Dr. Stephanie Waggel Explains the First Oral Drugs Approved for Postpartum Depression

0:00 Hello, Today I have with me yet again Dr Stephanie Waggle. Dr Waggle is the mother of two and a psychiatrist specializing in perinatal mental health. To connect with Dr Waggle, go to improvelifepllccom. This will also be in the show notes. Today she's returning to share important information about the new drugs that have been FDA approved to specifically treat postpartum depression. Dr Waggle, welcome and thank you for joining me. Hi, I'm so excited that I get to actually do a topic on a medication that's FDA approved for postpartum depression, because this is the first time in world, medication has actually ever been approved for postpartum depression, so it's big news.

0:44 I know I'm so excited. I can't wait to hear about it. So what I want to do, but I can't, is to tell you what I've seen clinically like. Oh, I've had some patients on it and this is what happened and this is how it works. But it is not available for 90 more days, so I will not be able to tell you about any of my actual personal experiences prescribing it. But what I can get into is some of the studies that have occurred regarding it's. Zuranolone is what we're going to be talking about. For short, I guess you could just call it ZOO, in case you don't want to say the whole thing. So I'm going to start off by saying that the typical treatments for postpartum depression would be your everyday round the mill.

1:29 Most people know SSRIs, sertraline, fluoxetine, those sorts of things and then you also have SNRIs, atypical and endopressants, and the medications are typically for depression and they're just using them for postpartum depression, although they are not specifically FDA approved for postpartum depression. But that's just the standard right now. So the medications I'm going to talk about and Zuranolone is one of them they work differently than your typical antidepressant that you're familiar with. But before we get started with how it works, I just want to explain some well known examples of steroids.

2:13 There are sex hormones, like most people know about testosterone, progesterone, estrogen, and this is just to get a warm up for people that aren't familiar with these kind of things. Pogestrone is an endogenous meaning, like occurring in your body, steroid hormone produced by adrenal cortex. I will try not to get too technical, although I probably still will, but whoever doesn't want to hear it, I guess, can just fast forward. So, talking about progesterone and I think anybody who's taking a break control pill is at least familiar with progesterone there is something called allopregnanolone and this is also endogenous meaning, in the body, naturally occurring inhibitory neuro steroid, and it kind of works as an anti anxiety sort of mechanism.

3:04 So instead of thinking allopregnanolone, you can just think anti anxiety. So this anti anxiety hormone drops after childbirth. So if something that gets rid of your anxiety decreases, your anxiety probably is going to increase. The drop that occurs after childbirth leads to overactivity of the HPA axis and that leads to anxiety and depression not in everybody, obviously, but that's just the thinking of what is going on here. So for following me so far, you have this hormone that decreases anxiety and then it decreases after you have a baby, so then anxiety increases.

3:48 Now they made a medication called brexanolone, which is like this allopregnanolone that occurs in your body anyway, to administer to women postpartum. But there is a problem with it. Well, there's a couple problems with it. One is that it's IV infusion the last 60 hours. You can't really do that at home, you have to go into the hospital. So I have a hard enough time convincing women to get their postpartum depression treated. It can be real hard to convince them. Why just short hospital stay? Why not Side up? It'll be fun. And then the other thing is it's $30,000. So pretty pricey.

4:29 I wouldn't say it's easily accessible. But the idea is there and it's a good one. So we're talked about that hormone that occurs, that drops, and how there's something similar. But you got to take an IV and you got to sell your car to get it, the brexanolone. So let's see, I'm going to explain how it works in a little bit. So the big breakthrough here is that the Ziranolone is like that IV infusion, only it's in pill form, which is so much more readily accessible and hopefully cheaper than $30,000.

5:10 So brexanolone is the IV very expensive, but they have taken a similar mechanism of action, made Ziranolone, and it's a pill. It'll be out hopefully in the next 90 days. Now, hopefully no one falls asleep here. The way it works is it's a neuro-steroid. So I talked a little bit ago about sex hormone steroids, that sort of thing. So GABA is what's called an inhibitory neurotransmitter. A neurotransmitter is a chemical in your brain and, just very simplistically, think GABA, think calming effect. Okay, zaranolone is what is called a positive allosteric modulator of GABA, which is a fancy way of saying that it just enhances the activity of GABA, which means enhancing a calming effect.

