions, and a systematic review examined SSRIs versus CBT for PMDD. They found that SSRIs tended to be more effective for anxiety symptoms, but CBT improved the use of adaptive coping strategies, and there's actually better maintenance of treatment effect at follow up with CBT. Interestingly, the study found no added benefit from combined SSRI and CBT treatment. And then, let's talk about SSRIs. So, these are the gold standard medication treatment for PMDD. So, they have a few kind of unique characteristics, and this could be sort of its own talk, so I won't go into a ton of detail, but just to give you a quick idea. So, SSRIs in PMDD have a fairly rapid onset of action compared to treatment for major depression, where it can take several weeks to see clinical improvement. With PMDD, it tends to work in 24 to 48 hours. We think that this is because it's working through a non-serotonergic mechanism, namely affecting the conversion of progesterone to one of its metabolites, allopregnanolone. It also works at fairly low dosages in PMDD. And then, there are a few different dosing regimens that you can use in PMDD, so I'm going to run through those. So, the first one is called continuous dosing, and this is just like you would use for major depression, where the person takes the SSRI every day. There's also intermittent dosing. This is also called luteal phase dosing. And so, in this scenario, the person takes the SSRI from the time of ovulation until menses onset, so they're taking it usually for about two weeks. And then, you also have symptom onset therapy. So, in this scenario, the person is taking the SSRI just from the time of symptom onset until menses. So, this tends to work for people like patient A, who I showed you earlier in the slide, who has symptoms just in the few days before menses. Maybe they're only having symptoms for two or three days. All right, let's move into hormonal treatments. So, there's actually pretty mixed evidence for the efficacy of oral contraceptives for PMDD, and this is interesting because a lot of women with PMDD come to our clinic saying that their providers have given them oral contraceptives to try to treat the PMDD symptoms. Interestingly, in some women, this seems to work and helps the symptoms, but in other women, they report that it makes the symptoms worse. So, again, mixed evidence for this. The one oral contraceptive that is FDA-approved specifically for PMDD is Yaz, and in a meta-analysis, Yaz did reduce PMDD symptoms pretty well, although there was a large placebo effect. Another interesting question with oral contraceptives is, do we administer them in the typical intermittent fashion, where you have a week of placebo pills, or do we give them continuously to try to avoid some of the hormonal fluctuations that might happen? So, one of my colleagues at University of Illinois Chicago, Tori Eisenlur-Mell, who does really nice work in this area, she did a really nice study to look at this question. So, she gave Yaz either continuously, so no placebo pills, versus the usual 21-7 paradigm, and she compared this to placebo. It turns out that the continuous versus the normal 21-7 regime both worked equally well, although there was, again, a large placebo effect here. And then GnRH agonists, or antagonists, as well. So, these are medications that reduce gonadal hormone levels to postmenopausal levels. So, this can be a good treatment option. 60% to 70% of women with PMDD respond to these medications, which include things like Lupron or Luprolidacetate. However, these medications have pretty significant side effects, so the cost-benefit ratio should be should really be assessed carefully. And then I also want to give a really quick mention to a medication called Sopranolone. So, this is a GABA-A receptor-modulating steroid antagonist, also known as isoallopregnanolone. And so, this showed really promising results in the initial open-label clinical trials that seemed to really reduce PMDD symptoms. Unfortunately, back in the spring, Osirena Pharma published the Phase IIb trial results, and they found that there were no significant differences in placebo versus Sopranolone, mainly due to a large placebo effect. And so, unfortunately, not super exciting news there, but I think there was initially some promise. And then a few treatment challenges with PMDD. So, again, this could be a whole separate talk. I'm not going to go into a ton of detail about it, but a colleague and I have a manuscript coming out hopefully soon that covers some of the treatment challenges with PMDD. So, these include things like medication non-response. We talked about the treatment algorithm. So, again, kind of working your way through the algorithm and, you know, trying the next step if the initial treatment didn't work. Comorbidities. So, again, these could be things like if the person has PMDD as well as generalized anxiety disorder, for instance, trying to make sure you treat both of those effectively. And then also reproductive transitions. So, things like pregnancy, postpartum, perimenopause. So, to wrap up, I just want to point out a few key facts from this talk. So, PMDD is fairly common. It affects three to eight percent of reproductive age women. There can be challenges in diagnosis, but I think one of the key diagnostic challenges is just being aware of PMDD. In terms of treatment, I talked through some of the key first and second line treatments. And then, you know, my main take-home message here is that PMDD is a treatable disorder, but that awareness on the clinician side is really key. So, with that, I want to wrap up. I want to thank my mentors, particularly Dr. Jennifer Payne and my amazing colleagues at the Hopkins Women's Mood Disorder Center. Thank you very much. Hi, everybody. This is Dr. Jennifer Payne again, and I'll be talking about designing a psychiatric treatment strategy for pregnancy. These are my disclosures, and this is my talk overview. First, we're going to talk about how common perinatal depression is and why it's actually quite important for us to treat depression during pregnancy. I'll then talk to you about my general clinical approach to designing a medication plan during pregnancy and lactation. So, first, perinatal depression and treatment. How common is perinatal depression? First, we're going to start with a case example, and I'll come back and talk about this case at the end of my discussion. Lisa is a 29-year-old female who's just discovered, whoops, that she's pregnant. The pregnancy, though not planned, is welcome. Lisa has a history of recurrent major depression since the age of 16. She's been hospitalized twice for suicidal ideation, has had no hospitalizations in the past seven years. She's currently stable on Velazodone, a newer antidepressant. She presents to her psychiatrist having stopped the Velazodone for three days asking whether she should change to another antidepressant. What should the psychiatrist advise her? Hopefully by the end of this discussion, you'll be able to give her good advice. How common is perinatal depression? Well, it's actually pretty common. You should know that there's no evidence that the risk of major depression increases during pregnancy. This is nicely illustrated by the 2002 National Epidemiologic Survey on Alcohol and Related Conditions, in which they studied 14,549 women who had a pregnancy in the past year. There was no increased risk for major depression during the pregnancy compared to non-pregnant females. However, the postpartum time period was clearly a period of increased risk and had an odds ratio of 1.52 for developing a major depressive episode. Despite this, approximately 10 percent of all pregnant women meet criteria for major depression, which is about the same rate in the non-pregnant population. The rate is higher in women from lower socioeconomic status and in women with a pre-existing mood disorder. That rate bumps to about 20-40 percent in women with a pre-existing mood disorder. We know that the postpartum time period has an increased risk of developing a depressive episode, but who exactly is at risk? Well, about 25-50 percent of women who have a pre-existing mood disorder will develop a postpartum depression. That rate is even higher in women who stop their psychiatric medications for pregnancy. About 70-90 percent will get ill in the immediate postpartum time period if they stop taking their medications. We know that environment plays a role and we know that genetics plays a role. One screening question that you can ask your patients is, has anybody in your family had postpartum depression? Why is it important to treat perinatal depression? Well, maternal suicide is an obvious reason. It's actually a major cause of maternal death in pregnancy and accounts for up to 20 percent of all postpartum deaths. In general, psychiatric disorders are the leading cause of indirect maternal deaths in the year following pregnancy. Suicide in general is rare during pregnancy and is lower than the rate in the general population, but it does cause a significant number of deaths every year and is a preventable cause of death during pregnancy. Perhaps just as important though is that adverse pregnancy outcomes are associated with being depressed during pregnancy. When mom is depressed, there's an increased risk of preterm birth, low birth weight, gestational diabetes, preeclampsia, and