This transcript has been edited for clarity.
John Whyte, MD, MPH: Welcome, everyone. I'm Dr John Whyte, the chief medical officer at WebMD and Medscape. We spent a lot of time talking about glucagon-like peptide 1 receptor antagonists (GLP-1s) and obesity, especially as it relates to cardiovascular disease and metabolic disease. But what about its role in depression? Which is coming first: the depression treatment and then obesity, or the other way around?
To sort out what might be the role of obesity medications is Dr Roger McIntyre. He is a professor of psychiatry and pharmacology at the University of Toronto. Dr McIntyre, thanks for taking time today.
Roger S. McIntyre, MD: John, great to be with you and especially speaking on such an interesting topic.
Whyte: You cannot read medical news and not be seen about the latest in obesity treatment. When it comes to depression and even other mental health conditions, sometimes we see that the treatment causes obesity and then other times, we know people are depressed because they don't exercise, they don't eat healthy, don't go to the doctor. So how do you sort all this out, Dr McIntyre? How do you know what's the root cause of everything?
McIntyre: Such a great starting point, John. There's really been a confluence of study findings, and where they converge is on a fairly consistent finding that people who live with depression are much more likely to also have obesity. That's quite a statement because, as you know, the rate of obesity in the general population is already very high to begin with. What's important to underscore is that this relationship between depression and obesity is bidirectional; it goes both ways.
In other words, depression can lead to obesity, and obesity can lead to depression. In the case of depression leading to obesity, you touched on a couple of matters with respect to not being as active, perhaps being exposed to psychiatric drugs. But in addition, there's a biology of depression — that is, a biologic signature of depression that predisposes the phenotype of obesity. There's a number of conspirators here that are increasing the likelihood of obesity and depression.
Whyte: You recently sent me an article that you were involved with, a study about this phenotyping as it relates to depression and obesity. What else did you find?
McIntyre: What's interesting is that we have found that people who have obesity and depression, when compared with people with depression and without obesity, are persons who more often tend to have what's called inflammatory balance. They tend to have elevation of markers in their blood that are an index of inflammation, acute phase reactants like high-sensitivity C-reactive protein (hsCRP) or increase in proinflammatory cytokines like interleukin 1.
Whyte: But to be fair, these are nonspecific in terms of what might be the source.
McIntyre: Absolutely. Also a nonspecific probability is higher; you'll see more impaired insulin signaling in this group. Here's the part that really grabbed my attention: Everyone knows that people who live with depression struggle with their cognitive functions as well as with what we call anhedonia or hedonic tone.
If someone has obesity and depression, the extent of those cognitive difficulties, the extent of the impairment in hedonic tone or reward function, is even greater. Therein is why we think there's something overlapping not just neurobiologically but also phenotypically.
Whyte: As we think about the management of obesity and some of the latest medications, such as the GLP-1s, depression doesn't factor into most decisions around treatment right now as it relates to what medications we should use for the treatment of obesity. How should we be thinking about the latest therapies as we think about this confluence of obesity and depression? Roger, what needs to change?
McIntyre: What fundamentally needs to change is still what appears to be an attitude that obesity is something other than a chronic disease. It is a chronic disease. Second, I think most people, when put on the spot during a pop quiz — What are the medical complications of obesity? — are going to list some of the familiar ones, such as some forms of cancer, cardiovascular disease, diabetes, and others.
What people should be really contemplating is brain health and disease. In other words, we know that the brain, which is about 3%-5% of our total body weight, consumes about 25% of our total body energy. Well, guess what? The brain is especially susceptible to changes in energy, and we know that energy or metabolism is affected by obesity.
That's why I coined a phrase in an article I wrote a few years ago, "the metastasis of obesity to the brain." Obesity threatens brain health, increasing the risk for a variety of conditions. We're focusing on depression.
Whyte: You say that biologically, it's about energy consumption, but what else is it? A change in biomarkers? If they're not the things we're thinking about obesity in terms of leptin and ghrelin and others, is it cortisol? What are we seeing?
McIntyre: There's about a half a dozen of what we call effectors. You've named a few, including the appetitive proteins. We also think about one of the most important trophic proteins in the brain, which is insulin. When that's impaired in its ability to affect the brain, as so often accompanies obesity, that not only takes away the trophic support from the brain but also sets in motion a molecular cascade that results in the increased deposition of very unwanted proteins like amyloid and phosphorylated tau.
Whyte: As physicians, we don't typically think though about insulin in the brain, do we? We think about it in the pancreas. We think about it in glucose management. But you bring up an important point, which many of us haven't thought about in our training.
McIntyre: This was a light-bulb moment for me when I started my career, but what was revealing is that, as you mentioned, we know insulin's role in peripheral metabolism. It's a brain-trophic factor, it's a brain-protective factor, and it's also an antiapoptotic. It keeps our cells alive and reduces premature cell death. Now, the prevailing view in psychiatry today across just about every psychiatric disorder is that there's a problem with what's called neuroplasticity.
