But we have a wonderful, the reward is a wonderful talk. I have the honor of introducing our two speakers today. Dr. Kimberly Yonkers, who is the Katz Family Chair of Psychiatry at UMass Medical School, UMass Memorial Medical Center. And as a physician scientist, her impact on the field of mood and substance use disorders in women is substantial. She conducted numerous studies supported by the NIH. These projects, sorry, focused on exploring optimal ways to identify, engage, and treat mood disorders and substance use disorders in women. In a cohort of 2,700 women, she mapped the course of mood, anxiety, and substance use disorders and examined their relationship with adverse birth outcomes. Wow. And our second speaker is Dr. Gina Civella, who is a third year psychiatry resident at UMass Chan Medical School. And before attending medical school at the University of Maryland, she worked on several projects as a research coordinator at the MGH Center for Women's Mental Health, which sparked her interest in perinatal and reproductive psychiatry. And she had just told me beforehand she had almost gone into OB-GYN, but things shifted. Lucky for us. And they're going to talk today about psychiatric update on reproductive mood disorders. Dr. Yonkers. Thank you. And it's so good that you gave, we gave each other a hand. We're all in the same boat here. Something, a couple years ago, maybe it was like 10 years ago, some of us noticed that a lot of the women's health issues happened at the end of the meeting. They were all clustered at the end of the meeting. I see somebody shaking her head. And we were like, is this purposeful? Maybe we need to do this. Let's just go to the second half of the meeting. Why do we need to go to the first half if all of our stuff is at the second half? But I don't know if that's still going on or if this was just unintentional. But it is great that people are here. So we're actually going to structure this. We're going to have sort of three components to this presentation. So, you know, just buckle up and we will go through them. And I will start by doing the first two. I'll be talking about PMS and PMDD. And then depressive disorders in perinatal individuals. And then Dr. Civella will be talking about menopause. And we will have questions afterward if that's okay with folks. And I think we have, we must have people online or do we not have people online? Okay. All righty. So let me go ahead and begin. I'm going to first start with disclosures. I'm an author for Up to Date. And I edit the APA journal, open access journal, Psychiatric Research and Clinical Practice. Shameless plug. Send us your manuscripts. We're very interested in them. You can find us online. We have the full support of APA. And it's just a very clinically oriented journal. So it's nice to be part of that. And I have grants from NIMH, NIAAA, and PCORI. Dr. Civella has nothing to disclose. No conflicts. So we hope that you folks will be able to understand some of the current definitions, as well as the epidemiology of mood disorders that are influenced by the female reproductive cycle, or at least associated with. We're making a little bit of leap of faith there that there's a causal relationship there. But there probably is. Appreciate what is known about the biological underpinnings of these mood disorders. And make evidence-based decision about effective treatments for reproductive-related mood disorders. And as I said before, we've broken this up into three sections. So we'll be talking about PMS and PMDD, as well as perinatal mood disorders, and then perimenopausal depression. So this is obviously a cartoon. I'm fine. I hate you. I love you. I want ice cream. Come here. Get away. Oranges. People can probably relate to that. And the world is replete with cartoons about PMS. But for the people who have PMS or PMDD, it really isn't a joke. When you consider that month after month, or cycle after cycle, they have five, sometimes seven, sometimes 14 days of symptoms. And during that time, it really can wreak havoc on their lives, or at least lead to some degree of disability. All the criteria for a psychiatric disorder, which includes functional impairment or disability. Symptoms during the premenstrual time do range. So for example, there's premenstrual melimina, which can be like bloating and breast pain. That's not so severe. It's annoying. Eat a lot of potato chips, you get a lot of bloating. But it's not leading to some adverse effect on your life necessarily. And then PMS, which has more impairment, and premenstrual dysphoric disorder, which is in all likelihood the most severe and less common of these various premenstrual conditions. So for these conditions, it's kind of like what we see with many psychiatric conditions. Depression can be normative in a response to, for example, loss. But then when you have a constellation of symptoms that are pervasive and enduring, it becomes a disorder. The symptoms associated with PMS and PMDD, the candidate symptoms, I should say, are similar, although what's required for a diagnosis is quite different. So for PMS, you don't have to have a mood symptom. But for PMDD, it's obligatory. And that can be affective lability. I think a lot of people have heard their patients talk about mood swings, for example. Anger and irritability, which is probably the, that's the sentinel symptom that people complain about. I mean, they certainly complain about depression and low mood. But the sentinel symptom is really anger and irritability. Depression, hopelessness, this anxiety, feeling tense, feeling on edge, like you're going to lose it or something. So decreased interest, difficulty concentrating, fatigue, over or under sleeping, change in appetite, feeling out of control, and then physical symptoms. So a lot of this is not unique to premenstrual dysphoric disorder, right? We can look at the symptom criteria for major depressive disorder, for dysthymic disorder. And a lot of the candidate symptoms can be quite similar. But what's really unique is the on-offness of the symptom expression. So that's really reflected here. So here you can see is the menstrual cycle and the follicular phase, the luteal phase, premenstrual phase. Technically, somebody's actual menses are part of the follicular phase. Ovulation happens here. These 14 days are generally set. So if somebody has irregular cycles or a longer cycle or a shorter cycle, it's because these days during the follicular phase are varied. And unless your patient has luteal phase defect, this is going to be about 14 days. Helps us with research because we can actually count back when we look at a calendar and we know where someone is. And I'll talk a little bit about that. The patterns that we see for this on-offness can vary. The most common pattern is really just about five days. And it often will traverse the onset of menses and maybe linger a day or two into the menstrual period. So if you have a patient, and I'll talk about intermittent treatments, if you have a patient that's having a tough time the first couple of days of her menstrual period, you may not want to stop treatment because she's still symptomatic. But she had the onset during that premenstrual phase. Some women will also have some symptoms during ovulation. Not just physical symptoms, but mood symptoms. And then there are a group of people who have symptoms solidly for 14 days. In my clinical experience, these are the folks that, you know, they're sort of on the line between premenstrual dysphoric disorder and another mood disorder. Often they'll have dysthymic disorder. Often they'll have dysthymic disorder that worsens during the premenstrual phase. Or they'll have major depressive disorder. Some of our epidemiological research, some of the research from my lab, shows that even though DSM-5 stipulates five of those candidate symptoms, four really predicts a diagnosis of PMDD. And maybe we'll see something happen in the next iteration of DSM to correct that. Symptom severity is greatest just before the onset of menses, about four days before, but also a couple days after. So it's important to attend to that. And I mentioned that depressed mood is not the most common symptom. It's really more irritability and mood swings. Now, there are two mainstays of treatment for premenstrual dysphoric disorder. And I should back up and say, most of the research, the clinical trials, as well as the biological research, focuses on premenstrual dysphoric disorder because that is well operationalized. ACOG did not even, they had a definition of PMS years ago and then they pulled it. And they didn't really reintroduce a diagnosis of PMS until more recently, within the last couple of years. And now it's included in the guidelines that were just published in their