The Emerging Role of GLP-1s in Psychiatry with Roger S. McIntyre, MD, FRCPC

Journal of Clinical Psychiatry: psychiatrist.com/jcp/

Dr. Roger S. McIntyre: https://www.linkedin.com/in/roger-mcintyre-976bb167/

Ben Everett, PhD, is the creator and host of The JCP Podcast, a series that brings together leading voices in psychiatry to explore the latest research and its clinical implications. Everett earned his PhD in Biochemistry with an emphasis in Neuroscience from the University of Tennessee Health Science Center. Over a two-decade career spanning academia, publishing, and the pharmaceutical industry, he has helped launch more than a dozen new treatments across psychiatry, neurology, and cardiometabolic medicine. His current work focuses on translating complex scientific advances into accessible, evidence-based insights that inform clinical practice and foster meaningful dialogue among mental health professionals.

This transcript has been auto-generated and may contain errors. Please refer to the original recording for full accuracy.

00:00 – Why GLP-1 Drugs Are Transforming Mental Health Research

Dr. Ben Everett: Hello and welcome to The JCP Podcast, where we explore the science and stories shaping mental health care today. I’m your host, Ben Everett. On this podcast, we speak with clinicians, researchers, and thought leaders advancing the fields of neuroscience and psychiatry, with a focus not just on what’s new, but what’s meaningful for our listeners in their clinical practice. And today, we’re diving into a topic that has rapidly moved from the periphery to the central conversation across medicine, that is the role of GLP-1 receptor agonists. And I’ll just be saying GLP-1s moving forward in psychiatry.

Originally developed for metabolic conditions like type 2 diabetes and obesity, GLP-1s have been demonstrated to reduce major cardiovascular events, improve heart failure. Additional data demonstrate they also reduce chronic inflammation, protect kidney function, decrease liver fat, and potentially reduce addictive behaviors. And there’s a lot of other emerging themes in neuroscience and psychiatry, and that’s really what we’ll be getting into today. And it’s really exciting, what we’re looking at for brain function, mood, cognition, addiction. So the question becomes, are these simply metabolic drugs with some psychiatric benefits? Are we looking at a fundamentally new class of therapeutics that bridge metabolism and mental health?

To help us unpack this, I’m joined today by one of the leading voices in the space, Dr. Roger McIntyre. Dr. McIntyre is professor of Psychiatry and Pharmacology at the University of Toronto and serves as the head of Mood Disorder Psychopharmacology Unit at the University Health Network. He is also Executive Director of the Brain and Cognition Discovery Foundation in Toronto and has held multiple leadership roles advancing research and education in mood disorders, cognition, and mental health. 

Dr. McIntyre is widely recognized as one of the leading voices in modern psychopharmacology. He’s contributed more than a thousand scientific papers to the literature and is a frequent contributor to international treatment guidelines, including the Canadian Network for Mood and Anxiety Treatments, or CANMAT, where this work has helped shape how clinicians approach the treatment of mood disorders globally. His research has consistently pushed the field to link beyond traditional neurotransmitter models, with a particular focus on the intersection of metabolism, inflammation, and brain function. 

More recently, Dr. McIntyre and his colleagues have been at the forefront of exploring how GLP-1 agonists may impact central nervous system function, with potential implications across depression, bipolar disorder, addiction, and cognitive health. 

With that, Dr. McIntyre, welcome to the podcast.

Dr. Roger S. McIntyre: Thanks for having me. I’m looking forward to this discussion, and thanks for preparing all that background.

Dr. Ben Everett: Yeah, absolutely. Always takes me a minute to get through all that, but I think it’s good for our listeners to know who we’re talking to. 

Well, look, before we jump into today’s topic, I always want to take a step back. We do this pretty formulaically but ask a few questions just to kind of ground, you know, you’re a real person and try and get to know you on a little bit of a personal medicine. So, in the beginning, kind of what drew you to medicine? Was this something you knew you were going to do from, you know, the time you were a young boy in school or did you come to it later in life?

03:08 – The Career Shift That Linked Metabolism and Mood Disorders

Dr. Roger S. McIntyre: I think the answer is probably more later in life. Later in life meaning later in medical training life. I actually did see myself going into medicine and, you know, my personality is one where I’m a procedural person. I’m a hands-on person. I’m probably quite impatient, quite frankly, as a person, and I like to see things right away. And so I think these factors, these aspects about my personality, probably played a role in my decision. I wanted to become a surgeon quite early in my medical school training. In fact, as a medical student in a very old university in Halifax, Nova Scotia, Dalhousie University, I was very clear, as much as we can be clear about anything at, you know, the age of 24, 25, whatever age I was, 23, that I was going to, you know, become a surgeon and in the area of neurosurgery. And in fact, I shaped all my electives around that and I shaped all my background reading and all my extracurriculars all around that and so on and so forth.

And I had noticed, and again, everyone’s different, everyone’s got, you know, some like Coke, some like Pepsi, and I started noticing that I was sort of becoming very, very bored, which almost strikes people as odd. How can you be bored doing that? I do have a monotony intolerance that I think is pathologic. And I thought, wow, but maybe it’s just, maybe it’s just me. You know, when you’re a junior in the OR you’re not really doing the most sophisticated of things anyways. But nonetheless, I did notice that, but I didn’t really sort of read too much into it. Thought this was just part of who I am. And then late in my medical school training, by this point most of the students had already made their mind up what they want to be when they grow up and decided through the matching system where they’re going to go. I actually had a psychiatry rotation which was sort of left at the very end. And then law enforcement had brought a gentleman in who, while I was doing my psychiatry rotation, which of course is compulsory, that had bipolar disorder, something I’d never actually seen before. He had mania.

And I often mention this to people because at the time, I can remember like it happened a minute ago. Love all kinds of music, especially classical. And when he came in, it was almost as though it was like he was. What I was hearing was more like Rachmaninoff 3, one of my most favorite pieces. And I said to the chief resident, I said, what does this gentleman have? She goes, oh, that’s mania. I said, whoa, that’s pretty interesting. And I literally changed my career path overnight. I said, I got to study this. So here I am, whatever it is now, I don’t know what’s that, 35, 40 years later, here I am and I’m still studying it. And what’s interesting is that that gentleman also, in addition to having bipolar mania, was a man who was severely overweight, obese actually. And I’ve been throughout my career been studying the intersection of metabolism and inflammation and bipolar disorder. So it came up very organically, driven entirely by curiosity. You know, the thing that’s very privileged is here I am, you know, this stage of my life, I’m doing this for so long and I enjoy it as much, if not more now than I ever did. So it’s been an awesome, surreal, privileged life.

Dr. Ben Everett: That’s pretty amazing. Well, you know, to recognize as a young man that, “Okay, maybe I’m not really called to be a surgeon,” and then to have a couple of patient interactions that just really, you know, shape the course of your life and, and for the better. It’s wonderful when you love what you do and you yeah, you can wake up and get ready to go to work. 

