Good morning or good afternoon, everyone. I wanted to welcome you to today's webinar on Medication in Early Psychosis. I am Judith Doberman, the program manager for PEPMED at Stanford University School of Medicine. We also have with us today Dr. Kate Hardy, who is a clinical pathologist and clinical associate professor in psychiatry and behavioral sciences in the Stanford School of Medicine, and also joining us is Dr. Steven Adelsheim, who is a clinical professor at the Stanford Department of Psychiatry and Behavioral Sciences, the Associate Chair for Community Partnerships, and the Director of the Stanford Center for Youth Mental Health and Well-Being. Both Drs. Hardy and Adelsheim will be co-facilitating with our presenter your questions for today. Today's webinar is brought to you as a partnership between PEPMED and SMI Advisor, which is a SAMHSA-funded initiative implemented by the American Psychiatric Association. And now I'd like to introduce Dr. Jacob Ballin. Dr. Ballin specializes in the treatment of people with psychotic disorders, including schizophrenia. He is the co-director of the Inspired Clinic at Stanford University, which provides interdisciplinary care for people experiencing psychosis. He is also the Medical Director of the H2 Acute Inpatient Unit, and Dr. Ballin completed his residency at Stanford in 2001 and the Schizophrenia Research Fellowship at Columbia University in 2011. And now I turn it over to Dr. Ballin. Thank you very much. All right. Thanks, Judith. Well, good morning, everybody, or good morning on the West Coast, I guess. My pleasure to be here to talk about this. We'll just start off with the quick disclosure slide. You can see that I do a little bit of consulting work for places, and then we do clinical trials here at Stanford, and so those are some of the sponsors for that. Let me go to the next slide, please. There we go. So we're going to talk today about a variety of topics relating to the use of medication in both first episode for psychosis, as well as for people who are at clinical high risk. And we're going to talk about some of the key differences there in terms of how we use medication for these two groups. There obviously is some overlap, but there are some key distinctions that we're going to go over. We're going to spend the beginning, though, of the talk actually talking about medication, because in many ways, the choice of medication is actually that which specific medication is less of a challenge than sort of medication or not medication, and how to approach that with patients or clients and families. And then we're going to go over some of the newer medications that are out, and also general ideas on how to think about medication, especially in that first episode for psychosis when somebody has demonstrated that they have psychotic symptoms and are not just at high risk any longer. Next slide, please. So the talk is marketed as medications and early psychosis. And so why are we going to start here with a discussion on working with families? Shouldn't we be talking about medications and this receptor and that receptor? Why this medicine and why that medicine? And that may be true and all that, but I want to start off with just a quick vignette to give a sense of at least how I experience these kinds of conversations. And I recognize also that we may have a diverse group of folks attending this webinar and also watching subsequently. And so I want to at least call attention from the very beginning that the decision about medication is not a unilateral decision. So allow me to present this vignette. And it's a real mashup of a number of different clinical situations that I have had over the last couple of years. A 19-year-old man presents to the clinic for a routine follow-up. He says that since starting medications, he has been more tired than ever before and cannot concentrate on his work. Over the past year, he has been hospitalized several times for psychosis exacerbations, coming back into the hospital generally after a disruption in medication adherence. His work consists of watching YouTube videos and sending telepathic signals to politicians with his reviews on the videos. He says that he's not going to continue taking medications at this point because of his inability to work. His parents presented the appointment along with him. They note that he has been more drowsy than before, but they have stopped hearing him talk to himself while he is in his room. He has mostly stayed in his room, but it seemed to be calmer than before he started medication three months ago. I asked them about their impressions, given that they seem to have noticed symptomatic improvements and improvements in his demeanor and their ease of getting along despite the likelihood of continued side effects. I do this because I expect that their answer will validate my suggestion that he continue on medication and we think about ways to manage the side effects. However, they say that they want him to stop the medications as well because they don't like seeing him drowsy and feel like if he is drowsy to this extent, he'll never be able to return to full-time employment or resume his school programs. They thank me for my time and end the appointment early. I present this because I think from a clinician's perspective, for those of us who have worked with medications over time and have seen many patients and have seen the experience of medications being helpful and effective, it can feel like there's an automatic that we should be expecting that everybody is going to be on the same page about medication. Of course, here we are. We're offering medication based on our extensive knowledge and training and experience with all of the best intentions. We understand that the people who we're recommending the medication for may or may not see it the same way. I often, and certainly have evolved in this over time, expect that the families are also going to be on the same side for medication. It's just not always the case. I present this as a starting point because it's important to really know where you stand with everyone you're working with to get a sense of who in the room feels different ways about the medications. We'll move on to the next slide, please. I wanted to actually even try to facilitate a little bit of a conversation of sorts, although we'll do this through the chat. I want to begin even with, again, recognizing that there may be people from all kinds of diverse backgrounds as far as this medication conversation comes up, but why are we even talking about medications? That may seem like a silly question, but what is the point of this and how do we get from attention about medications to a shared vision of goals and using goals to tailor care? What are some of the common stuck points? From the clinician perspective, perhaps, and if there are other perspectives, that's welcome as well here, but why are we even talking about this? Are we talking about resolution of symptoms? Are we talking about functional changes? Are we talking about suffering? Is there stigma, fear? Where are all these different things? I welcome people to take a second and think about what are a couple of the main reasons that you want to talk about medication with people and thinking about where are you coming from in that conversation. I'll hold off for just a minute to let people put a couple of things in the chat. I'll take a look through there. Again, make sure to set it for all panelists and attendees so everybody can see what your suggestions are. Feel free to put in suggestions here, but also you can continue with also doing the introductions if you haven't done that yet. I see a few people. I'll just call out some of the answers here. I see from Layla, it looks like medication is pretty much the main treatment or their only treatment option at a state hospital. That comes from we have to use what we have available. I see a number of people talking about functional changes and helping people to live the life that they want to live and that medication may be able to help with achieving those kinds of goals. I see Tim saying that using medications to remove barriers to client specified life goals, which may be psychosis or mood disorders. For what it's worth, obviously, this is a conversation that we can spend the entire hour on too. Feel free to continue to put things in the chat even once we move on because I think it's important to even for oneself to take a step back and just remember why is it that we're reflexively even suggesting medications. Again, I don't say that to suggest that I don't think the medications are helpful, but I just think that it's important for us to always know where we're coming from and when. Again, I see things about reducing distress, helping to get one's life back, especially in the very beginning to things. These are all excellent points. Again, this isn't even to suggest that there's not one right answer to this. It's to challenge everyone to know where