Hi there. Good morning. Good morning all. I hope you are having a very good APM meeting. My name is Vikas Gupta. I'll be the moderator for this very exciting session, the title of which is The Emerging Role of Glucagon-like Peptide GLP-1 Receptor Agonists in Obesity, Mental Health, and Addictive Disorders. Personally, I have a strong interest in this topic because I'm a psychiatrist, but I'm also board certified in obesity medicine. I'm looking forward to hearing from all the exciting speakers today and learning more about this exciting subject. So I have a few housekeeping, note-keeping things to announce. Attendees must turn off or silence all cell phones and electronic devices. Videotaping and use of digital photography, including all cell phone cameras, are prohibited in this session. All presenters must verbally disclose any relevant financial disclosures or show their disclosure slides at the start of the presentation. If you have any technical problems, please contact the nearest APA admin personnel and I can assist you with that. All questions will be held until at the end of the session, so please hold on to your horses. We will wait till the end of the session for any Q&A options. There is also a Q&A option online, so if you have any questions which you feel more comfortable sending via the online platform, feel free to do so and I'll be happy to moderate those. If you would like to ask a question during the Q&A portion at the end, please use the mic at the front, walk up to the mic and announce your question. Please make sure your question is stated in the form of a question, not stated in the form of a dialogue. So not more than 30 seconds for any question. So please frame your questions accordingly. I have some very exciting speakers here, which I'll be introducing you to shortly. First of all, I'll go over the session description in brief. Obesity is a chronic medication condition that often coexists with mental health conditions. Demaglutide, liraglutide and terzapatide are GLP-1 receptor agonists approved for the chronic weight management in patients with BMI greater than 27 with comorbidities or with BMI greater than 30 with or without comorbidities. The most commonly reported side effects of these medication class are GI side effects in nature. Psychiatric adverse events comprise only 1.2% of the total reports of these agents. However the severity and fatal outcomes of some of these reports warrant further investigation. And we'll be hearing from our speakers more in detail. So without much ado, I'll be introducing our first speaker, Dr. Lofton. Dr. Lofton is a clinical associate professor of medicine and surgery at NYU Langone Health, where she has served as a director of the medical weight management program since 2012. There she designed the popular New You weight loss program to help her patients obtain results while fostering nutrition education and placing emphasis on a healthy lifestyle. You served on the board of the Obesity Action Coalition and on the Bariatric Medicine Committee for the American Society for Metabolic and Bariatric Surgery. Please put your hands together for Dr. Lofton. Thank you all for your attendance, your attention, and for the introductions. I'm Dr. Holly Lofton. This is my talk about GLP-1 receptor agonists. And I'll review some of the clinical trial data related to adverse events with more emphasis on the mental health aspect of those. These are my disclosures. And our objectives today will be to review the safety and efficacy data from GLP-1 receptor agonist obesity trials. And again, I'll emphasize the effects on neuropsychiatric hormones. So let's start with the mechanism of action of these medications. And I want the audience to leave understanding that we know quite a bit about how these medications work. There is some popular belief that we don't know how they work, but we have an idea about the mechanism, how they help with many disorders. Obesity, diabetes, and other disorders are soon to be elucidated. So let's dive into the mechanism. GLP-1 receptor agonist look just like the native GLP-1 that we make in our bodies with about 97% homology. And what our native GLP-1 does is a few things. As we start taking in a meal, our L cells of the intestine start to release GLP-1. And that then goes to the brain, the ventral nucleus of the hypothalamus, to decrease appetite signals. So when someone starts taking a meal, this is part of the reason that we eventually stop eating, because the appetite goes down. The hormone GLP-1, as well as the medication GLP-1 receptor agonist, also slows down the rate of gastric emptying. This produces an effect of satiety for patients. And thus, people feel not only less hungry, but more full. What's really important to remember about these medications is not solely appetite suppression and satiety inducing, but also hormonally, there is an increase in insulin sensitivity. And this mechanism, increasing insulin sensitivity, has some effect on fat cell or adipose tissue metabolism, which leads to shrinkage of fat cell size over time. So the medication does affect the fat cell itself as an endocrine organ. And we know that the GLP-1 is released from the L cells of the intestine, also from the nucleus tractus solitarius. And so these medications are really working very physiologically to induce weight loss. So I'll go through some of the specific medications. Liraglutide 3 milligrams is approved for chronic weight management and for treatment of obesity. So you may be aware of this drug and another dose for type 2 diabetes. I will stick to the doses that are intended for obesity treatment. And here you see the results from the scale trial, which determined the safety and efficacy of liraglutide 3 milligrams versus placebo. And the other comparator drug you see here is oralistat. And I'll simply point out the gray line is the placebo. And in this trial, the placebo group lost about 4 kilograms. Oralistat is another medication I won't be discussing here. But at the time, it was sort of a more popular medication for weight management. And that's why it was used for the comparator. And you see in the various shades of purple and blue the different doses of liraglutide. So we saw weight loss greater than placebo with all the doses that are listed here from 1.2 up to 3 milligrams. And the 3 milligram group lost 12 kilograms on average compared to the placebo group, which lost 4 kilograms. And if you're looking at this closely, you'll see that the placebo group eventually, two years later, ended up in the same place as everyone else. So this was a crossover study. And at one year, the placebo group was then given the dose of 3 milligrams. And they all ended up pretty much around the same place. These are some of the adverse events that are reported with liraglutide 3 milligrams. And I'll just point out that because these are GI-secreting hormones, most of the adverse events are GI-related. I want to point out what the contraindications as well are to these medications because they are not for everyone. Contraindications are personal or family history of medullary thyroid cancer or immune to neoplasia. So these are the screening questions we should be asking people when thinking about prescribing a GLP-1. These are more of the warnings that are associated with the medication. I won't go through all of them, but at the bottom, the prescribing information does state to monitor for depression and suicidal thoughts. And the prescribed information states to discontinue liraglutide if symptoms develop. With obesity management, we're always screening for depression, other mental health disorders at baseline and as patients continue to be seen for weight management. So it is important to note that the side effects that I listed in the previous slide are very similar for the other medications I'll discuss, although they may be at different percentages as we talk about different medications. So maglutide 2.4 is another medication that was prescribed GLP-1 for treatment of obesity. And you see here the results of the STEP trial, which demonstrated the efficacy versus placebo. Placebo group did pretty well, I would say here, in losing about 8%, which is quite high. Usually in the placebo groups, we see about 3% on average. Now every one of these trials, I will state that's on placebo and the drug is receiving lifestyle management. So it's not meant to give the medication with no diet, exercise, and behavior. So that should be a part of the treatment plan. Placebo group here lost about 8%. But you see about six months in, there's a slight regain that starts to happen. And this is a very common factor and feature that is noticed with specifically only behavioral interventions for obesity. And in the maglutide 2.4 group, the weight loss was 18%. And you can see the categorical weight loss at 68 weeks was more impressive with the semaglutide than placebo. I'll move on to terzepatide, which is a slightly different compound. So this panel today will talk about GLP-1 receptor agonist. Terzepatide is a GLP-1 and GIP receptor agonist. So it is in its own class. The additional benefit of the GIP is that it can further delay the stomach emptying effect. But there's also improvements in insulin secretion, insulin resistance decreases, and there are some effects on the white adipose tissue, which are unique to terzepatide, in that there's increased lipolysis and lipogenesis and less fat cell deposition. These are the results from the trials, Surmount 1 with terzepatide. And this slide is quite busy, but basically it states that 90.9% of the participants responded with at least 5% weight loss with terzepatide. There's only about a third of people responded with that much weight loss with placebo. And as we move to higher degrees of weight loss, about 20% or more, you can see that over 50% of those