- [Dr.

Borenstein] 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.

(gentle music) Today on "Healthy Minds."

(gentle music) - You know what?

I hate to sound cliched 'cause we've probably heard all of these things before, but they really are true.

And if we can implement these things in our own lives, we can not just prevent stress, but we can promote long-term health and longevity.

And those things are exercise, sleep, and diet.

Those are the three most important factors that drive our stress systems and tune them in ways that are either adaptive or maladaptive.

- That's today on "Healthy Minds."

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

(gentle music) Welcome to "Healthy Minds."

I'm Dr.

Jeff Borenstein.

What is the relationship between our brain and our body?

And how does stress result in various conditions?

Today I speak with leading researcher Dr.

Scott Russo about the relationship between the brain and the body.

(gentle music) Scott, thank you for joining us today.

- It's a pleasure to be here, Jeff.

Thanks for having me.

- I wanna jump right in and ask you about the relationship that we all know exists, but we don't fully understand that relationship between the mind and the body.

Give us first the broad strokes of that relationship.

- So I think the best way to understand it or think about it is when we get sick.

You know, if you've had the flu or any kind of cold, or even if you, know, you've been exposed to bacterial toxins from food poisoning, it's not just about the physicality of your body and its response to that, it's something in our minds as well.

We feel melancholic, we feel maybe even a little bit depressed.

And that's really how the field began to think about this mind-body or brain-body connection and to start to then interrogate and understand how these processes might be related to mental illness.

- Could you give us some examples of physical and psychiatric conditions that may be affected by, sort of with that relationship?

- Sure.

You know, I think it extends even beyond psychiatric disease.

I would argue that every brain disease that we've characterized to date is associated with physical comorbidities, so Alzheimer's disease, depression, anxiety, schizophrenia.

If you look at the risk for other systemic illnesses, or illnesses of the body, there is a substantial increased risk for developing many of those syndromes.

For example, an individual that suffers from depression may also have an increased risk for developing bowel disorders; irritable bowel syndrome is one of them.

We've long known that patients with depression have a much larger risk for developing atherosclerotic cardiovascular disease.

And you can pretty much pinpoint those connections across brain diseases and across systemic illnesses, suggesting there's some type of interaction between our brain and our peripheral organ systems that might be driving that shared pathology.

- And what is that connection?

What are we learning about that relationship?

- I think it's probably more complex than our discussion would allow for today.

But for sure, one of those shared features is disturbances in our immune system.

Many of the conditions I just mentioned are either characterized by something called inflammation, which is a response of our immune system to damage, or it may even be a bonafide immune disorder, for example, like multiple sclerosis, where we know that autoimmune reactions against the brain are causing the illness, but potentially also causing some of those comorbidities that I mentioned earlier.

- And with regards to that, I know that stress is an important issue.

So I'd like you to talk a little bit about how stress relates to these inflammation and immune responses.

- Yeah, for sure.

You know, with respect to depression, the relationship is very clear.

The genetics that drive depression are fairly complex and weakly associated with the condition.

And so what we know about the disease is that in most cases, depression is precipitated by stress.

But even in conditions where environmental factors share more of the risk with factors like genetics, stress seems to be a precipitating factor in all brain diseases.

It makes them worse and it seems to make the illness progress at a much more rapid clip.

- So I'd like you to speak... You are the director of the Brain-Mind or Mind-Body Institute at Mount Sinai.

What exactly is the institute doing?

What's the approach in terms of learning about these issues?

- Yeah.

First of all, we're very excited.

We just rolled this out last year, and we're looking forward to sustaining growth in the area.

It's an institute that's really focused on bringing partners to the table across clinical and basic research specialties.

It has no boundaries.

We're embedded within neuroscience here, for example, but we have partners in dermatology, we have partners in cancer biology, across the spectrum of the health center.

And it really was born out of this idea that comorbidities exist between brain disorders and systemic illnesses, yet our understanding and our inclusion of those, of that information into treatment plans is really lacking.

For example, I was speaking with our chair of internal medicine recently, and one of the things that she noted was that in a lot of the patients that she treats for asthma or other respiratory illnesses, depression or stress is a very important factor in driving the progression of that illness and the severity.

And so they're keenly aware of it, but our treatment plans don't necessarily bring to bear that information, for example, stress reduction protocols, medications that operate on similar pathways.

And so the institute is really focused on bringing those two worlds together and really innovating in the area of therapeutics development for these brain-body illnesses.

- It's obvious, but we don't necessarily do it as a profession, you need to treat the whole person, not just one organ system.

You need to treat the whole individual.

- Exactly.

And oftentimes, you know, when we look at our patient cohorts, it's a much more complex picture than what our treatment modalities are developed on.

You know, early on in my career, I'm a psychologist by training, I remember very clearly doing my internship in an inpatient drug rehab clinic in Dallas, Texas.

This was during my postdoctoral fellowship.

And every patient I saw was a very unique, complex history.

And every person that I spoke to required something slightly different, if you will, a personalized approach to their treatment plans.

And I think that's what really drove my feelings and thoughts on brain-body sciences as I matured into a more senior scientist and now as the director of the Brain-Body Research Institute.

- So I wanna ask you about your research looking at stress and its effect on people.

And tell us what you found and what you're looking for with regards to stress.

- Yeah, so, you know, my group is really broadly interested in the impact of stress on all organs throughout the body.

Started out with questions on how stress impacts the brain and how those effects on the brain regulate our emotional behaviors.

And we were particularly interested in negative stressful experiences.

