- [Jeff] Welcome to Healthy Minds.

I'm Dr. Jeff Borenstein.

Everyone is touched by psychiatric conditions, either themselves or a loved one.

Do not suffer in silence.

With help, there is hope.

(inspirational music) Today on Healthy Minds.

- We believe that the causes of depression, bipolar, obesity, and diabetes are overlapping.

We are trying to identify what causes depression and more narrowly what causes the symptoms.

There's a brain-body communication here.

- That's today on Healthy Minds.

This program is brought to you in part by the American Psychiatric Association Foundation and the John & Polly Sparks Foundation.

Welcome to Healthy Minds.

I'm Dr. Jeff Borenstein.

We're all concerned about the increased incidence of psychiatric conditions in our population.

We're also concerned about the increase in obesity and diabetes.

Is it possible that these trends are related?

And if so, what can be done?

Today, I speak with leading researcher, Dr. Roger McIntyre, about potential new approaches to treating depression, bipolar, and other psychiatric conditions.

Roger, thank you for joining us today.

- Jeff, it's wonderful to be with you to have this discussion.

- I want to jump right into the discussion and speak with you about what many people refer to as a mental health crisis around the world and also an obesity and diabetes crisis around the world, and how perhaps there may be a relationship between these.

- Jeff, you've summarized it nicely in the question, and that alone just is startling.

We are witnessing more than one crisis, a mental health crisis and obesity epidemic around the world.

This is not coincidence, this is happening because both mental health-related problems like depression and obesity, they don't lend themselves to a simple explanation as to what's causing this.

But what we do know is, is that there are many identified reasons why people might end up with depression or obesity that are in common.

For example, especially since the pandemic, we've seen an amplification around the world of people reporting themselves as being socially isolated and being lonely.

Secondly, we are hearing about people talking about how stressful it for them financially.

In fact, reports of financial insecurity have taken off the last five to seven years.

And thirdly, people talk about how difficult it is for them to predict the future.

They talk about a dire view.

We hear surveys that people are very unhappy and very mistrustful of the situation they're in with respect to their government, with respect to their current life situation.

Jeff, this is a combustible mix.

Loneliness as well as financial insecurity and just general insecurity with the future increase the likelihood someone may have a mental illness like depression, as well as obesity, triggering a whole set of biological changes that result in people having more depression and obesity now than they had say 10 to 20 years ago.

- I want to get into some of the details of the mechanism and start off by you speaking about the role of insulin in obesity, diabetes, and potentially in a number of psychiatric conditions.

- It's such an interesting story, Jeff.

I'm a psychiatrist, as you know.

I'm an academic, I'm a researcher, and I would never have guessed that my research would've taken me in this direction looking at insulin as a potential explanation not only for metabolic problems like diabetes mellitus and obesity, but also mental illness like depression.

Most of us are familiar with insulin and what it does.

Insulin is a protein.

It's a protein produced by our body, a place called the pancreas, and most are aware that it's relevant to controlling our sugar levels of what we call glucose.

That's well described.

And in fact, the very first person in the world who ever received insulin to treat their diabetes was back in 1923 in Toronto, the University of Toronto.

And since then, there's been insulin treatments to help people who are struggling with diabetes and related metabolic problems.

Then what happened, Jeff, is something really interesting.

A discovery was made in the labs that insulin is not only a critical protein for you and I and everyone to have proper sugar control, but it's also playing a key role in allowing our brain cells, which we call neurons, to function normally.

In fact, they're critical for our brain cells to function normally.

And when we look at this in what we call animal models or look at this in the scientific lab or we look at this in people living with diabetes, what we find is that the brain structure and function begins to change.

So taken together, Jeff, what we've learned is, is that our brain cells are obviously critical to our living and our function, and brain cells are really under threat in people who have mental illness like depression or PTSD or schizophrenia.

And we've learned that one of the critical reasons why those neurons are not as strong, not as robust, have a shorter lifespan is because there's something wrong with insulin signaling in the human brain.

- You noticed this or took note of it early on in your training as a psychiatrist, and I'd like you to share that experience and then how that led to the work that you've done throughout your career.

- I started my career with a view that I really wanted to better understand how I could improve the lives of people living with depression or bipolar disorder.

And very soon after I started my career, one of those questions that really came to mind was interacting with people who have lived experience of depression or bipolar.

I was always curious, Jeff, why is it people who live with depressive disorders or bipolar disorders, why do they report so much more difficulty in their ability to think?

They would always tell me, "My brain's foggy.

I can't focus, I'm so distracted."