who were enrolled in the trials were able to achieve greater than 20% weight loss with using the medication in addition to lifestyle recommendations. Now if you look at the placebo group with terzepatide under the C figure here, you see only about 3% of those on placebo were able to achieve 20% weight loss. As we use these medications, I always think clinically in how we treat our patients. I always ask them, how much weight would you like to lose? And while we know that clinically 5% is significant, patients want to lose more of like that 20%. So we're seeing as these medications are in development and come onto the market that we're achieving greater success with what patients consider to be clinically meaningful weight loss and also improvements in their health. The graph here that's linear I think is much more telling. And you can see the differences in placebo where, again, there was about 2.5% weight loss. And 5 milligrams terzepatide, there was 16% weight loss. And at the highest dose, 15 milligrams, there was 20.9% weight loss. I know the slide states there was 22.5, but there's differences in the intention to treat group versus the completers. So we're seeing about 20% to 23% weight loss at the highest dose of terzepatide. So I'll move on to talk about some more psychiatric and neuropsychiatric hormonal regulation. The Usual Vigilance Database compiled all of the adverse events related to all three of these medications at the time that was available from January 1st, 2021 to May 30th, 2023. And you see the number of total events for somaglutide and loraglutide were about 14,000. The reason that the number for terzepatide is much lower is that the medication came out about a year before this database analysis was done. So there just weren't as many patients on the medication at the time of the analysis. So more investigation does need to be done with terzepatide to look at these outcomes. With somaglutide, the number of total adverse events was 44.4%. Loraglutide 53.2%, and terzepatide 2.3%. Again, we had a small end there. As far as psychiatric events, there were 372 psychiatric adverse events reports, which represents 481 adverse events. You can see here the table where depression was clearly the most highly reported side effect amongst all of these ELP1 receptor agonists, anxiety being the second. There were some reports of suicidal attempts, suicidal ideation, and depression with suicidal ideation. One thing I want to point out about this slide, which looks into the gender data, is that interestingly, most of the females did not disclose their age when we were looking at this. So we did see about 65% of those who reported these adverse events to be female, but we're not sure what age range everyone is exactly in. It looks like 18 to 65, but it could be very different across the board because of some failure to report ages. Depression, there were 187 events reported, and that represented 50% of all of the psychiatric adverse events. Anxiety, 38.7%, which was 144 events, and suicidal ideation, 73%, which was 19.6% of all of the adverse effects that were reported. There were nine deaths, eight of those related to loraglitide and one related to semaglutide, and 11 life-threatening events. But of all of the psychiatric adverse events reported, of all of the adverse events reported, 1.2% of those were determined to be psychiatric adverse events. I'll move on to this meta-analysis that looked at some of the changes in neuropsychiatric hormones relative to use of GLP-1s overall. So you can see that there were some influence on dopamine systems, reduced food reward behavior, cocaine self-administration also decreased, and there were some effects on GABA, glutamate, serotonin as well. So there has been quite a bit of evidence looking at the effects of GLP-1 receptor agonists on neuropsychiatric hormones. And it's interesting to know, how is this mechanism? Again, we don't know everything about these medications. So depression is linked to neuroinflammation and neurotransmitter imbalance, as well as impaired gut-brain access, and that's a big part of how these medications work, connecting the brain and the gut to get the signaling and the right mechanism to help patients lose weight and be able to tolerate a caloric deficit for a long period of time. Depression is also associated with appetite disturbances and gut hormone abnormalities. On the converse, GLP-1s promote production of anti-inflammatory cytokines, improve responses to neuroinflammation, can increase neurogenesis, increase dopamine turnover in the amygdala, and increase release of GABA, dopamine, serotonin, and glutamate. There's also evidence of increased memory and cognitive function by enhancing synaptic function. And we can see in this pathway where we see a lot of the depression symptoms and psychiatric events are essentially conversely noted when patients are administered GLP-1. So this could possibly be the reason that we're seeing some improvement in these mental health disorders with these patients. In summary, loraglitide, somaglitide, and terzapotide have demonstrated significant efficacy with regards to chronic weight management, and the data reveals that psychiatric adverse events are reported in 1.2% and pooled analysis of patients taking these medications. More reports in women of ages 18 to 64. It could be a bit skewed there. GLP-1 agonists may improve inflammation, neuroinflammation, increase neurogenesis, enhance synaptic function, and neuronal signal transmission to the brain. But of course, we need more research into the effects on actual patients and as well as how the GLP-1 agonism can affect our neuropsychiatric hormones. Thank you. The intricate interplay between obesity and psychiatric disorders underscores the complexity of weight management, particularly in patients concurrently taking the psychotropic medications. This next presentation aims to shed light on the long-term effects of FDA-approved and off-label pharmacotherapy for obesity within real-world clinical practice settings, focusing on individuals with both overweight, obesity, and psychiatric comorbidities. And our presenter is going to be Dr. Shukla. She's an Associate Professor of Research in Medicine and the Director of Clinical Research at the Comprehensive Weight Control Center at Weill Cornell Medicine. She's a physician-scientist focused on obesity and metabolic research, patient care in obesity and diabetes, and mentorship of clinical and research trainees. Dr. Shukla and her research group is focused on novel interventions for management of obesity and type 2 diabetes, including behavior modification, pharmacotherapy, and endoscopic slash periodic procedures. She has over 60 publications and peer-reviewed journals related to her research and clinical expertise. Please put your hands together for Dr. Shukla. Thank you very much for that kind introduction, and it's a real pleasure to be here today. I'm delighted to be here today and have the opportunity to share our group's research on the practical management of patients who have obesity as well as psychiatric illness. And in fact, I want to say that really if you want your patients, we want our patients to do well, then you and I, we have to work together to get that best outcome for the patient. And I'll, over the next 15 minutes, we'll talk a little bit more about that. So, these are my disclosures. So, looking at the relationship between psychiatric disorders and obesity, you know, it's kind of like the chicken and egg thing, you know, and I think all of us really do recognize that there is a bidirectional relationship between these two conditions. And we know that in people with psychiatric illness, adverse health behaviors, how many of us have heard of a patient saying that when they're depressed or anxious, they're going to, you know, they use food as comfort, you know, and so it lends to eating more, you know, high caloric foods, you know. Adverse health behaviors is one of the ways in which, you know, psychiatric illness could drive weight gain, neurohormonal imbalances. Dr. Loftin alluded to some of those previously. And another very important area that actually influences weight gain is psychotropic drug-induced weight gain, about which we'll talk a little bit later. On the other hand, you know, in people who have obesity, what we do know is that there is a state of inflammation, and really there's a shared pathophysiology, if you think about it, between these two conditions. There's also hypothalamic pituitary adrenal axis dysregulation that we do, that is common to both of these things. I want to add stigma of carrying excess weight, you know, and I think it's something that we don't talk about as much, but that's also a huge driver of psychiatric disorders in patients who have obesity. This is a really nice cartoon, you know, which actually illustrates, you know, the shared pathophysiology of chronic inflammation that occurs in both, you know, with obesity or weight regulation, as well as in depression. And you can see that hypothalamic inflammation, you know, leads to energy dysregulation or disturbances in energy balance, whereas inflammation in the hippocampal neurons leads to mood dysregulation. So, in fact, you know, longitudinal studies have very well confirmed this reciprocal relationship between obesity and depression. And you can see that in this meta-analysis of 15 studies, which included over 50,000 people. So it's not small, it's huge. And what stands out is that individuals with obesity have a 55% increased risk of developing depression over time. And individuals with depression have a 58% increased risk of developing obesity. So you can see how intricately linked these two conditions are. So a little bit about psychotropic drug-related weight gain. And I think, you know, you'll find a lot in the literature, you