they're coming from when they're facilitating these kinds of conversations in a little bit more detail. Feel free to keep putting things in the chat. We'll move on to the next slide. One of the starting points often here, especially in the first episode or even a clinical high-risk situation is anastagnosia. I know that this is a topic that comes up a lot. Used to be maybe we would talk about this as lack of insight. I prefer to think of it as anastagnosia because I find that insight is a tricky concept to really, as you dive in, what does insight really mean? Certainly, the ability to name what is going on in a way that we can now share the dialogue as to what we're all even talking about. If there's a fundamental disagreement about what we're even here for in the clinical visit, then you're going to be talking at cross-purposes. This, again, is a subject of lots of study and lots of suggestions, but I want to encourage people to think about the kind of Amador leap approach to working with people and not necessarily making that as a... I'm not plugging the program particularly, but just certainly thinking about the concept of using listening, empathy, agreement, and partnering to help people find... If you can find something that you can agree on, it doesn't necessarily have to be you have schizophrenia and we agree on that statement, but it certainly can be let's find some areas where we can agree about what's happening in a person's life and is it working out the way that they are hoping for? Can we find that there's some feelings that we can find areas of agreement on feeling scared or feeling... Without necessarily putting labels on it that are going to show that this is... I'm making a diagnosis, I'm finding something very clinical here, but what's going on? How are we in this together? How are we here to partner on trying to get things a little back on track? Finding areas where you can agree and partner is going to make a big difference as far as how are we also going to talk about medication and how are we going to figure out if the medications are even doing anything that we want them to be doing? We'll move on to the next slide, please. It's pretty common, especially in the beginning stages of things, to find that there are areas of dissent and difference of opinion. I was talking about in that vignette where finding some surprise in terms of areas of disagreement between me and parents or there could be other family members involved, but it's important to recognize when there isn't disagreement. Think about what is perhaps at the core of that disagreement and how to refocus. Sometimes it means needing to agree to disagree. We're not going to come to an agreement today. Let's take a break. Let's move on. Again, some of this also is very context dependent. I should say, too, that where you have these conversations also matters. If you're on an inpatient unit, it's much different than if you are in a clinic where there's differences in acuity and things like that. In the bigger picture, are there cultural factors that can be making things challenging? Who's projecting their ideas onto whom? But to be aware of what's happening there in terms of ability to build trust and to be able to get everybody feeling like they can be comfortable together. Just to remember, there may be different kind of factors and who's allied with whom. Not that you necessarily want to set up a situation where you are now allying yourself with family in a way that gangs up on the client, but just to understand what are those dynamics in the room so that you can have a conversation about managing some of these dissents and come together to return back to this shared approach that we're trying to get to. Next slide, please. One of the things that also comes up a lot is this psychosis, or what are we dealing with here? A lot of times, especially working at a university like Stanford, people are coming, seeking second or third or fourth opinions on what's going on. The more that you focus a microscope on an individual situation, the less it might seem like a canonical and typical path to something like schizophrenia. There's a lot of temptation to do extensive medical workup. That is, I think, very valuable. There may be times where you find reversible causes of psychosis in doing the workup that can help save people from having to take certain medications or having things go in a direction that is very challenging for them in a way that you can help change very suddenly. These workups can be very hard to do, and they can take a long time and are, frankly, often not going to find something. Hopefully, you find something, but if you don't, it may take three, six months, a year of searching and thinking it through and considering this consultation or not. What I want to always make sure to recommend is that we are pursuing all of the various aspects of treatment. Here, we're talking about medications, but this involves more than just medication, whether it's cognitive behavioral therapy or occupational therapy or all of the various components of treatment, but that we're making sure to include those, that antipsychotics and these other treatments have powerful evidence base behind them, and that it's okay to continue to search for something that might either change things or could shape things a little bit differently, but to do that at the cost of starting treatment means that we're delaying the time that people are actually engaged in treatment, and if it turns out you don't find something, or even if you do, you're often losing valuable time. To know that this is often on people's minds, too, as we're talking about medication, well, maybe we should hold off on medicine while, and I get this question a lot, maybe we should hold off on medicine while we're doing an MRI or an LP or taking various markers for inflammation or down the line, and my suggestion is that we should be doing the things that we can to treat that which we can see, and maybe someday we will think about it differently, but for now, that's the best way we have to proceed is to see what's happening with the individuals and recommend the treatment based on that while simultaneously we can think about finding things in the background that are worth pursuing medically as well. We'll go to the next slide, please. And then similarly, how is stigma influencing the conversation, right? So stigma finds its way in all different areas, and so important to always be mindful of what does it mean to somebody to be on medication? Does it mean to that person that, well, they have this pill bottle in their medicine cabinet, and if somebody were to ever come over, open that cabinet and see it, well, then their whole life would be ruined, or if they were to go somewhere with their friends and, you know, let's just say that we were able to do these things again at some point and go on a camping trip or something and they wouldn't want to bring their medicine unless somebody see it, well, you know, that is showing that this is, you know, already something that a person is not so sure that they want to be doing, and so it's important to be sensitive to that and to talk it through. There may be cultural considerations there too, but certainly to know also that stigma, especially internalized, and by internalized stigma, I mean the stigma that an individual feels against themselves, because I take medication, because I have experienced psychosis, therefore I cannot do X, Y, or Z, that that may be something that is limiting, but then there's also the externalized stigma, which, you know, comes from other folks and saying, well, you know, whether it has to do with all the various stigmas, whether it has to do with perceived risk of violence, perceived inability to have social or occupational functioning, etc., that these are all topics that are happening in the room, and so to bring them out and be explicit about them, especially when it becomes very clear that they're influencing people's decision making. Also, this is where making sure to keep a very, as best as possible, a clear line of communication open, that if people are going to stop medication, or if it's not working in some way, or they're not getting the benefit, that there's an open dialogue, and that, you know, that it's not going to be something that a person is going to be made to feel like they can't be authentic in what they're doing, and therefore need to, you know, kind of hide in the shadows, lest there be other, they feel like there's repercussions or things. Move on to the next slide, please. So, in the outpatient world, especially, but we do this plenty on the inpatient is, and to the extent that it's available, family meetings are really essential. The medication decision, while ultimately, you know, the person taking the medication always has 51% of the vote, outside of, you know, court-ordered treatments and the like, you know, the vast majority of cases, the person actually putting the pill