So, well, you, you actually covered in that answer a couple of follow-ups. But let’s just kind of look at where we are now with this intersection of gut health and, or metabolism and the brain. We know so much about this like gut-brain axis now. You’ve had a front row seat to some of this over the last 30 years. You know, where do you think – we’re really going to get into this GLP-1 thing today – but like where do you think this sits in terms of potential for paradigm shifts without, you know. Well, go ahead and give us some teasers if you want.

06:45 – Moving Beyond Serotonin to Metabolism

Dr. Roger S. McIntyre: You know, I think it starts off with just a general statement. And, you know, many of our listeners today would be aware, but many may be less aware, that in science, like many things in life, you know, the, you know, the Hemingway quote, “things happen gradually, then suddenly.” And so there’s a gradual and then there’s a sudden. Now things change. And in science, and especially in medicine, paradigms, well, paradigms have a shelf life. We revise, re-edit, we update paradigms of how we think about diseases and how to treat them. And I would expect psychiatry to be no different.

Secondly, I might say also that these paradigms shift in part because of contextual factors, but also because of advances in technology, greater insights, looking under the hood, so to speak, trying to find out what’s really happening at the mechanistic level. So I think what’s happened in the last two decades is there has been a substantial update in reconsideration of what’s causing major, very severe mental disorders, e.g., major depression, bipolar disorder, schizophrenia. And you probably know, Ben, that for seven decades we’ve really been at this altar of serotonin, norepinephrine, and dopamine. And I think almost everyone who knows anything about mental health says, oh, it’s a chemical imbalance in your brain. Well, that really is, in fact, I suppose, not totally untrue, but it’s not exactly comprehensive. And that paradigm has been remarkably, remarkably durable. As I said, seven decades. We have many, many treatments that are FDA approved, approved around the world to target these systems. And I guess there’s two points. One is that it probably has some explanatory value in terms of understanding what’s going on in the brain. Secondly, it’s also provided treatments that have helped and changed and saved people’s lives. So it clearly has been, if you will, it’s been instantiated. It certainly is a powerful paradigm, but it’s not been fully explanatory and most people don’t benefit adequately from current treatments.

This observation, along with the technology advances, has shed new light. And it’s not about throwing babies out with bathwaters. We love babies, we love bathwaters. We don’t throw them out. It’s about updating. And one area that has been a consideration over the last, well, frankly, going back many hundreds of years, but really came into sharper focus, I would say the last 10 to 20 years, is the possibility that there’s something that’s gone awry, something’s gone off the rail, so to speak, with the metabolism of the human brain. And the way we currently think about the pathophysiology of most brain-based disorders, like the ones I mentioned, is something has gone wrong with the brain’s ability to develop at the cellular level to form connections. There was a famous psychologist, Donald Hebb, who talked about how neurons fire together, wire together, and when they don’t fire together, they don’t wire together properly. And therefore you have an impairment in brain function. And this is the prevailing view, it doesn’t matter what disorder you have, something’s gone wrong. Of course, the medical term is plasticity in the brain.

And as we drilled into plasticity at the molecular level to try to identify what are the participants in this very important physiologic process, when it goes wrong, we call it pathophysiologic, it turns out that metabolism is playing a key role. And what’s interesting is, as this was occurring, my own clinical observations. The famous physician Osler, former dean at Hopkins, talked about, just listen to your patients, they’ll tell you their diagnosis. I might even say they also will tell you the underlying lesion. And I had patients that I had noticed that when they were living with depression or bipolar illness, if they were obese, if they were diabetic, if they had metabolic syndrome or some condition related to that, they were much more likely to have severe pathology. Their illness was more severe, they had very pronounced difficulties with focus and concentration, and motivational deficits were so profound that they really couldn’t function. So I coined this notion that obesity does metastasize to the brain, referring to the fact that there is this crosstalk. You talked about gut-brain. I agree with that. But there’s some type of bidirectional crosstalk between the periphery and the brain relevant to these diseases. So I think that clinical observations, along with the advances in the science, the technology, began to shed light these things about where does the streetlight shine? And the streetlight still shines on almighty, serotonin, norepinephrine, dopamine, these don’t operate, you know, independently. It’s like a tapestry with threads all woven together. But there is in fact now a compelling story that something has gone wrong with the metabolism at the cellular level in the brain and that is causing the underlying illness, not just associated with it, and causing some of the very often encountered comorbid conditions that people with these conditions often experience as well.

Dr. Ben Everett: That’s really good. That really resonates with me. So when we think about the GLP-1s in particular, you know, like you mentioned, there’s gradual and sudden when it comes to paradigm shifts. So. And this is- it’s kind of germane to me and how I think about this also because- so I came out of a dopamine lab in 2005. Exenatide, or Byetta, was first approved by the FDA, at least in the United States, in 2005, and actually went- my first part of my career, I worked in cardiometabolic health. And so I was talking to endocrinologists, a lot of whom were just like, “Whatever, this GLP-1 thing,” you know, not early adopters. And then you talk to some early adopters and they’re like, “Oh, this is. Yeah, okay, you’ve got to counsel your patient. They can take a shot a day or twice a day or whatever.” But it was- but some endocrinologists really thought of these medicines as being transformative for their clinical practice. And, you know, you fast forward with, you know, 25 years later, and you can’t turn on the YouTube or TV or anything here without getting an ad for- Unfortunately, I don’t think it’s really. I don’t think it’s the medical model we want patients to access their drugs. But, you know, all these different companies selling compounded GLP-1s. 

So with that, you know, so what changed? Because even with endocrinologists and cardiologists, it was slower to kind of get to this point. But what do you think? Where was the big change among psychiatry and neuroscientists to really start paying attention to GLP-1s?

13:18 – How GLP-1 Drugs Influence Brain Function and Neuroplasticity

Dr. Roger S. McIntyre: Yeah, I think where for us, and we, we took an early interest in this, I certainly did, and began sort of initial insights in the field of neuroscience looking at this really derived from what you were alluding to, and that is, is that at the time when I had started my career, I was primarily interested in delivering insulin to the brain. And maybe it’s an important sort of first episode in the story, so to speak, because we kind of stumbled a little bit across GLP-1 as an opportunity, a little bit by serendipity. Now, just for everyone’s awareness, I mean, when I started in the field, I just assumed that insulin was in the human brain, along with its receptor to, well, involve itself in glucose and uptake glucose to the cell. That’s what it does in the periphery. Everyone, I think everyone knows that. But turns out my understanding was not correct. Insulin is not in the brain primarily for that purpose. It’s actually in the brain primarily to promote new cell formation, so-called neurogenesis, and plays an integral role, not just integral, I might even say chief executive officer role in the process of plasticity to the human brain. And if you have a deficit in insulin availability and/or its signaling at the receptor, you can fill in the blanks. It results in impairment in plasticity.