Green Journal about six months ago. But the mainstay of treatment for premenstrual dysphoric disorder are the serotonin reuptake inhibitors. By far, the data are strongest for use of these agents in PMDD, stronger than what we see actually for major depressive disorder. The uniformity of the clinical trials is very robust. Some of the SRIs have FDA approval. Not all of them do, but people certainly use them interchangeably for treatment. And what's unique about treatment for premenstrual dysphoric disorder compared to major depressive disorder or panic disorder or some other conditions is that these treatments, even though they're SRIs, can be used full cycle, half cycle. And we now know that treatment can be initiated at symptom onset. So that's really different. For major depressive disorder, we're all taught, medical school, residency, that somebody has to be on medication for at least two weeks to show the therapeutic benefit. But that's not necessarily the case for PMDD. The other treatment that is a mainstay are oral contraceptives. I will say that the data are not as strong for oral contraceptives at all. They tend to be stronger for there's one compound that has a shortened hormone-free interval and a unique progestin. It's called Yaz. And the progestin is drosperinone. It's very much like spironolactone, which is a diuretic. And so there may be some of those properties that are helpful for not just the physical symptoms, but actually for mood symptoms. There's some work that was done 30, 40 years ago that showed spironolactone may have mood-stabilizing effect for individuals with bipolar disorder. So that may be the active component of some of these compounds with the shortened hormone-free interval. That is a reasonable choice for people who desire contraception or for people who are not bothered as much by mood symptoms, but they're having a tougher time with some of the physical symptoms. OK, how do you treat PMDD? Well, as with other psychiatric conditions, you need to start with a really good medical and psychiatric history. And you want to know if there are any concurrent medical conditions that can contribute to somebody feeling poorly or be exacerbated or exacerbate a psychiatric condition. The tough part of this is asking your patient to keep some sort of menstrual calendar. And a lot of people who I see will come in and they'll pull out, well, in the days we had paper calendars. Now they bring out their phone. And they've jotted notes of when they started to be symptomatic and what symptoms they had. And that can be helpful to get going. And it can also be helpful in terms of working with them and convincing them of the value of a calendar. And I can't underscore that enough if we can have them do it. Because it can really illustrate whether symptoms do have that on-offness that I was just talking about, or whether there may be some symptoms all the time and somebody is just getting worse permenstrually. It can also tell you how many days they have symptoms. And it can tell you which are the worst symptoms. So that is your segue after you have the calendar in a discussion with your patient about what kind of treatment would she like to try? Would she, is she a candidate for daily treatment only because she always has some sort of symptoms? Or is she a candidate for half-cycle treatment or symptom-onset treatment? You know, this is a calendar that I've used in research, it was designed by Jean Endicott at Columbia, and it, but it can also be used clinically. You know, if somebody doesn't want to keep the entire calendar, they can just, you know, mark the symptoms that they identify as particularly problematic. So it's called the Daily Record of Severity of Problems. And according to my daughter, who does all things tech, and she's like in her 20s, so they find all of these things online. You can find these things online and just, you know, download them and mark it. They can mark it, as long as they can share it with you, as long as they have some sort of format. I'm sort of a dinosaur when it comes to digital things, so I like to see the paper if it's possible, but it doesn't always happen. So as you may have gathered, having these markers of when is, I could stand here and say half-cycle treatment works, or symptom-onset treatment works, but it may be difficult to implement that. And as you might gather, it's very, very useful to have that calendar to know when to begin that half-cycle treatment. Many women will, when they pull their calendar up, they'll show you that they have some physical symptoms and then the mood symptoms start. So maybe they start with breast pain, maybe they start with fatigue, and then that can be helpful so you know when to start treatment. Some people, when they ovulate, they have middle schmertz, some discomfort, that can also be helpful. But some people have to rely on dates, and that's why I said before, the luteal phase tends to be 14 days. So you can count back if somebody's regular, and you can identify when they should start their half-cycle treatment. And if they're really motivated not to take pills every day, they can do it. But sometimes it doesn't work, and before they know it, they're in the middle of their premenstrual episode, and they're like, oh my God, I didn't take my pills. So you do have to be mindful about it. And that's part of the treatment, right? We know this, being mindful and managing, observing, can be part of the treatment. Symptom onset treatment can also be very tricky. People who are a candidate for this, or people who have delimited symptoms toward the end of their cycle, but they have to come up with some physical cues or other cues. And again, that's where you as their clinician sit down with them and review their calendars and say, well, you know, it looks like from these two calendars, your symptoms started about five to seven days before, and you were already having bloating and feeling really tired. So that's the time to start your pills. And then you have to evaluate the outcome. And if they're able to do it, that's great. If they're not able to do it, they may have to move to half-cycle or even daily treatment. A couple of things to just be mindful of. Physical symptoms don't seem, at least in the clinical trial literature, physical symptoms don't seem to respond quite as well to intermittent treatments as does daily treatment throughout the menstrual cycle. And I don't know if that, you need a certain blood level or whatever, but if physical symptoms are really prominent, you may notice that your patients are not doing quite as well. I already mentioned that it can be a challenge determining when to start treatment. And those are questions that you'll have to ask your patient and work over that. And if one SRI doesn't work or it's not well tolerated, you can try a different one and see if that is helpful. So what about the hormonal treatments? Well, I put up here, this is a daily patch. It has levonorgestrel and ethinyl estradiol. And this particular treatment has no hormone-free interval. So it can be helpful for PMS. One word of caution that I'll say, some people cannot tolerate the daily treatments that have no hormone-free interval at all. And they will get markedly worse. So if your patient has that, just tell them to stop it, go to something where they have a hormone-free interval for three to five days and not no hormone-free interval. And these are some of the data with YAS, which is drosperinone and ethinyl estradiol. So you can see here, these are the adjusted mean differences. And here are the p-values. So really, pretty much everything benefited, which we wouldn't have expected from an oral contraceptive. But I really think the progestin and the stability of a shortened hormone-free interval augured well for this group of patients. There may be some new treatments on the horizon. I'm going to talk a little bit more about neurosteroids when we talk about, when I move to talk about treating individuals with perinatal mood disorders. And not surprisingly, some of these agents may be helpful for PMDD as well. Here you see, what I'm referring to are agonists of allopregnanolone as well as antagonists of allopregnanolone. Here you have isoallopregnanolone. This was given as an IV injection to individuals who had premenstrual dysphoric disorder. It's called sopranolone. It was developed by Toby Backstrom in Sweden. And I think it's being developed by a pharmaceutical company. But that actually was found to be effective. What it did is it blocked the, I don't know if I can go back to this slide. It blocked that progesterone peak that I showed you earlier. So progesterone would be metabolized to allopregnanolone. It blocked that peak so you didn't have this withdrawal right at the onset of