Hello and welcome. I'm Dr. Rob Cotez, Director of the Clinical and Research Program for Psychosis at Grady Health System and Associate Professor at Emory University School of Medicine. I'm so pleased that you're joining us for today's SMI Advisor webinar, Metabolic Comorbidity in Severe Mental Illness, Treating the Brain While Mining the Body. SMI Advisor, also known as the Clinical Support System for Serious Mental Illness, is an APA and SAMHSA initiative devoted to helping clinicians implement evidence-based care for those living with serious mental illness. Working with experts from across the SMI clinician community, our interdisciplinary effort has been designed to help you get the answers you need to care for your patients. Today's webinar has been designated for one AMA PRA Category Credit I for Physicians, one Nursing Continuing Professional Development Contact Hour. Credit for participating in today's webinar will be available until November 14, 2022. Slides from the presentation today are available in the handouts area found in the lower portion of your control panel. Select the link to download the PDF. Please feel free to submit your questions throughout the presentation by typing them into the question area found at the lower portion of your control panel. We'll reserve 10 to 15 minutes at the end of the presentation for Q&A. Now I'm so pleased to introduce you to the faculty for today's webinar, Dr. Margaret Han. Dr. Margaret Han is a Clinician Scientist in the Schizophrenia Division at CAMH and an Associate Professor of Psychiatry at the University of Toronto. There she holds the Megan Family Chair in Psychosis Prevention. Dr. Han's research interests lie in translational work focused on the complex interplay between illnesses, antipsychotic treatments, and cardiometabolic risk. Given the early accrual of metabolic risk leading to a 20% reduction in life expectancy for patients with schizophrenia, she has an interest in early episode individuals and prevention strategies. She currently co-leads the Mental Health and Metabolic Clinic at the CAMH within the complex mental illness program, which specializes in metabolic monitoring and interventions for metabolic risk factors in individuals with serious mental illness. Thank you Dr. Han for leading today's webinar and I'll turn it over to you. Okay, thank you so much for that introduction. So I just have one disclosure related to today's presentation. So maybe some of you have had a chance to review the learning objectives. So I hope that upon completion of this activity, you'll be able to describe why people with schizophrenia have such high rates of cardiometabolic comorbidity, to discuss the disparities in metabolic care, which unfortunately exist in this patient population, and finally gain a general knowledge of approaches to best practice management of metabolic comorbidity in this population. So we know by way of background that patients with severe mental illness, including schizophrenia, lose 15 to 25 years of life and that's directly attributable to cardiovascular disease. And then that's in keeping with rates of metabolic syndrome, as well as rates of type 2 diabetes that are quite a bit higher in our patients as compared again to individuals without mental illness. The other point I wanted to make is that we understand that metabolic risk likely accrues early on in the illness. So this was a cohort study that was published, I believe out of the Netherlands, and they looked at rates of metabolic syndrome in the general population and in schizophrenia across different age spans. And so what you can see is that in the general population, at like a younger age span of 35 to 45, rates of metabolic syndrome are low, so under 7%. And when you fast forward by 10 to 15 years, that rate actually doubles, so it goes up to 14%. If you look at patients with schizophrenia, you see that already at this young age of 35 to 45, rates of metabolic syndrome are very high, exceeding 30%. And in fact, when you fast forward the 10 to 15 years, they don't change much, so the accrual has already happened, so to speak, like the damage has been done. So when we ask ourselves why we see coexisting metabolic disorders and severe mental illness, as you might guess, it's not a straightforward phenomenon. We have contributing effects of lifestyle factors, so high smoking rates, poor dietary habits. I think we all know that unfortunately, healthy food is much more expensive than less healthy food options, as well as lower activity levels. There are also fascinating genetic links, in particular between schizophrenia and type 2 diabetes, but also with type 2 diabetes and other severe mental illnesses that actually predated the introduction of our psychotropic treatments, which we'll discuss also, of course, contribute. And we have social health care determinants, so that speaks namely to reduced access to medical care, and is probably related to this historical silo working or separation between physical and mental health care. And then finally, adding fuel to the fire are treatments for mental disorders, and unfortunately, across all psychotropic medication classes, most agents have some sort of metabolic side effect profile, and arguably the worst offenders and certainly the best studied agents in terms of metabolic side effects are in fact antipsychotic medications. But no matter how an individual gets there, we do know that having comorbid severe mental illness and metabolic comorbidity bodes poor outcomes. So you can imagine if someone gains a lot of weight by taking a medication, they may be more likely to discontinue it and come off of it against medical advice, which can result in relapse and hospitalization. We also know that metabolic comorbidity is linked to more depression, lower self-esteem, lower quality of life. As well, I think of recent interest to the field is we're beginning, we've, you know, known that obesity and diabetes, for example, are severe chronic medical illnesses, but we're beginning to understand that they can also negatively impact the brain. And this seems to apply for people with schizophrenia as well. So as was