So this provided the impetus to conduct experiments which we did looking at whether the delivery of insulin to non-diabetic people who are living with mood disorders could have some beneficial effect on the brain. And the results we got were promising. They were mixed. We got some wins, we got some misses, but something was going on there and towards this sort of overarching aim of trying to deliver a treatment that could enhance insulin’s performance in the brain. Because what we had to do, people have to intranasally take it, which is not hard, but it’s not, it’s not as easy for some people. We stumbled across GLP-1. Now GLP-1 has a history like you might expect. And the GLP-1 protein is one of many incretins. And just so everyone’s on the sort of the glossary, how do you define an incretin: An incretin is a protein that is facilitating insulin release when you take an oral glucose load. So it’s glucose-stimulated insulin secretion, and in addition, it suppresses glucagon. And so that’s sort of a complementary effect, slows down the gut motility which reduces the glucose spike and also suppresses your appetite.

And it was discovered in 1986. It wasn’t the first incretin. The first incretin was GIP which is glucose-insulinotropic polypeptide, had a previous name before that, GIP 1970. And many may not be as familiar with GIP, but it is the target of one of the incretins, Tirzepatide analogs, better known by its trade name Mounjaro. That’s a GIP GLP co-agonist. Anyhow, it was certainly known in the field of endocrinology that there was this beneficial effect on a variety of metabolic but also weight-related measures. The field of, you’re right, diabetes and so on, I think really took notice especially when the weight loss effects were being seen. I think that along with the fact that this, to be very frank with you, became part of social media and the influencer world and the consumer world, really took over this storyline to be quite frank about the opportunity for weight loss. And it was sort of touted on these sort of group chat forums and so on and so forth. That’s all to say that the weight loss effects, I think by now everyone knows, are unprecedented and transformative, almost really to the same level as going for bariatric surgery. So that I guess, as they say, the rest is history.

But as it relates to the brain, there was the discovery made – and we of course paid close attention to this, and I didn’t know this at the time – the GLP-1, which is produced in your bowel in a group of cells called the L cells and the GIP is produced by the K cells, and that was the story. This is a peripheral story. It wasn’t a central CNS, central nervous system story. But then there was a light bulb moment. And the light bulb moment happened when it was discovered that there are cells, there are neurons, maybe glia as well, but neurons for sure, in the hindbrain, the back of the brain, an area called the nucleus tractus solitarius. And that hindbrain was producing GLP-1. And that production of GLP-1 was not for peripheral purpose, it was for the brain’s purpose. So it was basically producing its own GLP-1 protein. Which then begs the question, well, what would be the purpose? And you can learn a lot about the function of a protein by, you know, where’s the receptors located, where are the projections going? So you know, location, location, location can tell you a lot.

And it turns out that in addition to having a well-established role, that GLP-1 was anti-inflammatory and as a protein it could enhance insulin receptor activity. That was well established. It was then discovered that the GLP-1 tracts were projecting and they were projecting to areas of the brain that we lean on for motivation, for reward function, the striatum and various components of the striatum. It also projects to parts of the brain that we lean on for cognition and thinking, the cortex and other related areas like the subcortex, like the hippocampus. And that was like, wow. It’s projecting to areas of the brain that we depend on for reward and motivation, areas of the brain that we depend on to think and to have cognitive processes, but also projected to other parts of the brain as well, relevant to other brain-related functions like anxiety and arousal. 

And that was a wild moment because that occurred almost simultaneously with an observation we had made with some colleagues in Korea, where I have an appointment, that when we were subjecting animals to a chronic stress – it’s a chronic stress paradigm, again for those maybe less familiar, depression is a condition of abnormal stress response – and we try to recapitulate that in the environment in an animal model. Now we’re going to agree that a mouse and a rat is probably not the same thing as human being. We’re going to agree on that. But it’s where we start. And when you subject a rodent to a chronic stress paradigm – there’s many stress paradigms we have – the rat behaviorally appears very despondent, there’s despair, the animal’s very immobilized. It’s kind of a learned helplessness paradigm. And what we discovered with some early work we did is that when we pre-treated the animal with one of the early pharmacologic mimics of GLP-1 called liraglutide, that drug would have preventative effects against the hazards of that stress. The animal was less depressed-looking. And we also discovered that the brain trophic factors in the animal which was compromised under stress was protected. And that was wow. 

So there’s something about this GLP-1 that was almost resiliency enhancing. It was protecting against maladaptive stress responses. We did subsequent experiments showing that when we knock out key elements of the glutamate system, and glutamate is very important to plasticity, when we knocked out some of its receptors, the beneficial effects of liraglutide were substantially reduced. So that told us, wow, this is not just simply in quotes, a “diabetic protein”. This is not simply just a protein for weight loss and diabetes and so on. This is a critical, critical protein projecting to regions of the brain that are abnormal across all psychiatric disorders, reward, motivation, cognition. And it is having a critical effect, modulatory effect on key, the most abundant excitatory neurotransmitter, glutamate. Interestingly enough, glutamate is named after gluten. Isn’t that interesting? So Carl Rithausen, he actually discovered it in 1866. He was actually looking at wheat. So here’s the most famous neurotransmitter, the most abundant glutamate, named after gluten. So kind of comes together in some respects.  Anyway, that’s all to say we thought this is really interesting, maybe in fact that this protein is not just integral to normal and abnormal brain function, but maybe the pharmacologic modulation of its signaling could hold promise as a potential treatment, maybe even a prevention against brain-based disorders characterized by disturbances in reward motivation and cognition. And that is a lot of conditions. But the lead candidates would be alcohol, substance, tobacco use disorder, mood disorders, and certainly major neurocognitive disorders such as Alzheimer’s or Parkinson’s disease, and so on and so forth. So it was about connecting dots. There were some light bulb moments that happened. 

And as I said, these things happen gradually and suddenly. And then, you know, you can learn a lot by looking at other areas. And what’s interesting is that you had mentioned some of the indications for the incretin agonist. Like the indications, among others, is that these drugs have protective effects on the heart, protective effects on the kidney. They also have protective effects on the pancreas. And what’s interesting is if you really drill into that science, what you discover is that the hypothesized mechanisms that are mediating those protective effects are similar mechanisms implicated in what’s damaging the brain in people who live with mental illness. So we thought, “Well, okay, if that’s the case in the periphery, why can’t we just repurpose these to protect the brain?” And that’s where we then really took the story forward and then moved into human studies and then moved into patient studies, which we’re in right now.

23:40 – Can GLP-1 Medications Reach the Brain? What the Evidence Shows

Dr. Ben Everett: I’m not sure I’ve ever heard anybody summarize maybe 30, 40 years worth of literature in such an eloquent manner. But this isn’t your first rodeo talking about this either. So I tell you what, I’m always learning, so I don’t want to say, like, “Oh, I never learned anything new,” but the gluten and glutamate thing, I’ve never heard that. That’s pretty crazy. As much as people talk about glutamate, and gluten. Now of course, ketamine’s all in the, you know, on the, in the news, and a lot of really exciting research, I think, in mental health on, on glutamate. 