menses. So the whole notion is a compound like a metabolite of progesterone is available during the luteal phase. It's gradually increasing. The metabolites, which may have, those are the neurosteroids, which may have therapeutic benefit are also accruing during the luteal phase. But then the onset of menses, that shuts down and there's a precipitous withdrawal. And this blocks that. So in summary, PMDD is treatable. I think SRIs remain the first line treatment. Some contraceptives may be helpful. It's not a class effect though. They're really, some are effective and some are not. I think we're going to have some new treatments on the horizon, which will be helpful and first in class. Now I'm going to move to talk about the care of pregnant individuals with mood disorders. And I just want to start off by giving you some statistics. And we think about three to nine percent of individuals who are perinatal have major depression or who are pregnant have major depressive disorder. Now there, you may have heard other statistics of the rate of depression in pregnancy, you know, and I've certainly heard a whole bunch of them. I've heard 15 to 20 percent. That's really high. I don't even believe that, but that probably includes minor depressive disorder as well as major depressive disorder. But I don't even think that's an accurate number. It's really the best research, epidemiological research suggests is much lower. And then there are six to nine percent of women who are depressed after delivery. These rates, by the way, are not substantially higher than the general rates in women in general who are not perinatal. And there, you know, I know we hear a lot about postpartum depression, but it's not like there's this huge spike after delivery in the rates of depression. They're actually fairly, they're fairly tight in terms of the rates of depression after delivery. It's just, I do think that severity may change and there are a lot of issues that people have to contend with when they're depressed and pregnant or depressed in postpartum and what some of the adverse effects of medication and illness are. Importantly, about 50% of episodes of postpartum depression began during pregnancy. And even some of the research I'm going to present to you on some of the newer agents, when they were recruiting people for the studies, they allowed people who had an onset of their depressive disorder in the third trimester. So depression is more common in women. It's pretty common in reproductive age women. We treat them. We treat them with psychotherapy. We also treat them with medication. It is not unusual for them to come in and say when they're on treatment, oh, I just found out I'm pregnant. Every study that I've done, I've done a lot of clinical trials with reproductive age women and everyone that I've done, we can send people, we say, you know, we would like you to use some form of contraception. We would prefer if you do not get pregnant during this trial. We don't know what this particular compound will do vis-a-vis your pregnancy. And it's just better to wait until after you're done with the clinical trial. Every study, at least one person gets pregnant. So your patient shows up. They're pregnant. What do you do? And in reality, it's much better now, but boy, 10 or 15 years ago, if you had a story to tell or if you had a clinical trial saying that either depression or medication was harming the baby, you were in the New York Times and the Washington Post. We have to appreciate that our patients are being bombarded with the media and now social media. And what they see in the media and social media does not necessarily track with science. Sometimes it does, but sometimes it doesn't. And they can hear some pretty, you know, worrisome things and they can hear their experiences of friends. So they may think that depression can harm their baby. And can you imagine what a message that is? People do not generally seek out the state of depression. And so here you have somebody who's suffering because they have a mood disorder and on top of it, they're hearing these things that this illness that they don't want and they're miserable about is also harming their baby. That's just a terrible message. And you know, I try and work with patients and discuss this because it's not like they willfully want to harm their baby. But then on the other hand, they also hear the message that antidepressants can harm their baby. So what do you do? I think one of the things that's incumbent upon us is just what you're doing here. We have to get educated. We know what the science shows so we can share that information with our patients. The other thing I think is really important to just when you begin this discussion is to disabuse them of really what some of the causative factors are in the research. And in fact, unhealthy habits are more problematic than any psychotropic treatment. So smoking is highly associated with low birth weight. Drinking is associated with fetal alcohol effects as well as fetal alcohol syndrome and low birth weight. Other substances, cocaine, stimulants are associated with intrauterine growth restriction, preterm birth, abruption, opioids, very highly associated with preterm birth even when they're taken as prescribed. And over half of pregnant women will take a prescription medication in pregnancy. That's a lot. More than half take a non-vitamin over-the-counter treatment and we don't always know what these compounds are doing. It's not like they're being tested in gestating individuals. About 5% take an antidepressant but that's like fluctuated a lot depending on what is out there in the media. So what are the consequences of antidepressant treatment during pregnancy? So this is just, if you will, a summary and a number of birth outcomes have been investigated. In my own research we've looked at a number of these as well. So spontaneous miscarriage, mixed results but there isn't a strong signal. Fetal demise is not associated with taking an antidepressant. Preterm birth is and these are also in my data they are but they're small effects associated with using an antidepressant. Small for gestational age and low birth weight. Mixed results but they're weak. We don't find it in our work. Major congenital anomalies, I'm going to drill down into that. Weak results, the standout in that is with paroxetine. Persistent pulmonary hypertension and I'll talk a little bit more about that. That is mixed but the better replicated studies find that exposures in late pregnancy have a greater association with that. Genital adaptation, very highly replicated. Autism mixed results but I'll show you some data. Better controlled studies are negative. Preeclampsia and gestational hypertension are associated with antidepressants, specifically SRI use in pregnancy. And ADHD, of course I'm talking about the outcomes in the offspring. A mixed but weak results in the better studies are negative. Okay, I've shown you what a dinosaur I am with tech. Because I can't advance the slide. Let's see, let me try a different way, okay, nope, not working. All right, let me see if I skipped something. I got it. OK, good. This one worked. All right, so this is an interesting study. And I think it nicely illustrates what I'm talking about in terms of the quality of the study. So this particular study was looking at various antidepressant use in pregnancy and cardiac malformations. Anybody remember hearing stories in the media about, oh my god, SRIs can cause cardiac malformations? Anybody? Thank goodness that many people haven't heard that. But your patients may come up with that. But for a while, it was a real concern about SRIs. So here you see, these are the unadjusted data. Much of these data that I'm going to show you, they're unadjusted. So they don't adjust for, what did I say when you're evaluating a patient, that health habits have a major impact on some of these outcomes. So they didn't necessarily adjust for things like smoking or alcohol use, which can be major confounders. So here you see instead, this panel here was a very robust adjustment using propensity scores. So they were able to adjust with a number of factors that could have confounded the results. And you see, these are 95% confidence intervals and point estimates. If the 95% confidence interval crosses here, crosses one, it is not significant. And here it is in text. But just visually, you can see, wow, what a difference controlling for this. So really, was the causative factor the antidepressant or these other exposures? It probably was the other exposures. Now, this was a really clever, I love this, this was a very clever way to look at this problem. So one of the problems is you have a large epidemiological database. In our country, we have a Medicaid database. 