exemplified by two recent systematic reviews and meta-analysis, individuals who have schizophrenia and components of metabolic syndrome perform worse cognitively than individuals without metabolic comorbidity. So moving on to antipsychotics, why do we care? Well, these drugs are approved now beyond schizophrenia across other severe mental disorders. And what's also really concerning is they're increasingly being prescribed in an off-label fashion, and that is highest among children and adolescents. And we'll come back to this, but that's one of the more vulnerable populations for metabolic side effects, unfortunately. So this is a slide that comes from one of the first seminal meta-analyses that was published when concerns arose around antipsychotics and metabolic side effects. And what it shows you is that indeed, these medications aren't all created equally in terms of metabolic risk. And unfortunately, our two best medications, sorry, this slide got cut off, but clozapine and olanzapine have the worst metabolic profiles. What we also learned in this study that was first published back in 2005, actually, is where the population that you're studying and starting antipsychotic treatment with makes a difference in terms of the magnitude of the weight gain that is seen. So this was one of the first studies published in antipsychotic unexposed first episode psychosis patients. And what you can see with an agent like olanzapine, the mean weight gain is 17 kilograms or over 40 pounds. So if you go back one slide, you can see that olanzapine in chronically ill patients, that magnitude of weight gain is much less. So it's about three to four fold higher in these young first episode psychosis individuals. And moreover, even an agent like haloperidol, so it's a first generation antipsychotic, which historically was not really known to have any metabolic risk. But again, if it's studied in this particular population, we see a not insignificant weight gain, approximating about 20 pounds over time. Similarly, as you may know, there's been this move to try to develop newer antipsychotics with the hope that some of them would be metabolically neutral. But even some of these newer drugs, like you can see aripiprazole here in blue, when you look at antipsychotic naive populations, not the case, they're still experiencing a pretty significant weight gain. Similarly, when we think about diabetes, there was this very large Danish population based cohort study that was published back in 2017. And it also exemplified that regardless of which antipsychotic was studied in this population, or what class of medication, all these medications increase the risk of developing diabetes with antipsychotic treatment, another two to four fold above the risk that was conferred just by having the illness of schizophrenia itself. So again, we do not, as of yet, have a metabolically neutral antipsychotic, unfortunately. When we think about why weight gain and other metabolic side effects occur with these drugs, it's still not entirely understood or the mechanisms aren't elucidated. But likely, this involves complicated alterations in peripheral and central hormone action, hormones that are involved in metabolism and regulation of appetite. As well, when you speak to patients, and we also did a systematic review on this, but many patients will experience a severe and persistent increase in appetite that's very biological, and some people in fact develop a binge eating disorder. So this is all just to say that this is a biological phenomenon. Often, when we see patients in the metabolic clinic, they're family members or themselves, they blame themselves that they're not eating properly, they're lazy, and so forth. But that's really not the fact. The fact is that these drugs really do have a biological underpinning, and they cause these serious metabolic problems. And one way I kind of like to think about it is with some of our older drugs, what came to light were movement disorders or extrapyramidal side effects. And somehow as psychiatrists, we feel quite comfortable managing extrapyramidal side effects with medications that actually have very systemic effects. But I think as a field, we're more reluctant to treat these metabolic problems. So we'll come back to that and review what perhaps as a field we can be doing in this issue. So to summarize the first part of the talk, we know that severe mental illnesses are burdened with cardiovascular disease. And unfortunately, our management strategy causes or worsens metabolic problems. And these have far reaching consequences that extend beyond cardiovascular morbidity. And certainly, metabolic repercussions add to the burden of illness. So what can we do? Because we know these medications are unavoidable, and in fact, they're lifesaving drugs. So while they may cause metabolic side effects, they still in general, improve people's lifespans. So how do we tackle the metabolic issues? So first of all, the point to highlight is we can't really intervene unless we screen. And it may not come as a surprise, but people with psychosis actually show lower rates of metabolic monitoring than in some cases, individuals without metabolic risk conferred by psychosis in the general population. And this is really worrisome, because we know that illnesses like diabetes, high cholesterol, hypertension, smoking, as well as arguably obesity, are considered modifiable cardiovascular risk factors, which means that if they're diagnosed, they're actually treatable conditions with potential significant impact on health and life expectancy. So are we seeing this happen in our patients? You may guess again, unfortunately not. So this was exemplified by this JAMA psychiatry study that was published back in 2014, which looked at prevalence risks of cardiovascular risk factors in first episode psychosis patients across 34 non-research affiliated mental health centers, again, in the United States. And I'll point you to, first of all, that the mean age of this population was 20 years old. You can see that at this very young age, already rates of dyslipidemia are approaching 60%, and close to half are smoking, and