in their mouth or agreeing to take the injection has at least 51% of the vote. They either do it or they don't. And at some point, all the begging and pleading one can do, and all of the various ways that one can try to tip the balance in favor of choosing the medication or not choosing the medication, you know, ultimately, it's that person who's going to do it or not going to do it. But making sure that the family is included in that conversation, certainly in the beginning, but at various stages throughout is really important. And so I wanted to talk a little bit about making sure that the concept of a family meeting is something that is really paramount to the act of choosing medication. And so thinking about who should be there, you know, I usually like to leave it to, you know, to check in with the patient to find out, you know, who do they feel like is going to be someone that they would feel comfortable there. Ideally, you know, if a person is living with other members of their family, those are the people that should be there because they're all going to be playing a role in the medication treatment and understanding what is going on. Ideally, that also opens up lines of communication if things aren't going well or are going well to be able to get, you know, more 360 degree view of what is happening for an individual so that, you know, I'm not left making assumptions based on 20 or 30 minutes once a month or once every couple of months in the office. And that if something happens in the interim, of course, we all know each other. But it's important when we're having a family meeting to make sure that the agenda is very clear and that everybody has the ability to now put some things on the agenda. Ideally, we are able to address all the things in the agenda in the course of one meeting. But sometimes, you know, it may require ongoing dialogue and there may need to be a second meeting. But it's important to make sure and that, you know, from that beginning of understanding who is coming in with what sort of opinions, it's helpful to have a sense in advance of what, where folks are coming from to be able to sort of not get caught unprepared in a meeting. So to know in advance that likely what we're going to be talking about in this family meeting is going to be some version of parents want medication, the child doesn't want medication or nobody wants medication and they need to understand a little bit more about what are the risks and benefits or what is the evidence or this is a conversation about side effects. But to know exactly what is it that is causing people to feel either uncertain or to just get everybody on board together and know that, hey, we're all in this partnership and we've all decided and we're all feeling good about the plan. Next slide, please. So often, you know, because early psychosis affects young people primarily, you know, late teens, early 20s, a lot of time, I talk about this often in terms of parental concerns. It isn't necessarily only parents, of course, it's really all family members, but so often it can be related to parents and sometimes that can be difficult. And people reasonably, understandably are very worried about what does it mean for someone to start antipsychotics and we're going to talk a little bit more about that later on as far as, well, how long should they be on that and what does that mean, you know, for their life and all these things we were talking about as far as the stigmas that can come up and what is this, you know, how long should they be on that and what does it mean, is this the end of things for my child, you know, is there room for optimism or not, are they ever going to find a partner, all these different things that come up. And a lot of times, as the psychiatrist, I find myself, you know, in the line of fire for taking on these concerns. And so I think it's important to recognize and different people are going to do, you know, handle these concerns differently. And, you know, whether it's that there's an intense desire to find the medical answer and leaving no stone unturned, including going to places that maybe aren't evidence-based to perhaps find answers or to, you know, call up multiple second opinions and things and feel in a way like they're undermining the treatment or, you know, all these different things that people do. And it's important to remember where that is coming from, to recognize that it's largely can be about fear. What is the source of that fear? Maybe it's something that can be mitigated. Maybe it's something we can talk about. Maybe it's something that people have to kind of work through. It's where I find that, for those who work in CSC model programs, or like we have in the Inspire Clinic, where working in a team situation is very helpful, because it makes it so that there isn't necessarily just one person who has to be there on an island to manage these concerns. And that people can take turns, or that the beauty of having different disciplines is that maybe one approach resonates better than a different approach with an individual, or people can get along better. But just to know that this is something that happens, I'm sure many of you who are clinicians in the audience have experienced it, but to really make sure to pause, like that pause to reflect, I think is really critical, because people might be emotional, and that emotion may set off emotion, certainly it has for me at times, but to take a step back to remember, okay, well, what is it that we're talking about? And it gets back to that very first beginning slide of what is it that we're talking about? Why are we talking about it? And how are we gonna take a minute to try to get back into some sort of alignment if at all possible? And so taking a break, but making sure to reflect on where it is that people are coming from can be really helpful. All right, so we're gonna transition from here into talking about the clinical high risk, but maybe now's the moment to take a pause and look in the chat and see if there will be, if there are a couple of questions, and I don't know, Steve, if you were following along, if there's a couple you would recommend for right now? Well, part of the question, yeah, so how do we navigate the conflict between medications and culture and religious beliefs? There's a question from Peter that just came up. Sure, well, I mean, that's an excellent question, right? And so no one's gonna be an expert on every culture, right, and so there's always gonna be that aspect of things where everybody is bringing to the meeting aspects of who they are and their experience, and so certainly I think that the way I try to approach it, and it may or may not even be the best way, but I wanna do as much listening as I can to understand what is going on. If it's a culture that I have more familiarity with, then perhaps, then maybe I might feel more empowered to address things that I feel like have worked in the past as far as been understandable. If it's a culture I'm less familiar with, I'm gonna need to do more listening and more learning to understand. Ultimately, at the end of the day, again, it comes back to having to respect people and families' autonomy, and that in a scenario where people have the free choice to take medication or not take medication to allow people to exercise that choice, I think part of it as well, and it goes beyond just the cultural religious beliefs, but allow people to exercise that choice means also allowing them to make a choice that isn't the one that I would make, but that I try to make sure to hold on to people within the clinic or within the clinical context so that if they change their mind, they have a place to go. And so that certainly can, it certainly is hard, and there may be, there are certainly some folks who are gonna be really much more dug in on medications are absolutely not possible for me and for my family or for my child, and it can certainly be challenging when a young person wants to take medication and they're getting pressure from a family not to, and certainly it's something we often have to discuss and rediscuss and continue to work through. Well, and that was Melissa's question, particularly for someone who might be a minor, and if they actually wanna take medication, but their family maybe isn't that supportive of it, how do you address those kinds of questions and Ashley had raised earlier, related to that, how do you explain the risks and benefits around refusing to take medication? Sure, and again, some of these things will be things that come up in some of the later slides too, but I'm happy to address some of it now as well. Yeah, 51% of the vote is a little bit different when a person is a minor, then it is a little bit more complicated, especially when that minor is 16 or 17 years old, and for all intent and purpose is an adult physically, but in the eyes of the law is not adult and all that, so it definitely can get a little bit more sticky. If parents are not on