know, in lots of papers. And I saw that this is most recently came out in the American Journal of Psychiatry, where it very well illustrates the different groups of drugs and their propensity for weight gain. But as a obesity medicine physician and somebody who treats, who actually sees patients referred to our practice, you know, after they've developed weight, I think the two things that I want to highlight are that drug dose and duration are really important factors that influence weight gain. So, for example, you know, it's commonly, you know, accepted and believed that SSRIs, a lot of the SSRIs, like fluoxetine, you know, they're generally weight neutral. We don't expect people to gain weight. And in fact, you know, in the older studies, we recognize that fluoxetine was actually used for weight loss, you know. So the initial studies actually showed that you could get weight loss with higher doses of fluoxetine because of the, you know, the effects on the SSRI, on the serotonin, you know, levels. As you know, there was a drug called lorcasarin, which was based, you know, on 5H2C receptors, which was subsequently withdrawn. But, you know, so there's good rationale to believe that these drugs would be weight neutral or at least not cause weight gain. But what we do see is that with prolonged use of these medications, we will see weight gain over time in some patients. And, you know, it's possible that there's a down regulation of the serotonin receptors and, you know, and typically what the patients report is you just don't feel full, lack of fullness. Sorry, I don't know. So I still want to, I still have one more point to make on that slide. So I think the duration is an important factor. The second thing is that this great inter-individual variability in the propensity to gain weight. So while, you know, you can look at the data and, you know, and analyses and you'll see this is the average weight gain that you might, that might happen, but we don't, you know, you cannot really tell how one person, how much weight they are going to gain. And there are some pharmacogenomic studies that have been done and some predictors, but in, which are not currently used in practice, but so there are some people who gain a lot and some people who won't. So you just have to, you know, follow up the patient and manage them accordingly. So with that in mind, you know, considering, you know, how complex the interplay of, you know, these two conditions is, you know, how does long-term weight management look like in patients who have obesity and also have a psychiatric illness? Do these patients do just as well as, you know, other patients who come to our practice? And so this was a question that was of interest to us at the Comprehensive Weight Control Center, and I'm going to share with you some of our results. So in this study, so this cohort of patients is established in the, you know, in 2014 to 2016. And so we looked at 885 patients who had about 6 to 12 months follow-up. And we looked, and we stratified the data by psychotropic medication use. And in fact, about 30% of our patients in our practice were on psychotropic medication. And we looked at, you know, how they did in terms of meeting the weight loss goals. So when you look at the average weight loss, we did find that the patients who were on psychotropic medications at one year, they did have inferior weight loss outcomes. So they lost about 7.5% on average versus 9.1% in the other group. When you look at the categorical weight loss, so I think this is an important thing to understand because I think it's good to know what percentage of your patient population is likely to respond, you know, with clinically meaningful weight loss. And clinically meaningful weight loss means losing at least 5% of your body weight because that's a benchmark that's actually associated with clinical improvements in health parameters, you know, like your lipids and, you know, sugars. And so, you know, that's where it starts. And so we looked at the percentage of people who achieved 5% or 10% weight loss. And you can also, you can see over here from the slide that is the bar graphs that the people who were on psychotropic medication, there are fewer of them actually achieved those benchmarks. So there definitely were inferior outcomes. So the next question is what happens when you follow them up? You know, obesity is a chronic disease, right? It doesn't just last for one year. And we're not going to see these patients in one year. And then, you know, it's said you're cured. So there's an ongoing management. So the question was, what does long term weight loss look like? And you know, I have to say this is, it is strange, but you know, in a condition that is essentially chronic, you know, there's so little long term data. And so we felt that this was something that we as a center should do, given that we have wealth of clinical experience at our center between the multiple physicians. And so we examined five-year weight loss outcomes. And I'm going to share with you what we found. So our population, like most, you know, cohorts at different centers where patients present for weight management, the majority of them are women. Average age was 51. And the average BMI was 35.5. And on average, they had about two comorbidities. So importantly, and of interest to you, a third of our patients had a psychiatric disorder. That's a fairly high number, as you can see. So when we looked at the weight loss outcomes, you'll see over here two slides, you know, and I put them side to side because I think it's interesting to understand the heterogeneity of response, you know, to any treatment as far as weight management is concerned. So you see over there, it's a waterfall plot. And the average weight loss was about 10.4% of their body weight at the end of 4.4 years, which is, you know, clinically very significant. But there's marked inter-individual variability, right? So you can see that there are people who gained weight, but on the other hand, there are patients who lost as much as, maintained as much as 40% weight loss over that period. We still don't quite know why some people do so much better. And obviously, in this particular cohort, we didn't, we, it was retrospective, so we were not able to examine those specific predictors. But we could see that people who had more follow-up, had more visits with their providers actually did better. When you look at the categorical weight loss on the other side, what you'll see is that 50% of the patients actually maintained that weight loss over the 5-year period. In fact, about a third of our patients even maintained 15% weight loss, which is what you'd expect from one of the GLP-1s like, you know, the semaglutide. Now you might ask, how did our patients achieve these results? Because, you know, as I mentioned earlier, the cohort was established in 2014 to 2016. And so it's a time when a lot of the GLP-1s were not commonly available, and in fact, they only started being available later on. So I want to speak two minutes about our lifestyle, you know, modification advice that we give our patients. And so while I think the key thing to understand is really what works for people is what they can do. I think that's the best diet. That's the one what patients can actually do. But in general, what we have found is that focusing really on food quality and, you know, advising our patients to do a low-glycemic diet, this is what has worked in practice, you know. So somewhat moderate carb restriction, and also advising them on a carbohydrate-less macronutrient sequencing approach. Now you might ask, what is, what am I talking about? So this approach is grounded in our own research, which we've been doing for several years. And what I've put up over here actually are two graphs, you know, and this, what this graph actually shows, you know, you see three lines over here, this graph over here. So this is actually the glucose graph, you know. It's showing how the blood sugar looks after you've had a meal, same meal, right? So this is the same meal, which has grilled chicken, it has ciabatta bread, and it has some vegetables or a salad. So the yellow line, you see, you see the sugars, they go up, really spike up, and then they go down later on. So it's a very, there's a lot of fluctuation. So if you started that meal, you ate that meal, you ate the bread first, and then you ate the vegetables and proteins, that's how your sugar is going to look. If you ate the same meal, the exact same meal, the same amount of bread, the same amount of calories, but you switch the order, and you save the bread for the very end of the meal. So you see the blue line? You see the blue line, which looks really, really flat? Yeah. So that's, if you save the bread, sorry, I'm getting ahead of myself. So if you save the bread for the very end of the meal, you find that the sugars are so much, so much flatter. So if you think about it quantitatively, your glucose peak actually is reduced by almost 50%. It's like a drug effect. So this is something that we, and we know that our patients are inherently, either they have diabetes, or they have prediabetes, or they're predisposed to develop these conditions, right? So for everybody, so pretty much it applies to most of our patients. The other graph actually shows you the effect of this intervention on the hunger hormone ghrelin. And what we found is that when people save the carbs for the very end of the meal, the hunger hormone ghrelin is suppressed for much, much longer. As you see the blue line, it stays down, whereas if you start off with the carbohydrate, the bread first, the hunger hormone levels drop, but they actually rebound again. So this is a strategy that we actually have been using for our patients, and we've found it quite helpful. In terms of medication, because