50% of pregnancies are covered by Medicaid. So they have a lot of pregnancies they could look at. But there's social determinants of health, there are exposures to other agents, there's race, ethnicity, all these can bear upon birth outcomes. So they need to be controlled for. And the database may not have all of these features. Sometimes they do have them, sometimes they don't, sometimes they're accurate, sometimes they're not. So this particular study used sibling comparisons because a lot of the social determinants of health, race, ethnicity are shared among siblings. So you're able to look not only at adjustments, but you can look at the siblings and see is an antidepressant associated with preterm birth? Is an antidepressant associated for small, for gestational age? And here you see the baseline, and if you were to look at this, they both do not cross one, so there is a significant association. But when you adjust for it, it's smaller. And then interestingly, when you put the sibling comparison, like why would a sibling who is not on an antidepressant have a higher rate of preterm birth? It's not because of the antidepressant that her sister is taking, it's because of all of these other features. And the same thing for serotonin reuptake inhibitors. I wanted to kind of give you some context as I'm throwing a lot of numbers at you and a lot of figures. I wanted to show you the estimated absolute risk for true teratogens, and I also wanted to include serotonin reuptake inhibitors on this list. So for your patient, and take note of this, I'll talk about it in a little while, who is undergoing treatment with valproic acid, the estimated absolute risk of any major defect is 11 out of 100 exposed. That is a teratogen. Isotretinin, it is 18 out of 100. Alcohol, 25 out of 100. SRIs, three out of 10,000. So where's the problem there? Porneonatal adaptation. We all know that abrupt discontinuation of a serotonin reuptake inhibitor, if a patient's been taking it for months and months, can lead to some discontinuation syndrome, right? That can be they can feel jittery, they have the electric shocks, a variety of things. This is in all likelihood what we're seeing in some of these infants that are exposed, that are born and they were exposed to serotonin reuptake inhibitors in pregnancy. But it can be different. It can include jaundice, hypoglycemia. Developmentally, babies are not adults, so there are gonna be some differences. And they often are admitted to a step-down or neonatal ICU. The more worrisome condition is PNAS, which is characterized by respiratory distress, heart defects, so that occurs in about 2.2-fold of babies that are exposed. And there is a seven, almost an eight-fold increase in tremors. And I think the data are strong enough that it's worth discussing all of this with your patient so they're not taken by surprise. This is just another study for ADHD. I mentioned that the data for ADHD and autism are kind of mixed and a lot, this particular project used, they compared people who were exposed to those who were not exposed. But their clever take on it was they took the people who were exposed pre-pregnancy and unexposed. So people had two pregnancies, right? One was exposed, one was not exposed. And if the exposure was only the antidepressant, you would just see it high in that group, but it wasn't. Just the characteristics of the individual led to an association here. So what does this suggest? It suggests it's more than the antidepressant at play here. And you can explain this to your patients. This was a sibling design, as I talked about before. And even paternal exposure, like why would a husband or male partner who is taking an SRI, why would they have, the mom have a higher rate of ADHD or autism? Because it's not a causal association, that's why. Breastfeeding, now your patient's delivered. Breastfeeding is generally recommended with antidepressant use. And that's just because breastfeeding is really good for babies. You can minimize, or you can have your patient minimize exposure by pumping and then not using the next feed. That's sort of hard to do, but it can be done. I think that rather than monitoring levels, I think the wisest thing to do is monitor the baby. Is the baby sleeping OK, eating OK? Is the baby fussy? And if there are problems, then you may want to take a look at levels or go a different route. Now, I want to talk a little bit about some of the novel treatments of postpartum depression. When I was talking about premenstrual dysphoric disorder, I was talking about neurosteroids. So what are neurosteroids? Neurosteroids are C21 steroids that are derived from cholesterol. And here you have cholesterol. And it is cleaved to pregnenolone, which is the precursor for progesterone. It's reduced to 5-alpha-dihydroprogesterone. And then either to epialopregnanolone, which is an antagonist, or allopregnanolone, which is a compound which has been developed for treatment of postpartum depression. So allopregnanolone is actually a compound that binds at the GABA receptor. And here's a picture of the GABA receptor. So neuroactive steroids, they bind here. They have a very novel binding site at this receptor. And there's multiple subunits in the GABA receptor. This is the gamma subunit, which is needed for this activity, and alpha and beta. Benzodiazepines bind here. So they actually bind at a different site. And what they do is they facilitate the opening of this ionophore here. So chlorine can go in and out more easily. And it changes the threshold of firing. They act actually very similarly to barbiturates, much more like barbiturates than benzodiazepines. But they're not as strong. So the ranolone, which you've probably heard of, and I want to show you structurally. I'm not going to be talking about brexanolone, which was the first compound. Brexanolone, which was given IV, is this. It's allopregnanolone. But IV has a number of issues. It was a 60-hour infusion. People had to go to an infusion site or be an inpatient. They had to pay a lot of money. So be separated from their family for days. So this is the PO version of allopregnanolone. And they made this stable by adding this nitrile moiety to it. So the data showing that it's effective were published in JAMA Psychiatry. And the pivotal trial took 150 women. And they randomized them to either ziranolone, which was taken by mouth, or placebo. And they treated them for 14 days. So the notion behind this is this particular treatment can be used for two weeks. And then you're good. So you're resetting whatever was put awry in the brain through this treatment. They had 27 clinical sites. People had to have a Hamilton rating scale score of 26, which is sick. It's more than minor depression. It's really major depression. And here you see the results of these. This is time in days. So the treatment was initiated for two weeks. You see this separation after about two or three days between placebo and ziranolone. And then it was maintained for 45 days. And this is what led to FDA approval for the first compound specifically designed to treat perinatal depression. So how do you use ziranolone? It comes in 20, 25, and 30 milligram capsules. 50 milligrams daily for two weeks is the recommended dose. But if people are having side effects, and the kind of side effects that they experience may be sedation, they can lower it into 40 milligrams. And then if they can tolerate, go back up to 50. Best to take it at night, because it can cause some sedation. People may want some sedation at night. They will not want to be so sedated, however, that they don't hear their baby. So you have to talk with them about that. It is absorbed best if it's taken with fatty foods. And of course, you want to recommend that your patient not drive or use hazardous machinery. But we're early in using this particular medication. So we have more to learn, and more work needs to be done. So for example, can 14 days of treatment protect somebody against relapse of a major depressive disorder for months or years? We don't know. There are some data with brexanilone, the IV version, that go out to 60 days. But we need to know about many months and years. Should xeranilone be the first line treatment? What if somebody has recurrent major depressive disorder, and they get depressed in the perinatal time period? Should they just receive xeranilone, and that's it? Or should they be put on a different antidepressant afterward? Or should they be started on maintenance therapy during that time? And then what about the cost? Because I understand it's going to be $12,000 or $14,000 or something like that. But that's what we're seeing with a lot of new agents. I did want to talk a little bit about bipolar disorder in pregnancy. You probably know that bipolar