5:59 So it works both intracynaptically and extra synaptically and that's important. In a second and just for funsies, an allosteric modulator is a group of substances that bind to a receptor and changes their receptor's ability to respond to a stimuli. Just in case anybody's sitting around wondering what the allosteric modulator is, okay, I promise I'm gonna try to speak in English. So I think most people probably know what Xanaxes if they ever listened to music. So if you think about a benzodiazepine, I'm gonna try not to say brand names, but I mean, if I wanna relate to people, people know what Xanaxes.

6:39 So that also works on GABA. Gaba A receptor specifically. So benzodiazepines only work intracynaptically. But the Zuranolone, the medication that I'm talking about today, we're just gonna nickname it zoo so it's easier to understand the zoo. It works on both. So benzodiazepines are only working intracynaptically, whereas the zoo is working intracynaptically and extra synaptically. So it's got this extra mechanism of action. That's new and exciting. Okay, now Zuranolone for postpartum depression. So pathophysiology, postpartum depression, which is, like you know the things that are going on here multifactorial.

7:26 So, like I said before, with that decrease in that particular hormone that could be causing it and the extra HPA access, which is like stressing people out. So this kinda addresses that. Now, like I said, it should be available in 90 days, since it acts similar to benzodiazepine. Benzodiazepine is a controlled substance. Zuranolone is also going to be controlled. So you would need a prescriber that has a DEA license and that sort of thing, and it's gonna require closer monitoring than your typical run-in-the-mill antidepressant. So, because it's not out yet, I don't have any data from any patients who've taken it, which is something I'd love to come back and talk about once.

8:09 I gather that. But we have to at least wait a couple months until it's out and then a couple months to see how my patients did. But I can talk about the trials that have occurred. So, just so that people can follow along. There's different phases of clinical trials. There's the preclinical phase one, phase two, phase three and then phase four is like after it's already out there. So phase two, that's seeing if it works and there's like maybe a hundred, a couple hundred patients involved. And then phase three is to see the safety and efficacy, and that involves more patients. So I'm gonna be talking about phase two, phase three trials of this new and exciting medication.

8:55 Okay, so Zuranolone for postpartum depression. There was a study in June 30th 2021. So this study was basically Zuranolone versus placebo Placibos just sugar pills with nothing in them. So they had women that were postpartum less than six months, ages 18 to 45 years. 76 of them were taking placebo sugar pill that doesn't do anything, and 77 of them were taking Zuranolone. In this particular study, the dosage was 30 milligrams and you have to take it each evening with food. I will tell you why you have to take it in the evening in a little bit.

9:36 In this study found a significantly greater reduction from baseline ham D17, and you're probably like what's a ham D17? So that is a scale to assess depressive symptoms. So a reduction would indicate a less depressive symptoms, and they found this as soon as 15 days after. So significantly, the people that were taking actual medication the zoo versus the people that were just taking sugar pills in 15 days, the people that were taking the zoo were doing much, much better. And this is a big deal, because most antidepressants like I mentioned at the beginning, your typical SSRIs, the fluoxetine, sertraline, your normal antidepressants that you typically think of oh, I mean they take six to eight weeks to start working with this.

10:26 This actually spoiler alert. There's another study that starts working about three days. It's really fast. And so this study that I'm talking about now, at day 45, 54% of the women in the serenaline group were seeing remission, whereas only 30% in the sugar pill group were seeing remission. So that's one study. There's another phase two study also found a significant change in the ham D, which is the depression scale. Also found that it starts working as early as three days. And another thing is that they only have to take it for two weeks. A lot of people, pretty much everybody, was like how long do I have to take this antidepressant?