All right, so you really unpacked a whole lot there. So, you know, one of the things I think about biologics and drug discovery is, is, are these things, you know, blood-brain barrier penetrant? The blood-brain barrier is pretty stingy, especially when it comes to biologics and these larger proteins. So, you know, what evidence do we have right now? You mentioned an intranasal delivery. There might be different deliveries, but is there, you know, what’s the evidence that, that some of these, all of these agents are actually able to, to access the CNS?

Dr. Roger S. McIntyre: It’s a really great question, and I think this is an area that we’re still looking at right now in discovery and development. I might just summarize by saying that the available evidence we have right now very much accords with what you just mentioned. These are fairly large molecules and they don’t cross the blood-brain barrier in an easy way. And again, just going back to our many people joining us today, sort of pharmacology, sort of 101, there’s different processes wherein a protein or a drug that mimics a protein can get across the blood-brain barrier. It could be passive diffusion, active transport, cellular delivery and so on. And at some point, I mean, size matters. I mean, if this thing’s too big, you can’t fit a gigantic molecule through a very small hole. And, and to put it sort of, you know, kind of superficially, and that’s an issue.

And people have looked at- now, there’s been studies in rodents and we’re going to agree that’s not a human being showing that there is some degree of blood-brain barrier penetration, but not a lot of. And I think we should also mention that we now have, you know, over half a dozen of the GLP-1 agonist pharmaceuticals. I wouldn’t refer to them all as identical. They’re different with respect to some of their receptor effects. They’re also different physiologically – what they’re doing. They’re also very different pharmacologically in terms of their structure, their weight and so on. So this is a general statement, but there’s going to be exceptions. There has been some work done in humans where you can take someone, and you have someone take a GLP-1 pharmaceutical agonist, and you can take a CSF (cerebral spinal fluid) sample from a lumbar puncture and measure the level. And it is getting in. There are detection, but the concentration’s quite low.

Another way we kind of infer this, that being blood-brain barrier penetration, other than, of course, this very unpleasant procedure of bending somebody over, doing a lumbar puncture – that’s not a very pleasant procedure for the patient – you can infer it. In other words, you can put someone in the scanner, which is what we have done, and you can look at MRI and you can also do an EEG (electroencephalogram). And when you administer the GLP-1 receptor agonist, you can look at the effect. And if you see an effect in areas of the brain, or you see the EEG, the bandwidth changing, you infer that you’re getting blood-brain barrier penetration. But some might say, well, that inference is reasonable, but that doesn’t prove it because that could be a peripheral effect that is then just then communicating to the brain. And that is a very good point and I agree with that.

That being said, there has been, as you might expect, some very careful medicinal chemistry and pharmacologic work looking at what are the mechanisms where it can access parts of the brain. And this has been now well reported. The blood-brain barrier is fairly tight. It’s like a bank vault. It’s pretty tight, but it’s not fully protecting all aspects of the brain. In areas close to the ventricle, the so-called circumventricular area, there is in fact, I’ll say easier access to the brain in that part of the brain area. And there is evidence that that might be an opportunistic portal for the GLP-1 to get across. And there’s been efforts to look at cells called tanycytes that are responsible for translocating the GLP-1 pharmaceutical into the brain. People are looking at this. This is all to say that you’re right, the field is not entirely clear yet whether or not we are getting adequate blood-brain barrier penetration. 

Then the next question is how much penetration do we need? For example, there was a recent publication that summarized- there’s a company out of Denmark, Novo Nordisk, that conducted two very large studies with semaglutide to look at whether or not this drug could slow the progression of cognitive impairment in people who have early Alzheimer’s disease. And the effort was to try to slow it down over a period of one to two years. And the study reported out as negative, it wasn’t able to slow the progression versus the placebo in these persons. And one conclusion could be that the theory is strong, but it just is maybe not going to work. I guess that’s one, in conclusion, this doesn’t work. And there’s lots of examples in medicine where the theory doesn’t quite translate into a therapeutic. The second could be that the disease is the wrong disease to study. And again, we have commonality across diseases in psychiatry, but there’s important differences. So maybe, and we have lots of examples where drug works in condition A but not condition B, although there’s some similarities between the two conditions that could be the issue. The third is, is that maybe in fact there wasn’t adequate blood-brain barrier penetration. That certainly hasn’t been ruled out. And so this question about blood-brain barrier penetration is not academic. It’s critical because we typically don’t develop therapeutics for psychiatric disorders unless we are convinced they have some degree of relevant access to the brain regions that are subserving the pathology that defines the condition, like reward, motivation, cognition. 

So that’s all to say, in summary, that we do in fact think there is some degree of access, although there’s probably more uncertainty around this than there is certainty. And there are in fact efforts by many very smart people and technology companies who are, as you might guess, thinking about this: Are there ways wherein the delivery to the brain could be enhanced through some other vehicle and so on, so forth? And maybe one final point might be that what we have discovered with other work that we’ve done is that when you are living with a condition like depression, that bank vault known as your blood-brain barrier becomes a bit more leaky. In other words, it’s not quite, doesn’t quite have the integrity it would under normal physiologic conditions. Which raises the possibility then that the pharmacokinetic access, that access to the brain might be different while you’re experiencing, say, depression versus when you’re fully remitted. So, these are, these are a lot of questions we don’t have answers to. But right now I would summarize by saying we have leads of access, but it’s not a consistent finding.

Dr. Ben Everett: So thanks for that. Yeah, and I remember being at ASCP meeting last year and several sessions on this and just trying to highlight a lot of this work that you’re looking at. And I think kind of regardless of whether it’s in right now- so let’s just kind of maybe switch and talk through some of the basic science, some of the rodent studies where we do have some promising data and we’ve talked about some of the neuroplastic changes, neurobiology of disease, neuroprotection, what is known in the literature. And again, we’ll agree that yes, we aren’t rodents, but it’s where we start and we learn a lot from rodent studies and, and frankly, rodents are a lot easier to work on than primates. So,

32:00 – The Four Key Brain-Protective Effects of GLP-1 Therapies

Dr. Roger S. McIntyre: Sure. You know, there’s four different mechanisms that we’ve learned GLP-1 engages that has translation to the human understanding of mental illness. I call it Neuro-GDP. And the GDP is an acronym for not just gross domestic product – but I purposely say this because this is the greatest debaser of gross domestic product, being major mental illness – but it’s referring to genesis, differentiation, and plasticity. So, first area is neurogenesis, differentiation, plasticity. Second is neuroprotection. Third is anti-apoptotic. Again, apoptotic is premature cell death. And then finally is autophagy, which is a self-repair, self-regenerative mechanism. GLP-1 is playing an integral, not a bystander role, an integral role in NeuroGDP, neural protection, anti-apoptosis, and autophagy modulation. I’ve often said, kind of just to be a bit silly about this, that if you’re on a dating app and the dating app picture has Neuro-GDP, neuroprotection, anti-apoptosis, and autophagy modulation, I would swipe, I’d go on a coffee date with that person in an hour. That’s all. We love to see that. That’s all the sweet zone, if you will, that you want in a potential mechanistically informed therapeutic.