C-section. Treating mom during pregnancy is important not only for the mother, it is important for the baby as well. In general, it's a myth that women should tolerate being depressed during pregnancy and during the postpartum time period for the sake of the baby. The truth is that depression during and after pregnancy leads to poor outcomes for mom and the baby. If mom is depressed during pregnancy, she has a far increased risk of being depressed during the postpartum time period. Postpartum depression is considered the most common complication of having a baby, and depression during pregnancy increases this risk. Importantly, postpartum depression is associated with lower IQ, slower language development, increased risk of ADHD, behavioral problems, and psychiatric illness in babies who are exposed to their mother's postpartum depression. In addition, postpartum depressed moms are more likely to smoke and use substances, they're more likely to use the emergency room for health care, they're less likely to talk to their babies or give them vitamins or put them in car seats, and they're less likely to get their kids vaccinated or go to checkups. Therefore, it's actually quite important to treat mom during pregnancy and during the postpartum time period in order to improve outcomes not only for mom, but for the pregnancy and the infant as well. Now we'll turn to some general rules for medication plans during pregnancy. First of all, it's important to point out that you're not really having a risk-benefit discussion when you're talking about prescribing a psychiatric medication during pregnancy. You're having a risk-risk discussion. There's a risk associated with medication exposure for the pregnancy and the exposed infant. However, there are significant risks associated with untreated psychiatric illness for mom and exposure to illness for the baby. Therefore, you really have to compare the risk of medication exposure to the risk of untreated psychiatric illness. Rule number 1, we should all assume that all women of reproductive age will get pregnant. I think it's important to discuss potential complications for the baby with the medication that you're prescribing at the time that you're prescribing it even if a woman is not currently sexually active. I do think it's important that as a psychiatrist, you should know what form of birth control your patient is using and emphasize the need for a planned pregnancy regarding psychiatric medications. Remember, 50 percent of pregnancies are unplanned in the United States even today. You will have a patient get pregnant unexpectedly at some point. It's also important to note that just because a woman is using contraception, she can still get pregnant. Over the last few years, I've had a patient get pregnant who was using an IUD. Another one got pregnant while using birth control pills, and a third got pregnant after her husband had a vasectomy that apparently did not take. Rule number 2, consider exposure to psychiatric illness in utero and exposure for the baby. I hope I've convinced you that there are poor infant outcomes associated with exposure to maternal psychiatric illness during and after pregnancy. You have to consider psychiatric illness and exposure. Rule number 3, you really want to limit the exposure and exposure to psychiatric illness counts. The goal is to keep mom well during pregnancy. It does not make sense to prescribe a medication and keep it at a low dose if mom continues to not do well. It's important that she be well so that the psychiatric illness is not affecting outcomes for the pregnancy and the baby. We try to maintain mom on as few medications as possible, but again, the goal is to keep her well. If you're going to make medication changes, it's generally preferable to do them prior to pregnancy and to make sure that mom is stable before she gets pregnant. Rule number 4, use medications that we know something about. Therefore, older medications generally have more data and are easier to judge whether they're safe during pregnancy. I think it's also important to note that we use a lot of anti-seizure medications in psychiatry and the epilepsy literature increases sample sizes, so we actually know quite a lot about our anti-seizure meds during pregnancy. The FDA categories are being phased out and they're being phased out for a reason. They're actually not very useful and are quite confusing. I'll just give you one example here of the FDA categories because I continue to hear from psychiatrists and even OB-GYNs who continue to use them. The most confusing category is actually category B. Category B means either animal studies have revealed no evidence of harm to the fetus, but there are no studies in pregnant women, or animal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus. Therefore, category B means either we have no evidence in humans whatsoever, or we do have evidence that it is fairly safe in pregnancy, though animal studies indicate there may be a risk. It's important to note that newly approved FDA medications are typically rated in category B. Category B is therefore not necessarily safer than C or D, and may actually have fewer information about its safety in pregnancy. Rule number 5, every case is different. In other words, there are no rules. Designing a treatment plan for a patient is a very individual process, and I think it's quite different when someone has a history of serious suicidal ideation, suicide attempts, and hospitalizations compared to a woman who's taking an SSRI for a moderate episode of depression. Therefore, you have to make decisions based on the history of the individual before you. Rule number 6, make voluntary medication changes prior to pregnancy. Make changes during pregnancy only if you need it. In other words, if mom is ill or there's a difference in blood levels, and don't make the mistake of undertreating during pregnancy. Rule number 7, monitor blood levels when possible, and consider making prophylactic increases or decreases in order to maintain the blood level of the medication during the course of pregnancy. Pregnancy causes a whole host of different metabolic effects, and moms gain weight, their kidney function increases, as does their liver functioning. Therefore, there are many metabolic effects that result in blood changes during the course of pregnancy. It's important that if you increase a medication during pregnancy, you should consider decreasing it in the postpartum time period as those metabolic effects go away. Rule number 8, it's a team sport. It's important to know that there are a lot of other people involved with your patient. There's the patient's partner, the patient's family, the patient's mother-in-law. There's also the pediatrician, the obstetrician, gynecologist. And I think as the psychiatrist, it's important that we play the role of communicator and try to communicate to anyone and everyone who will listen what the plan is during pregnancy and why. That way, the patient does not get conflicting signals from different people in her life. Unplanned pregnancy. Rule number 1, don't panic. Taper medications that you want to try to discontinue. I once had a patient refer to me whose doctor stopped prescribing a very large amount of Xanax the moment he found out that she was pregnant. And she was in benzodiazepine withdrawal, which is not good for pregnancy. If you want to discontinue a medication, try to taper it and do so safely. Also, don't switch to an older medication. The baby is already exposed. So a very common scenario is a woman's on a newer antidepressant, she gets pregnant, and she gets taken off the newer antidepressant and put on an older one that we have a lot more information about, like Prozac, for example. That really doesn't make a lot of sense. You're exposing the baby at that point to the newer medication that she got pregnant on, the older medication that she switched to, and you have the potential of relapse of the psychiatric illness during pregnancy, which would be a third exposure. It makes a lot more sense to continue the medication unless there's a known problem with it. So I hope I've convinced you that antidepressants during pregnancy are not associated with poor infant outcomes, and that well-controlled studies do not find associations with adverse long-term infant outcomes. Now, I have a whole talk on this, and I'm not going to bore you with that, but I want you to take a look at this table that I've made. And on the left first column, you can see a whole host of infant outcomes that have been studied with antidepressant exposure in utero, cardiac defects, preterm birth, persistent pulmonary hypertension, as well as autism. It's important to note that psychiatric populations have a whole host of different behaviors and other risk factors associated with having a psychiatric illness. Women with major depression are more likely to be obese, to have diabetes, to smoke and use substances, and to take other medications during pregnancy. If you don't control for these other confounding behaviors and risk factors, you might find outcomes associated with taking a medication during pregnancy that aren't really due to taking a medication during pregnancy. There have been a number of recent studies that have really tried to adjust statistical analyses to control for these confounds. And what you can see here is in the second