11:08 I mean, sometimes people take antidepressant their whole life, sometimes it's yours, this particular one Two weeks, it's so nice, it'll be easy to follow because after two weeks you don't have to take it anymore. There was another is this one's a phase three study? It's called the Waterfall Study. It also showed an early onset of efficacy at three days it starts working. And antidepressants starts working in three days. That sounds nice. And then another phase three study called the Coral Study. That actually looked at people on the regular run of the mill antidepressants that you think about versus people on those antidepressant plus Zoranolone, and so those are the two groups, and the people on the zoo plus the antidepressant also had a rapid onset and the reduction in depressive symptoms maintained.

12:03 It was maintained over time. So we have some studies that's like sugar pills versus the zoo. We have some studies that are antidepressants versus the zoo plus antidepressants. So they looked at a variety of things in these studies. And then finally, there was the Shoreline Study and that looked over a longer period of time to see how long does it last. It's great it starts lasting in three days, but does it last after that? And so this was a year long study. 80% of the patients responded to the treatment positively and 80% only required one or two treatments. Remember, the treatments are about two weeks long, so the one 14 day or perhaps two separate 14 day treatments were enough to sustain the decrease in depression for at least a year.

12:53 So some of the studies show, ok, it starts working quickly. But this study shows, hey, it even lasts a while. So this is all very good. So fast and lasting this is nice. This is something new 45 days. The effects of the oral medication, the zoo, are similar to the effects of the IV1 that I was speaking about at the beginning. Hopefully it's cheaper than $30,000 when it comes out, but definitely it's not something you need to be in the hospital for. So everybody's like what are the side effects? So the side effects shown in the studies are similar to what the side effects of just having a baby are anyway, like drowsiness, headache, dizziness, that sort of thing.

13:39 They kept saying it's generally well tolerated. There were two big adverse problems. One was that somebody got pancreatitis, but they were on the placebo group, so it wasn't the the Rana one that caused it. And then another person had, like some, altered consciousness. They were very disoriented and that sort of thing. So remember earlier I said you got to take it at night. That's because it causes sedation, which may be a good thing, because a lot of women suffer from insomnia. So if it helps you go to sleep, that might be good. But if it helps you go to sleep, you definitely don't want to take it when you wake up in the morning and you don't want to take it before operating heavy machinery. You just like. Pretty much every medication says don't operate heavy machinery.

14:22 Okay, I know it was an exaggeration, but a lot of medications say don't operate heavy machinery. I mean it would be annoying if you have to go to work, but it's about 12 hours. So if you take it at night, you should be able to drive the next day. Of course it affects everybody differently, but those are some of the biggest drawbacks. However, maybe you can recruit somebody else to take the night shift. I imagine that it would just. One of the factors would be you have a new baby. You got to wake up, take care of the baby. But maybe you can recruit in-laws or husbands or friends or somebody to take the night shift, because if you're going through substantial postpartum depression, you need sleep anyway.

15:05 So maybe sedation isn't the worst side effect. So this all sounds fantastic. The studies were done by the pharmaceutical companies that are manufacturing it. So, yeah, a little bit controversial. I mean, it's not uncommon occurrence for the manufacturer to be the one doing the studies. You just have to keep in mind that these studies were conducted by the people selling it. So that's why I'm going to come back and tell you what I see in real life like. Does it reflect what was found in the studies? So we'll see when, hopefully, the studies reflect, because if they do, then that's going to be really promising Fast acting, long lasting.

15:48 Well, I'll stop. I'll take any questions. That was a lot. All right, thank you. I'm happy to defund. Can I raise my hand? Is there anything that I hear? I took notes. I was like, all right, we're going back to med school. Ok, let's see. So when we talked about scheduling this episode, I was bragging to my coworkers and so they wanted to be able to ask questions. Oh OK, labor delivery nurses would like to know. You already talked about how it works and what is it. They want to know if you can breastfeed on it. That is a fantastic question because I had the same one and it is actually unknown because they had the women in the studies.

16:30 They actually asked them to stop breastfeeding. They were like, well, this, we didn't commit to all this, we just want to find out if it works. We're not ready, we just need to get it out there. We're not ready to do the studies to see if it affects or if it is transmitted in the breast milk. I mean that would be good, but you have to remember what they're putting their time and effort into and I think that I don't want to speak on behalf of the researchers or the pharmaceutical companies, but I would surmise that they were just efficacy, safety for mom and then the whole like can you breastfeed?