disorder occurs in about 1% of the female population. And it's highly associated with postpartum psychosis. So about 50% of perinatal individuals who have a psychotic episode at the end of pregnancy or after delivery go on to express a clinical course consistent with bipolar disorder. The onset of typically dysphoric mania, it can be either pre-delivery or after delivery, often is expressed at dysphoric mania. And they can kind of have a roughening of their mood, or they could have a frank episode occurring and escalating into mania. Lithium has a bad rap in terms of its use in pregnancy. There were older data suggesting that its use or its treatment was associated with cardiac valve defects, primarily Epstein's anomaly. And it was controversial for a while. But it probably does have a slightly increased risk. So if you can avoid it during the first trimester, it doesn't mean that your patient is automatically going to get Epstein's anomaly or a heart valve defect. But if there's a bad outcome, it's better that if you can avoid it, don't use it. Because in pregnancy and medication, there's a lot of true, true, and not related. And we don't really know. I talked a lot about health habits. Somebody who's smoking and drinking may take lithium and say it's not the alcohol, it's not smoking, it's the lithium. And if they hire a good attorney, it could be difficult. It's important to monitor levels through pregnancy and adjust the dosage. Dosage tends to increase. What you need increases over time because GFR increases. A lot of experts suggest right around delivery to either holding a dose or two or cutting it in half because there are huge fluid fluctuations when somebody delivers. And that hydration stat, you don't want somebody to become toxic. You should tell your patient to avoid breastfeeding if they're undergoing lithium treatment postnatally because lithium equilibrates totally in breast milk. So it will be giving the baby lithium. And we know babies are not mature. Their livers are not mature. Their renal system is not mature when they deliver. So in summary, perinatal depression is common, probably not as common as some of the data from the media. But nonetheless, patients really should be informed of the risks. But antidepressants such as SRI, in my view, should not be considered frank teratogens. Some new treatments show promise. But a number of issues need to be resolved before we can really figure out where they belong in our armamentarium. And now let me turn this over to Dr. Civella. I don't know why this is. Here you go. Thank you. I'm going to steal your water bottle spot, there we go, alright, alright. Hi everybody, so I'm going to spend the remainder of this session discussing symptoms related to the menopausal transition and their treatments. Just to set the scene a bit first, what is menopause? Menopause refers to when a woman goes 12 consecutive months without a menstrual period, and this marks the permanent loss of fertility and ovarian function in those individuals. The average age of menopause in the United States is about 51, but when we talk about mood symptoms and symptoms in menopause, we're really focusing more on this menopausal transition or perimenopause that precedes menopause. Women tend to start perimenopause in their mid-40s, and this period lasts about 4-5 years on average, but can be much longer, up to 10 years in some individuals. And the younger an individual is when they enter perimenopause, the longer this transition usually lasts. So like the other major transitions in the reproductive years that Dr. Yonkers talked about, perimenopause is marked by fluctuations in reproductive hormones. So as the number of ovarian follicles starts to dwindle, there'll be an initial fluctuation followed by a drop in estradiol, and an initial fluctuation followed by an increase in follicle-stimulating hormone. Individuals will begin to notice irregular menstrual cycles with longer and longer and longer durations of amenorrhea between each period until they go those 12 consecutive months, and then they're considered post-menopausal. And individuals can experience a host of somatic and psychiatric symptoms during this menopausal transition. The three that I'm going to focus on today are vasomotor symptoms, sleep disturbances, and mood changes like depression. So vasomotor symptoms, this refers to night sweats and hot flashes. Some people refer to them as hot flushes because I think flash implies that they're really quick and sometimes they can last a very long time. And these are very common in the menopausal transition. So up to 80% of individuals experience vasomotor symptoms in perimenopause. And these symptoms are due to disruptions in core body temperature homeostasis in the hypothalamus, due to those fluctuations in estrogen and reduced sensitivity to feedback in the HPA axis. And they're actually the most common reason that perimenopausal women seek treatment. So this just shows how impairing and bothersome they can be. And the median duration of vasomotor symptoms is about seven and a half years. So the study of women's health across the nation or the SWAN study, they looked at factors that affect the duration of vasomotor symptoms and found that vasomotor symptoms last longer in some individuals than others. So if you can look to this graph on the left here, this horizontal line going across represents the median. This green dotted line, that's all participants in the SWAN study where the median duration was about seven and a half years. And it found that the women whose vasomotor symptoms began early in perimenopause had a longer duration of symptoms, almost 10 years. That's this orange line. They also found that the duration of vasomotor symptoms varied depending on race and ethnicity, with African American women having the longest duration of vasomotor symptoms, over 10 years, and Japanese women had the shortest duration, that's this dotted orange line, about five years. The duration of vasomotor symptoms was also longer for women who were younger, women who had ever smoked tobacco, women who reported greater perceived stress and symptom severity, and women who reported higher anxiety and depressive symptoms. The SWAN study also collected data on sleep disturbances. These were self-reported sleep disturbances. Every two weeks for seven years of the SWAN study, they looked at three different types of sleep disturbances, difficulty falling asleep, difficulty staying asleep, and early awakenings. Here you'll see these are the age-adjusted odd ratios for each of those types of sleep disturbances at different stages across the menopausal transition. As you'll see, as women aged across menopause, they reported significantly more likely to report these sleep disturbances compared to their premenopausal baseline. In some cases, even doubled the prevalence of sleep disturbances. It may not surprise you to know that the greatest risk factor for sleep disturbance in the menopausal transition was sleep disturbance in the premenstrual years. Mood symptoms are also quite common in perimenopause. Not only depression, but irritability, mood lability, and anxiety as well. Clinical studies have been somewhat inconsistent in detecting significantly increased incidence of depression in perimenopause, but the longitudinal studies that follow women across this transition do show somewhere between a 30% to 80% increase in the prevalence of clinical depression. There was actually an article that came out just this past March that suggested we may be grossly overestimating the increased risk of depression and menopause. But what everyone can agree on is that the women who are most vulnerable to depression and perimenopause are the ones with a history of major depressive episodes, and they have an increased risk that's about fourfold. Other factors that increase risk for perimenopausal depression are increased sensitivity to ovarian hormone fluctuations, so these would be the patients with a history of PMDD or history of postpartum depression, poor sleep and vasomotor symptoms during perimenopause, a longer duration of perimenopause, psychosocial stressors like unemployment, lack of social supports, some major negative life event before menopause, as well as smoking. So next I'll be talking about the treatments that we have for vasomotor symptoms and depression. And as you'll see, there's a lot of overlap between these two. So for individuals that have mild vasomotor symptoms that maybe they're not too bothersome, lifestyle changes might be sufficient. So this would include things like lowering the thermostat, putting a fan on at night, dressing in layers, avoiding certain foods like spicy foods, alcohol, or caffeine, and losing weight if indicated. But for those with moderate