column, these are the unadjusted odds ratios for exposure to SSRIs for each of the outcomes I've just listed. And you can see that they're all positive. In the third column, these were studies that adjusted for underlying confounds in psychiatric illness. And what you can see is that except for preterm birth and persistent pulmonary hypertension, those associations become negative. And finally, in the fourth column, these are studies that adjusted for severity of psychiatric illness, as well as a few other confounds. And what you see is that only preterm birth is associated with exposure to antidepressants in utero. Now, you should know that preterm birth is also associated with untreated maternal depression during pregnancy. So in this population, you can expect some mild preterm birth outcomes no matter what you do and how you treat mom during pregnancy. And what about other psychiatric medication categories? Well, this again is just a brief overview. But generally, you want to avoid valproic acid and carbamazepine during pregnancy. In fact, I don't prescribe them to women of childbearing age until they have failed almost all other psychiatric medication approaches for their illness. Lithium has a bad reputation for use during pregnancy, but it actually is only associated with a less than 1% chance of Epstein's anomaly, which is a cardiac defect that you have to know for the boards. But it's a very rare outcome, and lithium can be used during pregnancy. Lamotrigine and gabapentin are generally considered safe. And remember, we have a lot of data from the epilepsy literature for them. We generally try to avoid the use of large amounts of benzodiazepines as babies can be born dependent on the benzodiazepines. And it can also suppress their respiration during the birthing process. Atypical antipsychotics have been associated with a mild developmental delay at six months that appears to resolve completely by one year. And therefore, they can be used during pregnancy. They are not associated with major organ malformations. There's very little evidence for stimulants, but what exists is pretty reassuring. Buspirone is Category B, but that is because we have no evidence for safety during pregnancy in humans. Another point I wanted to make is we are probably under treating perinatal depression. This is from some data from our own studies. And what you can see is that the dark green lists women who met criteria for depression for depression during pregnancy and during the postpartum time period. And the lighter green notes the number of them that actually received a medication change. And you can see that across pregnancy, particularly in pregnancy, but really across pregnancy as well as the postpartum time period, women who were meeting criteria for depression were not receiving medication changes even though they met criteria. Please don't under treat our pregnant women. You're then exposing the baby to the illness in addition to the medication. So here are my take home points. Active psychiatric illness during pregnancy and postpartum is associated with poor outcomes for the infant as well as for the mom. Literature on the safety of psychiatric medications during pregnancy is frequently poorly controlled and is confounded by indication, meaning it's confounded by other risk factors and behaviors associated with the psychiatric illness. And so you really need to look at the literature as a whole to determine the safety of medications during pregnancy. In general, with a few exceptions, most psychiatric medications can be used safely during pregnancy. And it's important to note that we are probably under treating psychiatric illness during pregnancy. So let's go back to our case example. What should the psychiatrist advise her? Well, this is a good example of a woman who's taking a newer antidepressant, finds out she's pregnant, stops the antidepressant, and then asks, should I switch to a different medication? So the option to switch to an older antidepressant is there. However, the baby was already exposed to the velazodone and it is likely given Lisa's history of hospitalizations that Lisa failed trials of older antidepressants. In addition, switching to a different antidepressant at this point increases the chance that Lisa will relapse and this course of action would increase the number of exposures for the baby, which would include velazodone, the other antidepressant, and possibly the illness. Thus, a more conservative course of action would be to continue the velazodone for pregnancy, thus limiting the number of exposures to only velazodone. And we'll stop there. Our goal is a healthy mom and healthy baby. And I want to thank everybody in the Women's Mood Disorders Center for their hard work and wonderful support. And we'll turn now to Dr. Lauren Osborne, who will be talking about postpartum psychiatric illness and treating during lactation. Thank you very much. Hello, everybody. I'm Lauren Osborne, the Associate Director of the Women's Mood Disorders Center, and I'm going to pick up where Dr. Payne left off at the end of pregnancy and talk about treating postpartum depression and other psychiatric disorders during lactation. I have one disclosure, just a paid CME lecture for the Psychopharmacology Institute. Here are the objectives of what we're going to try to cover today. I want everybody to have a very brief understanding of the three main mood syndromes of the postpartum, understand how to distinguish postpartum depression from the other mood syndromes and also from postpartum OCD, which is more common than you would think, and also have an understanding of how to treat psychiatric disorders during lactation. So we're going to start off talking about a patient and I'm going to bring her back throughout the presentation so you can see how we can think about her case in the setting of these illnesses and then the setting of a decision for breastfeeding. So Mary is a 34-year-old woman. She's just had her first baby. She's presenting at three weeks postpartum and she's referred to psychiatry by her OB because she's had two weeks of difficulty sleeping, worries about her health and the baby's health, poor appetite and concentration. She's feeling really ashamed because she's having difficulty with breastfeeding. She's had a lot of nausea, her stomach's in knots all the time and her partner has been reporting that she's standing by the window looking out for long periods. She's had a medical workup that's benign and so she's referred to psychiatry to see what's next. In the postpartum period, Mary's presenting at a time that's a time of great vulnerability for women to psychiatric illness. This is one of my favorite graphs showing this from a great study by Trina Monk Olson's group that shows the incredible incidence of psychiatric illness in that immediate postpartum period comparing your first child to second and third children. So you can see after a first baby, there's a huge vulnerability to postpartum psychiatric illness and in fact, a woman is about 23 times more likely to be hospitalized for the first time psychiatrically in that first month postpartum than at any other time in her life. What is the differential of postpartum psychiatric illnesses? So we saw those symptoms that Mary was presenting with. Well, that could be postpartum blues, postpartum depression, postpartum psychosis or postpartum obsessive compulsive disorder. What are all of these syndromes? Postpartum blues is not actually a psychiatric illness. So it's a common thing that occurs in most women up to about 75% of women in the postpartum. Its onset is quick after parturition and it generally lasts for a couple of days. It must last for less than two weeks. If it lasts for more than two weeks, it's not the blues. So as I said, it's not a psychiatric illness. So it's not related to your prior history in any way. It's likely related to the onset of postpartum It's likely related to these abrupt hormonal shifts that all women go through at parturition and the severity of symptoms and the time course are the keys to the diagnosis. So if a woman is presenting with really severe symptoms, it's not the blues. If she's presenting with symptoms that last more than two weeks, it's also not the blues. So does this fit with the symptoms that Mary presented with? Not really, right? We've already talked about the fact that she's presenting with two weeks of these symptoms and they seem like they're relatively severe. She's having difficulty sleeping, she's had nausea, she's feeling ashamed, probably more severe than the blues. So could it be postpartum depression? Well, postpartum depression is really just a major depressive episode occurring in the postpartum period. In fact, the DSM doesn't define postpartum depression. It says you can have a major depressive episode with peripartum onset. And that means the onset could occur during pregnancy or within four weeks postpartum. Biologically, these actually might be two different entities, depression occurring in pregnancy and depression that has its onset postpartum. But for the DSM diagnosis, it molds those two together. It occurs in roughly 15% of women differing by the population. And risk factors are prior psychiatric history, a family or personal history of postpartum depression. And some of the factors that are risk factors for other psychiatric illnesses as well, women