Brain & Body: Connecting Depression and Obesity

[MUSIC PLAYING] Welcome, everyone. I'm Dr. John Whyte, the Chief Medical Officer at WebMD and Medscape. We spent a lot of time talking about GLP-1s and obesity, especially as it relates to cardiovascular disease, 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 all this out as what might be the role of obesity medications is Dr. Roger McIntyre. He is professor of psychiatry and pharmacology at the University of Toronto. Dr. McIntyre thanks for taking time today.

John, great to be with you and especially speaking to such an interesting topic.

You cannot read medical news and not be seen about the latest in obesity treatment. And when it comes to depression and even other mental health conditions, sometimes we see that the treatment causes obesity and then other times when we know people are depressed 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?

ROGER MCINTYRE: Such a great starting point John and you know there's been really 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 be obese. And that's quite a statement because as you know John the rate of obesity in the general population is already very high to begin with. And 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 biological signature of depression that predisposes the phenotype of obesity. So there's a number of conspirators here that are increasing the likelihood of obesity and depression.

And you recently sent me an article that you've been involved with, a study about this phenotyping as it relates to depression and obesity. What else did you find?

What's interesting is that what we have found is that people who have obesity and depression when compared to people with depression and not obese are persons who tend to have what's called inflammatory balance more often. They tend to have elevation of markers in their blood that are an index of inflammation, acute phase reactants like hsCRP or increase in pro-inflammatory cytokines like interleukin-1.

But to be fair nonspecific, these are nonspecific in terms of what might be the source.

Absolutely and also a nonspecific probability is higher that you'll see more impaired insulin signaling in this group. Here's the part though that for me really in fact grabbed my attention John, everyone knows that people who live with depression struggle with their cognitive functions as well as struggle 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.

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?

I think what fundamentally needs to change John is still what appears to be an attitude that obesity is something other than a chronic disease, it is a chronic disease. Secondly, I think most people when put on the spot during a pop quiz, what are the medical complications of obesity? They're going to list some of the familiar 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 maybe 3% to 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.

Biologically why you say 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 like leptin and ghrelin and others, is it cortisol? What are we seeing?

There's about a half a dozen 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 that being 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 in fact sets in motion a molecular cascade that results in the increased deposition of very unwanted proteins like amyloid and phosphorylated tau.

As physicians though 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 an important point up here which many of us haven't thought about in our training.

This was a light bulb moment for me John when I started my career but what was in fact revealing is that insulin, of course, as you mentioned we know its role in peripheral metabolism it's a brain trophic factor, it's a brain protective factor, and also it's an antiapoptotic. It keeps our cells alive, it reduces premature cell death. Now the prevailing view in psychiatry today across just about every psychiatric disorder, there's a problem with what's called neuroplasticity.

In neuroplasticity 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 maybe insulin but maybe insulin sensitizers or maybe related drugs like GLP-1 agonists could benefit the brain and more specifically improve aspects of symptoms in people living with mental illness.

So 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?

ROGER MCINTYRE: Yeah, absolutely. I think it really begins with education on the cross talk of metabolism and the brain. And if anything what the obesity pandemic, the diabetes pandemic has created is tremendous interest in neuroscience because of the hazards posed by metabolism in the brain.

Secondly, 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 these persons are at risk of mental illness, not just depression but other conditions like cognitive impairment. They can become a major cognitive impairment like dementia and so on. I think also quite frankly, John, we need to be thinking about other conditions in psychiatry that associate with obesity, ADHD, binge eating disorder are a couple as many others.

One final comment would be is that of course is the charge for us in research is 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 we're now in the research world beginning to see some early signs that GLP-1 receptor agonists may have benefit in treating conditions wide ranging, 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.

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, some other aspects. But then I have to throw out Roger maybe some people could argue you're talking about the brain but maybe it's really the gut.

Absolutely.

And you should be focusing more on the gut, pro-inflammatory, the second brain so to speak, is that where the action is maybe as it relates to depression and obesity?

You know what I've landed on John 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. I think that there have been--

You've been watching a lot of criminal shows. [LAUGHTER]

I think this is certainly a crime that we've got a couple of people in that lineup that 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 John, there's so many medications that are in psychiatry now that were originally designed for diabetes or weight loss, drugs including but not limited to memantine, topiramate, there's a couple of examples. And many drugs in psychiatry have been cross purposed into the world of diabetes or metabolism or weight related problems.

So we've had a convergence if you will of physiology and pharmacology between these two worlds for so long. I think just now we're becoming a little bit more contemplative about it.

So what practical advice would you leave our Medscape audience with, those practicing clinicians that are treating obesity, treating depression, addressing the issues of these new medications, but what would you leave them with today is the teaching point?

I think the takeaway message for today John is to close the implementation gap, the gap between our knowledge and the gap of 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.

Secondly I think when we talk about these issues, it's not a fait accompli because you have depression, you're going to become obese or if you're obese, you can become depression. There are preemptive strategies, there's 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.

But I also think what's important to keep in mind is that when we are thinking about treating people with psychiatric medication, abundance of reason 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.

We'll get to those next time. Dr. McIntyre, I want to thank you for taking time today.

Great to be with you John, thanks for covering this topic. I've really enjoyed discussing this with you.

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