this was a time when a lot of the GLP-1s were not actually available, the drugs that were most commonly prescribed were actually off-label medications. So metformin, topiramate, and fentanyl. These were the most commonly prescribed medications in this cohort. So of interest to all of you, you must be wondering, this is all about the whole group, how did the patients who had psychiatric illness, how did they do in the long term? I showed you earlier that they had somewhat inferior outcomes. The good news is that when we followed these patients up to five years, there were no differences. It did just as well as the rest of the cohort. It did just as well. And I think, so we thought about this, and we wanted to understand, you know, why this might be the case? Why would the results actually got better over time? And you can see over here, you know, one of the things that we thought was maybe the medications actually looked different, and there was, in fact, some change in the type of psychotropic medications being used at baseline versus at the end of the five years. And you'll see that there's much greater use of, you know, weight neutral or weight-reducing psychotropic medications like bupropion versus the other medications at baseline. Also, what we saw was that almost 20% of our patients were no longer on psychotropic medications by the end of the five years, which sort of, you know, goes to show, which we believe is because they no longer needed it, you know, but there was an improvement in their psychiatric co-morbidity, because I think, you know, possibly because of improved self-image and, you know, multiple mechanisms, some of which I think Dr. Loftin also alluded to. So that's as far as our own data is concerned. This is what we've published. But I want to share, you know, two patient stories with you, which are taken from our five-year data set. So this is Tina. She's a 60-year-old female patient, BMI of 34. She has prediabetes, dyslipidemia, and long-standing major depressive disorder. And she's been, you know, you know, she's been on yo-yo diet since childhood and has been on antidepressants, various antidepressants, for over the past 30 years. When I met her, she reported binge eating almost on a daily basis in the evenings. And what you see there are the medications that she was taking, fluoxetine at 40 milligrams, and then a statin and some medications, as needed for migraine. So this is Tina's journey, you know. And again, you know, so it's interesting, you know, I put this up specifically because I want to put it out there that, you know, we have highly effective medications today, and so we really live in a good time, you know, when it comes to managing our patients. But we also recognize that access and cost are major issues, which will limit the use of these medications. So there's still hope. I want to say, I put this out that there's hope for patients because we have managed patients before, before these things were available. And there are patients who will do well with just off-label medications as well. We just don't have really good tools to predict which one will do that well. So in this patient, what I did was, you know, well, what I always do is with patients who have major psychiatric illnesses, I will always discuss with the psychiatrist. I will always pick up the phone when I'm making, you know, changes in medication or advising things because I want them to be monitored closely and make sure that they're on board with the things that we're suggesting. So for her, I, you know, we put first on metformin, which we found to be very effective in mitigating psychotropic weight gain. Her psychiatrist, I asked whether she thought it would be, you know, worthwhile to use bupropion if it was appropriate for her, you know, obviously for her psychiatric condition. And she felt it might be, it was reasonable, we could try it. And fortunately for us, you know, she did well on it. And her fluoxetine was actually cut down to 20. She had this habit, this tendency to binge eat every day in the evening and I, we discussed about adding low-dose topiramide. So one has to be careful, right, because these drugs can also have, you know, mental side effects and they require close monitoring, but the psychiatrist was on board with that. And we started really slow with just 25 and gradually we increased to 75. That's what the patient's taking right now. Her binge eating is completely controlled and she's maintaining 23% weight loss with this combination of just metformin and topiramide and, you know, Welbutrin really is more for her depression. But, you know, I would say it has, serves a dual purpose in this patient. One minute, okay. So this is just one more patient because I think I must touch upon GLP-1. So this is one case where we used a GLP-1 and so this is a 73-year-old retired electrician and, you know, so the case is interesting because this is a patient who had bariatrics. He had a gastric bypass and then he regained weight, you know, two years later and his weight gain was really triggered by alcohol abuse, you know, and anxiety and we know that alcohol abuse disorder is something that is a complication, if you like, you know, and can, we have seen greater instance of that in patients with bypass surgeries. So when I met with him, you know, he had met with our dietician and he actually, so I met him at this point where his initial weight was 357, you know, he had regained the weight and he met with the dietician and he'd actually been counseled to stop drinking and he actually was successful. He could stop, but he met me, he said he was experiencing intense cravings and he was so terrified that this was going to derail his whole journey again, you know, he's going to regain and go back. So the first drug that I actually used was naltrexone, bupropion, you know, and it reduces cravings, you know, he lost a little bit of weight, but he still didn't feel full. And then when we added the semaglutide, gradually increased over time, you know, his, as you can see, he lost very significant weight and in fact is at a weight that's lower than the lowest weight he had been after his surgery. So with that, I'll finish and I'll hand over to Dr. Aleman. Thank you. A prevalent factor contributing to obesity, specifically in veterans, is the metabolic effect of atypical antipsychotic agents prescribed for severe mental illness. Use of atypical antipsychotic agents is complicated by their substantial adverse effects, including weight gain due to increased appetite and insulin resistance due to direct effects on muscle and adipose tissue. GLP-1 receptor agonists are FDA approved for the treatment of both obesity and type 2 diabetes and they alter appetite centrally and augment insulin action peripherally, making them excellent candidate therapies for preventing and mitigating these complications of atypical antipsychotic treatment. Our next speaker will be elucidating in detail more on this synopsis. Born and raised in Puerto Rico, Dr. Jose Aleman is assistant professor in the Holman Division of Endocrinology at New York University Langone Health, where he directs the Laboratory of Translational Obesity Research, or LTOR. His group has a mission to understand and prevent complications of obesity. Clinically, he sees patients at the Margaret Corbin Campus of the VA-NY Harbor Healthcare System, where he leads the NY MOVE Endocrinology Weight Management Clinic, incorporating weight-centric clinical care of veterans, clinical research, and trainee education. Please welcome Dr. Jose Aleman. Thank you, Dr. Gupta, for the kind introduction and Dr. Leggio for organizing this panel. I think you can hear from our speakers that this is a very exciting time to care for and treat patients with obesity because we finally have effective therapies to do so, and I think there's a lot of opportunities to collaborate with our mental health colleagues, such as we do in the VA and you here. This interest in the specific research line within my group came about because one of my most frequent consults when I care for veterans is medication-induced weight gain and in several cases, several severe cases, antipsychotic-induced weight gain. This is a model of fat that sits in my office that is a teaching tool of the 5% that Dr. Shukla alluded to that is needed to improve health by weight loss. A few disclosures. I advise a number of companies. I do consult for Novo Nordisk. We've been fortunate to be funded for our research by several agencies, and I speak because as we all attest, there isn't enough education about obesity, the disease, and its treatment, and I will discuss off-label use of metformin and semaglutide, as you've heard in the earlier talks. A lot of people to acknowledge. We have a very comprehensive team, previously at Rockefeller and Cornell, where I trained and met Alpana, my lab now, the different members at NYU, a number of collaborators, including folks in the VA, and the funders. So my lab is interested in, as you heard, in figuring out how does obesity lead to complications, and the complications can be varied. In endocrinology, we focus on the metabolic complications, but there's many others like mechanical or mental health. We focus on adipose tissue, which is an organ, as you heard, a hormonally important organ that also has nerves, immune cells like every other organ, and produce hormones and metabolize in homeostasis in the healthy state that prevents disease. Something happens in obesity, whereby adipose tissue and adipocytes specifically, increase in size, recruit immune cells, and change that milieu to pro-inflammatory, and leads, we think, to the development of complications. And you can switch the heart, shown here for cardiovascular disease, for many other diseases, diabetes, cancer, COVID, and I think in this audience, mental