In neuroplasticity, there is a replicated finding in conditions of stress. Guess what? Insulin actually is critical to plasticity. This light-bulb moment not only got us thinking about insulin but maybe about insulin sensitizers or related drugs, like GLP-1 agonists, and whether they could benefit the brain — and more specifically, improve aspects of symptoms in people living with mental illness.
Whyte: What do we need to be doing in educating our clinical colleagues about the management of depression and obesity — not as separate diseases per se, but how they're correlated?
McIntyre: It really begins with education on the cross-talk of metabolism and the brain. If anything, what the obesity pandemic and the diabetes pandemic has created is tremendous interest in neuroscience because of the hazards posed by metabolism in the brain.
Second, I think all clinicians providing care to people living with obesity are fully aware of the metabolic comorbidities, but I think they also need to be reminded that these persons are at risk for mental illness — not just depression but other conditions, like cognitive impairment. They can become a major cognitive impairment, like dementia and so on. Also, quite frankly, we need to be thinking about other conditions in psychiatry that associate with obesity: Attention-deficit/hyperactivity disorder and binge-eating disorder are a couple, as are many others.
One final comment is that in research, I think clinicians are hearing more and more that some drugs, like GLP-1 receptor agonists, are helpful not only for glucose and weight management but also for other conditions, like fatty liver, nonalcoholic steatohepatitis. But now, in the research world, we're beginning to see some early signs that GLP-1 receptor agonists may have benefit in treating a wide range of conditions: Depression, Parkinson's, Alzheimer's, traumatic brain injury, stroke, and alcohol use disorder are all under study as potential mental illnesses to be benefited by GLP-1s.
Whyte: But you're looking at it from a different pharmacologic perspective as opposed to necessarily the impact on mood. You might be looking at energy balance or some other aspects. But I have to throw it out there that some people could argue that you're talking about the brain, but maybe it's really the gut.
McIntyre: Absolutely.
Whyte: You should be focusing more on the gut, proinflammatory, and then secondly on the brain, so to speak. Is that where the action may be as it relates to depression and obesity?
McIntyre: You know what I've landed on over the years? I've landed on that this crime called mental illness has many suspects in the suspect line. In your highlighting another suspect for us, I agree with you.
Whyte: You've been watching a lot of criminal shows!
McIntyre: I think this is certainly a crime where we've got a couple of people in the lineup who we can point to. Certainly, there's no question that there's a lot of interest now in the gut, the gut biota, the gut biome or so-called gut enterotype, and the diversity of the gut and its cross-talk with the brain directly through the nervous system, indirectly through metabolism inflammation.
That's why we're so excited about thinking about repurposing drugs that are better known in the world of metabolism or obesity as potential therapeutics. I always bring this point up: There are so many medications that are in psychiatry now that were originally designed for diabetes or weight loss — drugs including but not limited to memantine and topiramate. Many drugs in psychiatry have been cross-purposed into the world of diabetes or metabolism or weight-related problems.
We've had a convergence, if you will, of physiology and pharmacology between these two worlds for so long. I think that just now, we're becoming a little bit more contemplative about it.
Whyte: What practical advice would you leave our Medscape audience with, those practicing clinicians who are treating obesity, treating depression, addressing the issues of these new medications? What teaching point would you leave them with today?
McIntyre: The takeaway message for today is to close the implementation gap, the gap between our knowledge and what we actually do. What I mean by that is we know that people with depression and mood disorders are differentially affected by obesity and vice versa. We also know that most persons are not screened for the other condition if they have the other condition, so that has to start.
Second, I think that when we talk about these issues, it's not a fait accompli that because you have depression, you're going to become obese, or if you're obese then you can become depressed. There are preemptive strategies, there are prevention strategies; and that begins, of course, with treating the underlying condition according to the best available evidence. It also invites the need to speak to some of these nonpharmacologic approaches with respect to exercise, diet, and things like that.
What's important to keep in mind is that when we are thinking about treating people with psychiatric medication, there is an abundance of reasons why we should be prioritizing treatments that are not susceptible to weight increase and/or glucose disruption. I think that if we can just get that right, that start, I would call that the 1.0. We can get to the 2.0 recommendations another time, but let's close that implementation gap.
Whyte: We'll get to those next time. Dr McIntyre, I want to thank you for taking time today.
McIntyre: Great to be with you, John. Thanks for covering this topic. I've really enjoyed discussing this with you.
This video originally appeared on WebMD on April 16, 2024
COMMENTARY
Brain & Body: Connecting Depression and Obesity
John Whyte, MD, MPH; Roger S. McIntyre, MD, FRCPC
DISCLOSURES
| April 16, 2024This transcript has been edited for clarity.