to severe vasomotor symptoms that are bothersome and impairing, hormone therapy should be considered and is the most effective treatment for vasomotor symptoms if certain criteria are met. So the current Endocrine Society clinical practice guidelines recommend hormone therapy for women who are less than 60 years old, less than 10 years post-menopause, and who have no contraindications to hormone therapy and who do not have high cardiovascular or breast cancer risks. So if women do have high cardiovascular risks, they should seek non-hormonal treatment. If they have moderate cardiovascular risks, they are candidates for hormone therapy, but it's advised that they use the transdermal estradiol instead of oral. And if they're low cardiovascular risk, they can take oral estradiol, which is shown to be more effective than the transdermal. If women have a uterus, they should be on treatment with both estrogen and progesterone to lower that risk of endometrial cancer with the unopposed estrogen. If they don't have a uterus, if they've had a hysterectomy, they can be on estrogen monotherapy. And these are very effective for vasomotor symptoms. So they have been shown to decrease hot flash frequency by 75% and decrease hot flash severity by 87%. I'll add that placebo effects were quite robust in these studies, somewhere around 50%, but these were still significantly reduced symptoms in comparison. So I mentioned hormone therapy is the most effective treatment for vasomotor symptoms, but what about individuals who can't have hormone therapy? Maybe they have contraindications or they don't fit the demographic criteria, or maybe it's just personal preference and they don't want to be treated with hormones. So the next line therapies that are shown to be effective are SSRIs and SNRIs. Also gabapentin and pregabalin. And if all of the above are not effective or not well tolerated, there's some evidence for clonidine with the patch preferred over the oral. I'll just add that some therapies that have not consistently shown benefit for vasomotor symptoms include herbal supplements and botanicals, omega-3s, acupuncture, and hypnosis. And there's been several clinical trials comparing various SRIs to placebo for the treatment of vasomotor symptoms. So here is a compilation of those findings. This graph up top shows percent reductions in hot flash frequency, and the bottom here is a percent reduction in a severity frequency composite score. These white boxes are the placebo, and the colored boxes are the active treatments. And what we've found is that paroxetine, venlafaxine, desvenlafaxine, citalopram, and escitalopram have all shown statistically significant reductions in hot flashes, decreasing those severity frequency composite scores by somewhere between 27% to 61%. The efficacy data has been inconsistent for fluoxetine and sertraline with trends towards significance but not statistically significant reductions in hot flashes. And lower doses are typically needed for the treatment of vasomotor symptoms compared to the doses that we would use to treat major depressive disorder. I want to just highlight two of these medications. So paroxetine and venlafaxine do show the greatest efficacy among these medications. There's a low-dose paroxetine that has been FDA-approved for treatment of vasomotor symptoms in menopause. It's a 7.5-milligram capsule taken once nightly. It goes by the brand name Brisdell. They made it all pretty and pink, but not to say you can't just use regular low-dose paroxetine. There was also a placebo-controlled study comparing 75-milligram venlafaxine with placebo and hormone therapy. And that study actually found that the 75-milligram venlafaxine was just as effective as hormone therapy in reducing vasomotor symptoms. A new medication was just FDA-approved last year for the treatment of menopause-related vasomotor symptoms. I'll only say this name once, but fezolinatant is the generic and it goes by VEOSA. This is a non-hormonal treatment. It's actually an antagonist at neurokinin 3 or NK3 receptors. So how this works is there are these KNDY neurons in the hypothalamic thermoregulatory center that depend on this balance and signaling between estrogen and neurokinins. So when estrogen levels drop in perimenopause, there's this unopposed stimulation from neurokinin B at that NK3 receptor. This kind of sends the neurons into overdrive and this can cause hot flashes. So what VEOSA aimed to do is restore this balance in signaling between estrogen and the neurokinins by blocking neurokinin at the NK3 receptor. And there were two similar double-blinded placebo-controlled trials called the Skylight Trials. For these studies, for the first 12 weeks, patients were randomized to get either placebo or one of two doses of VEOSA. And then it was followed by a 40-week extension where the patients who had been taking placebo were re-randomized to receive one of those two doses of VEOSA. And their primary endpoint by 12 weeks, but even earlier than that, the medication showed significant reductions in both hot flash frequency and hot flash severity compared to placebo. And these benefits were maintained throughout that 40-week extension out to 52 weeks. It was pretty well tolerated. The most common side effects were abdominal pain and diarrhea. And standard antidepressant treatment is effective for perimenopausal depression. So you would approach treating perimenopausal depression the same way that you would treat a depressive episode in the premenopausal period. You can choose SSRIs or SNRIs as first-line treatments. One caveat being that if someone is also reporting impairing, you know, moderate to severe vasomotor symptoms and you want to kill two birds with one stone, you may consider paroxetine or venlafaxine, which we know have the best efficacy data for reducing hot flashes. Hormone therapy has been shown in some studies to improve depression symptoms even independent of its effect on vasomotor symptoms. So when hot flashes were removed from the equation, hormone therapy was still helpful. And hormone therapy was also shown to prevent clinically significant depression in the menopausal transition in a 12-month randomized controlled trial. So here's data from that trial. So for this study, women who were euthymic to begin with and in that perimenopausal stage, they were randomized to receive either a transdermal estradiol and oral progesterone or a placebo pill and patch. And at the end of the 12-month study, the women who were taking hormone therapy were significantly less likely to develop clinical depression, which they defined as a score of a 16 or greater on the CESD. So overall, they had lower mean depression scores. In this study, these results, they were adjusted for any changes in vasomotor symptom burden. So in summary, perimenopausal individuals are at risk for subclinical and clinically significant depression. A history of premenopausal depression, postpartum depression, or PMDD increases risk for perimenopausal depression. Hormone therapy with estradiol plus or minus progesterone is the most effective treatment for vasomotor symptoms in select populations. Low-dose paroxetine is FDA-approved for the treatment of vasomotor symptoms, and serotonin reuptake inhibitors should be utilized for the treatment of perimenopausal depression. You might want to consider paroxetine or venlafaxine or some of these other SRIs if there's comorbid vasomotor symptoms. Thank you all for staying with us to the last hour of the last day, and we could take any questions that you have. I'm forgetting where you're supposed to be. Well, I'll come up there and help you. Yeah, that's all right. That's fine. Or I can ask my question from up there. Go ahead with, go ahead with your. Just for, to be clear, perimenopause actually means premenopause, does not include postmenopause. Okay, I wonder if anyone's trying to make an effort to clear up that language in the field, because we all used to peri meaning around, and it does create some confusion in talking with patients, and also in understanding the literature. We're talking about incident rates of depression. And attached to that question, what is the, is there a change of incidence rate of depression, or at least new onset, or recurrence in the immediate, in the period of time of vulnerability to hot flashes? And what about even beyond that? Is, does the, does the probability of a new onset change, or does the probability of recurrence change, if compared to the lifelong history of depression? Does that make sense, the question? About the semantics of perimenopause, I agree with you on that. There's some, with the menopausal transition, some people refer to that as kind of going into postmenopause, that perimenopause is that, you know, period before the 