Or they would tell me that they just didn't have much motivation, enough energy, enough interest.

So a combination of having what we call cognitive problems, in other words, the ability to think, as well as motivational problems were much more common in people that I would provide care for who had either type two diabetes and/or had obesity.

And at the time, we didn't really think about this.

This was not a focus in the field.

As you know, Jeff, we've had a crush, we've been worshiping at the altar of serotonin and psychiatry for so long, and that was the paradigm for so many decades that mental illness was something wrong with serotonin and related neurotransmitters.

And we didn't think about at the time that maybe what the patient's reporting is something insightful about what's happening in the brain.

And so what happened was we began to look at this and we did a number of tests in the lab and we discovered what in fact patients were telling us.

And that is is that when they have diabetes or when they have obesity, often both, their performance on cognitive testing, that is the ability to pay attention, memory, organized themselves, as well as measures of how motivated they are were greatly reduced.

Then what we did is we looked at their brain.

Now I often say CNN, Jeff, CNN, circuits, nodes, and networks, the brain is comprised of these circuits and networks that are connected by nodes.

Our brain is a lot like a motherboard on a PC.

In other words, all these circuits and networks all delicately inter-playing with each other.

What we then found was interesting is that people who had diabetes or had obesity or both, the degree of abnormality in how these circuits and networks were connecting was even more pronounced.

Now, to be clear, let's say you have depression.

We now know that people who live with depression have something wrong with CNN, the circuits, the networks, the nodes.

But if you have obesity and/or diabetes or both, the alteration, the abnormality is even worse, especially in those regions of the brain that you and I depend on to think clearly, to plan, to be motivated to enjoy what we do.

So we thought, wow, maybe there's something going on here.

So I coined this phrase, Jeff, called obesity and diabetes metastasizes to your brain.

We really think there's a brain-body communication here.

And some might be saying, "Well, what's all this possibility?

He's obviously an academic, lots of time on his hands.

What's the output of all this?"

Well, the output, and what we hope for, we are trying to identify what causes depression and more narrowly what causes the symptoms like low mood or loss of interest or the inability to think clearly.

These are the cardinal features, the debilitating features of depression.

And if it's the case that people who have diabetes, obesity, or both have even worse problems there, that may give us a little hint as to what the mechanism could be.

And a convergent mechanism, in other words, a mechanism that kind of brings a lot of these threads together, is insulin.

And that provided the basis for us to say let's test how resistant the brain is to insulin.

Maybe we should be treating mental illness with therapeutics that target insulin.

- I think that, first of all, that was an excellent explanation on a complicated issue.

And I want to get back to something that you've made reference to, which is the significant percentage of people who have bipolar disorder that also are experiencing diabetes or pre-diabetes, that association.

Could you speak a little bit about that in this context?

- This is such a critical part to the conversation because initially when the field began to look at this, I don't think we had a sense of how often people living with depression or bipolar are affected by the conditions you mentioned.

And just to be clear and to keep it, I think just to summarize the worldwide literature on this, it's been highly replicated.

Up to half of people living with depression or living with bipolar disorder either have obesity or have type two diabetes.

These often march in the same direction.

They go together.

Relatedly, people have problems with too much fat in the liver, which we call fatty liver disease.

And these are all examples of something's wrong with metabolism.

Now, generally speaking, when you find in medicine or life in general two occasions occurring at the same time, in this case a mental illness and a so-called physical problem like diabetes and obesity, we start scratching our head.

We have a light bulb moment.

We say, are these kind of related?

This is happening more often than by chance.

And when I started my career, what I was told and what the working idea was is this is just all a side effect of the medication.

Unfortunately, many of our medications can cause weight gain and could adversely affect some of these metabolic parameters we're talking about.

But that wasn't able to explain the whole story.

In fact, many people take medications that don't cause much weight gain or metabolic problems, and this was still the case.

So we looked under the hood, so to speak, just like looking under the hood of your car, and we wanted to look at this more carefully and we had no idea that even if you're a lean mean Olympic athlete and you have depression or bipolar disorder, we can see changes in your blood that indicate to us there's something wrong with metabolism.

So I think most people know that diabetes is a problem with insulin and glucose.

I don't think it's as well known that the brain, 5% of our total body weight is our brain, but it consumes about 25% of our overall sugar.

So any problem in glucose or sugar availability or insulin availability, "aha!

", might affect the brain.

So this is something interesting and we've come to learn now and, you know, going forward, our science has changed so much, we believe that the causes of depression, bipolar, obesity, and diabetes are overlapping.

Yes, this begins with some of the comments I made earlier.