John Whyte, MD, MPH: Welcome, everyone. I'm Dr John Whyte, the chief medical officer at WebMD and Medscape. We spent a lot of time talking about glucagon-like peptide 1 receptor antagonists (GLP-1s) and obesity, especially as it relates to cardiovascular disease and metabolic disease. But what about its role in depression? Which is coming first: the depression treatment and then obesity, or the other way around?
To sort out what might be the role of obesity medications is Dr Roger McIntyre. He is a professor of psychiatry and pharmacology at the University of Toronto. Dr McIntyre, thanks for taking time today.
Roger S. McIntyre, MD: John, great to be with you and especially speaking on such an interesting topic.
Whyte: You cannot read medical news and not be seen about the latest in obesity treatment. When it comes to depression and even other mental health conditions, sometimes we see that the treatment causes obesity and then other times, we know people are depressed because they don't exercise, they don't eat healthy, don't go to the doctor. So how do you sort all this out, Dr McIntyre? How do you know what's the root cause of everything?
McIntyre: Such a great starting point, John. There's really been a confluence of study findings, and where they converge is on a fairly consistent finding that people who live with depression are much more likely to also have obesity. That's quite a statement because, as you know, the rate of obesity in the general population is already very high to begin with. What's important to underscore is that this relationship between depression and obesity is bidirectional; it goes both ways.
In other words, depression can lead to obesity, and obesity can lead to depression. In the case of depression leading to obesity, you touched on a couple of matters with respect to not being as active, perhaps being exposed to psychiatric drugs. But in addition, there's a biology of depression — that is, a biologic signature of depression that predisposes the phenotype of obesity. There's a number of conspirators here that are increasing the likelihood of obesity and depression.
Whyte: You recently sent me an article that you were involved with, a study about this phenotyping as it relates to depression and obesity. What else did you find?
McIntyre: What's interesting is that we have found that people who have obesity and depression, when compared with people with depression and without obesity, are persons who more often tend to have what's called inflammatory balance. They tend to have elevation of markers in their blood that are an index of inflammation, acute phase reactants like high-sensitivity C-reactive protein (hsCRP) or increase in proinflammatory cytokines like interleukin 1.
Whyte: But to be fair, these are nonspecific in terms of what might be the source.
McIntyre: Absolutely. Also a nonspecific probability is higher; you'll see more impaired insulin signaling in this group. Here's the part that really grabbed my attention: Everyone knows that people who live with depression struggle with their cognitive functions as well as with what we call anhedonia or hedonic tone.
If someone has obesity and depression, the extent of those cognitive difficulties, the extent of the impairment in hedonic tone or reward function, is even greater. Therein is why we think there's something overlapping not just neurobiologically but also phenotypically.
Whyte: As we think about the management of obesity and some of the latest medications, such as the GLP-1s, depression doesn't factor into most decisions around treatment right now as it relates to what medications we should use for the treatment of obesity. How should we be thinking about the latest therapies as we think about this confluence of obesity and depression? Roger, what needs to change?
McIntyre: What fundamentally needs to change is still what appears to be an attitude that obesity is something other than a chronic disease. It is a chronic disease. Second, I think most people, when put on the spot during a pop quiz — What are the medical complications of obesity? — are going to list some of the familiar ones, such as some forms of cancer, cardiovascular disease, diabetes, and others.
What people should be really contemplating is brain health and disease. In other words, we know that the brain, which is about 3%-5% of our total body weight, consumes about 25% of our total body energy. Well, guess what? The brain is especially susceptible to changes in energy, and we know that energy or metabolism is affected by obesity.
That's why I coined a phrase in an article I wrote a few years ago, "the metastasis of obesity to the brain." Obesity threatens brain health, increasing the risk for a variety of conditions. We're focusing on depression.
Whyte: You say that biologically, it's about energy consumption, but what else is it? A change in biomarkers? If they're not the things we're thinking about obesity in terms of leptin and ghrelin and others, is it cortisol? What are we seeing?
McIntyre: There's about a half a dozen of what we call effectors. You've named a few, including the appetitive proteins. We also think about one of the most important trophic proteins in the brain, which is insulin. When that's impaired in its ability to affect the brain, as so often accompanies obesity, that not only takes away the trophic support from the brain but also sets in motion a molecular cascade that results in the increased deposition of very unwanted proteins like amyloid and phosphorylated tau.
Whyte: As physicians, we don't typically think though about insulin in the brain, do we? We think about it in the pancreas. We think about it in glucose management. But you bring up an important point, which many of us haven't thought about in our training.
