A conversation about using GLP-1s to manage antipsychotic weight gain, with Mahavir Agarwal, M.D., Ph.D.

While antipsychotics are an effective treatment for schizophrenia, patients often trade their symptoms in for unpleasant side effects such as weight gain, which puts them at risk for conditions such as diabetes, high blood pressure and certain cancers. As a result, treatment adherence can be jeopardized.

The rise in popularity of obesity medications such as semaglutide may provide an alternative for patients, according to recent research published in JAMA Psychiatry.

Mahavir Agarwal, M.D., Ph.D., is the co-author of ‘Pharmacological Interventions for Weight Reduction in Patients With Schizophrenia Treated With Antipsychotics: A Systematic Review and Network Meta-Analysis.’

Agarwal is a psychiatrist and scientist in the Schizophrenia Division at the Centre for Addiction and Mental Health (CAMH) in Toronto and an associate professor in the Department of Psychiatry at the University of Toronto. He recently sat down with Managed Healthcare Executive to discuss the results of his study and why he wishes readers to see them as a message of hope for the future of weight management in this population.

MHE: What are some of the adverse effects of antipsychotic medications?

Agarwal: Antipsychotic medications are the cornerstone of our treatment, so they are the treatment to go to in cases of severe mental illness, and they do bring about a lot of good in terms of helping people with their symptoms, managing lives, and ensuring that outcomes are good. Having said that, they do have side effects. The so-called second-generation antipsychotics, which we prescribe more commonly nowadays, have various side effects such as weight gain, increased risk for diabetes, hypertension, metabolic syndrome and insulin resistance. So, each of these can impair quality of life and contribute to cardiovascular diseases down the line.

MHE: What is the reason behind some of these side effects?

Agarwal: I wish we knew more about the mechanisms. We don't fully understand them yet. What we do understand is that antipsychotics bring about a large change in our appetitive machinery. So, how we feel full after eating food or our hunger cues — they often get compromised when somebody's on antipsychotics. Antipsychotics have also been shown to cause insulin release from the pancreas, and that can result in hyperinsulinemia, which is more insulin in the body, and that over time can have effects such as increasing weight gain, insulin resistance and risk for diabetes. They can also interfere with neurohormonal control in the brain, so that goes back to the first point on appetite control, and so all of these can add together to create a situation where the body tends to put on weight, appetite tends to be higher and these follow-up effects happen right after.

MHE: How do these side effects impact treatment adherence?

Agarwal: They have a large impact, unfortunately. Try to imagine a young person not only being diagnosed with an illness as severe and life-changing as schizophrenia or a related severe mental illness but also being told that they now need to be on an antipsychotic, which, while it will make them feel better, will also give them this complement of side effects, including weight gain. Not only does the sense of self change with the diagnosis, one's sense of how one sees themselves in the body also can potentially change. Weight gain is a rather common side effect, and so it so happens that weight gain is the number one reason why young people go off their medications, so clearly, this is a big problem that needs to be appropriately managed.

MHE: Can you give us an overview of your JAMA Psychiatry study?

Agarwal: Our group here in Toronto is co-led by Maggie Hahn, M.D., Ph.D., and me. We work together in the mental health and metabolic clinic here at CAMH, and our research interest is to improve the metabolic health of individuals with severe mental illness and related psychiatric conditions when they go on antipsychotics. We have a range of studies that look at both understanding the pathophysiological basis of these challenges and treatments. While we run our own clinical trials, a part of our research enterprise is to collate all the available evidence. As the first part of this, we collated all the studies that look at preventing antipsychotic-induced weight gain, and we published that in 2022-2023. That was a smaller piece of work because there are fewer prevention studies. Then there was this larger piece of work, which is now in the published paper. We have 95 studies looking at 39 interventions, and so that has been several years in the making. We wanted to provide as comprehensive as possible an overview of all available treatments in this field. We took all the randomized control trials that are out there, obtained data from them and ranked interventions based on relative efficacy.