17:12 And we'll figure that out later. Now, if I had to take an educated guess, the biggest issue that I have, if I have to prescribe somebody a benzodiazepine while they're breastfeeding, I always say look for how your baby responds and your baby's super sleepy. That might be an indicator that it's transmitting and having an effect on your baby. And you have to remember that this medication works similarly to the benzodiazepines. The biggest issue I have with benzodiazepines is I worry that it's going to knock mom out and she's going to be breastfeeding and fall asleep with the baby and drop the baby on the floor or whatever. You want mom to not be knocked out. So my worry wouldn't be so much transmission of the milk I mean, probably make the baby really sleepy but my worry would be mom would be super, super tired and if she's breastfeeding while on this medication she might just be like, ah, you know, and then the baby will be like, excuse me, what's going on, mom?

18:11 Why are you? You know, and even if the baby's like crying, if you're knocked out, you're knocked out right. So that would be my concern with breastfeeding on this medication. So anybody that is a co-sleeper probably would not want to co-sleep during the treatment period. Right, because you roll over. I'm not advocating for co-sleeping. Well, I was going to say I mean, but I am acknowledging, you're acknowledging it's, I'm acknowledging the existence. You have to because it happens. You have to because it does happen, right, yeah. So if you take this, you roll over yeah. Anyone that co-sleeps knows they're not supposed to co-sleep impaired. It is a parental choice that I am acknowledging. It's similar to alcohol. Exactly, alcohol also works on the same receptor, so it would be like analogous to getting drunk and then falling asleep next to your baby.

18:57 You don't want to do that Exactly. Additionally, my wonder is I've always asked this, and this is probably a little rabbit trail that we might need to do another podcast for. Well, that's okay. I like that We'll just do it Right. So my thought is they have those little milk strips that you can use to test for alcohol. They do. Why are we not doing that for everything? Because we can't test the baby, and I think the answer is money and time and research. Women are the consumers. Yeah, women harness our power as women consumers. Women can fix harder Like let's put the money into this? Yeah, let's do it. We should be able to test for everything. Yeah, I'm sure that there is a way to correct it in breast milk.

19:38 I'm sure that it exists. Does a company want to put in the research and development into that? I don't know. Maybe if we showed them that there would be a demand for such a thing, but until then it's not as if it's impossible or scientifically impossible. It could happen, but somebody has to want to do it and that somebody has to be pretty rich. So we'll see. And that was another point that my immediate, before doing any research, my immediate thought was this is a great sign that they came out with this, because that means somebody somewhere cares about pregnant women enough to put this in, Because you know it's 2023 and this is the first pill that's ever been approved for postpartum depression.

20:21 Someone finally cares about us. It's great, it's so crazy. Maybe they figured out that the mom being well affects the baby. Oh my goodness. But even with that, we please care about mom though, so that, but like I mean if the only way we can get some care while we're by way of the baby. I guess it's better than nothing. Right. Well someone cares, and I'm delighted about it, someone cares. Well, I think you've kind of answered the other questions. The next two questions are can it be used antipartum and why don't we put everybody on it? But I think maybe you could kind of spell it out for us, like why we wouldn't be able to use it antipartum probably because of the hormone levels, right?

21:04 Well, so that's a good question. The studies did use different time frames. That was less than six months postpartum. Again, it's probably they were like we just we have a very narrow objective Does it work postpartum? We didn't ask if it's okay for breastfeeding, we didn't ask if it's okay for pregnant women. We're just focusing and so that would be really good for future studies. So, again, if I had to take an educated guess, but the hormone doesn't drop right. The hormone drops after childbirth. That hormone is higher. It goes like this If we had a graph, yeah, so it goes up and then it drops, and I think that taking hormones while you're pregnant is generally a no-no.

21:46 However, at least because it has the extra mechanism of action that benzodiazepines don't have. But at least we know benzodiazepines aren't fantastic for taking while pregnant, but I mean, you can if that's all that works. So taking it while pregnant and taking it breastfeeding have not been studied. However, once it's out and about in the world, it's going to happen, and then that's. That would be the last phase in the clinical trials, the phase four when it's already out. Yeah. The phase four, experimenting on regular people yes. Post-marketing research. Where it is, you index the substance Exactly.