with poor social support, single moms, women of low socioeconomic status, marital discord and stress at any time. In order to distinguish it from the blues, you wanna think about the time course, two weeks of course to make a major depressive episode, the severity of symptoms, the degree of functional impairment and the woman's history. So does postpartum depression fit Mary's symptoms? It could be, it does seem like it fits a lot of the symptoms she presented with. Postpartum psychosis is the other affective syndrome in the postpartum. It's poorly named, it's really an affective syndrome, not a psychotic syndrome, although there are psychotic symptoms. And it's characterized by confusion, disorganization and a waxing and waning of consciousness. Women will present with decreased sleep and often increased activity and energy. Manic symptoms are very common, but you could also have a postpartum psychosis with mixed or depressive symptoms. Psychotic symptoms are more likely to be delusions than frank hallucinations. And the strongest risk factors are personal and family history of bipolar disorder. In fact, postpartum psychosis is often the initial presentation of bipolar disorder for women who have no previous history. It's extremely rare. It occurs in only 0.1% in the general population, but at least 20 to 30% in women who've previously been diagnosed with bipolar disorder. It's a true psychiatric emergency. And the reason for that is that high risk of suicide and infanticide. If you encounter a woman with postpartum psychosis, she almost certainly needs inpatient hospitalization. So what about this? Does this fit Mary's symptoms? Well, maybe. We heard that she was having difficulty sleeping, although we didn't hear why, we didn't hear about activity or energy. We heard that she's standing by the window looking out for long periods of time. What's that about, right? Could that be something that's indicating that there are psychotic symptoms that we haven't uncovered yet? So I'd say it's in the differential. Finally, we have to also think about postpartum OCD. This typically presents with intrusive thoughts and images, and they're often concerning harm to the baby. It's not entirely clear what the prevalence is. Some studies show it could be as much as 9%. And onset in pregnancy and postpartum will present with slightly different presentations. So a woman who has OCD with an onset in pregnancy may have contamination obsessions, cleaning and washing obsessions, whereas those whose onset is in the postpartum are often intrusive thoughts of infant harm, and the compulsions are more likely to be avoidance and checking. Overt compulsions are less common than covert behaviors and situational avoidance. So for example, someone who is seeking reassurance a lot as a compulsion, or someone who's calling multiple doctors to ask about the health of the child or her own health. Situational avoidance might be someone who is afraid she'll drop the baby going down the stairs, so instead she sits and bumps down the stairs because she's so afraid of holding that baby dropping while she's walking. The important distinction here is that the thoughts, these intrusive thoughts are egotistonic and with preserved insight. So the woman is aware that the thoughts are not rational, and she's horrified or disgusted by any thoughts of harm to the infant. So that's a way to distinguish them from the delusions of postpartum psychosis. So what about this? Does this fit Mary's symptoms? Could be, right? She's standing by the window for a long time. Is that because she has a fear of the window? Is there something going on with the window? We heard that she had worries about her health and the baby's health. So this remains in the differential as well. One more word on postpartum OCD and postpartum psychosis, just to make that distinction. It's a really important one because you don't want to overreact to a woman who has intrusive thoughts of harm if she's not in any danger of harming the baby. But on the other hand, you don't want to underreact if there's a situation where there might be harm coming to the baby. And this handy chart just tells you how to tell the difference between intrusive thoughts, obsessions, and delusions. Apologies, I went forward. So as you can see, the intrusive thoughts are unwanted and horrifying to the patient, whereas delusion is a fixed false belief that isn't necessarily unwanted or horrifying to the patient. Those thoughts that are obsessions cause considerable distress and result in avoidance or engaging in compulsive behavior, whereas delusions don't. So why is it important to distinguish among these different mood symptoms? We've said that Mary might have postpartum depression, she might have postpartum psychosis, and she might have postpartum OCD. Why does it matter which one she has? We're treating them all, right? Well, the treatment differs, of course. So there's no treatment for the blues, that resolves on its own within a couple of weeks. For postpartum depression, we're gonna treat it as a major depressive episode. For postpartum OCD, probably still use similar medications, but higher doses are likely required. And we also have CBT with ERP as a gold standard treatment for OCD. For postpartum psychosis, lithium is the standard of care, possibly also with an antipsychotic and benzo. And if a woman is having manic or mixed symptoms, of course you don't want to treat with an antidepressant. So let's go back to Mary. As we said, those symptoms that I outlined at the beginning could be compatible with all the syndromes presented except for the blues. So when we ask her some further questions, what we find out is the following, that she does have a prior history. She had a history of anxiety in high school. She had psychotherapy for that. One episode of major depressive disorder in college, and she took 15 Benadryl at that time to escape. She denies that it was a suicide attempt. She didn't have any treatment and that episode resolved on its own in six months. She clarifies that her difficulty sleeping is due to ruminations. She does not have any excess energy. She has no intrusive thoughts or bizarre beliefs, but she does feel that she's a terrible mom and she wonders if her baby would be better off without her. So you put all those things together. We've discovered no intrusive thoughts, so no obsessions, no compulsions, no bizarre beliefs, no excess energy or activity. So we can fairly safely rule out both postpartum psychosis and postpartum OCD. And we're gonna say that Mary most likely has postpartum depression with no prior medication trials. So should we treat her? Yes. Postpartum psychiatric illness, as Dr. Payne mentioned, has devastating effects on women, children, and families. It's associated with poor bonding, family discord, and poor child outcomes. And that's independent of the association with antenatal depression, right? So both antenatal and postnatal depression will have those associations with poor child outcomes. It's also, of course, associated with suicide and more rarely with infanticide, postpartum psychosis being more associated with infanticide. And suicide is actually the leading cause of maternal death in the first year postpartum in many countries that track it that way. Suicide risk increases about 70-fold in that first year postpartum. So it's really important to treat postpartum depression, not just for the mom, but for the health of the whole family and the child. So what's a general approach to treatment during breastfeeding? Well, one thing to be aware of is that all psychiatric medications enter the breast milk. So you can't make a choice that avoids the medication getting into the breast milk. That's just not possible. But that doesn't mean you can't use them because most psychiatric medications are actually compatible with breastfeeding. Remember that about 84% of women in the U.S. will at least initiate breastfeeding and 6% will actually pump exclusively, not nursing their babies, but feeding exclusively breast milk. So for almost any woman you treat in the postpartum period, there will be at least some exposure to breastfeeding. So that has to be a consideration for medication choices. Some of the general things you want to think about are what's the woman's history of prior medication use? Well, in Mary's case, she hasn't had any medication trials. So that gives us a lot of freedom. But if a woman's responded to a prior medication, you want to think about that. Consider the time of onset. Was it during pregnancy? Is it in the postpartum? Consider the age and health of the baby because that helps you to make decisions about whether a medication will be safe to use. And remember that if a woman was treated during pregnancy, there's usually no logic to changing treatment for lactation. So if she was on a particular med in pregnancy, most likely you're going to be continuing that med during breastfeeding. I'll give you a little more information later about why that isn't a logical thing to do. So let's think about how medications get into the breast milk. What are the things you have to think about when choosing a medication for breastfeeding? Well, as you can see, there's an enormous number of things that affect how a medication gets into the breast milk. The molecular weight is probably the most important thing, right? So larger molecules