rates of diabetes in the subset that had blood work available was approximating 20%. When they also looked at the percentage of individuals receiving any kind of medication intervention for, again, for these modifiable risk factors, you can see that it was just non-existent. So on, I guess, a brighter side, I was quite excited as myself and other Toronto and Calgary colleagues were invited to participate in the updating of the adult obesity clinical practice guidelines in Canada, where for the first time we actually had a section on mental health. So I'll share with you what came out of those guidelines, focusing on pharmacological and behavioral interventions for comorbid obesity and mental illness. But before we get to some of those recommendations, why, you know, are we doing this work? Why do you need specific guidelines for our patients? Well, this is just a reminder that how our patients arrive at metabolic comorbidity is more complicated than how individuals without mental illness get there. And that includes, of course, our antipsychotic treatments where, you know, they contribute through poorly understood mechanisms. And that's why you'll see that there are many off-indication weight loss agents that have been studied in the context specifically of antipsychotic-induced weight gain. As well, because of this complicated sort of picture of how metabolic comorbidity arises, this may mean that interventions for obesity and other cardiovascular risk factors may not work in the same way in our patients. Furthermore, especially for anti-obesity medications, the earlier ones, many were centrally acting, so acting in the brain. So, I think it's also fair to assess safety of these drugs as our patients may be at risk for mental health relapse in some cases. So, when we think about psychotropic medication-induced weight gain, so whether that's antipsychotic-related or another medication, there are in general four possible management strategies one can consider. So, one is reducing the dose of the offending agent. One is switching from the offending agent to a lower metabolic liability compound. And then finally, we have pharmacological adjunctive treatments or lifestyle interventions. So, first looking at dose reductions, unfortunately, there's not very much data out there looking at whether reducing antipsychotic dose is safe and whether it results in metabolic improvements. What little does exist is that probably you need to lower the dose of these drugs below their therapeutic effective range before you really see significant weight loss. So, in absence of more data, in general, dose reductions are not recommended to treat metabolic comorbidities induced by antipsychotics. Having said that, it's always best practice to use the lowest effective dose possible when treating our patients. Looking at switching strategies, my good friend and colleague, Dan Siskin from Australia, recently published a systematic review and meta-analysis that divided current literature into switch versus stay studies. So, studies which would randomize people to switching the antipsychotic they were on or staying and looked at metabolic outcomes with a focus on weight and then before and after switch studies. So, this is where everyone switched and then they assessed metabolic parameters. So, first looking at the switch versus stay studies, there was only sufficient data to meta-analyze two antipsychotics. So, switches to aripiprazole or switches to olanzapine. And what they found is that switching to aripiprazole was associated with significant weight loss as well as improvement in lipid parameters, whereas not surprisingly, switching to olanzapine was associated with weight gain. And the studies that looked at safety ratings are, as we know, switching strategies may carry a risk of mental health relapse. The good news was that there were no differences in dropouts between the groups or worsening of psychosis ratings. However, overall study quality was low. When they looked at before to after switch studies, out of the, I believe, eight agents that were examined, only a switch to zaprazodone or aripiprazole was associated with embodied but significant weight loss. And then not surprisingly, a switch to olanzapine or clozapine was associated with significant weight gain. Again, not all studies, very few reported on safety issues, but there were no concerns, RE relapse. However, again, overall study quality was low. So, certainly, I think switching strategies can be considered on an individual basis. However, we do have to consider some limitations working off some of these meta-analyses where safety findings are collected in the context of controlled clinical trials where patients have very frequent follow-up, so those results may differ from real-world practice. As well, trial duration was usually short. And finally, treatment superiority of clozapine precludes, of course, switching strategies in treatment refractory patients who are receiving clozapine. Moving on to pharmacological interventions. So we're actually quite fortunate. If you looked at the guidelines 10 years ago, there would have only been two federally approved agents for management of weight loss, one of which was removed off the market. And now we have five medications. Well, in Canada, we have four. You have an additional medication that's FDA approved in the U.S. And there is hopefully another one coming on the market very soon as well. So currently, we have oralostat available, which essentially inhibits fat absorption in the gut. We have liraglutide that's approved for chronic management of obesity. This is a GLP-1 receptor agonist. It's a self-injectable daily medication, and we'll come back to this class of drugs. Then we have Contre, which is a combination of the antidepressant bupropion and the opioid antagonist naltrexone. And finally, the newest kid on the block and currently the most powerful weight loss agent is semaglutide, which is a weakly injectable GLP-1 receptor agonist. It's also approved for treatment of type 2 diabetes, but it's used at higher doses for management of obesity. In Canada, we don't have this medication