illness, potentially. Our vision is that if we believe that obesity is a chronic disease, then it likely will require multiple tools and cycles to treat it. And those cycles come in different forms. You heard some cases from Dr. Shukla, but hypothetically, a cycle might start with a procedure like a balloon, which are increasingly gaining in popularity, followed by medications, followed by a combination, and followed by bariatric surgery. Or for a different patient, you might start with medications and choose a procedure to different medications. And we're figuring out the tip of the iceberg of the phenotypes that live under this disease we call obesity, to figure out who should get what first from the effective tools we have. I'm gonna make this very brief, because you know this better than I do. Just to mention that antipsychotics have been around for some time. The first generation had different profile of side effects. The more recent second generation has more metabolic side effects that come to my attention in endocrinology. In particular, the weight gain and the diabetogenic side effects. This is from a nice review recommended by some of my VA psychiatry colleagues. Estimating the weight change that occurs from antipsychotics that were approved at that time in this list, for better or worse, hasn't changed that much. You can see that some of the offenders listed in red, like Clozapine, Risperdal, and Olanzapine are still used quite a bit. I think probably the most exciting change to this list is the addition of the Olanzapine-Semidorphin combination that potentially mitigates weight gain. But data is controversial, as I'm told and as I've read. But comparing to what you heard Dr. Shukla tell you and Dr. Loftin tell you, when you're giving these medications, you're potentially exposing patients to up to a four to five kilo weight gain and late start in their weight loss journey. That's the reason to potentially intervening and intervening early. Wrong direction, yeah. We learned a lot about this through work like Dr. Leggio and his colleagues have done. And also with the approval of one serotonergic agonist, Lorcasorin, which is now removed from the market, that serotonin specifically was very key to the weight changes that these medications can cause. If you go from the first generation to the second generation, antipsychotics or atypical antipsychotics, they had added agonism, added antagonism, I should say, at those receptors, specifically the 5-HT2 family and 5-HT2C, which then we think led to increased weight gain and feeding and insulin sensitivity secondary to that weight gain. And that is somewhat illustrated by mouse work by Joel Elmquist at Texas, where they modeled what would happen in mice if you gave olanzapine and then tried to mitigate that weight gain with lorcasorin over time. And what you can see in the graphs shown here is that treatment with olanzapine in this mouse model, and I should say a regular mouse model causes weight gain that is driven by increased weight intake and is very much coincident in time with the dosing of olanzapine. And that if you give this lorcasorin agonist of the receptor, you mitigate those body weight and glycemic effects. More recently, colleagues in the metabolism world have focused on other targets, leptin being a recent one by the SHARE group also at Texas. And in this paper, what they show is that in mouse models that are treated with risperidone, one of the same antipsychotics I mentioned, if you then give leptin-blocking antibody, you can actually mitigate the weight gain that occurs. So in the blue line here is between the control diet and risperidone-treated animals that were given a control antibody. And similarly to what you saw with lorcasorin, this was driven centrally at the appetite centers. Leptin, we know as a hormone produced by adipose tissue that causes satiety, has not been really made it to the market as a treatment for obesity because common obesity has leptin resistance that we haven't figured out how to treat. So I showed you two potential mechanisms, but there's many mechanisms by how antipsychotics might induce weight gain and other potential receptors involved might involve H1 histamine receptors or muscarinic receptors. And I think there's a lot of really interesting science and that Dr. Leggio and colleagues are doing to elucidate these pathways and potential targets for these. You've heard about the different therapies available for obesity. Our governing society, the endocrine society, it's now a little bit lagging, I think, in publishing guidelines for obesity with all the new agents that you heard Dr. Shukla and Dr. Loftin mention. This is the version of the guidelines for management of obesity from 2016. And I've purposely edited them to cross out lorcasorin. I'll just mention that this is the toolbox that Dr. Shukla used mostly in her study. And even with agents that induce in the order of three to 8% weight loss from baseline at a year, you can still get really effective outcomes if you understand what are the outcomes, what are the phenotypes of that patient. Many of these medicines are either combinations or like GLP1 receptor agonists are pleiotropic targets that act in multiple places. Many of them have real side effects, which is an issue that we deal with, as well as condor indication. So we have to be very careful in who receives these, and that's part of what we do in clinic. From that same document, this is how we in endocrinology think about the neuroscience of appetite. It's a little cartoonish because we need to understand more. I'll say that. We do know that the homeostatic appetite centers in the arcuate nucleus, there are orexogenic and anorexogenic nuclei that are either agonized or antagonized by these targets, and then they signal to other parts of the brain, carrying those signals to drive feeding, and then receive also feedback from the organs tasked with harvesting energy, like the gut, adipose tissue, or storing energy. And if we focus on some of the anorexogenic nuclei here, you see a convergence of some of the targets that I mentioned here in the POMC nuclei of GLP-1, driving this nuclei, as well as leptin, 5-HC2C, which was the target of the former drug, seeing one of the specific brain areas that our neuroscience colleagues focus on. We have taken a different tack. We track, as Dr. Shukla does, the outcomes of our patients, and leverage the power of the VA national database to look at how many patients my colleagues and I have prescribed medicines that affect weight, and in our obesity paper in 2021, categorized in the order of a million patient medication pairs that received medicines that we know have weight effects. And what you see here is the slope of the weight as a key parameter for patients that were followed a year before, so we have weights the year before, and then you introduce the medication, and you follow them by weight through the medical record system for the year after. And what you can see is that all these targets that we use to treat obesity change the slope of the weight from red, so causing weight gain, to blue, causing weight loss. And they do so to greater or lesser extents. This is real-world data. This is not the placebo-controlled studies, so the effects are mitigated. But you can see that even diabetes indication, semaglutide at the time, was quite effective, as was liraglutide, fentermin to pyrimid, and even medications that don't have indications like metformin. We further then looked at our own data of about 500 patients in 2021 that we had cared for in our VA Weight Management Clinic. About 100 of them had been exposed to atypical antipsychotics, and about 70 of them had good enough weight data for us to look at what happened to their weight change in the six months after we introduced these medicines. And categorizing, again, by the medications, you see that the weight change that you get with GLP-1 receptor agonists, it's closer to 4%. So you can see here, listed on the right, and metformin, about 4%. So I would say for a very effective agent like Saxenda or semaglutide at that time, that's really a mitigated effect. Mitigated beyond what you expect by just being in the real life. So that speaks to the counter-upward pressure that's happening on the weight set point by the antipsychotics. And one of your own, Maggie Han, Dr. Maggie Han, psychiatrist at Toronto, has taken the next step, which is to start using semaglutide to treat these patients with severe mental illness, specifically schizophrenia, with semaglutide, so co-treatment of schizophrenia with antipsychotics and semaglutide. And in this interesting case series, she shows really outstanding benefits in some of these patients upwards of 18 to 20% weight loss at six months by the addition of semaglutide. We in the VA are trying to do our part. We are actually running, with the US tax dollars, the placebo-controlled study, to test whether metformin actually reduces cardiovascular events. But in this, we can actually leverage this placebo-controlled study to look at typical antipsychotic effects and to also look at the weight effects of metformin proper. So stay tuned. We're hoping to finish recruitment in 2029. And we, as you heard, obesity is heterogeneous, so we're interested in applying some of the methods to study this heterogeneity with a talented resident, Diana Torres, and attending now Jay Penza. We categorize the outcomes of our patients. In our clinic, you can see that our patients treated with semaglutide, regardless of self-identified race, do very well in terms of glycemia. However, the outcomes in terms of weight are quite variable. And that variability, I think, is a big-picture goal for the field of obesity, much like you try to figure that out for mental illness and who will benefit. So with that, I think atypical antipsychotics