can't get in, but the drug concentration for the mom is important, whether or not the molecule is lipid soluble, its degree of protein binding and its degree of ionization, its half-life. All of these are important considerations when you're thinking about which medication to use. And how does the medication get into the breast milk? So this gets back to that question of why it doesn't make sense necessarily to switch to a different medication for lactation. During pregnancy, most drugs get across the placenta. And that means that the level in the fetal serum equilibrates with the level in the maternal serum. So what's in the fetus is what's in the mom and vice versa. That means that the dose that the mom is taking and her ability to clear that drug and eliminate that drug is what governs the serum level in the infant. That's not the case during lactation. So in lactation, the infant is actually exposed only to a very small fraction of the maternal dose. And what governs the serum level in the infant is not mom's ability to clear it or mom's dose, but rather the dose that the infant receives and the infant's ability to clear it. So why is that? Well, it's fairly basic. The mammary gland is actually not a major drug eliminating organ. So anything that gets into the breast milk is not gonna be eliminated from the breast milk. It's gonna sit there, but it's also not a drug reservoir. So milk doesn't sit and pool in the breast while you're waiting to feed. Milk is produced and let down each time the baby nurses. So there's not drugs sitting there building up over time. What that means is that the exposure to the infant is just the amount that's secreted into the breast while the infant is feeding. And that's actually a relatively low amount. What are the things that you have to think about that have to do with the mom and have to do with the child when you're thinking about how to calculate how much drug a baby's getting? Well, remember that the amount that the infant takes in and the baby's ability to clear the drug together will determine the dose. In the first few days after birth, the baby isn't very good at clearing drugs out of the system because the system is just getting ramped up, but intake is very low. In the first few days after birth, babies aren't really even drinking milk. They're drinking colostrum, this pre-milk that has in very, very small quantities. Remember that infant pharmacokinetics are not the same as adults, so their clearance abilities are different. And premature babies will not have the same kinds of clearance rates as more mature babies. Kidney and liver function obviously being crucial to clearing drugs. And the more premature a baby is, the more likely there is to be some kind of dysfunction in the kidney or the liver. You also have to think, and this is something that very few people think about, what proportion of total nutrients is made up by breast milk? So some women breastfeed exclusively, other women may combine breast milk and formula. That means that the amount of nutrient that the baby is taking in through the breast milk is smaller and therefore the total exposure or total dose of the drug that the baby takes in is lower. In addition, older infants will add other sources of nutrients, for example, solid food. So again, the amount that they're taking in is much lower than for a baby who's exclusively breastfed. And so that will affect the dose that the infant is taking in. Things to think about with the mom that govern this. Well, you have to think very carefully about the need for the drug by the mother. What are the adverse effects on the mother and on the family if the mom is not treated? Does the mother have access to, and does she respond to non-pharmacological treatments? So how crucial is it to use the drug in the mom? And also what's the effect of that drug on milk production? You know, we have a case here, Mary, who was already feeling shame and guilt over some difficulty that she's having with breastfeeding. If we were to give her a drug that affected her ability to produce milk, that would not help the situation. So you have to think about that. So how do you estimate the amount that the infant is getting? I'm gonna briefly show you how you do that, but I'm also gonna tell you that you don't need to do it. It's not something to be done on a daily basis because it doesn't really affect the actual reaction that the child is gonna have, which is the most important thing. So if you look up in the literature about the drug use during lactation, you'll often see a milk to plasma ratio. That's milk to maternal plasma. And it's just the ratio of the drug in the milk to the drug in the mom's plasma. And that will represent the average concentration in milk over the dosing period, but it doesn't really tell you anything about the toxicity. You can also do a more complicated calculation called the relative infant dose. And that's something that's not gonna be reported in the literature. You would have to carry it out for each drug, for each mother and child pair. And it's a function of both that ratio and the drug clearance. So if two drugs have the same milk to plasma ratio, but one is cleared more rapidly than the dose that the infant gets is going to be lower. These can be helpful tools if you have a situation where there's a premature infant or some other reason that the infant may not be good at clearing the drug. You may wanna make these kinds of calculations to help you understand in that particular case, is there something unusual about the exposure? But what really matters for the vast majority of babies is whether the exposure results in adverse reactions. And no matter what the infant dose, adverse reactions are actually quite rare. So how do we understand adverse reactions? The first thing to remember is that nothing that we know about adverse reactions in breastfed babies is based on a randomized controlled trial. Everything's observational. And people who expect to see an adverse reaction from a baby during breastfeeding are probably more likely to notice it than if you had looked at it through a randomized controlled trial. The drugs that are most likely to cause adverse reactions are gonna be opioids or CNS depressants. And that's because there's a heightened permeability of the blood brain barrier in the baby. So those drugs are more likely to get through. The effects that you might see would be sedation, lethargy, respiratory depression, sometimes GI effects are noticed. And the basic rule of thumb is the less mature the baby is, the more likely an adverse reaction. So that goes for premature babies, but it also means the closer to birth a baby is and the less mature, that's also means more likely an adverse reaction. Older babies are less likely to have reactions. Any reaction that the baby does have could be related to high dose, high passage into the breast milk or low infant clearance. And if you give more than one drug, obviously you're gonna increase the risk of reaction. It's also important to think about maternal dosing considerations. So Dr. Payne mentioned that some drugs have to be increased during pregnancy due to heightened maternal clearance during pregnancy. It's important to remember to readjust that in the postpartum, right? The PR is gonna go back to normal. The action of the cytochrome P450 enzymes is gonna go back to normal. So you have to readjust doses in the postpartum. And there's no evidence that timing of the dose relative to timing of the feeding is important. I'll often get people saying, well, should I feed the baby first and then take my medicine? We don't have any evidence that that's gonna make a difference. So let's talk now about some specific classes of drugs and how you can use them in breastfeeding. Spoiler alert, the answer in almost all cases is that the drug is compatible with breastfeeding and keeping the mom healthy and treating her illness is the most important consideration. So antidepressants, there's good literature on antidepressants. Again, it's observational, but there's a fair amount of data. All the SSRIs have low passage into the breast milk with sertraline being particularly well-studied. Fluoxetine theoretically could be of more concern because it has that long half-life. So it's gonna stick around longer in the baby. And there were early on increased case reports of problems with fluoxetine, but that doesn't mean you would wanna switch from fluoxetine. If that's the medication that works for the baby, the advice would be to continue fluoxetine and observe. And unless there's an issue with the baby, unless you observe adverse reactions, it would be safe to continue. We have more evidence with older drugs, just as is the case for pregnancy. TCAs have been studied. They can be used in breastfeeding with the possible exception of doxepin, for which there have been more case reports of adverse reactions, particularly sedation and respiratory depression. Bupropion theoretically might increase the seizure risk, but unless you have a baby who's at increased risk for seizure, we don't have evidence that that would be problematic. We don't have very much evidence for the newer drugs, but again, remember that keeping the mom healthy, avoiding that postpartum depression is really key. And so unless there's evidence of actual risk, you can try using the drug and observe the baby