approved, but in the U.S., you also have casima. So that's a combination drug of sympathomimetic, phenteramine, and the antiepileptic medication tapiramide. This is just a summary table we prepared when we were working on our Cochrane meta-analysis, which should be published soon, which included all RCTs examining pharmacological interventions for weight gain in schizophrenia spectrum disorders. What I did in this table is I bolded the medications that were better than placebo and I put in brackets the number of RCTs that were studied for each medication. So first of all, you can see that a large number of medications have been studied, most of which are off-label. And then we can see that two studies examining the FDA-approved weight loss agent naltrexone bupropion actually didn't show this compound to be better than placebo. This is specifically, again, in the context of antipsychotic induced weight gain. And similarly, oralistat, the other medication that has FDA approval, was not better than placebo across two studies. Subutramine, we won't talk about as it was pulled off the market a number of years ago because of cardiovascular concerns. Nozetadine is a histamine agonist, however, study quality supporting its efficacy was low, so not recommended. Aripiprazole is a really interesting one. So I showed you that aripiprazole in antipsychotic naive individuals causes significant weight gain. However, interestingly, it's been studied to reverse or mitigate clozapine-induced weight gain. And it actually has a small, modest weight loss compared to placebo in this context. However, again, study quality was low. And moreover, one of the RCTs looked at DEXTA scans and found that the weight that was being lost was actually lean and not fat mass. So probably not something that should have widespread recommendation. Moving on to the other agents. So then we were left with metformin with 11 RCTs supporting its efficacy and safety. Metformin, you may be aware, is the first-line treatment for prediabetes and type 2 diabetes in the general population. So in this context, it's being studied off-label to mitigate antipsychotic-induced weight gain. Then there were two studies supporting tapiramate. Tapiramate is approved for epilepsy and migraine prophylaxis. So here it was studied in an off-label fashion. And while it was effective as compared to placebo, the concern with tapiramate is that at least in epilepsy populations, it can cause significant cognitive side effects. So that's something that we think needs to be examined closer before, again, recommending its use. And only two trials were, again, supporting it in this kind of off-label way. And then there were four studies at the time examining GLP-1 receptor agonists. There are now, in fact, five with a sixth one coming out soon. So this is just a forest plot of the metformin data from our meta-analysis. And you can see that across all the studies, there's a modest weight loss of about three and a half kilograms, so approximating eight pounds. But what was interesting is actually when we divided the study by first episode psychosis versus chronically ill populations, what we saw is a greater magnitude of weight loss in the first episode psychosis population. So five kilograms, so more like 12 pounds versus two kilograms in non-first episode psychosis. So that just suggests that perhaps prevention strategies may be more effective than intervention strategies once all these problems have kind of set in. So you may wonder why I have a picture of a lizard on the screen. Well, this is a poisonous lizard called the glia monster. And the reason he or she is sharing my screen is because this lizard secretes a compound in its saliva, or that's found in its saliva, which allows it to only have to eat once a year. So this compound, when it was isolated, they found out it is also produced by humans, but in much smaller quantities. It's called glucagon-like peptide one. And glucagon-like peptide one, or GLP-1, has many pleiotropic effects on metabolism, including improvement of glucose homeostasis, reduction of appetite through central nervous system, as well as other mechanisms. And of interest to psychiatry, at least in rodent models, it seems to improve cognitive function and synaptic plasticity. So when we collected the studies and meta-analyzed them, looking at GLP-1 receptor agonists, again, in the context of schizophrenia spectrum disorders and patients taking antipsychotics, we found that across the studies, there was a mean weight loss of about five kilograms. There's now an additional study that's not included in this meta-analysis that also shows nice weight loss properties. And I don't have the slides here, but this class of compounds also results in improvement in glucose parameters. So what were the recommendations from our updated 2020 obesity guidelines? Well, we were quite excited in Canada, as for the first time, we actually have a recommendation for off-label use of metformin in the context of antipsychotic induced waking in people with severe mental illness. As I mentioned before, for other off-label medications to peer-mate, needs further study before recommending for widespread routine use. Now, moving on to licensed weight loss agents, at the time that we were writing these guidelines, there were only three RCTs published for GLP-1 receptor agonists. Now there will be six. So at the time, while it was said that this class of compound appears effective and well tolerated, there wasn't a recommendation made. I have a feeling this will change in the next iteration of the guidelines. So we'll see. And as I mentioned, in the context specifically of antipsychotic induced waking, there is not sufficient evidence right now to recommend routine use of oralistat or naltrexone bupropion. Naltrexone bupropion, maybe it doesn't work for antipsychotic induced waking, maybe it's too early to tell, but it may be applicable to other populations. For example, there was a smaller study showing promise in women with major depressive disorder and comorbid obesity. So I think it's an interesting compound in the future. Moving to behavioral interventions, these are