In the animal studies, what has emerged, we have- you can take a rodent, you can create an amyloid brain, in other words an Alzheimer’s mimic. You can also take rodents and create alpha-synuclein deposits of Lewy body, you can knock out their dopamine system, your area of expertise with MPTP, and create a Parkinson’s model. When you create these so-called dementia models, and there’s different ways people have looked at this, you are seeing some protective effects of the incretin in these models. In the chronic stress paradigm which I spoke about, you also see what’s interesting, you also see protection against the hazards of chronic stress like immobility, but you also see a facilitation of reward. And this is really interesting because it goes into the third area we’ve discovered in animals. And that is if we turn an animal into a drug addict, keep in mind that food is a drug and we already know that people who take these medicines are very quick to mention that they don’t have the same food preoccupation and chatter and so on. And many- I certainly would be a proponent that sugar is a drug and its effect on the human brain is a lot similar to other drugs that we think about that are misused, like alcohol and cocaine and so on. Frankly, glucose is quite addictive and it has an effect which you can imagine from an evolutionary perspective which is highly rewarding.

34:54 – How GLP-1 Reduces Cravings, Addiction, and Food Noise

Dr. Roger S. McIntyre: And in animal models, when you are creating an addiction paradigm. In the animal model, rodent models, the GLP-1s significantly reduce the foraging, the pursuit of the drug, the use of the drug and so on. And this kind of maps very nicely onto some of the mechanistic work where people have tried to dissect what is the molecular and cellular mechanisms that explain why people are telling their clinicians, “I’ve got less food chatter. I don’t- I’m not preoccupied with food all day long.” And I think it’s important to just go back to the whole concept of reward. When Ribot, called Théodule-Armand Ribot, coined that word in 1896, “anhedonia,” the absence of pleasure. What he described it was decreased sensitivity to pleasure. And obviously as human beings, we need pleasure, and pleasure is not just something we need, it’s essential for life. But it’s more than that because we’ve- in the last two to three decades, reward has been very carefully scrutinized from a neuroscience perspective. And there’s really three separate but related dimensions to reward. The first is reward salience. How much, if you will, salience does a reward have? For me, I would imagine that $200 has a lot of salience for someone who’s economically precarious. I would suggest if you met with Elon Musk, I don’t think 200 bucks probably has the same salience for him. So it’s context-dependent. And so that’s one aspect of reward. A second is reward response, which is how much we’re anticipating a reward, how much pleasure we get from the reward. And finally is reward learning, which B.F. Skinner and Ivan Pavlov taught us. Reinforcement based on pleasurable experiences. They are very much operant or classical conditioning.

All three of these areas of salience, response and learning can go wrong in the brain, and they’re all very different. And in someone who has an addiction to food, drugs, alcohol, tobacco, sex, gambling, shopping, you name the addiction, what’s gone wrong is across all three of these dimensions, especially in the salience, food drugs take on more salience than it should. And the anticipation of that reward is much, much amplified. And what we’ve learned about the GLP-1s at the mechanistic level, they don’t take away pleasure. They don’t take away your favorite neurotransmitter, dopamine. What they do is, is by their projections from the back of the brain to this striatum, they modulate it. In other words, they reduce the exaggerated salience. They reduce the exaggerated anticipatory pleasure. They don’t take away the pleasure, they take away the exaggerated salience, the exaggerated anticipation. And that’s the essence of maladaptive consummatory behavior. That is the essence of addiction.

And along with that, they also have benefits on cognitive functions, because all of us crave. If you go to the buffet table, you see the dessert table, you crave, “I’m going to have one of those and one of those and one of those and one of those.” And you think to yourself, “You know, I probably shouldn’t have maybe eight different desserts. Although I’d like to.” So that requires some degree of cognitive function – the executive atom, to be exact. And the executive atom is responsible for planning, initiating, sequencing, monitoring, and really, in fact, organizing our thoughts, feelings, and behaviors. So it says, “No, don’t do it.” But people who have addictive behaviors don’t have the same impulse control. And so you have this volcanic mix with exaggerated reward salience for whatever the reward is, along with anticipation that’s really powerful colliding with difficulties with impulse control. Abracadabra, you’ve got addictive behavior.

And so GLP-1s are primarily regulating the salience and reward anticipation, but not taking it away. They’re just regulating it. And then they are also, to some extent, we think, having some effect on impulse control. Taken together, it’s reducing the abnormal consummatory behavior. And that is not just relevant to substance, alcohol, tobacco use, food addiction, maybe other addictions, but it also plays a role in depression because people who have depression go to their healthcare provider, they never say, “I’ve got a-” “Why are you here today?” “Oh, because I’ve got a problem with salience.” No one speaks like that. What they’ll say to their clinician, they’ll say, “I’m here because I’m tired. I’ve got no interest, and I don’t get off the couch. I think I’ve got chronic fatigue syndrome, and I just don’t have any sort of desire. No joie de vivre.” What they’re really saying is, “I’ve got a problem with reward salience. I’ve got a problem with reward anticipation.” They say they watch their favorite show on Netflix. They don’t enjoy it. That’s a problem with reward response. And they keep making decisions that are not really in their best healthy interest. That’s a problem with reward learning. People with depression have an incredibly impressive ability to reinforce negativistic behaviors and a very impressive inability to reinforce positivistic behavior. That’s problems with Pavlovian and operant conditioning from Skinner. 

So we know that these alterations in reward writ large but across each of these dimensions, are transdiagnostic. All to say, it isn’t just the purview of substance and alcohol, tobacco use disorder, and food addiction, but cuts across other disease states. Hence, when people look, for example, on ClinicalTrials.gov, a repository of clinical trials that are underway right now, around the world, you’re going to see studies of the GLP-1 drugs in psychiatry, but not just in depression, but across many conditions that share in common this transdiagnostic psychopathology.

Dr. Ben Everett: That’s interesting. It’s a lot to unpack. I just come back to I definitely think sugar is a drug. Very much so. And I think if we understand sort of the impact of the Western diet on so many of the diseases of modern civilization, I think a lot of it just goes down to sugar. Yeah, it was a classic study where rodents, you know, you give them access to cocaine or sugar, they’d rather have sugar than cocaine. So that’s kind of an old one. 