12 consecutive months without a period. And your second question was more about? Oh, I saw a study a couple years ago, I have no idea how valid it is, or anyone's replicated it, which indicated that at a certain point beyond menopause, when there is a dramatic reduction in production of estrogen, the onset of new episodes of depression starts to drop and be more similar to men. Right. I have no idea if that's valid, that data. Yeah, no, it is valid. So the notion is, so the straw criteria are the ones that define these various stages of premenopause or perimenopause and postmenopause, but the notion is that it's the variability and the fluctuations in gonadal steroids that are contributing to mood symptoms, and perhaps partly to hot flushes, but NK seems to be a bigger player in that area. So if you look postmenopausally, when people have gone through the transition, which can be 10 or 15 years, it's not just a couple years. We used to think it was just a couple years, and now we know it's a long time, because we've had this natural experiment where a whole group of women were taken off their hormones, so now we can actually see how long the perimenopausal transition, or how long the menopausal transition is. But after that, the risk of mood disorders does decrease. So in the perimenopause, you see both an increased risk of recurrence as well as new onset. So we're really looking at what is about a 10-year period of increased risk. Could be, yeah. Thank you. Thank you very much. We're trying to alternate with the online questions, so hold on just a second. So there is a kind of a little series, a stack of questions that have to do with PMDD, and ask about how the SSRIs work for PMDD. And also a question of whether or not SNRIs have a role at all. And another one about munk? Munk pepper? Munk? Munk pepper for PMDD. Okay. I don't know data on munk pepper. I don't know what munk pepper is. It may have a different name. Do you know what munk pepper? Okay, you went off to look that up. SNRIs are effective for PMDD. They're probably just as effective as SSRIs. And with regard to the mechanism of action, I think it's fair enough to say that we don't know. So there are two sort of leading issues with regard to SSRIs. The first is, for major depressive disorder, people are often symptomatic or sick for months or years. And there is this notion that the longer time that you've had the illness, the more difficult it is to treat. Maybe. Could be hand-waving. But that may be one of the... The fact that you have these short intervals of mood dysregulation and then people stabilize and then they're short and stabilize. The notion is that because it's so short-lived that you can get them out of this mood episode more easily. As well, I talked about allopregnanolone for depression and possibly PMDD. There are preclinical data to suggest that show that progesterone metabolism is actually altered by fluoxetine in some SRIs. So you actually may be increasing allopregnanolone in some of the neurosteroid levels endogenously. You can't measure it. It's very difficult. That's why these are preclinical data done in rats. But we may actually be increasing some of those reactions by inhibiting other reactions and changing progesterone metabolism. Yes. Thank you very much for the talk. Would you share some thoughts about women having first episode of psychosis during perimenopausal period? First episode of psychosis when? During the perimenopausal period. During the perimenopausal or perinatal? Perimenopause. Yeah, so that is a psychiatric emergency when somebody has postpartum psychosis and typically has a very abrupt onset. You may get a call from a family member. I don't know what's going on with my wife. She's pacing. She won't sit still. She's really agitated. She's saying these bizarre things like the devil is after her or her baby's been switched in the nursery. They took her baby and they gave her a baby that... I'm sorry. Around menopause. Oh, menopause. You. Psychosis? Yeah. First episode psychosis because I've seen a few ladies and I'm not sure if it is... Yeah, I mean, psychosis can occur anytime, right? I am not aware that it is something that actually occurs at a higher rate in perimenopausal women, but I will say that we are appreciating... There was just an RFA actually, a couple of requests for applications from NIMH to try and look at psychosis writ large in people of, in perimenopausal people. And there is this notion that if you have a reduction in estrogen, estrogen, of course, is antidopaminergic. So it does some of the same things that we think that antipsychotics do. So if you have a reduction in that, then you increase the risk of psychosis, whether it's full-blown clinical psychosis or sort of smoldering psychosis. Yeah, so this gentleman was accurately pointing out that there is a late-onset psychosis, and it seems to be associated with the loss of estrogen, and it's in the older literature. And the notion is that you lose estrogen, you lose that protective antidopaminergic effect so psychosis can present itself. So, there's some questions out there about dealing with pregnant women, well, with ADHD who might need a stimulant. There's also a question about Wellbutrin, as well as Seroquel, all during pregnancy. Right. Well, so, we used to, when we were worried about heart defects and SRIs, we actually started relying on Wellbutrin, but there probably are some less reassuring data with Wellbutrin as well. I think the same thing holds, though, that none of these are really serious teratogens, whether it's Wellbutrin or SRI. I think that one of the roles for Wellbutrin is actually for smoking cessation in pregnancy, because we know that smoking is terrible for, well, it's terrible for mom, it's terrible for her baby. And NIDA has actually tried to do clinical trials with Wellbutrin in pregnancy for female smokers, and at least on two occasions, it was kind of a fail. They just couldn't recruit, so it's really tough. It's really tough to recruit a cohort of people and then put them on medication in pregnancy for a whole host of reasons. For Seroquel, I think we're, one of the things about pharmacopoeia in pregnancy is we like, we don't rush to use the first compound that is released in pregnant individuals. We rely on a case literature of serendipity, if you will. So we like to see, you know, what's happened over time as people have kind of, like I showed you the picture, I'm pregnant now, what, when that has happened, because it's very difficult to do clinical trials, and in some instances, they probably should be done, but to do them in pregnant individuals. So when somebody's been out, when a compound has been out for a decade or so, then we have an accrual of case literature, and we can start to look at what's going on, I think, more clearly. At this point, you know, initially, the second-generation antipsychotics is not something that we had recommended using because we just didn't have the data on it, and I think now we have more data just on case reports, and we actually have some of these larger epidemiological studies that I showed you, and they, and it shows that the second-generation antipsychotics are not true teratogens. They do cause weight gain, so, you know, you have to be cautious about that, but in terms of malformations, the signal tends to be very small. Yes. Hi. Thank you for the excellent presentation. It goes, you know, towards what you're talking already about, the antipsychotic. So my question would be, you have a mood disorder, bipolar patient during pregnancy. Is there any antipsychotic that so far we know that we should avoid, just like we know, for instance, with paroxetine, that we have that data? As far as antipsychotics, we would rather, you know, we would try to use what the patient is already using, if that's okay, but anything we should not use that we know so far? Definitely don't want to use carbamazepine or valproate. If you can get away with not using lithium, that's, you know, whether it's a true-true not related or whatever. I think you want to rely on what, you know, the best thing to do for a patient who has recurrent major depressive disorder or a patient who has bipolar disorder, a patient who has schizophrenia that wants to get pregnant, is to do a dry run before they actually get pregnant. See what can at least hold them for X number of months, right? So Haldol is probably not as effective as a mood stabilizer, as, I mean, I think olanzapine is kind of problematic because of the weight issue in pregnancy. Same thing with quetiapine, but, you know, what can hold them for that period of time that they, before they get pregnant and, you know, if something, if they're brittle and they're going to get manic and Haldol or, you know, whatever your