usually split up into cognitive behavioral or nutritional and or exercise interventions. This was a meta-analysis that was published while we were updating the Canadian obesity guidelines. And it divided lifestyle interventions based on a kind of shorter term versus greater than 12 month duration interventions. And while overall, the intervention was better than the comparator or no intervention, you can see that the effect on weight loss was quite modest. A year later, this RCT was published by Richard Holt in the UK. So this is the largest RCT to date in schizophrenia spectrum disorders that examined a very pragmatic lifestyle education program. And you can see it was a big study, so 414 individuals. And there were actually no differences in any of the study outcomes. So no differences in weight, no change in physical activity levels, diet, blood work parameters, or noted cost effectiveness. So while behavioral obesity management or lifestyle interventions were still recommended in our guidelines, they came with that caveat that it's possible that these interventions may need to increase in intensity for individuals, especially with more severe psychopathology, which unfortunately, places some limitations in terms of scalability of these kinds of interventions in community practice. Other key messages, of course, we need to monitor and screen for these abnormalities. So in terms of guidelines, they really haven't changed over the years. So it's recommended anyone starting or switching to metabolically active psychotropic medication should have a lifestyle review at baseline, anthropometric measures, and metabolic blood work. By the way, blood work is preferred fasting, but you can also use non-fasting blood work. You can screen for diabetes with HbA1c, which doesn't need to be fasting. And lipid profile is actually pretty accurate non-fasting aside from triglycerides, which can change by about 20%. Then afterwards, it's recommended that weight be monitored fairly frequently. And the reason for that is that early rapid weight gain is the best predictor of future ongoing significant weight gain. So I think it's important to monitor and that's kind of the point where at least in our clinic, we intervene. And then at 12 weeks, blood work should be repeated. And the reason for repeating blood work is in fact, and you should repeat it regardless of whether someone is gaining weight or not. And the rationale for that is antipsychotic medications in some individuals without causing any weight gain can actually cause high glucose and high cholesterol levels. Then if everything is normal at three months and not changing, people can move to annual monitoring. From a pragmatic standpoint, I know clinically it's hard to remember about these monitoring timelines. So what we do at our institution or try to do is we have an annual metabolic monitoring week where we try to get as many folks as we can to have their annual screening. So just some practical sort of tips. Other key messages from the guidelines, first do no harm. So when initiating an antipsychotic treatment, don't start with the big guns like olanzapine, which have kind of the worst metabolic side effect profile. In fact, in some parts of Canada, it's legislated that olanzapine can't be started as a first line treatment in first episode psychosis. So I think some of these guidelines are changing. Again, switching strategies can be considered, but in consideration with the individual's past psychiatric history, severity and treatment response and should be done along with guidance from their treating psychiatrist if possible. And off-label use of antipsychotics should be avoided if possible. I didn't show you, I didn't because of time, but we actually recently published a systematic review and meta-analysis that shows that in adults off-label use of these antipsychotics, even at lower doses, can cause significant weight gain. Now, we talked a lot about obesity and management of antipsychotic induced weight gain. What about some of the other major cardiovascular risk factors? So first looking at type 2 diabetes, perhaps not surprisingly, there is a great lack of intervention studies looking at treatment of dysglycemia in patients with severe mental illness and type 2 diabetes. Similarly, all the huge diabetes population intervention trials systematically exclude our patients. And once again, like with the obesity field, we don't know if these medications have the same efficacy, for example, in our patients. So to get at this question, we actually started doing some animal work. So my lab actually is a translational lab, so it has an active preclinical as well as a clinical component. And we decided to pre-treat rats with the first-line treatment for type 2 diabetes and prediabetes in the general population and see if it would prevent olanzapine-induced dysglycemia. And we found that metformin partially reversed antipsychotic-induced insulin resistance. So it reversed it at the liver, but it didn't touch insulin resistance in other peripheral tissues. So we followed up this work recently with a double-blinded pilot randomized control trial in humans, looking at 16 weeks of metformin or placebo. And we chose young individuals, so age 40 or younger, with severe mental illness who already had type 2 diabetes or prediabetes and were being treated with antipsychotic drugs. And our primary outcome of interest were glucose-related measures. So this was a small study with 2-to-1 randomization favoring metformin. We had 22 people complete the study. And what we saw is, as was hypothesized, over 16 weeks, there was a nice separation between metformin and placebo on this measure called HOM-IR, which is a measure of insulin resistance, and it's reflective of what happens at the liver. So kind of similar findings, which is cool, to what we see in rodents. Similarly, we saw a nice separation favoring metformin with fasting glucose. But interestingly enough, when we calculated another index of insulin sensitivity called the Mitsuda Index that's derived from glucose tolerance tests, we didn't see a difference between metformin and placebo. And that's, again, kind