board, and certainly in a minor, often the parents are gonna hold sway, I mean, it can be a little bit difficult to fully execute, but to get people medication when they're not, but yeah, certainly, and I see, certainly Lauren's suggestion here about using shared decision-making, ultimately, I think that using shared decision-making models is what's gonna help bring people all to the table, that idea that everybody is gonna come in with their own expertise, I might be bringing in expertise as far as my experience in using medications and in seeing people who've experienced certain things that are similar to what is going on, but the person taking the medication certainly brings in their own expertise as to what is it like for them when they take medication, what are the side effects that they can and can't tolerate, what do they feel like, it brings them even to how people think they need medication, and the families are gonna bring in their own fears and concerns, which may be culturally bound or may not be, well, I mean, everyone's bringing in their culture, but it may be that it is something that is kind of bigger than themselves or maybe unique to their own perspective, either way, making sure that everybody's able to kind of get out their ideas on the table, and then we can work to weigh the risks and benefits and come up with a plan, and that plan might be that we say, well, let's try medication right now and see how it goes, that plan might be, let's try holding off on the medication, it seems like that's what everybody wants, but we'll try some other aspects of treatment, I think the important thing is to make sure that there's some level of engagement that can be maintained, because medications are, I'd like to think that medication is always gonna work, but it's not, and neither is anything else, nothing is 100% certain, so we need to make sure that everybody feels like there's the ability to come in and share their experience so that we can make decisions and pivot if needed. All right, why don't we move on to the next slides? So we're gonna talk a little bit about the clinical high risk, and again, I don't wanna give a whole talk on that, because it certainly is its own topic, but there are screening measures that one can use, the PQB, you can look that up and find that online, and you can use that, that's something that people can use, works well in primary care settings and other places for screening for clinical high risk, and then certainly can use the SIPs, SIPs and SOPs for helping to decide either for tracking purposes or really for also making a decision as to whether a person is in the clinical high risk state or has developed what we would consider to be above the threshold for a psychotic syndrome, and the various kind of subtypes within the clinical high risk that we typically look at are attenuated psychotic symptoms, so usually the way this works out, especially if you're looking at the SIPs ratings, is that there's some cognitive flexibility still maintained around the symptoms, so a person hasn't necessarily changed their behavior because they're experiencing either some paranoia or maybe auditory hallucinations, they're able to hold it and seems odd, I'm not sure what's going on, there also are the brief and limited psychotic symptoms, sometimes known as blips, which tend to last less than 24 hours and resolve on their own, tend to be more associated though with further and future development of psychosis, so it's certainly important to keep those in mind, and then people with family history and a notable functional decline will often find themselves in this clinical high risk category. In the clinical high risk stage, negative symptoms and cognitive symptoms may already actually be there, and so it's not necessarily, positive symptoms are what gain attention from folks, but certainly as a person who's in this period, some of how they have been brought to attention is there's something that's not going well for them and there's some need for, or some desire for engaging in treatment, but to be really mindful of negative symptoms and cognitive symptoms and how that can impact school and social, as people tend to start to withdraw a bit and have some functional decline is important because those can really predate the onset of some of the positive symptoms. Go to the next slide, please. So the goals of treatment when people are in the clinical high risk stage is a little bit different than further on because we don't actually have, we don't have a defined diagnosis at this point. This is a nebulous diagnosis. To work with people at this stage requires a willingness and ability to tolerate uncertainty. People coming in with, and into the clinical high risk stage, maybe have a 20 to 30, maybe as much as 35, 40% chance of eventually developing something like schizophrenia. Now that is notably higher than the general population, but it's not 100% and it's not even probably 50%. So people who are brought into these clinics often will develop other psychiatric diagnoses, whether it's depression or bipolar disorder, anxiety, substance use, I mean, all the various things that you might expect, but this isn't necessarily, that's why we don't call it prodrome or the psychosis prodrome any longer because we actually don't know that it's a prodrome to schizophrenia. I would only really determine that down the road, right? And so the goals of treatment here really need to stay consistent with the patient's goals. And it's important that we're, and we're gonna get into this more in one of the next slides, is that meds aren't really there to prevent that kind of quote unquote conversion to psychosis. They can be helpful, but actually one of the challenges can be that if you're using an antipsychotic and you don't really have full psychosis, it's unclear whether, what is the antipsychotic working or the person just not go on to develop psychosis. You set up a counterfactual that becomes a little bit tricky. So really it's important to target what are the observable symptoms? That means often these are anxiety and mood. They may be social anxiety, but what is it that is clearly there? And then to keep in mind to be mindful when things might transition into something that's a little bit more severe. There are a number of different risk calculators out there. I mentioned that because it's important to know that they exist. There aren't really able to help out in the clinical frame, but at some point perhaps. Okay, we'll go to the next slide, please. So medications at this stage, antipsychotics generally no, right? There isn't to say that there isn't a time and place where you might need one. Maybe there is mood instability and one of the mood stabilizers that they haven't really helped. And you get to the point where you're like, well, maybe I need an antipsychotic for mood stabilization. But ideally you don't wanna contaminate the picture by putting an antipsychotic in for somebody who doesn't really have a threshold level of psychosis. It can be tricky because again, there is no defined marker. Even if you get trained in the system in terms of making these distinctions, you're relying upon history, you're relying upon other people's reports, you're relying upon observable behaviors. And so you have to make your best judgment as to whether a person really has psychosis or is in that high risk stage. But if you feel like the person is really still in the high risk stage, I would encourage you to hold off on the antipsychotics and to continue to be paying close attention. It may be a very fluid kind of situation and then to consider using medications that will treat the more observable symptoms. And so we'll go on to the next slide, please. And so that means more likely you're gonna be using things like antidepressants, SSRIs, Wellbutrin, et cetera, to target depression. You may find yourself more likely to want to use a mood stabilizer, especially if it's kind of a bipolar depression picture, something like that. Antipsychotics, stimulants, I mean, these are things that people... So it's very common that I will get somebody coming into me who is being referred because of a question about psychosis, but the person coming to me thinks they're being referred because they're having a hard time focusing in school and they'd like to take or continue taking stimulants. And of course we have to decide whether that's safe. And the answer is almost never that it's okay, especially in that high risk period. We can talk a little bit at the end about whether or not stimulants are okay to use in somebody who already has psychosis, which again is very risky and requires a lot of very careful consideration. But in the high risk period in particular, I wouldn't want to be using stimulants. But again, people are gonna come in on them. And so it's a matter of trying to figure out what's gonna be the right way to continue or not continue as the case may be. That's all I was gonna talk about on the high