lead to known complications of obesity. The mechanisms are varied, and we're still figuring out new ones. The average weight gain here is about 5%, for the worst offenders. And I think structured parallel treatment can really mitigate this weight gain. I would encourage you to consider metformin, an early collaboration with our endocrine colleagues, or, as Dr. Gupta did, if you're very, very interested, train in obesity medicine. It's open to you as well. And this is my group and the people that do the work. Thank you. Thank you. There is growing evidence that gut-brain neuroendocrine pathways, which are known to play a role in obesity, may also be involved in alcohol and substance use disorders. Consistent with this notion, growing preclinical evidence suggests that GLP-1 may be involved in mechanisms related to the development and maintenance of addictive disorders. Mouse, rat, and non-human primate studies provide strong evidence on the role of GLP-1 receptor agonists including semaglutide in alcohol drinking outcomes. Initial human studies provide further evidence on the potential use of these medications, especially in the context of alcohol use disorder. Our significant translational gap is a lack of results from RCTs. Of note, RCTs with semaglutide in patients with alcohol use disorder are currently ongoing. To discuss this more in detail, we have Dr. Lorenzo Leggio. Dr. Leggio is a physician scientist whose work primarily focuses on the treatment of alcohol and substance use disorders and their medical consequences, especially alcohol-associated liver and cardiovascular diseases. He currently serves as the NIDA clinical director and deputy scientific director. He was the founder and current chief of the NIDA slash NIAAA clinical psychoneuroendocrinology and neuropsychopharmacology section and the NIDA IRP translational addiction medicine branch. Please welcome Dr. Leggio. Thank you. Thank you, Dr. Gupta for your introduction and thanks to the APA for hosting this panel. So I'm moving to addiction and as you all know here, alcohol and substance use disorders is characterized by an impaired ability to stop or control alcohol or drug use despite a diverse social occupation and health consequence. We see alcohol and substance use disorders, as you all know, as a spectrum. And today, because of time, I will be focused on the literature on the GLP-1 and alcohol use disorder, but there is actually increasing and exciting interest and work on the GLP-1s and the substance use disorder as well, including opioids and cocaine. And specific to alcohol use disorder, despite alcohol use disorder is a leading cause of mortality and morbidity in the States, is responsible for $249 billion in terms of our economy per year. These are data from NAAA in 2010, but still we only have three approved medications by the FDA. That's all from Camposate and Naltrexone. And so even comparing what we have for alcohol use disorder compared to other mental health disorders, including psychosis and depression, the number of medications we have is very low. So the menu of options for practitioners is very low. So with the risk of stating the obvious, there is a critical need to develop more medications and more pharmacological treatments for patients with alcohol use disorder. We see, and I think in general, don't know 100%, but there is some agreement of seeing addiction as a brain disease. And our program actually focuses a lot on the connections between the brain and the body, including heart-brain connections and gut-brain connections. And actually it's within the framework of our interest on the gut-brain connections in the context of alcohol use disorder that many years ago, we and also many other labs in Europe and US became interested in trying to understand the role of GLP-1 in alcohol use disorder. So actually it's important to recognize that the literature on GLP-1 and alcohol use disorder started way before the GLP-1 medications became so popular. In fact, actually some early studies were from Sweden 2013, and then both our group and other groups have been looking in a different animal models of alcohol addiction, including mouse, rat, and non-human primate models, have looked at the potential role of GLP-1 receptor agonist in this model. So pretty much the animal data are striking in being consistent in showing that the administration of a GLP-1 receptor agonist in this models leads it to, for example, reduction in alcohol condition place preference, which is a proxy of alcohol reward, reduction in operant self-administration of alcohol, and the reduction in alcohol preference using, for example, two bottle free choice paradigm. When we look from a translation from animals to humans, actually there's not a lot already published and convincing, so actually there's a lot of work to do, to be frank. The most important work has been done by Dr. Anders Fink-Jensen, who actually is here in the audience from Copenhagen, and they were the first ones, they've been really pioneering the work on GLP-1 and addiction, and they were the first ones to conduct a randomized clinical trial looking at Xenotide, so the first prototype GLP-1 receptor agonist in patients with alcohol use disorder. And unfortunately, if you look here on your left side, there was no difference in this clinical trial between Xenotide versus placebo in the a priori primary outcome, which was the percent of heavy drinking days. Then they also conducted secondary analysis to look at the same primary aim, but by dividing patients based on BMI, and actually what they found was that in patients with alcohol use disorder and obesity, BMI above 30, they did find a difference between Xenotide and placebo. And by contrast, in those people with BMI below 25, placebo worked better than Xenotide, so when you pull all the data together, of course you don't have any effect. But this clinical trial does bring many questions, one about the placebo effect, one is about if the target may in fact work, the third question is about subtype of people who may have responded to this medication, so maybe GLP-1s may work only in people with addiction and obesity comorbidity, but the other question was whether beyond Xenotide, the newer GLP-1 receptor agonist may be better medications for alcohol use disorder. And in particular, in one of these preclinical studies in collaboration with Vince Marty and Igor Spielberman from UCLA, we look at levaglutide and semaglutide. This was in a male rat model of alcohol preference, and we did see that both levaglutide and semaglutide reduce alcohol drinking, actually I should say alcohol preference. The semaglutide was more stronger in terms of effect, which is the reason why, based on this pilot data, we moved to focus on the semaglutide as a potential new treatment for alcohol addiction. And in this set of mouse and rat experiments, we look at semaglutide in the context of alcohol addiction in collaboration with Dr. Leandro Venduscolo from NIH and Tremor Program, Marisa Roberto from Scripps, and the work was led by Vicky Chan, who was a post-bac, Medhi Farrokhnia, and Sophia Kohn. And in the first model, we look at a binge drinking model of alcohol drinking in a mouse model of binge drinking, both in male and female mice, and we did see that the semaglutide compared to placebo, those depend on the reduced alcohol binge drinking, both when we give alcohol as a sweet solution, when we give alcohol without the sweet solution, and also when we only give the sweet solution without alcohol. We also saw that the semaglutide that reduced water, saccharin, matodextrin, and corn oil. So the effects were quite nonspecific, which actually is something we were expecting, given that we're testing a medication with well-known effect on appetite and approved by the FDA for obesity. The question was, however, whether this effect could be a broad sedative effect, and whether mixing semaglutide with alcohol may have a farther sedative effect in terms of sedation and sleepiness. And overall, except that the highest dose of semaglutide, where we see a reduction in the spontaneous locomotion, overall, in our mouse model, we don't really see effects of a semaglutide or semaglutide plus alcohol in affecting locomotion, sedation, and the blood alcohol concentration. So the effect were non-alcohol specific, but were specific in terms of appetitive behaviors. Then we move to a rat model. This was actually a model developed by George Kube when he was at Scripps, where you actually make the rat alcohol dependent via a vapor exposure. Here, again, we tested both male and female rats, and we tested both dependent rats using this vapor model in non-dependent rats. And we saw that the consistent with the mouse data in rats as well, semaglutide dose-dependently reduced alcohol self-demonstration, both in the non-dependent rats and in the dependent rats. And finally, with Marisa Roberto, we started to try to unfold the potential mechanism by looking at electrophysiology. And we did see that in non-dependent rats, semaglutide does lead to an enhancement in the GABA signaling, both in the central nucleus of the amygdala and in the infralimbic cortex. But these effects kind of disappear in the alcohol-dependent rats. So it's suggested there may be a difference at the electrophysiology level between the brain of a dependent rat versus the brain of a non-dependent rat. In parallel to our study, actually a few weeks after we published this work in mice and rats, Elisabeth Jollig in Sweden published very similar consistent data in rats, also showing that the semaglutide reduces alcohol intake and relapse-like drinking, and also in this case without sex difference. While we have been conducting all this work in the past years, at the same time, the media have been really exploding in reporting anecdotical cases of patients basically