for reactions. Remember that maternal history of response is key. You wanna use something that's gonna work in the baby. There's a little bit of evidence that poor neonatal adaptation may be reduced in breastfed babies. So poor neonatal adaptation is this syndrome that seems to occur in about a third of babies born to moms who took SSRIs in pregnancy. It may be a withdrawal syndrome that the babies go through. It may be something else, we're not quite sure. There's a little bit of evidence that in babies who breastfeed, that syndrome is reduced and that may indicate in fact that it is withdrawal. We have a new drug for postpartum depression, Brexanolone, which was approved, first drug ever approved by the FDA for postpartum depression. We don't have a lot of evidence about whether or not it is compatible with breastfeeding. Currently, there isn't an indication to use it during breastfeeding because we just don't have the data yet. And I just mentioned it because this may be something that a lot of people ask about. What about antipsychotics? Same story, older is better studied, so we know more about it. But at this point, both typical and atypical antipsychotics are in large part considered compatible with breastfeeding. We have more data for the typical. Again, we have no information about the very new drugs like Brexpiprazole, Cariprazine, we just don't know anything about those drugs. Think with this class of medications, what the effect is gonna be on milk production. So for example, Aripiprazole may suppress prolactin, thereby decreasing milk supply. Risperidone and some other agents may increase prolactin, improving the milk supply. So just think about that when you're deciding which drugs to use. Of all of the antipsychotics, quetiapine has the lowest passage into the breast milk due to the large size of the molecule. Clozapine, however, is the only psychiatric drug that is nearly always contraindicated in breastfeeding. The risk for agranulocytosis for the baby is just too high, we can't take that risk. So Clozapine is the one drug for which we would say, no, this woman should not breastfeed if she needs that drug. Stimulants, very limited evidence. What evidence we have indicates low passage into the breast milk for both the methylphenidate and amphetamine families. They're not well studied, but on the data we have, they're considered compatible. Theoretically, we may have concerns about appetite suppression or infant growth, but we don't yet have the data to support whether or not those concerns are valid. Large doses of them will lower prolactin, so think about that. And also remember to think about the effect on the mother or the family of discontinuing. So for example, if you have a patient whose ADHD is so severe that she may get into car accidents when she's not taking the drug, the balance of decision may be that it's safer for her and the family to take the drug than to discontinue. Anxiolytics, for benzos we have case reports of infant sedation and respiratory depression. Levels may accumulate if dosed frequently, so it's wise to try to think about agents with shorter half-lives, which are preferred over the longer half-life agents, and not to use large doses and not to dose very frequently. Buspirone, we have extremely limited data, although low levels in breast milk. Mood stabilizers. This is one of the trickier things to think about. Partly because there's just a bad rap out there for mood stabilizers in the perinatal period. And remember that the most important thing to think about with mood stabilizers in lactation is not so much the lactation risk, but the risk of breastfeeding in a woman who has bipolar disorder. And that's because of the sleep disruption. So for many women, sleep disruption is a key risk factor for the beginning of a manic episode. And it's impossible to breastfeed exclusively and not have a fair amount of sleep disruption. So that decision should be undertaken with the woman before the baby is born, and has nothing to do with the risk of the drugs in breastfeeding. It's simply the risk of the illness and the sleep disruption. But once you've made a decision that the woman is going to breastfeed, she does have bipolar disorder, what do we know about the drugs and lactation? Well, we know that lamotrigine has pretty high passage into the breast milk, but adverse reactions are not common. Theoretically, there would be a risk of Stevens-Johnson, so it's important to monitor for that, but we don't have a lot of evidence that adverse reactions do occur. Lithium is complicated, but it is not contraindicated. We used to think that it was because of the risk for lithium toxicity, but the newer evidence indicates that that's not the case. It has variable passage into the breast milk. The average among studies shows a relative infant dose of about 14% of the mom's dose. Much lower passage into the breast milk than passage across the placenta, and adverse reactions have been observed in about 9% of babies born to moms who breastfed on lithium. So some adverse reactions, but certainly not universally the case. You have to use caution. The risk for dehydration in infants is severe, right? What do infants do? They pass liquid through all of their orifices, right? They spit up, they excrete, they urinate, and everything is liquid with them. So the risk of dehydration is severe, and of course that brings with it a risk of lithium toxicity. So it has to be a case-by-case decision. It requires motivated parents, organized parents, and cooperation with the pediatrician. That has to be key because the parents have to monitor and notice if there are any signs of lithium toxicity, and the pediatrician has to be on board with that. The anti-epileptic drugs, on the other hand, are considered compatible with breastfeeding. So you heard Dr. Payne mention that she doesn't ever prescribe valproic acid or carbamazepine to a woman of childbearing age unless she's tried everything else before, and that's certainly the case for pregnancy, but there isn't an increased risk in breastfeeding. So I have occasionally had women who have not taken their mood stabilizer during pregnancy but then resume it during breastfeeding because there isn't a risk. That goes for valproic acid, for carbamazepine, for any of the other anti-epileptic drugs. So let's go back to Mary and our case and think about, now that we know all of this information about the different types of mood syndromes she might have, the way that breastfeeding works, the way that drug exposure to a baby works, and what are the risks known with different classes of medications, how are we going to treat Mary? Well, remember we decided that she had postpartum depression. It seems like her symptoms were relatively straightforward. She didn't have any psychotic symptoms, but they might be severe. Suicide might be a risk with her. She mentioned that she felt that her baby might be better off without her. What that means is that pharmacological treatment is warranted, which is not somebody we're going to want to try treating without a drug and hope that she gets better. This is something we want to tackle as soon as we can. She's had no prior medication trials, so really the field is open for us, and that means that we begin with an SSRI. Why? For the same reasons that you begin with an SSRI with any other kind of depression, that these are medications that are effective and well-tolerated. All of the SSRIs are compatible with breastfeeding, so our choice would depend on the patient preference, a side effect profile and what she thinks about the side effects, or any family members with successful use of an SSRI. If she reported to me that she had a sister with depression who was very effectively treated with citalopram, I might go with that choice. In this case, she doesn't have any of those things. None of these considerations is important, so I'm going to begin with a medication that does not have a long half-life and that has low passage into the breast milk. I'm going to choose sertraline. We'll start at 50 milligrams, and I titrate up relatively quickly, about every five to seven days, until at least 150 milligrams, as long as she tolerates it, doesn't have side effects. Then I stop there to assess the response. I want to just go over a few resources that are important. I know this has been a whirlwind tour through how to understand lactation and how to understand the risk to moms and babies of either treating or not treating during the postpartum period, but you're not going to remember all of this. You're not supposed to remember all of this, because there are places that you can look it up. The things I want to point out to you are a website called Mother to Baby that has patient fact sheets in both English and Spanish. These are for both pregnancy and postpartum, so the risks in pregnancy and lactation. Similarly, Reprotox, it's not for patients. It's for professionals, and it's a subscription service, so you have to pay for it, but it covers both pregnancy and breastfeeding, and it has a great summary of the literature. For lactation specifically, there's a publication called Hale's Medications and Mother's Milk. This is a book that's updated annually and has good explanatory material about how the passage into the breast milk works, and my favorite, LactMed. This is part of the National Library of Medicine, and