risk. Are there questions relating to clinical high risk at this point? Okay, so let's move on then. We'll go to the next slide. So now we're gonna talk a little bit about medications in the first episode. So here we are 41 minutes into the presentation and here we get finally got to it, right? So first off, I think it's worth noting that the APA treatment guidelines have now been released for schizophrenia. It's a very long document. I think, honestly, even reading the table of contents is helpful just to see the things that made it into the document. But it is a worthwhile and obviously not without its own controversy and things, but there's a lot in there. It talks about medications, it talks about non-medication treatments. So, and it just came out in fact, as I was putting these slides together, we just changed it because it's my slides that didn't make it into the document. So I'm gonna go ahead and move on to the next slide. I know that it was pending release, but now it's out. So I want to encourage everyone to take a look at that. And then I will put in a plug for the book that Dr. Adel Simon-Hardy and I put together with Doug Nordsee as well. But there's a chapter in there about psychopharmacology for people in early psychosis, which I think is very helpful for laying a lot of this out there. I also, I think as we're starting out in the conversation, I think it's important also to think about how we frame diagnosis and how we think about diagnosis, which is to say, do you come from a kind of perspective that we're talking about schizophrenia or schizoaffective disorder or bipolar disorder with psychotic features or major depressive with psychotic features as kind of binaries. You either have it or you don't. And we're going to figure out which one you have. And then from there, pick a medication or pick a therapy and kind of put together a package of treatments. Or do you tend to take more of a dimensional approach to thinking about, well, this is a person who has kind of high positive symptoms and low negative symptoms with some cognitive changes or is relatively high anxiety or low anxiety. There may be aspects of relating to drugs and alcohol, cannabis, sort of parsing it out and thinking about it. I personally tend to think about it in that way because I find that that's helpful then also as I'm thinking about medication and what I want the medication to do. It just kind of helps. It helps me to keep things in a more granular perspective as I'm working towards things. So that's just, again, something to be keeping in mind. All right, we'll go to the next slide, please. So how do you choose an initial medication? Well, I mean, there's no real magic. I think that there's a number of things that are gonna obviously factor in. So if there's a first degree family relative or a family history, and there's a medication that worked well for a close member of the family, that's gonna be helpful. I would use that as a guide. But that's fairly uncommon that you're gonna get something quite like that to guide you. So most often then what we're doing is really, I'm considering what are the side effect risks? I'm assuming that any of the medications on the market are going to work for somebody that I don't know in advance who that somebody is going to be with any particular medication. So I don't have any, there isn't really like a, there's not really a way to say that. There's not really a way to say, well, this person is clearly gonna be a quetiapine responder, this person's an aripiprazole responder in advance. So we've gotta try it. But we certainly do have an idea of where things shake out as far as side effects. And we'll go through that because the first episode is where sort of the risk for some of the metabolic side effects is greatest. So I'll show a slide about that in a few minutes. So we wanna be thinking about metabolic side effects. We wanna be thinking about neurological potential side effects. But also, what are the things that are gonna help people get through the day? And what is a person doing with their day? And what kind of medication, can they tolerate a medicine that's gonna be sedating? Is that, does this person, are they trying to attend university full time and they're starting medication? And if you give them a medicine that's gonna be too sedating, they're just not gonna take it because it's not gonna work out. Because they aren't gonna be able to continue along. Again, it would not be in alignment with what their goals are, if their goals are to continue working, being in school at a high level. And again, that may not be for everybody's clinical practice may or may not involve folks in those kinds of areas, but it's important to really be thinking, how is this medicine gonna be tolerated? And then also, what are some of the options for administering? So we're gonna talk in a couple minutes about long-acting injectable medications, but in choosing that first medicine, maybe you wanna choose a medicine where you do have multiple options as far as how you administer it, that it can be given in a long-acting form, even from the beginning. And of course, there's some of the newest agents that are on the market, Lumetapron and Kiriprazine, that aren't gonna be included in a lot of the comparative studies. And so, how do you know exactly where to put them in? But then also at the same time, again, depending on your practice, you may have various insurance limitations that are gonna mandate that those drugs are relegated to third line or later anyway, before a payer is going to be willing to pay for them. So there are also those kinds of considerations that factor in as well. So, what would I like as a psychiatrist? What is the medicine that I think is absolutely best? You have to intersect that with, what is actually going to be available in my practice setting? Go to the next slide, please. I was asked to make sure to include a sort of topic on, is there impact on race or ethnicity on medications? And there's not really a lot of great data, frankly. Not surprisingly, a lot of the studies have been done predominantly in white males. It's been shown repeatedly that black people tend to get prescribed into psychotics more readily, often because studies have shown that people tend to be, that black people tend to be more likely to be diagnosed with schizophrenia instead of something like PTSD, and therefore end up being routed towards antipsychotics instead of other treatments that might be more appropriate. However, the exception to that is clozapine. And so, that's what the data shows. You can understand why that would be a disparity in healthcare, but also, it's certainly worth noting. There is also the aspect of benign ethnic neutropenia that can sometimes, and historically, have made clozapine use in some black people a little bit more challenging because of the likelihood of having lower neutrophil counts that, until the last, sort of most recent, clozapine REMS guidelines made it hard to manage. Now that's easier to manage, and so it shouldn't be a limitation any longer. So, a little bit of evidence that said that people of Asian descent were able to manage with lower doses. I'm not sure what to make of that, those findings, necessarily, or have an answer as to why that would be the case. Certainly, there's a lot more to be understood on treatment disparities and the like. We'll move on to the next slide, please. So, in the first episode, in particular, dosing ought to be low and slow. Treatment emergent side effects are likely to come up very quickly. Benefits also are likely to come up quickly, and so you don't want to necessarily find yourself in a position of having gone up on risperidone as fast as you could to eight milligrams before you realize that, in fact, maybe three milligrams might have been a sufficient dose or two milligrams, and now you're introducing an additional risk of side effects without necessarily achieving any additional benefit. The response is likely to be within very quick, so if you're not seeing a response within the first couple of weeks, it may be that you need to consider switching or augmenting, but it also might be that it's important to look at what is the trajectory, so you may not have full remission in one to two weeks, but you ought to be seeing at least that there's some movement in the right direction or else maybe that isn't going to be the right medication, and be prepared to pivot quickly, especially if you're on an inpatient unit where you have the ability to make changes a little bit more quickly than in the outpatient world. Next slide, please. Obviously, adherence is going to be the big topic, especially if they're out of the hospital. How do you know if people are taking medication? Obviously, one of the best ways is you know they're taking medication if, in fact, it's administered in an injection, but that's obviously going to be hard for some people to want to do, especially in the beginning, and there's no perfect