McIntyre: This was a light-bulb moment for me when I started my career, but what was revealing is that, as you mentioned, we know insulin's role in peripheral metabolism. It's a brain-trophic factor, it's a brain-protective factor, and it's also an antiapoptotic. It keeps our cells alive and reduces premature cell death. Now, the prevailing view in psychiatry today across just about every psychiatric disorder is that there's a problem with what's called neuroplasticity.
In neuroplasticity, there is a replicated finding in conditions of stress. Guess what? Insulin actually is critical to plasticity. This light-bulb moment not only got us thinking about insulin but maybe about insulin sensitizers or related drugs, like GLP-1 agonists, and whether they could benefit the brain — and more specifically, improve aspects of symptoms in people living with mental illness.
Whyte: What do we need to be doing in educating our clinical colleagues about the management of depression and obesity — not as separate diseases per se, but how they're correlated?
McIntyre: It really begins with education on the cross-talk of metabolism and the brain. If anything, what the obesity pandemic and the diabetes pandemic has created is tremendous interest in neuroscience because of the hazards posed by metabolism in the brain.
Second, I think all clinicians providing care to people living with obesity are fully aware of the metabolic comorbidities, but I think they also need to be reminded that these persons are at risk for mental illness — not just depression but other conditions, like cognitive impairment. They can become a major cognitive impairment, like dementia and so on. Also, quite frankly, we need to be thinking about other conditions in psychiatry that associate with obesity: Attention-deficit/hyperactivity disorder and binge-eating disorder are a couple, as are many others.
One final comment is that in research, I think clinicians are hearing more and more that some drugs, like GLP-1 receptor agonists, are helpful not only for glucose and weight management but also for other conditions, like fatty liver, nonalcoholic steatohepatitis. But now, in the research world, we're beginning to see some early signs that GLP-1 receptor agonists may have benefit in treating a wide range of conditions: Depression, Parkinson's, Alzheimer's, traumatic brain injury, stroke, and alcohol use disorder are all under study as potential mental illnesses to be benefited by GLP-1s.
Whyte: But you're looking at it from a different pharmacologic perspective as opposed to necessarily the impact on mood. You might be looking at energy balance or some other aspects. But I have to throw it out there that some people could argue that you're talking about the brain, but maybe it's really the gut.
McIntyre: Absolutely.
Whyte: You should be focusing more on the gut, proinflammatory, and then secondly on the brain, so to speak. Is that where the action may be as it relates to depression and obesity?
McIntyre: You know what I've landed on over the years? I've landed on that this crime called mental illness has many suspects in the suspect line. In your highlighting another suspect for us, I agree with you.
Whyte: You've been watching a lot of criminal shows!
McIntyre: I think this is certainly a crime where we've got a couple of people in the lineup who we can point to. Certainly, there's no question that there's a lot of interest now in the gut, the gut biota, the gut biome or so-called gut enterotype, and the diversity of the gut and its cross-talk with the brain directly through the nervous system, indirectly through metabolism inflammation.
That's why we're so excited about thinking about repurposing drugs that are better known in the world of metabolism or obesity as potential therapeutics. I always bring this point up: There are so many medications that are in psychiatry now that were originally designed for diabetes or weight loss — drugs including but not limited to memantine and topiramate. Many drugs in psychiatry have been cross-purposed into the world of diabetes or metabolism or weight-related problems.
We've had a convergence, if you will, of physiology and pharmacology between these two worlds for so long. I think that just now, we're becoming a little bit more contemplative about it.
Whyte: What practical advice would you leave our Medscape audience with, those practicing clinicians who are treating obesity, treating depression, addressing the issues of these new medications? What teaching point would you leave them with today?
McIntyre: The takeaway message for today is to close the implementation gap, the gap between our knowledge and what we actually do. What I mean by that is we know that people with depression and mood disorders are differentially affected by obesity and vice versa. We also know that most persons are not screened for the other condition if they have the other condition, so that has to start.
Second, I think that when we talk about these issues, it's not a fait accompli that because you have depression, you're going to become obese, or if you're obese then you can become depressed. There are preemptive strategies, there are prevention strategies; and that begins, of course, with treating the underlying condition according to the best available evidence. It also invites the need to speak to some of these nonpharmacologic approaches with respect to exercise, diet, and things like that.
What's important to keep in mind is that when we are thinking about treating people with psychiatric medication, there is an abundance of reasons why we should be prioritizing treatments that are not susceptible to weight increase and/or glucose disruption. I think that if we can just get that right, that start, I would call that the 1.0. We can get to the 2.0 recommendations another time, but let's close that implementation gap.
Whyte: We'll get to those next time. Dr McIntyre, I want to thank you for taking time today.
McIntyre: Great to be with you, John. Thanks for covering this topic. I've really enjoyed discussing this with you.
This video originally appeared on WebMD on April 16, 2024
Any views expressed above are the author's own and do not necessarily reflect the views of WebMD or Medscape.
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