it includes a summary of nearly all drugs in lactation, and it's my go-to source. I don't necessarily remember from time to time what the exact passage into the breast milk is of a particular drug, and patients often want to know, so I'll pull up LactMed and look at it while I'm discussing it with the patient. How do we summarize what we talked about today and just hammer home some key points? The postpartum is a time of really heightened vulnerability for affective disorders and for OCD. Treatment is crucial for the health of the mother, baby, and the family. All psychiatric medications pass into the breast milk, but they're nearly all compatible with breastfeeding. The one exception that is always contraindicated is clozapine. The mother's history of response is a crucial determinant of your choice of medication, and remembering that infant age and infant clearance are really important to determining what an infant's exposure will be. The goal, healthy mom, healthy baby, and I'm also going to end with a thanks to everybody in the Johns Hopkins Women's Mood Disorder Center, of course my colleague and mentor, Dr. Payne, and all of the other wonderful colleagues that we have. Hi everybody, I'm Lindsay Standeven, and I'm going to be talking about perimenopausal depression, the diagnosis and the management. I'm an assistant professor and assistant director at the Johns Hopkins Women's Mood Disorder Center. So I have no disclosures. I would like to thank some of my colleagues. Some of these slides are adapted from those created by Dr. Zathan, Dr. Smith, and Dr. Lysticow, and they can actually be found on the National Curriculum of Reproductive Psychiatry, which is the curriculum Dr. Payne referred to, created by Dr. Osborne and her colleagues, and I highly recommend it. So a quick overview. First, we're going to define what is perimenopause, what constitutes menopause, and then what's postmenopause. What are the symptoms of perimenopause? What are the risk factors for perimenopausal depression? What hormones have been implicated in perimenopausal mood disorders? What are vasomotor symptoms, and what are the different treatment options for women? I want to start with a case presentation. So Ms. B is a 49-year-old married woman who presents for a follow-up with her psychiatrist, Yu, and she has a psychiatric history that's notable for major depressive disorder that has been well-controlled over the last few years. Oops, sorry, I advanced. She also reports an increase in mood symptoms the week before the onset of her menses, typically, and she's also had a history of postpartum depression. Her pertinent reproductive history is that she had her last menstrual period was six months ago, and she started to develop hot flashes two months before that. Her medical history is notable for a mother who had estrogen-sensitive breast cancer, and she herself has type 2 diabetes that's being treated with metformin. She states in this visit that over the past three months, her mood has been worse than previously, with a notable decrease in motivation. She's had more anhedonia, irritability, and poor concentration, and she's currently experiencing hot flashes that are very bothersome during the day and overnight. So let's talk about the menopausal transition and use this case in order to really understand where is this patient in terms of perimenopause, menopause, and what are some different treatment options for her, and how do we assess and diagnose this? So menopause. So the mean age of menopause in the United States is 51, and a woman is assessed as postmenopausal only after a year since her final menstrual period. So it's actually a retrospective analysis, if you will, where after a year later of not having had a menstrual cycle or menstrual period that a woman is determined to be postmenopausal. The menopausal transition, what we call perimenopause, begins up to 10 years before menopause. The average duration of menopausal symptoms of that perimenopausal period is actually four to eight years. So this is a chart depicting what I just talked to you about. So basically from puberty until the early forties is what's termed the reproductive stage or premenopause. And then we have perimenopause, which is the period where a woman is having three or more months of reduced and irregular periods. And this is believed to be due to naturally waning estrogen levels. Again, this typically occurs in the mid forties and it averages about four years in length. And then there's the postmenopausal period, which again is 12 months after the last period. And symptoms actually can persist in some cases, even to this point. So this is a large period of a woman's life that we really need to be thinking about. And if you will, I actually think it's very understudied and very underdiscussed. So what are the symptoms of perimenopause? So there are hot flashes, which are termed vasomotor symptoms. There's irregular menses, there are headaches, there are palpitations. There's breast tenderness, there's musculoskeletal pain. There's restless leg syndrome or restless legs. There's vaginal dryness, and there's dyspareunia, there's insomnia, there's fatigue, there's low mood, there's irritability, there's impaired concentration, and there are memory problems. And I just want to note here the overlap between the symptoms in this column to your right and the symptoms of depression. It's really key. And when you're seeing a woman who's in the perimenopausal time period and thinking about, gee, what's my differential diagnosis? This is an assessment tool that I highly recommend. It's the menopause rating scale. I like it because it has a combination of, as I mentioned, both those physical and psychological symptoms that women can be experiencing so that you can really understand, okay, how many of the physical symptoms and how severe are these versus how many of the psychological symptoms is she having? And really what's sort of the thing that's bothering this individual the most? And that helps to inform not only the diagnosis, but also you'll see it really helps to inform what treatment you want to be considering. So this is one of my favorite charts. It sort of describes why reproductive psychiatry exists and why it is a subspecialty. And so what I want to sort of highlight here is what you're looking at are the rates of major depression in the US over time, over the age of onset. And what you can see is that overall women have far higher rates of major depression throughout their life, starting at puberty, right? So it's this period when the, you know, the HPG, the hypothalamic pituitary gonadal axis starts to come into development and we become physiologically different from men. And then it's periods when those hormones are changing. And when there's hormonal variability, when women are at increased risk for depressive symptoms. So you see it in puberty, we already heard about the increased risk in the reproductive years. You heard from Dr. Hanzo about the perimenstrual symptoms. And then here you see it in the perimenopausal time. So during perimenopause, 45 to 68% of women have depressive symptoms. That's not a, that's not major depressive disorder, but that's depressive symptoms. So it's really a significant amount. And then as the hormones slowly plateau and decrease and decline, we actually finally have rates of depression that are lower than men. So there's been some question about whether or not there are, you know, what are the rates of depressive symptoms versus a major depressive episode? So most commonly women experience subsyndromal depressive symptoms. The risk of experiencing a major depressive episode during menopause, during perimenopause is actually less clear. Some studies have shown an increased risk of major depressive episodes and others have not. It is clear, however, that women at highest risk for a major depressive episode during the perimenopause or the menopausal transition are those who have had prior major depressive episodes. The first, the first lifetime major depressive episode to happen during the menopausal transition is actually less common. So what are the risk factors for perimenopausal depression? Well, there are demographic risk factors. So being younger at the age of menopausal onset, being of African-American race, having less than a high school education, there are psychosocial factors. So having lower social support, having stressful life events occurring during this time and actually having trauma or adverse childhood events, something called ACEs is also increasing one's risk factor for having perimenopausal depression. There are medical comorbidities or medical things that increase one's risk for perimenopausal depression. So as I mentioned, having a prior psychiatric history, a prior history of a recurrent major depressive episode certainly increases your risk. And then having what we refer to as sort of hormonal vulnerability. So being somebody who experienced perimenstrual symptoms, maybe you're somebody who had PMDD or severe PMS, or maybe you're somebody who had perinatal symptoms such as postpartum depression or postpartum OCD. Those women are thought to maybe have a hormonal vulnerability that puts them at increased risk for perimenopausal depression when again, hormones are fluctuating. Having an elevated BMI, smoking, and other chronic medical conditions. There are also