telling to their providers, hey, doctor, you gave me this drug, ozambicuegove, for my diabetes, for my obesity, and guess what? I don't feel craving for alcohol. I don't drink alcohol any longer. Of course, it brings the question where we stand from a translational standpoint. There are some initial preliminary human signal, if you will, that what we see in mice and rats may be true. This was a retrospective analysis of electronic medical records done in Denmark, where they do see that the prescription of a GLP-1 agonist is associated with reduction in alcohol drinking. This were a few case reports put together by a group in Oklahoma State University, and in the two social media studies, actually a very interesting approach, they also saw this association between prescription of acemagrutide, or actually GLP-1s in general, and reduction in alcohol drinking. Of course, all of this work here is interesting, but none of this work is double-blind placebo control. In fact, together with Anders Fink-Jensen and many other people who are right now conducting randomized clinical trials, basically at the NIH in my program, in Denmark, in Oklahoma, in Colorado, in UNC Chapel Hill, we actually wrote this point of view together to basically say the data are very promising, but we do need to wait for randomized clinical trials, which are all ongoing, and we hope in a few years that all these clinical trials will be completed. That's basically where we stand in terms of GLP-1 and addiction these days. I want to thank all the people in my lab, in my branch, who have done the work. Our funding intramurally from NIDA and the Clinical Center, and I will be happy to answer any question, and I will give back to Dr. Gupta. Thank you. Thank you, Dr. Leggio. If you have any questions, please walk up to the mic and state your question in 30 seconds or less. Thank you. Hi, thank you for your talk. I have a question. What happens after we discontinue GLP-1s? Because we know with obesity, there's a lot of evidence that, well, recently they said you don't regain all the weight, but what happens with the mental illnesses or addictions? Because, for example, with topiramate, when you stop it after having bean-cheating disorder, a lot of patients come back to the bean-cheating. Thank you. Thanks for your question. I explain to patients that we, one, try to answer their clinical questions based on science, and then we answer them based on anecdotal information. So with regards to weight, this has been studied, the question about what happens with weight after discontinuation, specifically of semaglutide 2.4, that has been studied. And there was weight regain of about 7% over a year in people who had lost about 10% after discontinuing semaglutide. The other drugs that has not been studied, as far as I know, if you want to talk about some of the off-label drugs, maybe that's been studied. So scientifically, that's what we've seen as far as weight. The studies still need to be done for terzepatide and for loraglutide for discontinuation. I can tell you anecdotally, we see across the board, we see some patients maintain weight, we see some people regain. And a lot of it has to do with the lifestyle aspect of it, too. I've seen some people lose weight with one of the GLP-1s, do the recommendations for lifestyle and still regain weight. So a lot more research needs to go into this, because we lose the physiologic benefit of the medication when we discontinue it. It doesn't, right now, as far as we understand, continue to give that benefit after the medication is no longer being given to the patient. I'll add briefly that it's also been studied for terzepatide and the SIRMOUT4 study. And there's a suggestion that perhaps terzepatide, because it's a multi-agonist, the regain might be slower. But there is still regain. And with the regain, you could hypothesize that the metabolic complications would come back. Anecdotally, in my vets, that's a time where I really redouble on my efforts, and I contact my mental health colleagues. Because I think you could hypothesize that, yes, it would potentially worsen the mental health comorbidity, as well. So I guess I'll just add about the off-label medications, as well. I think it applies to all kinds of obesity interventions, really. And I think it just goes back to the understanding that it is a chronic disease. So it's the same thing. If you have hypertension, and if you stop your blood pressure medication, what's going to happen? Blood pressure goes back up again. And it's a very tough conversation to have with the patient, because the understanding that this is biology. It's not as simple as just saying that, people sometimes think that, I'll take this medication, and then I'll stop it. And then I'll just continue working on lifestyle. It's going to be a small proportion of people who will maintain their weight loss for variable periods of time. I want to be very clear. Remember, this is a chronic thing we're talking about. And nobody has really followed our patients that long. We have done until five years. I'm going to probably put out our 10-year data in the next year or so. But the understanding this is chronic, and patients will need to be on something, if not continuously, at least intermittently, to maintain that weight. But do you think that it will happen, like the same will happen with mental illness? Like as obesity, as a chronic disease, will medicate patients long-term for incheating and other mental illnesses? Yes. I think the short answer is that it looks, that's what we are seeing now. I think it's likely, like I said, that it could, the interval, in terms of dosing, some of the newer medications that are coming out can be even dosed once a month. It's a very early phase. Like I said, we don't know. Maybe patients are going to be able to take breaks for a few months, maintain the weight loss, and then maybe some of them will need to restart. It's too early for us to say, but I think some management ongoing, long-term, is going to be needed. Just like, as you say, for psychiatry. Thank you. You asked about addiction. Yeah. I think we don't know. That's the short answer. I think the clinical trials do have a follow-up to actually address that question. It's conceivable to think that if people stop taking the GLP-1, assuming that it does work for addiction outcomes, then they will relapse. But I don't know if the solution would be to keep on the GLP-1 for the longer term. There are safety considerations to keep in mind, in particular in people taking stimulants, for example, because of weight loss, et cetera. Also, in the addiction field, like for psychosis or depression, people don't receive a medication like a chronically for 10 to 20 years. So actually, that's an interesting question in terms of even shifting paradigm of whether we should treat people with addiction, well, kind of like we do for opioid use disorder with methadone and buprenorphine. But we don't do for alcohol or even for smoking. Thank you. Thank you all for a great talk. GLP receptor agonist is one of the most exciting developments in my life, practicing medicine. So I'm glad to see this is taking off. Two questions. One is, aside from alcohol, do we see a benefit in other substance use disorders? The second is, is there an argument to be made for taking medications like these, even if you're not obese? You talk about neuroinflammation, substance use, other benefits, maybe a smaller daily dose. But do you make the argument that there may be room for that as well? Yeah. So for the first question, there is a very robust preclinical literature suggesting that the GLP-1 agonist also work for smoking, opioid, and stimulants. We ourselves have published data showing that the semaglutide reduces fentanyl self-administration in a mouse model of fentanyl self-administration, as an example. But again, similar to the alcohol literature, the clinical work is actually missing. There is actually an interesting clinical trial in Texas where they look at GLP-1s in the context of smoking cessation and preventing regain. And the data seem promising. Actually, there was a JCI Insight paper just published on the alcohol outcomes in that clinical trial. So there is hope there as well, but we need clinical trials in other drugs, addictive drugs as well. Any anecdotal evidence with cannabis or stimulants? So with cannabis, actually, there is a pharmacopedemiology paper in Molecular Psychiatry. Dr. Nora Volker is one of the co-authors in that paper where they show the association between GLP-1 receptor agonist prescription and the decrease in cannabis use. It's a pharmaco-AP analysis, so it needs to be replicated in RCT, but it's very promising. I'll add briefly on the cannabinoids that that was actually a target about 15 years ago in our field, and it was marred by psychiatric issues. So as in the medicines made it to the market in Europe didn't make it to the market in the U.S. because there were very severe depression complications. So we have to tread lightly. And then as far as treating lean, folks, that's a really interesting question that gets to what we do in our field. If you believe that obesity is about excess adipose tissue that has health consequences, where do you draw the line as to where the excess is and the consequences? So it becomes a little bit teleological, philosophical. There is a paradigm for other medicines in the diabetes-obesity field, SGLT2 inhibitors specifically that are now expanded indications to folks with other diseases like heart disease. I'm not so confident about GLP-1 receptor agonists. I think neuroinflammation would be an interesting target, actually. And just to add to that for the second question. So terzevratide I mentioned is a dual mechanistic action. So GLP-GIP receptor agonism. And you have to think about how much GLP and how much