Some of what we call social factors like social connectedness, access to healthcare, economics.

But more narrowly, if we look at the biology, we now believe that many people end up with depression or end up with bipolar, not everybody, but many people because there's something wrong with metabolism in their brain or there's something wrong with related aspects, which we call inflammation.

And many people who have obesity or diabetes also show a higher rate of inflammatory problems like arthritis or bowel disease, migraine, thyroid disease.

And this all occurs more common in depression and bipolar.

So in short, we now know up the half of people have this, it itself obviously has its own problems with respect to impacting their lives, the quality of their lives, their function.

But what really grabbed me as an academic was interestingly, if they have that additional problem, they had more pronounced difficulties with their mood, more pronounced difficulties with their motivation and interest and as well their overall focus.

And to put that in context, if we look across the world, the number one reason around the world, people are living with a medical problem that they're not living a healthy life, in other words, years of healthy life lost as the World Health Organization calls it is because of depression.

Yes, it begins early in life, then people start having these other problems.

So that has impact for that person.

But for me, I'm also thinking not only as a busy clinician, but I'm thinking, can this give us some insight?

Maybe we should be thinking an additional way of treating.

Here's the thing I find so interesting, Jeff.

When people go and they have treatment for their obesity, whether it's diet or exercise, surgery, maybe medication, in the world of diabetes, there's a whole dropdown menu of approaches to treat diabetes.

It turns out that those interventions also benefit brain health.

People feel better, their mind is more clear, able to focus more and able to function better.

So this is what we call translational research, which really just means we kind of trespass in one area like diabetes and obesity and we're trespassing to learn new ideas and we bring this over to psychiatry.

And it's just incredible how it's changing how we think about new therapeutic approaches to mental illness.

- One of the ways that we develop new therapeutic approaches, maybe developing an entirely new medicine, but another way is repurposing medicines that are already in use.

And I'd like you to speak towards that.

- Yeah, absolutely.

And you know, it's interesting and I appreciate that not everyone is reading around the medications and psychiatry on a daily basis, but what's really interesting is called, you know, the street light effect.

Where's the street light shining?

And Jeff, you know this, that for psychiatry, we have been focusing on neurotransmitters, which are chemicals in your brain like serotonin and dopamine and norepinephrine.

These are three amigos, as I call them.

They're very well known neurotransmitters and many people have heard of these and these are common targets of many of our medications we prescribe.

Now, I would love to say that there's just a simple explanation to mental illness, but there's not.

We have many different causes and we also have many different portals of entry, so to speak, to try and treat it.

Historically, we've really focused on those three amigos, serotonin, norepinephrine, dopamine.

But there's other ways we can think about this and we can repurpose.

And what's interesting is, is that if we take the street light and we shine it just to the left or to the right, so to speak, we find out that well-known medications like Prozac, fluoxetine, well everyone knows Prozac, that's a medication that affects insulin signaling in the body.

Isn't that interesting?

Other medications like lithium, everyone's heard of lithium.

Some of our other drugs that we use for anxiety or to treat schizophrenia, I can keep going.

Every time we look at a psychiatric medication for this indication, for that indication, we find out that it also has effects on metabolism one way or the other.

So that then is another light bulb moment.

Maybe we can repurpose other medications into psychiatry, but now we have a new wave of therapeutics in diabetes and obesity.

Many people have heard of them called glucagon-like peptide one agonist.

It's almost become a phenomenon, Jeff, in the sense that people have heard these medications, semaglutide or liraglutide, these are drugs that are being talked about in the front page of the newspapers all around the world.

- We see commercials on TV all the time.

- Absolutely, of course, you have well-known superstar people in Hollywood and so on who talk about this.

That aside for a moment, what's really interesting, we discovered, just like insulin, we've discovered that these proteins that are being targeted for weight loss and diabetes, the protein is called glucagon-like peptide, GLP for short.

Well, you can take a pill for that to treat your diabetes and obesity, but guess what?

We have GLP-1 receptors in our brain exactly in the same region that controls our thinking, our thinking clarity, our motivation, our joy, our looking forward to things.

And that then in our lab, we said, Ooh, that's really interesting.

Can we repurpose these GLP-1 type drugs to treat mental illness in people who don't have obesity and diabetes?

If these treatments can affect the brain positively, that's obviously wonderful.

They also have been shown to reduce weight and metabolic problems.

And of course, that's more common in people living with depression and so on.

So that's something like a two for one, we'll take that.

But for now, we're just trying to determine is it safe, is it effective in treating mental illness?

Studies are ongoing.