MHE: What were the top five most effective drugs in your analysis?

Agarwal: Three of them happen to be GLP-1 receptor agonists, which is the newer class of drugs that we are all excited about. So, semaglutide, liraglutide and exenatide. The last two drugs are the older cousins of this class. And then we have metformin and topiramate. Each of these classes of drugs, I feel, has its own place in managing antipsychotic-induced metabolic dysfunction.

MHE: How does each of these drugs address antipsychotic medication weight gain?

Agarwal: Metformin is the one which has the most evidence, and it is the oldest drug. It has been around for several decades. We know a lot about its long-term efficacy and safety, and as some of our prevention work has shown previously, it is very well suited as an early course treatment. So, when somebody is starting out on an antipsychotic or is at high risk of developing metabolic problems with the antipsychotic, it can literally be started with the very first dose. It has the holy trifecta in my mind. It is low cost, it is well tolerated, and it is effective when used right in the right circumstances. We don't have many drugs that fit all three criteria. Further on, when problems become more established or they are not treated or they are not responding to metformin, GLP-1s become a very good management option. I'm super glad that we are living in times where treatment of obesity is finally possible. In that context, drugs like semaglutide certainly have their place when somebody is gaining a lot of weight, and metformin is either not working or they are not able to tolerate it, or the problem is just beyond what metformin can do. In those cases, GLP-1 receptor agonists are a very good option. Topiramate is sort of the third one in our system. In our system, for most patients who are supported by disability programs, metformin and topiramate are freely available to them, whereas there is an accessibility problem with GLP-1 receptor agonists. They are not covered by most public plans. In Canada, we have the fortune of having generic versions available now. So, our semaglutide costs about $100 a month. Even so, it is not accessible to many of our patients. And so, in those cases, or where there are other soft clinical indicators, topiramate can be a good option. Our research has shown that topiramate can lead to about five kilograms of weight loss, and one in every three persons started on it will show 5% body weight loss.

MHE: On average, how much weight do people gain when they go on an antipsychotic?

Agarwal: There's a lot of variability in individual response. It depends on the context — whether this is the first exposure to the antipsychotic. It depends on the age of the person; ethnocultural backgrounds might matter as well, as well as sex at birth.

Having said that, seven to eight out of every 10 young people starting their first antipsychotic will experience clinically significant weight gain, which is 5% body weight gain, so this is not an uncommon problem. In fact, it is more expected than not that the person starting an antipsychotic will see weight gain happen. There are some differences among antipsychotics. Some antipsychotics are more likely to cause weight gain than other antipsychotics, but when we are talking about young people who are starting their first antipsychotic, these differences are much more muted, and even the relatively safer antipsychotics can cause significant weight gain.

MHE: What are the next steps for this research?

Agarwal: I think there are so many ways in which this could go. This is just a synthesis of all available evidence, and so we need to do more studies with the newer agents that are coming. Then there are these newer agents like tirzepatide that we need to see what they can do in our population. We also need longer-term studies. Most of the studies that we were able to review were less than six months long.

MHE: What is one thing you’d like readers to take away from this study?

Agarwal: I would like readers to take away a message of hope. I would like us as a field, as well as consumers and patients, to feel that these are manageable problems. Historically, our field has not done as good a job as it perhaps could have managing these side effects. There has been some policy discrepancy as to who manages it. Should psychiatrists be prescribing these medications, or is it the purview of some other field of medicine? Those challenges have sometimes led to a situation where we have not been as proactive about managing metabolic health. I hope that this paper and related work that we have done show psychiatrists that this is a very manageable problem and they themselves can help treat it. Drugs like metformin and topiramate can be prescribed rather easily, and people are increasingly becoming comfortable with the idea of prescribing semaglutide or related drugs. I'm not saying psychiatrists should do that; depending on the system, the solutions may look different, but I think we need to be more aware and more proactive in managing this, and I hope this paper provides that support and hope.