way to know if a person is taking their medication or not. You're not likely to get drug levels all the time, although you can get them periodically if that's really important to understand, but really keeping an open line of dialogue, making sure that people understand that if they decide to stop or have decided to stop, they're not likely to get fired from your clinic, that there's still a place for them regardless, and that you're really at least among the goals should be that a person has had an index episode of psychosis that among the goals should be to prevent a second episode. Patients may or may not share that goal or not, but certainly I'm going to try to introduce that as a possible goal that I'm interested in trying to help them with. Go to the next slide, please. And then the question that, again, we could spend a long time on is, well, doc, do I have to take these medications forever? And that is, you know, there's no perfect answer here because, in fact, some people, admittedly very few, are going to have one episode of psychosis, take medication, they'll be able to stop and they won't have it recur. Maybe there was an extenuating circumstance in that first episode, maybe it was, you know, it was more drug-related than initially thought or the like. But most likely, if a person has an episode of psychosis, they're likely to have a second one. That might be, you know, the numbers are hard to put together, you know, for the literature, is it 60%, is it 90%? But, you know, everybody thinks that they're going to be in that percentage that isn't going to have another episode. And there's no way to really know without actually, to some extent, for them to run the experiment of, well, what happens if I stop the medication? Am I going to be one of those people who has another episode or not? And, of course, when is the right time to do that experiment? So, you know, I often frame it in terms of short-term versus long-term risks. You know, stopping medication means that there's a recurrent short-term risk. There's kind of always a risk that that episode could be, you know, a few days away or a few weeks away. We don't really know, it's kind of, ultimately, it's long-term, but it's really recurrent short-term risk as opposed to, you know, we do know that there's long-term risks to taking antipsychotics over time. Whether it's tardive dyskinesia, which exists even with second-generation antipsychotics, you know, or weight gain, which may be, you know, if a person gains 50, 60 or 100 pounds on some medicines, that even if they stop that medicine, they may have a really hard time losing that weight, and it can really fundamentally alter the trajectory of their life. So, but in order to have that conversation, there needs to be really open communication that people have to be able to feel like they're being heard, and I would much rather from a, you know, from a harm reduction perspective, I'd rather know that a person is considering stopping their medicine so that we can do it in a very gradual manner rather than have them tell me, well, hey, doc, last month I stopped my medication, and I'm fine today, but what do you think because then there's not a whole lot I can really do except watch and wait and see what happens. Whereas if we go slowly in terms of tapering, at least if we see things are kind of not going well, we can always go right back up, or we can at least be in on it together so we can, you know, be able to manage it in a partnership. And the next slide, please. So, I'm usually looking for, you know, one to two years without symptoms. I usually quote 80% or more chance of relapse, but, you know, those numbers are really hard to pin down, but, of course, everybody thinks they're in that, you know, in that 20%, and that, you know, if a person comes to me and says, well, I've been off my MedStock now for two months, and I've been fine, I guess I don't ever need them, I mean, it's hard to restart it at that point if they're not having symptoms and they're off their medication because there aren't really target symptoms or things to know if they're, you know, where they are, but the risk of relapse is still there. Even if it's two months or six months or whatever, there's still that risk of relapse hanging out there, and I don't like to leave people with that sort of doom and gloom, like I think you're going to relapse, I am not rooting for you or, you know, not optimistic for you, because I certainly want people to have a sense of optimism, but I also need to make sure that people are getting my authentic recommendation and, you know, that my experience and training is being factored into their decision. Next slide, please. So, long-acting injectables, I think, you know, in a first episode conversation, you know, many people would think that long-acting injectables aren't necessary, but I really think that it factors into my decision, you know, I am more likely to use Aripiprazole or Risperidone in that first medication decision because I have the opportunity to give a long-acting injectable version, you know, so I think it's worth having the conversation early. I also think that it's worth having the conversation early because I wouldn't want someone to think that the only reason I'm suggesting it is punitive, that, you know, you didn't take your medicine, you went to the hospital, so now you need an injection, right? You know, these injections are out there, and they can be really helpful, and so there's no need to necessarily wait until there's an adherence issue, and part of that is because long-acting injectables, while helpful for adherence, don't actually guarantee it, right? You know, it does, you know that once a person gets the injection, they will have medication on board extensively for the duration of that injection, whether it's, you know, two weeks or a month or two months or three months, but they have to show up for the next injection, and in some ways, it's a higher bar to get somebody to show up for an injection. It's painful. They have to, you know, they have to drive into a clinic or pharmacy or somewhere to get the injection. It's, you know, it's not as easy as each day just taking a pill, but it is, you know, in my opinion, something that is very helpful and worthwhile, and so therefore, I want to encourage people to do it. I think for young people in particular, the logic that tends to resonate the most is if you take this long-acting injectable, at least your parents know that you've taken it, and so if you have a bad day, they're less likely to, you know, say that you take your medication and, you know, kind of walk on eggshells, and so that, you know, that way, people can feel like, you know, they've been kind of heard, and they don't have to worry about that so much. We'll go to the next slide, please. I did want to bring up clozapine. Again, not necessarily something people think of in that very first episode because the algorithm would suggest you need to have tried two of the medications first, but there's some, you know, limited data, and it is worth keeping in mind. If, you know, if we think of sort of early psychosis as lasting for, you know, the first couple of years, some people really are going to, you know, need to go to clozapine, and so just to encourage people to go low and slow with that clozapine if you're going to start it in somebody within the first two years of diagnosis, and we put together a paper with a case series on that a couple years back, so you can take a look at that if you'd like. I wanted to talk, because I know there's a lot of questions about some of the newer medicines. Of course, they're new, so, you know, individual experience is still limited. Lumetaparone had the misfortune of coming out on the market in the midst of the pandemic, so certainly that has made it a little hard from the company's perspective to get the word out, but it is out there. It's a, you know, is it totally novel that it, you know, has some novel components to it, certainly how it relates to some of the other dopamine receptors and also the way that it responds to glutamate, which make it, to me, an interesting medication to consider as an adjunct medication to antipsychotics potentially, but also it can stand on its own. The hard part is that you have to try two other medicines, at least in my experience, before anyone will pay for it, and so that puts it up at the same kind of, you're deciding between clozapine and lumetaparone, and so, you know, there may be, like, from a metabolic perspective, it's certainly worth considering. I have had some people who've taken it that have had to stop because of drowsiness, so that's important. It is easy because it comes in basically, you know, one dose is mainly what you would do, and it should be taken with food. The other drug I wanted to spend a minute or so talking about was cariprazine. Trade name is Vraylar. I find this drug to be one that, you know, especially for folks who have had issues with