So. All right, well, this is great basic science. I love this sort of stuff. But let’s kind of delve into, you know, making this clinically relevant with what we know right now. So in terms of translating this to, you know, is there anything that, if I’m a practicing clinician in a mental health clinic or primary care clinic, where you’re hearing, “Hey, my patient says he’s tired, just not interested in this, that or the other,” you know, where are we right now with what’s known clinically and where, you know, you would feel comfortable off-label, on-label, depending on, you know, what we’re talking about, where you might feel comfortable saying, “You know what, let’s consider a GLP-1 for you.” So, you know, we’ve talked through depression a little bit. You know, where do you think we are with GLP-1s for depression in and of itself right now?

42:18 – When Clinicians Should Prescribe GLP-1s in Psychiatry Today

Dr. Roger S. McIntyre: I think there’s three potential applications today. Two, I think are fit for primetime, and one is promising. So two promisings. One’s primetime. The first is we started the conversation today with your introductory remarks, and you had mentioned some of the FDA indications. So just to bring everybody up to speed and maybe just to remind others, is that there are currently six – this is going to probably be updated very soon – but there’s currently six indications for the class. Each agent’s different. Not all agents have identical indications, but just as a class, there’s six indications, and those indications, every one of those six affects people with mental illness at a much higher rate than the general population: obesity, diabetes, obstructive sleep apnea, metabolic liver disease, kidney progression of disease in diabetics, and also cardiovascular disease and obesity. So this is, so already. Let’s pretend that these medications were free of charge. And that’s- remember the ice cream truck used to come to your neighborhood when you were a kid, just imagine that the ice cream truck has GLP-1, and that ice cream truck’s parked in front of your medical clinic giving out free GLP-1s, pharmacologic grade, not compounded, not some of that stuff, we don’t know where the heck it comes from, but real stuff. And it was free to the entire population. I would say, I can think of at least 75% of my patients should be on them because they already have indication in these six, one or more of these six. So that’s where your primetime is.

Second is off label, but sort of on label, but sort of off label. Mental healthcare providers know that many drugs that we prescribe in psychiatry can be highly weight-gain promoting and diabetogenic and very metabolically disruptive. And for those who maybe are a little less familiar with this space, they might say, “Well, why does the mental healthcare provider prescribe those? Why don’t they just prescribe an alternative?” And I would say, “I agree,” I agree we should prescribe – and not all drugs do this, not all psychiatric drugs do this – so absolutely we should prescribe drugs that are not causing, you know, weight gain and metabolic problems. We all agree, but that’s not an option for many patients. For example, clozapine, which is a remarkable drug not just for schizophrenia, it’s probably more effective in bipolar disorder than it is in schizophrenia. And it is a drug that has saved lives. It is a drug that is very effective in difficult-to-treat schizophrenia and bipolar disorder. And the challenge is it causes a lot of weight gain and a lot of diabetes and metabolic disruption. And frankly, you can’t stop it because the person just can’t live without it. So you have to, in fact, manage with what you have. And in that kind of situation, clinicians have reached to, beyond the behavioral strategies in diet, they’ve reached to things like metformin over the years to some success. And metformin still has a role, and metformin is still recommended. It’s relatively inexpensive, it’s pretty well safe. We’ve known about it for decades, etc. And there are some very nice controlled trials to show that it’s very effective as an antidote, probably more as a primary prevention than a secondary prevention, but it works. But the GLP-1s have now been studied in a number of very nice randomized control trials specifically targeting this issue. Now, again, it’s hard to maybe attribute all the excess weight in diabetes to the drugs because it’s the illness itself. But that’s all to say that clinicians would be certainly on a reasonable evidentiary base of practice. If they were prescribing a GLP-1 to target, for example, clozapine-induced weight gain or clozapine-induced diabetes, that would be reasonable. In fact, the effect sizes are much greater than metformin, which probably doesn’t surprise anybody. 

So I think that again, we already have six FDA indications. Those are primetime, those are already approved. Secondly, the used target psychotropic drug related weight gain is already, I think, very, very interesting and I think that’s clearly become our drug of choice. And I’m speaking as though the ice cream truck is parked in front of your house, your clinic. I appreciate access, availability, affordability has been the challenge.

Thirdly, what I might say is more the promise, in fact, I know many colleagues across the U.S., some- I meet  folks all over the world who are saying they’re giving them now to help patients with their psychiatric illness. I’m not saying that’s right or wrong. As someone who’s been studying this area for my whole career, I’m clearly on board with the concept. I would say we’re not quite there yet on primetime. And that’s obviously a metaphor. We don’t have the adequate, well-controlled studies to show that it actually works. And if it works, is it the same for all of the drugs? The drugs are very different. Is it a GLP GIP? This year we expect to get retatrutide, which is a triple. Is this- so which one is it? Also which disorder? I don’t assume it’s going to work for everything. I’m not a dour, sort of pessimistic person. I just don’t sort of see it that way. I think we’re going to see maybe an application more in one area than the other. That’s not to say you can’t have more than one indication. So which indication is it?

But look, I think it’s an interesting question and many may be aware of the fact they can go on ClinicalTrials.gov that there are now phase 3 registration trials that are been prepared and have now started in schizophrenia, in bipolar disorder, in major depressive disorder, beginning in opioid use disorder and alcohol use disorder with these drugs. So these drugs are now in major development, FDA type approved protocols to seek an indication. Those results aren’t in yet. So we’re just going to wait and see and cross our fingers something happens that’s positive but we don’t know what that’s going to look like. So I don’t think we’re there yet with respect to treating psychiatric illness. But many colleagues would say, “You know something? Got it. I fully understand they’re not approved there. But you want to know what? I have a patient, they have depression,” I get this all the time, “who has bipolar disorder or depression, they’ve got obesity. I’ve been managing their obesity with GLP-1 drug, X, Y or Z. They’ve lost a lot of weight. You want to know what? Their mood has never been better. They’re more stable, they’re doing so much better. They’re not smoking as much, they’re not getting post-smoking cessation weight gain, they’re not craving drugs as much.” I hear this all the time.

And which reminds me, by the way, people often ask me, “Is the benefit just simply because people lose weight and they’re just happier? Or is the benefit on mental illness, is it just simply because their diabetes and obesity is better?” No, it’s not explained by that. It’s a separate and independent effect. And that’s I think just an important interpretation part and obviously conceptually very relevant. But I hear this all the time that people are telling me that they’re getting a ‘halo effect’, so to speak, on other activities and other aspects of their patient’s life experience beyond its indication while they’re prescribing it. So we hope we’ll see where it goes. So we’ve got two that I think primetime that being on label use and maybe for psychotropic drug weight gain. But we have this promise for the future that maybe in fact it could be treatment.