of interesting, similar to animal models. That measure is more reflective of peripheral tissue insulin resistance. And metformin didn't seem to impact that. Other outcomes, what was quite interesting in contrast to all the RCTs I showed you in our meta-analysis that predominantly look at normal glycemic patients, we actually, in this study, did not see an effect of metformin on any weight parameters. And so that's perhaps not surprising because some of the newer anti-obesity drugs, like semaglutide that I spoke about, it's also been shown to be less effective in terms of weight loss properties once individuals develop type 2 diabetes. And this finding is probably also in keeping with data that suggests that early intervention may be more effective than intervening later on. So just to summarize the study quickly, the good news is that glucose lowering effects of metformin appear to occur independently of its weight loss properties. And possibly patients with severe mental illness and dysglycemia may require more intensive and combination strategies to target glucose dysregulation. Finishing off with dyslipidemia, we recently also completed a meta-analysis of RCTs examining any type of pharmacological intervention for dyslipidemia in patients with schizophrenia. And what kind of blew me away is out of 48 RCTs, we only found four studies that examined approved, so FDA approved, lipid-lowering agents. So one study, and only one of these studies looked at statins, which we know are life-saving cardiovascular medications. And moreover, within the intervention subgroupings of lipid-lowering agents, we did not see a reduction in key lipid parameters, which again may speak to the fact that our patients may need different and more intensive interventions. So in summary, I hope I've convinced you that severe mental illness is associated with very high rates of metabolic comorbidity. Metabolic risk is accrued early on and comes back to shave 20 years of life later on. And there is a lack of studies examining interventions outside of weight gain in a population that's arguably at highest risk for developing future cardiovascular disease. And finally, special considerations exist in our patients, possibly requiring early and more intensive treatment options, but at minimum, we should be probably following current best practice metabolic guidelines. So thank you so much for your attention and to my fantastic lab who made a lot of this work possible. Dr. Hunt, thank you so much. That was a really, really excellent presentation. And before we shift into the Q&A, I just wanted to take a moment to let you know that SMI Advisor is available from your mobile device. Use the SMI Advisor app to access resources, education, and upcoming events, complete mental health rating scales, and even submit questions directly to our team of SMI experts. Download the app now at smiadvisor.org slash app. All right, so, Dr. Hahn, we have some time for Q&A and for our audience. If you have questions, you can just enter them into GoToWebinar, but a couple of questions came up, and I wanted to start with some questions around the use of Metformin. So I'm wondering, Dr. Hahn, if you can just tell us a little bit about how you initiate Metformin for people, how you titrate it. Yeah, sure. So Metformin is generally really well tolerated. It has one rare life-threatening side effect, which is lactic acidosis, but that's only been reported in patients with kidney and liver failure. And none of the clinical trials looking at Metformin in our population have reported this side effect. And the most common adverse effect with Metformin is GI side effects, so nausea, diarrhea, sometimes vomiting. And that can be usually minimized by splitting Metformin dose, at least initially, and then people taking it with food. So depending on someone's history, if someone has kind of stomach issues, I'll start it slow, so 250 milligrams BID with food. If someone doesn't sort of have a history of bowel issues, sometimes I'll just start it at 500 milligrams, and then over the next week, increase it to 1,000 milligrams, or go slower, again, in patients who have a history of GI problems. And then I usually hold the dose at 1,000 milligrams. There's some evidence that perhaps going up to 2,500 may be more efficacious, but generally I find if someone's going to respond, they respond at, sometimes you can even get away with a dose of 750 milligrams. And I emailed today this pocket guideline too, that outlines how to titrate Metformin. So if anyone's interested in that, it's also available. This is a handout that was prepared kind of locally for Ontario. Great, thank you. And sort of staying on Metformin, I'm a little bit curious about the use of Metformin's prophylactically when going with sort of higher offending cardiometabolic agent antipsychotics like Olanzapine or Clozapine, is that something you typically start people on when those agents are initiated? That's a tough question. So if you talk to my colleague, Dr. Agarwal, who co-runs the metabolic clinic with me, he starts people prophylactically. His rationale is it's safe, well tolerated, the risk benefit of starting it is high, the number needed to treat is actually four people. And he doesn't run the risk of losing that person and then they come back a year later and have gained weight. I'm probably more cautious. I follow people more closely and if I see a rapid weight gain, then I'll start it. Just because not everyone develops weight gain. Some people don't gain an ounce. So I think more about adherence and people taking a lot of medications, we know it's tough for them. So usually I'll see and start it in people. You really see the people who are going to gain weight, they start gaining weight within the first two weeks of treatment usually. So again, I think early weight gain is kind of the best predictor who's going to develop these problems. So there's no right answer. So I think you can take and argue either approach. Another question around metformin is, for people who develop weight gain on even what's thought of as lower cardiometabolic risk agents like aripiprazole, have you