weight gain or had issues with drowsiness, even though that's among the side effects, I have found the drowsiness to be less of a problem for folks, and so for, you know, many of my patients who are in school or are working full-time have found that this drug has been helpful for them. One of the reasons I think it's also been particularly helpful is that it has a very long half-life of its active metabolite, and so that which can last up to two to three weeks, which basically helps to shield, you know, from a missed dose. It almost is like an oral long-acting injectable medication in some ways in that regard, and so especially for young people who may, and I apologize, there's some background noise, that, you know, that can be helpful to have that benefit, in the same way that we sometimes consider fluoxetine for young people with depression, because that also, with a long half-life, makes it a little bit easier to stick with it. Next slide, please. Sorry, I went through these without advancing the slide. So there's Lumetaparone for you. We'll go to the next slide, and there's curiprazine and some things, and then in the pipeline, just a couple things to be aware of. There's a lot of different medications in the pipeline, but some that are a little further along, you know, ALK3831, so this is, you know, it's not approved yet, but it's pending before the FDA includes, it's a preparation that is a lansipine plus semidorphine, where the semidorphine is intended to help kind of mitigate appetite and therefore the weight gain. It'll be interesting to see if it gets approved. It's, you know, it's pending for the FDA right now. Show that there was, you know, after, at least in sort of people who were not in first episode, there's a first episode study that's still ongoing, but that, you know, people gained weight kind of the same rate for six weeks, and then it leveled off in the ALK3831 group compared to the lansipine-only group, but some of the other metabolic parameters didn't actually level off, and so it'll be interesting to see how this drug proceeds, especially in the first episode population. There are some drugs that are using what's called a TAR1 mechanism or trace amine-associated receptor. These are interesting targets because they are inside the cell instead of on the cell surface, and they respond to very micro concentrations of these trace amines, and at least the TAR1 mechanism acts almost like a shock absorber to the dopamine and glutamate system, and so, again, these drugs may work very well as adjunct medications but also might be able to stand on their own, and the Lundbeck drug is in phase three right now, which means it's, you know, in that last phase before being able to submit for approval, so we'll be able to see, and then a drug that I think is just very interesting is called CAR-XT. It acts through muscarinic receptors, which is a different mechanism than the other drugs that we have, but, no, you can't use, you know, muscarinic receptors can cause a lot of GI side effects and things, and so this drug has a way of blocking some of those side effects in a way that is interesting. I just want to go through a couple quick last slides. Just about, we're going over a little bit. I want to make sure there's time for a couple questions, but this is just an old slide from the UFAS study, which is the European first-episode study, just to give a sense of the magnitude of weight gain in the first episode or early psychosis, right, and landscaping in blue there, over 50% of people gain more than 7% of their body weight. These are, you know, close to 60%, but that it's true for, you know, even the medicines that we think of as being relatively weight-neutral, like Haldol and, or Haloperidol and Zeprazidone, also were, you know, over 40% of people gain 7% of their body weight, so really important to be, you know, maintaining vigilance on that and to make sure that, you know, discussion of diet and exercise is part of every visit. Next slide, please. I talked about the neurological side effects. Of course, you know, there's the acute concern for EPS, dystonia, and akathisia, especially the first episode. People are, you know, maybe more sensitive. You don't know how they're going to react, so you want to be very mindful of those and let people know. Cardiomyokinesia, of course, is something that is less of a risk in this population, but something just to be aware of in general. Next slide, please. Things that people tend to complain about, though, fatigue, brain fog, you know, these are the things that people will feel like are limiting their ability to do the things they want to be doing and to be the person that they want to be, and so important to be taking these into consideration and giving them a lot of air time. We'll move on to the next slide, please. You know, so adjunctive medications for symptoms, you know, a lot of these are going to be off-label, and so I want to make sure that, you know, of course, making the off-label announcement, but also you're going to, you know, you want to follow some symptoms. If people have some depression, like, you know, an SSRI may be worthwhile. Occasionally even using a benzodiazepine. For some people, that's going to be necessary, but you need to be clear on what you're targeting, and this is where, you know, so stimulants is obviously a very, very tricky one. If a person is on an antipsychotic, preferably a long-acting injectable, a stimulant might be possible with very, very close follow-up. You know, about a third of people will find some benefit, and about two-thirds of people will actually get worse or won't notice any difference, so you're not exactly, you know, it's not exactly the most high-percentage thing to use, provigil or modafinil, rather, or armadafinil might be a little bit safer to use, certainly, than some of the sympathomimetic stimulants, like mixed amphetamine salts or methylphenidate, but in any case, you know, it can be really helpful if a person is experiencing that brain fog and fatigue, but you got to be very careful because, of course, the side effects of stimulants are psychosis. Next slide, please. And then some of the side-effect, you know, medications are out there, you know, anticholinergics to help with some of the movement side effects, like benztropine. Metformin has a little bit of data for weight loss, but, or for the metabolic side effects, but it's pretty weak. There's not really a lot of great options. Often, you have to change the medication if that's a real issue. Some people will use topiramate. There's the bupropion-altrexone combination, which hasn't really shown data in schizophrenia yet, and so, you know, I don't really use it. If people are on clozapine and they're drooling, of course, atropine drops sublingually, targeted right on the salivary gland can be helpful, so that's one thing to keep in mind. And then next slide. Of course, you know, and this is my last slide here. It's important to have some way of measuring your efficacy, whether it's symptom ratings or monitoring for functional changes, but really trying to make sure, like, okay, you know, going back to that very beginning, like, how do you think about, is the medication working? Well, the medication is working if it's helping people achieve their goals, certainly, and help people to, you know, ostensibly function at a higher level and be more on board with what they are looking for in their life. So with that, I will stop, and we have about 8 or 10 minutes or so to do some questions. Steve, do you have some there? Thanks. All right. And as I'm scrolling back, I see a couple of questions, and it's worth mentioning the PepNet Lister for those who found out about this talk through some other ways, that that can also be a great resource for program development and the like, so. So, Jake, there were some early questions. You know, one of them from Thomas was around recommending or not genetic testing for medication efficacy during an initial workup. Yeah, great question. That comes up a lot with families. The genetic testing is very well marketed, but it is of almost no value as far as I'm concerned. So where I find that those tests can be helpful is for people for whom they've either been exquisitely sensitive to medication and had side effects at doses far below what I would expect or have really shown no response to medication, even at doses that I would have thought higher than would have been necessary. And the reason for that is that the genetic testing can help at least identify how people metabolize medication, but that's about all they're really good for. They will tell a whole story about a bunch of other candidate genes, none of which is supported by literature or been able to be really well enough replicated to be useful. And so I generally don't encourage families to pursue that kind of testing. I rarely order it myself, but sometimes, you know, and sometimes you can get a sense also if you took a level for a medicine and