And one final comment I might say is I’ve noticed as a psychiatrist that psychiatry has a phobia – phobia of the word ‘prevention’. Psychiatry has this. As a psychiatrist, as an advocate, as a person whose life is so unbelievably advantaged by the field of psychiatry, I stand up and I say we wait too long to treat mental illness, we wait till it’s a five-alarm fire before we start to start doing things. No one else in medicine thinks this way. Why don’t we prevent mental illness in the first place? And there are now some interesting observational data. Observational data are not randomized, controlled studies. And so we get that out of the way. But they’re observational. And when people take GLP-1s for diabetes or obesity, the rates of other mental disorders are not as high. So that’s an interesting concept that I don’t think is just academic. That’s a huge concept and a huge issue for public health. Can we prevent the onset of mental illness by targeting metabolic systems? I think that’s an interesting question.

Dr. Ben Everett: Tell you what, you’ve, the way you talk, every time I think I’m going to ask a follow-up question, you go ahead and address it. So I’ve talked probably less than any other podcast before, but this has been amazing. I’m just learning so much. 

I think a couple of things come to mind right now, and one is that it certainly is important as a scientist, I want to understand as much as we can about the root cause, the pathways and these types of things. But sometimes I think if the patient gets better, the patient gets better, right? And okay, we could say is it a placebo effect or is it real? You know, I don’t know. Right now we certainly have plenty of correlative data that says that these things are really helping these patients, the halo effect, whatever it is. But anecdotally we are there, I think across so many of these different things and the evidence is strong enough beyond just correlation that, you know, these pharmaceutical companies do not go into spending fifty, a hundred million dollars on a phase three trial if they are not very certain of their hypothesis. Sometimes they don’t work out, right? A lot of times they don’t. And that can be for different reasons. You know, placebo effect. We’ve got the wrong endpoint, these types of things. But I, I think it’s a very exciting time for these agents and certainly like you said, for so many of patients with serious mental illness, they do have higher rates of, you know, obesity, metabolic syndrome, heart disease, all of these things, which is on label. So yeah, if I can get this patient on label access to medicine to, to help, even if we’re only addressing the metabolic issues, the cardiovascular concerns, that in and of itself is doing a great job. But, and then if they get these halo benefits and you know what, their mood improves or their MADRS scores get better or whatever, you know, whatever metric you’re using, that’s just great. And so, yeah, we get to keep the baby and the bathwater, I think, when, when, when this happens. 

So, all right, so we’ve talked through a lot of different things. One thing that I like to think through for patients is this has been efficacy, efficacy, efficacy, where there’s promise. You know, if you’ve got a patient that you’re thinking, okay, this is, let’s say it’s on label, you know, “You’re, you, you know, you’ve already got metabolic syndrome, you know, you’re, you’re probably three, four months away from diabetes. I think this is a good option for you to be on one of these GLP-1s,” what sort of, you know, safety things do you think through or the drug-drug interactions and then, and then patient counseling. Because I think sometimes we’re so short on time. The way that healthcare is practiced now, you know, we don’t have the time with the patients we want. So that patient counseling part I think is so important. So what are you, what are you thinking about as a prescriber and someone who’s going to counsel the patient on this is why I think this medicine is good for you.

53:10 – Safety Risks and Drug Interactions Psychiatrists Must Consider

Dr. Roger S. McIntyre: Yeah, this is such a critical part. I think we all know that GLP-1 agents do have side effects. And some of these side effects have become sort of almost front page of newspaper kind of talked about people who know them in terms of aspects around, for example, constipation. So maybe what I’ll do, rather than going through all the side effects, maybe it’s just sort of tailor it to the psychiatric ecosystem. In other words, in psychiatry we often prescribe drugs that can be quite constipating. And it turns out that a lot of these drugs that are quite constipating are also weight-gain promoting. So for example, I mentioned clozapine as an example earlier. Others like olanzapine, a few other drugs that we have, and again, there’s a long list. These drugs can be constipating. So when you add a GLP-1 type drug to that, you could in fact see maybe some additive constipation effects. By the way, I should mention this is not a contraindication, it’s just something to be aware of.

Related but different to that is many people who take GLP-1s are not consuming as much. That’s what we desire, including water. Now again, be clear. GLP-1s don’t decrease your water desire, they don’t decrease your thirst. But often people, most people don’t drink enough water and certainly now some psychiatric patients drink more water than they should. That’s more of a part of the illness where people consume too much water. But that’s, that’s not as common as the other direction in the sense that if you’re taking for example, a drug like lithium – a drug like lithium where levels in the blood are measured and there is a fairly narrow index that that level should be in or you can get into some tolerability and safety problems – if you’re someone who’s not drinking adequate water and you’re dehydrating yourself because you’re not drinking as much and you’re urinating a fair bit on lithium, you could get yourself in a bit of an issue there. So that’s something just again to be aware of.

Thirdly is you mentioned about drug-drug interactions. For now, these are, these are drugs that are mimicking the protein. They’re not known to inhibit or induce cytochrome P450 phase 1 enzymes or phase 2 conjugation enzymes. So we don’t anticipate that they’re going to instigate any type of drug interaction, at least in that sense. But a good question’s been raised: If you’re slowing the gut motility, what impact does that have on the famous ADME of pharmacokinetics? ADME meaning absorption, distribution, metabolism, elimination. If the drug is being exposed to the epithelium of the bowel for a longer period of time, will that not affect the concentration? And the answer is: Great question. I don’t think we really know. We don’t really know what the effect is vis-a-vis on the pharmacokinetic of the co-administered psychiatric drug in that regard. So that’s kind of a known unknown at this point in time.

Third issue is many might be aware of the fact that about 40% of the weight loss on GLP-1s is actually muscle. It’s lean muscle. And that’s a whole story in itself. And there’s been an interest now in trying to identify newer GLP-1s that are conjugated to other proteins that protect the muscle. I should make the point clear though, that GLP-1s are not known to be myotoxic. In fact, they may be myoprotective. People say, “Really? Then why are they losing muscle?” Well, because you’re losing weight. And if you- don’t forget, our muscles are there to keep us erect so we can stand up and walk against gravity. And so if you’re heavier, you need more muscle, if you’re lighter, you don’t need as much muscle. And so the weight loss, sorry, the muscle loss, not always, sometimes it exceeds, but it’s usually commensurate with the weight loss. If the muscle loss causes weakness, that’s called sarcopenia. And you can see this in someone’s grip strength. And this can be quite problematic for an older patient, for example, or someone who’s a bit more brittle. But I should mention if you’re someone who’s malnourished or someone who has substance use disorder, schizophrenia, bipolar, it has been reported rates of, higher rates of sarcopenia which are probably related to economics, nutrition aspects and so on, so forth. So just be aware of that. In other words, there could be an interaction with the sarcopenia risk.

There were some concerns about suicidality raised a few years back. Could these drugs be suicidogenic? And there were reports to health authorities and so on. And we’ve written extensively on this. We’ve done a lot of our own analysis on this. Our group and others around the world, most importantly the FDA, the European regulators, the UK regulators have all come out and said, “You know, there’s just no there there.” They don’t see causality. These are associations, but they’re not really causal. And just recently, the FDA even asked the sponsors to take suicidogenic effects out of their package insert. And I think that the conclusion was is that suicidality in someone taking a GLP-1 is more parsimoniously explained by the comorbidity of depression and other conditions. I might say- I certainly agree with that. That was our conclusion as well. But I’ve been in this area a long, long time. You can never rule out an idiosyncrasy. And I think one still needs to pay a little close attention to that.