had experience utilizing metformin for those patients? And I guess a sort of subsequent follow-up to that is, have you seen sort of racial or ethnic disparities in terms of how antipsychotics may cause weight gain for people and about the data that perhaps people of color may be more susceptible to antipsychotic induced weight gain? Yeah. Yeah. It's interesting. I think it's an understudied area. Coming back to the ethnicity question, the slide I showed you on metformin, what's interesting is there's actually bias in that slide because all the first episode psychosis studies were conducted in Asia. So we actually asked this question, is it early intervention or is it an ethnicity driven phenomenon where perhaps people of Asian descent respond better to metformin? I don't think anyone's done those studies and I think it's a very important work. And to your other question, yeah, we use metformin clinically across all antipsychotics. I don't know that anyone's, again, was able to power a study where you can see if it's more efficacious with a certain drug or not, but we do have naturalistic data that suggests that it sort of works across all these antipsychotics, including the aripiprazoles and lorazodones. Thank you. I wanted to now move a little bit to the GLP-1 agonists and I think that it's really exciting the work that's being done with the GLP-1 agonists now. And it kind of seems like medications like gliraglutide and semaglutide are the future of antipsychotic induced weight gain treatments. One of the things that we're finding in the U.S. is that practically there's sort of the administration issues and then also it can be difficult for the insurance companies to approve. So I guess I'm curious if you have any tips or tricks around that and I'm also curious about kind of what the climate is like in Canada and in CAMH about getting these GLP-1 agonists approved. So we have the exact same issue. So we get around it in Ontario for people who are on Ontario disability plans because of their mental illness, because semaglutide is covered for them, but then we can't go up to the obesity dose. We have to stay within the diabetes dose, so it's not as effective, but we have the same problem. So I think that really needs to change, like cost-effectiveness studies have to be done. If you get semaglutide, for example, this is in the general population, it's associated with a 12% body weight loss. There's a newer agent called terzepatide, which is a GLP-1 combined drug that's going to have FDA approval very soon. And that one has effect sizes the magnitude of bariatric surgery. So I think these are potentially very cost-effective drugs if you're preventing all this morbidity and premature mortality. But yeah, I think it will require legislative change, but we have the exact same issue. You just can't get access unless people have good private insurance plans for some of these newer medications. And to follow up, what has been your experience in terms of teaching patients to use the GLP-1 agonist with the subcutaneous injection? No problem at all. And people love the weekly. They just remember once a week to do the injection. And people think of injections, these long needles, but in fact, I think I have a picture somewhere in my slides, but the GLP-1 pen, the needle is so tiny. I pricked myself once because I was showing people how to use it and you can't even feel it. It's such a tiny needle. It's actually, we've had a really good experience with uptake and use. A couple of questions from the audience. One question is, for the GLP-1 agonist, do you have to have a certain percentage of weight gain required? I guess it's kind of about, you know, maybe just talking about what indications may be approved using the GLP-1 agonists. And then the other part of that question is, do you have to try metformin first? So what would you say? Yeah, such a good question. So usually we go with metformin first because sometimes if it works, it works really well and it's cheap and accessible for when you intervene. So there are kind of the FDA regulated, you know, criteria for FDA approved use. So that's a body mass index of 27 or greater with one weight related comorbidity. So a component of metabolic syndrome or sleep apnea, or a BMI greater or equal to 30, and then people don't need comorbidities. So those are the kind of FDA criteria. Then we use it off-label because we kind of use GLP-1 receptor agonist off-label. So it could be with someone with a BMI that's under 27 or under 30, you know, no comorbidities, but they're gaining weight like rapidly with antipsychotic medications. Or they develop central adiposity, but their BMI is within normal range. So then we intervene. And that cutoff is sort of like greater than 5% weight gain over three months. I mean, we kind of make those up. There's no specific guidelines or increase in waist circumference of greater than 5 centimeters over that period. But yeah, with off-label use, that's a problem. It's sort of an art in a way. There's no set guidelines for that. So we kind of 5% cutoff. Gotcha. And also just to go back to the waist circumference, can you tell us a little bit about the utility of monitoring waist circumference and kind of what that tells us? And you know, in my understanding in reviewing the screening literature on how well clinics do and actually keeping up with lipids and keeping up with weight, it seems like waist circumference is one of the things that has some of the lower uptake. Sometimes people kind of tend to miss that. Can you tell us a little bit your thoughts on the waist circumference and how you use that? So I just, especially since the pandemic, I get patients to buy a measuring tape at the dollar store and keep track of their own waist and just get a scale. Like, you know, these are things that can also be done at home. And I think it's just a waist circumference. It's really interesting, but I don't know if there's a literature on this, but we certainly find this in our clinic is again, some people, their BMI stays, you know, below 27, sometimes below 25, but they experience huge abdominal sort of weight gain and especially women