choice is, isn't doing the trick, you're not going to want to put them on that. But if you can be thoughtful and plan for that, then I think that is very reasonable. There's no number one compound, I mean, you can use olanzapine, the data are reassuring, you can use quetiapine, I think you just have to be cautious about weight gain. And also, you have to also let moms know that the baby may have some tremulousness when it's born. Because there is, you know, they're going to have, the baby's going to have some EPS. So it's good that they know about that. Do we have enough data on lorazidone so far? I'm sorry, what? Lorazidone so far? I don't know what the data are for lorazidone. I think it's probably going to end up looking pretty good. It's good for everything, right? It's the primary care doc's antipsychotic right now. So I mean, how much clinical work do I do as a chair, you know, but I'll use lorazidone. Thank you. Just the other day on this stage, Steven Stahl basically forbid us from using, is that Steven Stahl or Dr. Myers who was with him? They basically forbid us using Galproate any longer at all, any gender. I think he said in Europe, they basically have just boxed it to death. And that even for men, fertility is affected. Well, it's a moot point now, I guess. Yeah, no, especially with reproductive-age women and men, you're right. There's now data that even male fertility is significantly affected by valproate and that the frequency of problems for women of childbearing age is so considerable that there I think he said in Europe, or in the UK, it's basically forbidden in that age range. He was pretty adamant on the issue, I should say. For patients already on an antidepressant who may be stable for most days, but they have PMDD, sounds like maybe also, do you suggest increasing their dose during that premenstrual time window or switching antidepressants might be a better choice to see if everything is better controlled overall? Yeah, that's a good question. You know, I think you want to do some of the healthy things. You want to increase exercise. There's some data to suggest that complex carbohydrate diets, like not the Cocoa Puff diet, but complex carbohydrates may actually be helpful, minimizing salt. And if you have to, increase the antidepressant. I certainly have done that on a number of occasions. And sometimes when I've done that, the patient has said that they feel better when they're not premenstrual as well. So you know, they may be a little bit underdosed. But they also may have side effects, especially sexual side effects. So if you can decrease it, that's good too. So I think you want to do both. We don't, I mean, you know, I like to do a more comprehensive evaluation of somebody's life and what, you know, maybe they need psychotherapy or what their diets, what they're doing with their diet and how are they're taking care of themselves. And you know, exercise and diet can really deteriorate when you're premenstrual. So it's important to know that as well and make sure that you're keeping with that before you rush to just, you know, change medication or change dosages. Yes. Thank you guys so much for such an amazingly high yield and informative talk. To close out the APA this year is absolutely brilliant. My question was on premenstrual migraine headache. And I was wondering if you had any thoughts about overlap between either the underlying mechanisms or potential commonalities in treatment. Thank you. Yeah. Thank you. I don't know the mechanisms. I know that, you know, serotonin is putatively involved in that. And you know, we talked a little bit about allopregnanolone and serotonin. So SRIs do have some antispasmodic properties. So they, you know, we've certainly used them now. The triptans are just knocking it out of the park. So there are tons of people who have premenstrual migraine. And if they can nip it in the bud with a triptan, I think that that's fine. You just have to make sure that there are no contraindications with other psychotropics. Did you have anything you want to add? No problem. So postmenopausal ovaries produce testosterone at premenopausal levels. Is there an increased incidence of mood, energy and attention changes after postmenopausal oophorectomy? And then they added, there is a difference in prescribing testosterone depending on country. Are there scientific reasons for these differences? I am not familiar with the testosterone piece. Yeah. I am unaware of data suggesting that mood deteriorates with postmenopausal oophorectomy even though, you know, there's also going to be some testosterone that's made in livers. You know, so, but what was the second part of that question? Oh, you cut it. Okay. So, when, what is, is the use of testosterone based in science? It's trying to understand why there's differences, there's, there's differences about prescribing testosterone in different countries. Yeah, there are differences. What is the scientific basis for why, why is that? Right, right. So there is this notion that testosterone and androgens increase sexual functioning and desire and there are some older, you know, a little bit of older data. I think a lot of it has to, depends on the practice though. There actually, one thing that's interesting is antagonists for androgens, androgenic antagonists, which we don't typically use because they're also teratogens in reproductive age women, decrease irritability in premenstrual dysphoric disorder. So, you know, they do have some effect on mood and they can promote irritability. So in other countries, when people are using androgenic steroids to treat sexual dysfunction, they also have to be mindful that they don't want to increase dysphoria and irritability. Yes. Thank you very much to both of you for that great talk. I've got two brief questions. The first is thoughts on the vitamin B during the PMDD concerns. And the second was about a B or D, B, B, B6. And the other question I had was about a patient that I've had who has intractable depression since the onset of menses throughout two pregnancies and the only time of euthymia she had was during lactation when she was breastfeeding both her children, which was about 18 months. And then she returned to quite a depressive state after that. I wondered if you had any thoughts on her. Yeah, so what you're saying is that during breastfeeding, you know, there are many, many women who say pregnancy was the best time of my life. You know, I've been depressed my whole life, but when I was pregnant, I felt great. I don't know why, but it happens. And like you said, a lot of times they stay well until they stop lactating. Certainly there are endocrine changes. I don't think anybody really knows why that happens, but we certainly do see it. And you know, I have no reason to really question it. We know that depression is heterogeneous and probably has multiple causes. So it's entirely possible that, you know, whatever changes in gonadal steroids, maybe it's just making them quiescent and having fewer fluctuations in it. With regard to the B vitamins and PMDD, there are older data to suggest it has some mild effect, but there are also negative studies. It's really not a first-line treatment, but you want to make sure somebody's healthy. We are coming to the end of our time, so we have time for one more online question, I'm afraid. Sorry. Because I hear it's a good one. I just think it's good in the sense of there's a lot of curiosity about xeronalone. So since xeronalone is GABAergic, does it have any addictive potential? That's the first part. And then there's to what extent is insurance coverage or costs limiting the prescribing of xeronalone for postpartum depression treatment? So my understanding is that it is not addictive. I mean, we're really talking about agonists that are, you know, Brexanolone is allopregnanolone, and this is very similar. But we don't use it for that long. I mean, the treatment course is two weeks. So... It's how much, $16,000? $16,000. Yeah. But it's a Schedule 4. Yeah. I wish they would remove that label because there's no proof. Right. Well, there are studies that they basically ask how much you like it and they like it more. Well, they always do abuse potential studies, yeah. If you like it better, you're going to like it. Yeah, but you use it for two weeks. Drs. Yonkers and Stavelli, we want to thank you for two things. One for a wonderful presentation and reminding us men how privileged we are. Thank you.

reproductive mood disorders

Premenstrual Syndrome

Premenstrual Dysphoric Disorder

serotonin reuptake inhibitors

neurosteroids

perinatal mood disorders

depression during pregnancy

antidepressant use

menopausal mood disorders

vasomotor symptoms

hormone therapy

personalized treatment plans

Dr. Kimberly Yonkers