Finally moving into this issue of ketamine. Now, again, most people are not taking ketamine, but many people take ketamine for depression, difficult to treat depression. It’s a very, very important treatment in our arsenal for that. And there are recommendations. If you’re on a GLP-1, you may want to hold the medication. Depends on which one you’re on for a day or two, depends on the one, because there’s an increased risk of aspiration if you go for deep sedation, anesthesia. And ketamine is an anesthetic. And so the anesthetists or people who are skilled in anesthesiology are fully aware that GLP-1s can increase aspiration risk. Again, that’s a very sort of more narrow audience, but nonetheless, I want to put that out there. 

And then finally, this is somewhat indirect, but it’s something important to highlight. We know that people who are economically insecure, precarious, are more likely to access these drugs through, online, through these compounders. And we did a study showing that people who use compounding pharmacies are more likely to overdose on it, not because they’re trying to hurt themselves, but because you have to titrate it yourself. And by the way, we don’t recommend using these online compounders. You don’t even know what you’re getting and the FDA strongly discourages it. And I see ads on television all the time for this. It’s very concerning. How that links into psychiatry is a bit more nonspecific. But I think it does play in because our patients tend to be more economically insecure and economically precarious. And I know firsthand, many of the patients I’ve encountered and so on have used online pharmacies to access these medications. So that’s more a function of the economics, in part literacy, but I think economics is a big part there for our psychiatric population.

Dr. Ben Everett: Yeah. And I think it just kind of gets to the access also because a lot of people, you know, they want these things but they can’t get it, you know, on their, their doctor won’t prescribe it or whatever. But that kind of begs the other question is, well, maybe you should listen to your doctor. And there’s probably a reason why your doctor doesn’t want to prescribe it at this point in time. And that’s kind of what I said at the beginning is it was talking about the ads and whatnot. I can’t believe there hasn’t been greater enforcement, interaction or action. I mean, I see the one now with Serena Williams talking about, you know, she got on one, you know, world-class athlete, she got on one to lose a little baby weight, you know, and the big, big spokesperson for one of them, I was like, “Oh wow, is that really the message we want to be sending?” 

But look, you’ve, you’ve covered so much different stuff today. Really want to, want to thank you. So we’ll, we’ll kind of move to close here. So, you know, I want to ask, where do you think the field is heading? So you know, you, you’ve mentioned a number of phase two, phase three studies going on. You know, is there, is there something you think is more exciting or more promising than others? You know, where do you think we’re going to be in five years if I have you back on? And we say, hey look, this is where we are now?

01:00:57 – The Future of Treatments in Psychiatry

Dr. Roger S. McIntyre: Yeah, I think where we’re looking now is, and I think this is in many ways the last five to seven years has kind of given us a kind of a forecast for the future. Back in 2019, in March, the FDA approved esketamine Spravato. That was the first glutamate-based treatment for depression. That was the first non-monoaminergic we’ve had in psychiatry to treat depression. And in many ways I kind of see that as the first chapter in not just a new mechanism, but mechanistically informed therapeutics. We have other treatments like orexin modulators. You’ve seen the GABAergic drugs, you’ve seen the amyloid targeting therapeutics. I think in the next two to three years you’re going to be hearing a lot more about psychedelics and intermittent exposure to those types of drugs.

As it relates to our conversation and I think writ large the whole field, you’re hearing a lot, a lot more about different mechanisms. So the next three to five years, if we’re back in five years time, we’re going to say the last five years we’ve witnessed a lot of different mechanisms that are being target with drugs that are now available to us. Secondly, you’re going to see the drugs that are going to be approved and developed are drugs that are going to be informed by contemporary disease models that are not focusing on the almighty monoamines primarily, but are focusing on what you and I chatted about, aspects like metabolism, but there’s other mechanisms as well, like inflammation. And thirdly, I think you’re going to be hearing a lot more about treatments that may be taken intermittently or maybe they may not be taken every day. That certainly is a possibility as well. We already have that to some extent with neurostimulation and with glutamate like ketamine and esketamine. So I think you’re going to see new mechanisms, you’re going to see new paradigms of delivery and you’re going to see, I think I’d be surprised if in three to five years we don’t see at least something around this area of metabolism and its co-cousin, its cousin, inflammation getting over the wall as a potential treatment in psychiatry.

Dr. Ben Everett: Yeah, I agree with all that. I think psychedelics are very exciting, especially with this whole, hey, it might not be a daily oral that you have to take, but you’re going to come in and it’ll probably be patient specific. We don’t have enough data right now, but certainly the COMPASS long-term data looking at psilocybin for treatment-resistant depression seems- you know, a single dose of 25mg of synthetic psilocybin in a controlled setting certainly was durable for most patients with an effect size, you know, at least as good, but probably better than like SSRIs and that type of thing. And yeah, it’s just a different model from a daily oral. But yeah, I think, I think we’re really at the- well, I think about it this way, sort of, you know, if we go back to like 80s and 90s, maybe the golden age of sort of like cardiovascular medicine, cardiometabolics, with what we did with our ACE, you know, hypertension, we had all these different agents. And then I think we kind of started this century with neurology, all these new things for neurology. I think we’re really at the cusp with psychiatry, you know, really changing the paradigm. New classifications of drugs, new, you know, new new understandings of the underpinnings of disease and new ways to treat those diseases. So it’s been really good. 

So let me ask if you could just maybe summarize in one or two sentences. So almost like a sound bite. So if we were going to have an abstract for today’s talk that we were going to make like a 60-second reel or something like that, what would you say about GLP-1s and mental health right now in let’s say 60 to 90 seconds?

1:04:27 Summing Up GLP-1s and Mental Health

Dr. Roger S. McIntyre: In 60, 90 seconds, what I would say is that GLP-1s, without creative superlative, have the potential to transform the health span and the lifespan of people who are living with mental illnesses by targeting on-label considerations today and potentially targeting the underlying pathophysiology of the brain-based disorder tomorrow. So stay tuned.

Dr. Ben Everett: It’s really good, it’s like you’ve done this before. 

All right, well look, in closing, I really want to thank Dr. Roger McIntyre for joining me today. This has been a true pleasure for me. I’ve learned so much. I want to thank you again for joining us on The JCP Podcast. This has been a wonderful conversation. I know our listeners are really going to like this episode. I think there’s a lot of real clinical pearls here, basic science, translational science. So it’s kind of a little bit of everything for everybody. I really appreciate you taking the time, sharing your experiences and your expertise with GLP-1 receptor agonists. Been a real pleasure today. 

This has been The JCP Podcast, insightful, evidence-based, human-centered.