22:29 Right. Those are good questions, and nobody wants. Yeah, then the question of why don't we put everybody on it and-. I can answer that. One is not everybody has postpartum depression, which you wouldn't want to treat somebody for something they don't have. The other is that I am going to guess that it's only 14 days, but benzodiazepines are pretty addictive Because it works similarly. I'm not saying it's addictive, but I'm saying that I can see people getting addicted to it. You don't want to just give an 11-year-old a pack of cigarettes. You don't want to get started somebody on something that they might not have an easy time quitting.

23:11 I do like the idea, like, yeah, prophylactically and for people listening, that means to stop something before it starts prophylactically. Yeah, let's just put everybody on it, but not everybody needs it and some people may become dependent on it. Let's have a happy Goldilocks zone where not everybody's on it but not nobody's on it. Let's have them in the middle where people that need it are on it. I hope, really hope, it's not $30,000. Yeah, I hope so too. That would suck. It's like yeah we have this great med nobody can afford it so just kidding, we're just going to dangle the carrot for a little bit and then, well, we did our duty.

23:51 So too bad, you can't afford it. That happens with yeah, I know insulin and stuff like the new insulins and stuff. They're super expensive. Oh yeah, I know, that's just the example that comes to my head, right? Yeah, you know they can make these things cheaper. I don't want to go off on a tangent, I don't want to start sounding too cynical, because this is my happy talk. I'm excited about this medication. I don't want to be a friend. We can stay in the happy zone. That's fine. Did you have anything else that you wanted to add? I really want to come back and talk about what I've actually seen, not just what I read in a study that was one by the people that are selling it. But the idea makes a lot of sense from a scientific standpoint, like it's solid, but we just have to trust that the study was done morally and ethically.

24:44 Yeah, we'll see. We'll see. Well, I'm really glad that you had the opportunity to nerd out on the HPA access, because you teased me with that in the first interview. I play a hypothalamic pituitary analysis. So I was like, oh, you're not saying anything. And so this time I was prepared. I was like I'm taking notes, we're going to talk about it this time. Well, I just want to say I teach medical students but then I also try to teach patients and I always ask my husband did normal people know what idiopathic means? Because you get to this point and you just don't know what terms. What I said on my Facebook the other day. I was just randomly talking to my husband and I said incominantly and he's like what, and I met co-occurring?

25:26 And he's like that's not a word. Normal people say Like sequelae, like I just come up with it Right, but I hope I don't actually think I knew how to pronounce what is it concomitantly? I always said concomitantly. I never used the word like verbally. I always just read it and I was always too shy to try to no. I don't want to read one of those jargonapies, so hopefully I was able to make it make sense. I like analogies, so I'm trying to do more. Yeah, yeah, it makes sense to me. I was taking notes. I do recommend that. If I mean I took notes also so that I can put it out in social media, kind of written with like a diagram, so that people can kind of follow along, so yeah, hopefully, hopefully I'll get that taken care, but yeah, I mean just go back and listen a couple of times until it sinks in.

26:18 I suppose that's what I'm going to do. Yeah, we're fine, all right, you can do something else concomitantly. I can do something else concomitantly, now that I know how to pronounce that. Wait, but appease you on me, not appease you on me. See, we all have our things we need to pronounce that is true. Hey, you are ratting yourself out right now because I took that out of the last episode. No, I would never claim that I can pronounce all of the things. Actually, I read something really interesting. It said don't be embarrassed if you mispronounce something, because that meant that you read it in a book Exactly and I thought oh, that's how to I did. I read concomitantly in a book and I've never heard it pronounced out loud until now.

27:02 Sweet that just means that you read. I do read Yep. Well, dr Waggle, if there's not anything else, I'm going to let you go so you can get to your next appointment, because I know you're a busy gal. Yeah, I'm going to talk about this medication. It's very promising, yeah. And then definitely throw me your ideas, because I'll have you on any time. All right, I'll let you know once I get some clinical data from this. Thank you for having me.