GIP agonism there is. And with shifting the percentages of that, we've been able to see, for example, with pembidatide for patients with fatty liver disease, for example, they were having decreased ectopic fat deposition, but not as much actual weight loss. So it's possible that the new formulations of GLP-1 receptor agonists or dual agonists could help patients who are leaner have other benefits without so much actual fat mass loss. That's good potential for targets in the future. So I might just add one more area that's still developing in this field is the use of GLP-1s for Parkinson's. So it's in clinical trials. I think the early phase data, it looks promising. But we'll hear more about that. Yeah. Thank you. Sorry. A couple of questions more. One is, do you think we should not prescribe these medications for patients that has previous history of cancer, like thyroid cancer or pancreatitis? Because I know it's high risk for that pathologies, but should we just avoid prescribing it or just keep like examining them continuously or closely? So by label, all the medications that I alluded to today are contraindicated in people with a personal or family history of medullary thyroid cancer or into neoplasia, which is part of that. And then pancreatitis, no one in the studies had pancreatitis. So patients with pancreatitis were excluded, and it's considered a contraindication. However, clinically, there are some patients who had pancreatitis once, maybe gallstone pancreatitis, had their gallbladder removed that we still might clinically treat. But the medullary thyroid cancer is considered a contraindication. And in alcohol, pancreatitis, have you seen something? No. It's definitely a concern. That's why actually safety is one of our core primary aims, to look whether there is such a risk. Because of course, as you point out, alcohol is one of the leading reasons for people to have pancreatitis. In the Danish exonatitis randomized clinical trial, they only had, if I recall well, and Anders can correct me here, I think they had one case of pancreatitis in the exonatitis group and one case in the placebo group. So there was not that red flag. But we're still keeping a close eye. We are monitoring lipase. So far, we have not seen, anecdotally, any increased risk of lipase in people on the clinical trial. But of course, we are blind, so we don't know. And it's a small number. Thank you. And in your opinion, I have heard other doctors that prescribe it, like micro-dosing of GLPs for some prediabetes or hypertension. Do you have any experience? I know that's not the indication, but do you think that could help in mental illnesses or these other metabolic pathologies in micro-dosing? So I think I'll just take that. So I think the way most of us are using, when you say micro-dosing or lower dosing, we sometimes use clicks. We don't actually give the full dose. It's really more for tolerability, rather than actually using for indications where there's less evidence to use it. I would say it's micro-dosing or less than recommended dosing is more for tolerability. And of course, there are people who actually can get maximum benefit at less than the maximum dose. So less is better. So yeah, that's kind of how it goes in practice. Thank you, everybody. Thank you for the talk. A couple of questions. For the GLP-1, how often do you see the patients? Because I just started prescribing. And what side effects are you looking for? I'll start with that. So I initially started seeing the patients every four weeks. But we don't have the capacity to see patients every four weeks to titrate them up. So I see them every six weeks. I go into my office, see them every six weeks or make contact with the patient every six weeks. The way I specifically do at my clinic, there's variability, I'm sure, amongst the panel is I write the first two doses. So they have eight weeks of medication and see them in six weeks and repeat and repeat until they get to the tolerated dose or their maintenance dose. And then if they're tolerating a dose, their maintenance dose, I tend to see them every three months. But it's really up to your own clinic capacity and your patients and how comfortable you feel with doing that. And the thing that's important is not let the patient just ride with the prescription for six months. Let's just write every dose for six months and hope the best. That really doesn't work out because a certain degree of patients will not be able to tolerate it. If you look at some people, some of the studies as far as adverse events that led to discontinuation in a placebo group, about 1%, but as high as 7% of patients have GLP-1 intolerability that they can't take it anymore due to side effects. So those are things we look out for. Most highly reported side effects are nausea, constipation, loose stools, abdominal pain, reflux. Do you have to worry about the muscle mass loss? I'll add to Holly's point briefly that I usually prescribe three months at a time because it's a long titration, but I put in a phone call six to eight weeks. We try to meet diabetes prevention program frequency of visits. It's really important to set people off in the right direction. It's hard in the real world setting. That's DPP is 14 visits in six months. We get to 10. And with that, we have good outcomes. And then in terms of muscle mass, that's a really interesting target in development because, yes, out of every, and we've published on this and it's known that out of every pound you lose 10 to 20% is non-fat mass in obesity, i.e. water, bone, muscle. So that could accrue over time. And generally, we recommend the folks to work on building muscle when they've reached their weight goal and at the weight maintenance stage. But there are targets that are trying to mitigate that muscle mass, the inhibitant. There's a few targets that are going to try to do that. Do you end up doing any blood parameters or bone scans to avoid like every six months or once a year? No bone parameters, no lab parameters. If you have the benefit of having an impedance or some kind of fat content measure, I think that can be helpful. In people with osteoporosis, now this is more in the endocrine world, we do. I might do a DEXA scan in someone who might be at risk by FRAC score. One more question about metformin for Dr. Shukla. Do you do the regular metformin BID or do you do extended release? Typically use extended release, better tolerated. Thank you so much. You're welcome. We only have time for one more question. Thank you. I'll try to make it brief. Thank you so much for your informative talk. Two questions. One, preference for oral versus injectable, patient preference aside, your preferences. Then I can kind of guess by your statements about capacity, what are your feelings about us psychiatrists describing these LP1 receptor antagonists on our own without endocrine oversight being that we give out a fair amount of metformin without oversight? We can all share our answers to that for the last question. The second question. I'll do the second question first. I feel we all treat patients with obesity and there's no reason we need to leave that to obesity specialists or endocrinologists. All for it, 100%. And what was your first question again? Sorry. Oral versus injectable. Okay. So oral versus injectable GLP-1. So I stay on label, and right now we don't have an oral GLP-1 for weight management. And if I have a patient with diabetes, I'll give them the oral. There are orals in development for obesity. So when those become available for obesity, I'll use them for that indication. But right now, I use the medications as prescribed by label. So I do use oral medications off label if that's the patient preference, and it's covered by the insurance. So it's hard to get coverage, but I have managed to get coverage in a few patients if they have prediabetes. So yes, we will use it. And the trials are underway, and I think with not just the rebalances, but also newer GLP-1 molecules, which are looking highly effective. So it's very promising. So the second question, yes, I do think it makes sense for psychiatrists to also prescribe. And I think the key thing is to not just follow what the schedule says, which is like go up every month. That's the one thing to remember, because A, the key thing is to make sure that a patient actually tolerates the dose that you're giving. And you can stay on that dose for as long as it takes for them to actually get used to it, and then go up to the next dose. So that's my two cents. So I'll add the VA counterpoint. So we don't have the insurance restrictions that my colleagues here do. There are other restrictions that we have. So I think we all agree that at this point, the injected available GLP-1 agonists are a lot more effective than whatever oral one is available right now. That will change very soon, because the high-dose oral GLP-1 agents are in development, and they look to be comparable to the current injected GLP-1 receptor agonists. And absolutely, in the VA, we try to practice team medicine. My psychiatrists, I know several of them very well. Over my eight years, I've found child psychiatrists to be really good at prescribing metformin. Adult psychiatrists, a little less so. So this is part of my take on points. And absolutely, I think as long as you know who to call for help, and you have someone that you can, I think it's absolutely. Thank you so much. Thank you. That's all the time we have. If you have any further questions, I believe some of our speakers will still be here to answer them personally. But thank you for attending.

GLP-1 receptor agonists

obesity management

mental health

addictive disorders

semaglutide

liraglutide

terzepatide

neuropsychiatric hormones

psychiatric side effects

interdisciplinary treatment

atypical antipsychotics

alcohol use disorder