complain. I have patients that say, well, people are giving up their seat in the subway for me because, you know, they think I'm pregnant and it's antipsychotic induced central adiposity. So beyond implications of, you know, central adiposity, which actually is a worse risk factor for cardiovascular disease than, you know, just weight change or BMI change. I think it's a validating thing too, for patients, my BMI is normal, but, you know, my waist circumference has tremendously increased and it's a threshold for intervention for sure. One question that came up is in patients with SMI and coexisting alcohol use disorder, would you be keen to start statins and metformin earlier for them? You know, so if someone has a comorbid substance use disorder, I'll actually try to metformin first sometimes, just because it has some evidence to help with substance use disorders. So it's one of those cases where metformin might actually kind of trump metformin because you're sort of killing two birds with one stone, but with alcohol and the trick with alcohol use disorder is heavy use is a contraindication to metformin because of the risk of lactic acidosis. So I'm sometimes more careful and I'll often consult, like with one of our endocrinologists to see if it's safe, especially if the liver enzymes are sort of up, especially like, you know, using it off label, we always have to be more cautious. Yeah, comorbidities are challenging, but, and that's another one where the combination of bupropion and naltrexone can be handy too, is in people with comorbid substance use disorders. I think that's an excellent point. Another question about special considerations for children, people who are less than 18. So I'm not sure if you work with adolescents and children in your clinic, or if there are any special considerations for younger folks. Yeah, we don't. Sometimes we've had requests for referrals for individuals under 18. So, yeah, that's a clear area. There is a literature in autism spectrum disorders and antipsychotic use where metformin seems to be safe and efficacious, but as not being a child and adolescent psychiatrist, I guess I don't have too much experience working with that group. I also wanted to ask you another question from the audience a little bit about any type of counseling that you do for people around what kind of foods that they eat, any sort of specific diets that you recommend, and then also how does that play out given the social determinants of health that you talked about and food insecurity, food deserts. Curious, how do you think about the dietary counseling? Yeah, well, we used to have a dietician in our clinic and that was cut with all the budget cuts. But just some tricks that sometimes make a big difference is like people don't know that orange juice, for example, has a lot of calories, very little nutritional value. So like cutting out juice and pop, replacing it with like a club soda and using an app to count steps. And the other thing that seems to work quite well is portion plates. So, you know, going to the dollar store and buying a portion plate and having so much greens and vegetables, so much meat and sort of so much carbohydrate. So little simple things like that sometimes work because, I mean, we're just so limited clinically how much we can we can do. And as you saw in my slides, it looks like our population would need much more intensive sort of intervention approaches, especially individuals who are kind of on the more severe illness spectrum. So so it's a tough one. But sometimes these little things can make a can make a big difference. And and the changes are often, I think, gradual, but can make a difference. OK, terrific. So we are at the end of our time. I just want to thank you again, wonderful presentation and wonderful responses to our questions. I also love the idea of the sort of annual cardiometabolic monitoring week that you have at CAMH, and we'd love to implement something like that in us. So great, great suggestion. OK, so if there are topics that are covered in this webinar that you'd like to discuss with colleagues in the mental health field, post a question or comment and SMI advisors webinar roundtable topics discussion board. This is an easy way to network and share ideas with other clinicians who participated in this webinar. If you have questions about the webinar or any topic related to evidence based care for SMI, you can get an answer within one business day from one of our SMI advisor national experts. This service is available to all mental health clinicians, peer support specialists, administrators and anyone else in the mental health field who works with individuals who have SMI. It's completely free and confidential. Next slide. SMI advisor is just one of the many SAMHSA initiatives that are designed to help clinicians implement evidence based care. We'd encourage you to explore the resources available on the mental health addiction and prevention TTCs, as well as the National Center of Excellence for Eating Disorders and the Suicide Prevention Resource Center. These initiatives cover a broad range of topics from school based mental health through the opioid and through the opioid epidemic. Next slide. Okay, to submit a claim credit for participating in today's webinar, you'll need to have met the requisite attendance threshold for your profession. Verification of attendance may take up to five minutes. You'll then be able to select next to advance and complete the program evaluation before claiming your credit. And finally, please join us next week on September 23rd as my colleague at Emory, Dr. Benson Kuh, presents ZIP Code and Mental Health, Where You Live Matters for Individuals with Severe Mental Illnesses. I'm really looking forward to that as well. And again, this free webinar will be available September 23rd from noon to 1 p.m. on Friday. Thank you so much for joining us. Until next time, take care. Take care.

metabolic comorbidity

severe mental illness

cardiovascular disease

antipsychotic medications

metformin

GLP-1 receptor agonists

screening

monitoring metabolic parameters

insurance coverage

lifestyle interventions