some menopause associated symptoms that can increase one's risk for perimenopausal depression. So the presence of vasomotor symptoms can increase one's risk, sleep disturbance, independent of vasomotor symptoms can increase one's risk for perimenopausal depression. So I've mentioned hormonal variability a couple of times. And so what's going on with hormones? We mentioned, as you know, that hormones are changing across the perimenopause. So which hormones thus far have been implicated in the depressive symptoms that occur during the perimenopausal time period? So the first is estrogen, right? We know that estrogen levels are decreasing. And what we've found is that women who have previously had an episode of perimenopausal depression, when they were treated with exogenous estradiol, and then that estradiol was again withdrawn. So they basically induced, again, a variability of hormones, of estrogen hormone in these women that they had a recurrence of their depressive symptoms. And the other thing that has been shown is that the higher the one's estradiol variability is, meaning the steeper the slope, or the more that it kind of bounces around or goes up and down as the levels decline, the more likely one is to have perimenopausal depressive symptoms. So again, it's this idea that fluctuating, changing hormones, not necessarily absolute levels correspond to depressive symptoms. There's actually less data showing that progesterone is associated with perimenopausal depression. And then allopregnanolone, which is a breakdown product of progesterone and a neuroactive steroid that's been implicated in postpartum depression and premenstrual dysphoric disorder has also been shown to be associated with perimenopausal depression. So again, fluctuating levels of allopregnanolone associated with perimenopausal depression. So what's the relationship between perimenopausal depression and vasomotor symptoms? A lot of people sort of think that it's a sort of domino theory, that it's this linear sort of causal effect, right? So a woman will have vasomotor symptoms, which will cause her to wake up in the middle of the night and have sleep disturbance, and then she will have depression. So for some women, that might be absolutely true. But it's actually not that clear cut. And that's not actually what the literature shows. So what we do know is that depressive symptoms can actually precede vasomotor symptoms. Sleep disturbance is actually common, 30 to 60% of women experience it in the perimenopausal time period. And even in the absence of vasomotor symptoms, we know that severe vasomotor symptoms are not necessarily associated with the onset of depressive symptoms. And we know that nighttime vasomotor symptoms are linked to depressive symptoms, even if sleep disturbance doesn't occur. There are several studies that have linked vasomotor symptoms to depressive symptoms, while others say, no, no, no, vasomotor symptoms are more associated with an actual major depressive episode or major depressive disorder. So let's talk a little bit about the etiology of vasomotor symptoms, because you're going to see this, the most common symptom that occurs during the perimenopausal time period. And we as psychiatrists actually can help with the treatment. So what's the etiology? Well, there's a couple of different thoughts. The first is that plasma levels of serotonin are decreasing by about 50% after menopause, right? So there's this decreasing level of estrogen and estrogen and serotonin are very tightly linked. Okay. So there's decreasing levels of estrogen as along with serotonin. We know that activation serotonin induced activation of serotonin receptors, specifically 5-HT1-alpha and 5-HT2-alpha cause hypothermia and hyperthermia respectively. We also know that declining levels of estrogen actually affect the feedback mechanism governing neuroepinephrine production. So neuroepinephrine levels increase, and that leads to a narrowing of the thermoneutral zone. So again, putting this all together, the current evidence suggests that serotonin and neuroepinephrine and the way that they are affected by declining levels of estrogen are both involved in the dysregulation of the thermoneutral zone before and after menopause, and that this is getting narrowed as a woman pursues through perimenopause. And just sort of spoiler alert, this is why serotonergic and androgenergic agents that we use are actually useful in the treatment of vasomotor symptoms. So I want to talk a little bit about treatment. And the truth is, I could do a whole talk on the history of hormone replacement therapy and why it fell out of favor. And actually there's a wonderful talk describing just that on the National Curriculum of Reproductive Psychiatry. But what I want to focus on here is just to tell you sort of an overview of where we were and where we are. So hormone replacement therapy or menopause hormone therapy, MHT, are estrogen with progesterone to stop hyperplasia of the uterine lining. So they're estrogen derived products, right, referred to as hormone therapy. They gained popularity in the 1970s and they were widely used. And then they fell out of favor following a World Health Initiative study in 2002, which actually showed an increased, albeit a small, absolute risk increase of cardiac coronary artery disease, stroke, PEs, and invasive breast cancers. So more recently, the current sort of guidelines are that for women aged younger than 60 years or those who are within 10 years of menopause onset and have no contraindications, the benefit risk ratio is favorable for the treatment of using MHT or HRT, it's the same thing, for the treatment of bothersome vasomotor symptoms. What we know is that HRT is actually the most effective treatment for vasomotor symptoms. And a 2004 Cochrane meta-analysis actually showed that the treatment with HRT reduces vasomotor symptoms by 75%. So no question, if a woman is really coming to you strictly for vasomotor symptoms or really is not complaining of very many psychiatric symptoms, but is mostly bothered by vasomotor symptoms and doesn't have any contraindications, HRT might be appropriate for her. But what about some of the psychiatric symptoms? So what about cognitive function? Well, several studies have excluded any cognitive benefits of HRT in women over the age of 65. Sleep disturbance? Not really. It can help if sleep disturbance is secondary to vasomotor symptoms, but less so if there are other causes. And as I mentioned before, insomnia occurs in this period of time completely separate from vasomotor symptoms. What about depressive symptoms? So HRT can be considered in menopausal women with concurrent depressive and vasomotor symptoms. But if she's really presenting with primarily depressive symptoms, there's no indication that HRT should be selected over other standards of care, such as SSRIs. So what are some alternatives to HRT for vasomotor symptoms that we as psychiatrists or psychiatric providers can feel comfortable providing? Well, SSRIs, SNRIs, and then some other alpha-adrenergic pharmacologics. So venlafaxine, a fixer at lower doses than we usually use, 37.5 to 75, reduces vasomotor symptoms 45 to 63%, Cymbalta, duloxetine, 50%, Paxil, 58 to 63, fluoxetine, 50%, and then gabapentin, 900 milligrams, a 54% reduction in clonidine, a little less, 20 to 37%. But again, these are tools that we, that we want you to have, and also to be able to understand sort of what the biology that goes into why these work. So back to our case. So we have a young woman who is coming in and she is having mostly psychiatric symptoms, right? She's complaining of anhedonia and irritability, and she's also having vasomotor symptoms. So depending on what she's really concerned about and what she is or is not taking, it might be totally appropriate to start her on an SSRI or an SNRI. I want to go over to just sort of through these categories. So what if the woman has no mood symptoms, but she does have medical contraindications to HRT? Well, then some of these others might be appropriate for her, gabapentin, clonidine, low-dose SSRI or SNRI. And what if she has no mood symptoms and no contraindications to HRT? Well, then HRT might be appropriate. Lastly, what if a woman has no mood symptoms, no contraindications to HRT, but she really is not interested in medications? Well, there are some alternative treatments that have been studied. So firstly, cognitive behavioral therapy has shown some promise and has some good evidence behind it. Psychosis actually has some decent body of evidence behind it in treating vasomotor symptoms. And then there's less evidence supporting things like soy alternatives really have very low evidence. Weight loss also has low evidence. Mindfulness has some evidence. So again, there are some alternative treatments, and this is covered in more detail in the NCRP curriculum. I thank you very much for your attention. I speak on behalf of my colleagues. I want to thank my mentors, Dr. Osborne and Dr. Payne, Dr. Hanzo. Thank you so much for being here.

clinical approaches

reproductive psychiatry

Johns Hopkins Women's Mood Disorder Center

premenstrual dysphoric disorder

psychiatric treatment plans for pregnancy

postpartum depression

perimenopausal depression

Dr. Lisa Hanzo

Dr. Jennifer Payne

Dr. Lauren Osborne

postpartum psychiatric illnesses

Mary

perimenopausal mood disorders