then that level was notably higher or notably lower than you were expecting, of course, you know, that also is a reason that at least maybe check genetically to see if that's the explanation. Of course, there can be other reasons a person's drug levels might be a little bit low, especially if they're on a Lanzapine or Clotsapine, for example, when they smoke cigarettes, that metabolizes the medication or drink grapefruit juice for some medications or, you know, all those kinds of things, or it can be on medications that induce metabolism if they're on something like Oxtrapazipine or Carbamazepine or something like that. But so in general, I don't order them. I don't find them that helpful. I probably have ordered them, you know, three or four times. And of those times, one time it did find someone who was a fast metabolizer. So that was useful to know about, but otherwise I don't typically order those. Thank you. One of the, you know, some of the other questions earlier on were also really around the role of parents and families in terms of decisions about stopping medication. How do we interact positively to encourage adult clients around, you know, being able to have effective conversations with family members around their own decisions about care. So I'm wondering if you could just speak a little bit more. And then, you know, there was a question back from Seth around, you know, how do we support recovery when people actually want to stop medication in terms of addressing other symptoms that might then arise? Sure, sure. Well, maybe I'll start with that one and then I'll come back to some of the issues with families. I mean, I think, I hope that discussions around stopping medication are discussions that are able to be had, you know, proactively. It's my hope in having those conversations that people can feel that, you know, they're gonna be supported in their decision. They're always gonna know, you know, what I feel like, what my recommendation is, but at the end of the day, they're gonna feel supported. And if symptoms come up, that we've had a chance to talk about it in advance in a way that allows for us to, you know, make sure that everybody knows that there's not gonna be an I told you so moment or, you know, that kind of a thing. We're all trying to figure this out as best as we can with information that we have. And so, you know, if a person ends up symptomatic or back in the hospital or, you know, whatever, it's like, okay, look, this is what we learned. You know, I almost will refer to it like it was an experiment of sorts. And, you know, of course, it gets a little bit more tricky after the second or third time. Like on the first time, it is, I think, a legit experiment. Like, let's just see what happens. You know, after the second or third time, of course, you know, to me, it's less of an experiment and more, you know, there's, you know, to me, more likelihood of the psychosis relapse. And I, of course, will make that point clear. And, you know, there are gonna be some people for whom it just doesn't much matter how many times they relapse. And, you know, you have to, at some level, be comfortable with the discomfort. You know, you can get, you know, if you're thinking about medical legal aspects, make sure you're documenting exactly what you have recommended and offered, and, you know, the risks and benefits and all of that. But people are gonna make their decisions. And so that, you know, I have people who have come and stopped their medication, you know, five, six, seven times and resulted in hospitalizations at some point each time. And they're still welcome to come back and see me. Because maybe at some point, the equation will change a little bit for them and they will feel like that they're ready to re-engage with treatment. And, you know, but it, you know, working with this population requires a large amount of patience and a large amount of willingness to deal with uncertainty. And that all is part of what's gonna come up here. And I think that's largely the message that I wanna instill in with families is that I can't really predict 100% what's gonna happen. You know, I mean, I can do my best to have some sense of some things, but, you know, I think maintaining optimism, maintaining a positive frame on things, you know, recognizing that participating in treatment is not a guarantee of success, but certainly is helpful. That I will often tell people that, you know, we all know what can, if we're talking about schizophrenia in particular, we all know what that can be like for people, how, you know, how much havoc that can wreak in certain people's lives. But at the same time, we don't need to completely surrender ourselves to that and assume that nothing is gonna be able to be done, that there's a lot that we can do, whether it's medication or the other treatments that we all can offer or ought to be offering and go from there. But certainly maintaining that sense of optimism, that there's a reason why we're doing this because we think that it's gonna be able to help get people back on track and back to a quality of life is, I find that that's a helpful reframe to keep, at least to make sure, because we can all generally align on that as a reasonable goal. Steve, one last question. Yeah, so the one last question, I think is one from Tim really, and maybe you can speak to it in the context of overall treatment, but I think it also is relevant in terms of some of the issues around side effects and weight gain and dealing with metabolic issues. But it's really around the data showing cardio in terms of its benefit, in terms of treatment of psychosis and or mood disorders. I think both as an independent treatment, but then I also wonder if it's worth speaking to the role of that in terms of support around metabolic kinds of issues as well. Yeah, so I think that that's really important. And I think the more that as psychiatrists and as mental health clinicians, we can remember that people are not just from the neck up, that understanding how to help people with their whole body is important to helping with their mental health. And so certainly aerobic exercise can be very helpful in treatment for psychosis and mood disorders. In and of itself, I don't think of it as being quite sufficient. That isn't to say that there aren't some people who, and we even wrote a case report about somebody for whom that was very effective for them. They took up a, I believe it was a big rowing program and that worked out very well. But overall, I don't believe that cardiovascular exercises were gonna replace medication altogether. However, certainly it is helpful, both in terms of mitigating some of the risk and side effects, but we know that aerobic exercise has mood boosting properties. And so that can be helpful both for mood disorders, as well as for negative symptoms. Of course, it can be a real trick to have somebody with negative symptoms who is otherwise having difficulty with motivation to then take on an exercise routine. Of course, that's hard enough for people who aren't managing with negative symptoms to take that on. So all of those things are big challenges, but we're involved in an NIMH sponsored study, looking at the effect of aerobic exercise on cognition, having shown initial benefits in a pilot study. Now we're doing a larger study, which is hoping to get back online pretty soon. Obviously COVID has shut that down for a while, but should be getting that back up and running in the next month or two, hopefully. And so it certainly is a very important component. I mean, exercise is a line in every one of my progress notes I make sure to ask about it at every single visit, because I wanna encourage people to exercise. I wish we had an exercise studio in the clinic that people could exercise beforehand. In fact, we've also done some survey data and found that people who exercise tend to feel more cognitively flexible in the time right after exercise, which may in fact put them in the right frame of mind for psychotherapy or other, instituting other change in things in their life. So maybe we should have, we should in fact have exercise studios probably in every mental health clinic. But again, we could do another hour on that topic, but I appreciate the questions. It is very, very important. Thanks Dr. Ballin. Thanks so much. Thanks for a wonderful presentation. Thanks for a wonderful morning. And Judith, thank you as always for your guidance on this whole process. Judith, anything else we need before we can close for today? Oh, okay. No, actually I had to unmute myself. No, I think we're great. Thank you so much, Dr. Ballin and Dr. Edelstein for facilitating today's Q&A. Fantastic, and thanks so much for having me. I really appreciate it. Yeah, thank you all for joining us and we'll look forward to hearing from you and seeing you again, hopefully in a month or so. Thank you. All right, thanks. Have a good day, everyone.

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