- Right now, somebody's watching and they may be experiencing depression, bipolar disorder They may be in treatment and doing well or not as well as we would wish.

Are there lifestyle types of steps that a person can take that can at least push it in the right direction with regards to some of these issues?

- Categorically, yes.

And until the research informs the next pathway for us, there are activities that we can do that are implementable, that are inexpensive, that can make a difference that's relevant, not difference in terms of, you know, academic studies, but really make a difference to people's lives.

For example, what I have noticed, and this has been abundantly supported in our scientific literature, is that lifestyle aspects, whether that mean sleep, whether that means activity, being some type of activity, and diet clearly has been shown to have benefits, of course when they're on the, you know, when you're using a more health promoting way of doing this, on people's mental health.

Now, I appreciate that exercise is a very difficult pill to swallow, I understand that, but we don't need to become Olympic athletes.

That's not what we need to be, just some type of activity.

So remarkable the effect it has in the near term on wellbeing, focus, motivation, and interest.

The diet piece is really interesting.

People often ask me, what about a ketogenic diet, a Mediterranean diet, this diet, that diet, all interesting, we need to study them more.

Let's just have a healthy diet.

Let's start with that.

And that's been shown to improve mood just by correcting diet 'cause the literature shows that too often people with depression and bipolar, even more than the general population, have a unhealthy diet.

Someone's going to say, well hang on, it's pretty expensive to eat healthy.

It's easier to buy a very inexpensive taco or a burger.

I got it.

These are the economics.

People often live in what we call food deserts.

They're not close to healthy food and it's expensive.

I understand that.

But that's clearly an issue that we need to really emphasize.

Other things too, Jeff, sleep.

I mean my goodness, sleep is not just a symptom when it's impaired and so on, but when you're not getting a good night's sleep, you can't lose weight.

When you are not getting a good night's sleep, you gain weight and it really disrupts your metabolism, of course your mood.

So these are easy things, you know, behavioral strategies around this.

Now, I think what's going to be very interesting to observe, this is just me speculating, you know, here with with you right now is it's going to be really interesting to look at people who are taking some of these new medications we talked about, for example, these GLP-1 drugs.

Preliminary evidence that's coming out now is telling us that when people take these treatments, yes they lose weight, their diabetes is under control, but the requirement that they have for psychiatric medications is going down.

Now, what does that tell us?

Well, we need to be careful how to interpret that, but it gives us at least a little hint that maybe their mental health is improving.

So that tells me that weight management, whether it's through a medicine or through some type of behavioral strategy or lifestyle strategy, and some people it's going to have to be surgery, that could clearly improve their overall mental health and mental resiliency.

But to stay on this medication topic arbitrarily, 'cause it's the focus of our research, I would say that this is very, very interesting indeed, that this is a possibility, that we could be actually protecting the brain, giving more resiliency.

One final comment, Jeff, around this, I'm involved in a study in Asia right now, in China with some colleagues there.

And we've been taking people, young youth who are at risk of mental illness because their parents have a serious mental illness, their parents have bipolar disorder, and we're looking at these kids.

And these kids don't yet have a mental illness, but these kids are at risk because mom or dad or both has bipolar.

And what we're doing with the kids is we're giving them exercise.

I always say exercise is the great vaccine against mental illness.

And exercise isn't just good for you, feels good and all of that, get a sweat, but it actually builds up resiliency in the brain.

Those circuits, those nodes, those networks, the CNN, they become stronger and we like big muscles.

Well, we like big muscles in the brain.

They become stronger, they become tighter.

And that may offset, we hope fingers cross, that genetic vulnerability that they have to having mental illness, so it's just taken together.

We don't need to become Olympic athletes, just any kind of activity, paying attention to lifestyle factors.

People say, well this seems kind of, that's kind of a lightweight intervention, isn't it?

No, it's not.

It actually makes a huge difference.

We just got to get that right and then we add these really interesting scientific thoughts on top of that.

- Roger, I want to thank you for joining us and sharing all of this information today and probably in the near future we'll follow up and you'll give us sort of the next stage and maybe tell us what is ready for prime time.

- Would love to, Jeff, thanks for having me and my fingers are crossed that this is going to really change the game for us, not just in treating, but preventing mental illness.

So thanks for having me.

- Today, we spoke about potential new approaches to treating depression, bipolar, and other psychiatric conditions.

More research needs to be done.

With research, there is tremendous hope.

(gentle music) Do not suffer in silence.

With help, there is hope.

This program is brought to you in part by the American Psychiatric Association Foundation and the John & Polly Sparks Foundation.

(gentle music) (gentle music)