I should back up and say that stress is pretty much a all-encompassing term.

And maybe we should spend a few minutes thinking about what stress actually is.

Stress can be good and stress can be bad.

And a little bit of stress in our lives is something that's healthy for our systems to remain adaptive, plastic, and ready to respond to difficult situations.

In my lab, we're interested in, really, chronic forms of stress, you might call them traumatic stressors, those that overwhelm our body's systems and ultimately lead to depression or anxiety or PTSD or related syndromes.

And so we were very focused on understanding how these traumatic and chronic stressors impact brain circuitry, but one of the things that we noted was that they were having dramatic effects on peripheral organ systems.

Early on, I partnered with a psychiatrist and friend here at Mount Sinai: Dr.

James Murrough.

He leads our Depression and Anxiety Center.

And we decided to build a bio repository.

We collected patient samples, blood and cerebrospinal fluid, so that we could understand what some of those systemic effects of stress were on the body.

And we started to profile them and, lo and behold, we started to see dysregulation of immune-related factors in our bodies that were indicative of systemic organ disease.

I'll give you one example, Jeff.

We partnered with dermatology and we measured some of these immune markers in the blood of patients with dermatitis, this is an inflammatory skin disease, and patients with major depressive disorder.

And there was a lot of overlap between the inflammatory signatures between those two groups, which led us to hypothesize that maybe they have a shared inflammatory or immune signature that might be driving the illness.

- So understanding this, how does this help with developing new treatments for it?

What do we aim for in developing those new ways to help?

- It's a great question.

I would argue that all of the treatments that we currently use to treat psychiatric conditions broadly, not just depression or anxiety, but even schizophrenia, operate on the assumption that there is a deficit or an overactivity of neurotransmitters in the brain.

In particular, dopamine and serotonin seem to be the most popular targets of those drugs, and they certainly work in a subset of patients.

But I think that that approach ignores the heterogeneity of the illness and the possibility that there are many other causes of these diseases that might be targetable by drugs that affect alternate systems.

Now, the challenge has always been, in developing drugs for psychiatric illnesses, that the brain is somewhat unique as an organ system in the sense that it has a very developed and unique barrier system that prevents most compounds from getting in from the periphery and acting on the brain, this is called the blood-brain barrier, and so it's made drug development very challenging.

All of our drugs need to pass the blood-brain barrier and they all act on some neurotransmitter system in the brain.

They have lots of side effects, they don't work all the time.

We became very interested in this brain-body connection because it opens up a whole host of different therapeutic modalities.

Now we don't want drugs that penetrate the brain, rather we want drugs that stay in the periphery, neutralizing those toxic inflammatory molecules and preventing them from ever getting into the brain and causing problems in the first place.

So it's more of a preventive approach and doesn't require the complexities of typical central nervous system-penetrating drugs.

- So it's prevention and also it's, even in treatment, if it doesn't prevent, in treatment, it's getting to the underlying cause of some of those neurochemical changes that the current medicines treat.

- That's a great point.

Absolutely.

And, you know, most... It's thought that some of the side effects and the diminished effectiveness of these classic antidepressant medications might be due to the fact that we're not removing the underlying cause.

We're simply causing the nerve cells to fire a little bit more or respond a little bit more strongly, but that underlying cause, in our case, the inflammation from our immune cells, is still there and it's still driving alterations in brain function.

- Everybody experiences stressors to various degrees.

What can somebody do to minimize those negative effects that stress can have on a person?

- You know what?

I hate to sound cliched 'cause we've probably heard all of these things before, but they really are true.

And if we can implement these things in our own lives, we can not just prevent stress, but we can promote long-term health and longevity.

And those things are exercise, sleep, and diet.

Those are the three most important factors that drive our stress systems and tune them in ways that are either adaptive or maladaptive.

- So, for instance, exercise, how does exercise help in terms of our body's response to stress?

- So there's lots of different... Exercise has such broad impacts on our health, right?

So on the one hand, exercise reduces cardiovascular risk.

And what that means is it allows for our vascular system or the plumbing that brings nutrients to our body, it promotes health of that vascular system.

And so we know, for example, that depression is associated with disruptions in the vasculature, and so if we can maintain health of that, that's one way.

But broadly speaking, when we look at our patient cohort, patients that suffer from this form of inflammatory depression, if you will, tend to be slightly overweight.

They don't necessarily have diabetes, but they may be kind of nearing the edge, the pre-metabolic zone.

And exercise is gonna, you know, it's gonna promote better metabolic health, it's gonna help you to reduce weight, and we think that that's very important in kind of limiting the symptoms of this inflammatory subtype of depression.

- Good, that's helpful, 'cause sometimes people get the impetus to exercise or take action by understanding how it may actually really work and help them.

- Yeah.

- And how about sleep?

How does sleep interact with how our bodies respond to stress?

- You know, sleep is such an important aspect of our life.

I know we're told and taught that sleep is not critical and, you know, that you can get by pulling all-nighters and, you know, and you're just fine.

That's okay, but in the long term, if you're chronically fatigued, our body systems don't work properly.

Particularly a lot of the cognitive impairment, the brain fog that we experience, these are made worse by a loss of sleep.

There's also a really interesting area that's developing in the aging space that suggests that during periods of sleep, our brain is actually rinsing itself out, if you will.

The fluids that exchange different things back and forth between the brain and our body are pulling the toxins and related products that we don't want in our brains out of our brains so that they can be removed.

And so you lose sleep or if you're fatigued, you know, those resetting processes, those those rejuvenating processes that occur don't happen and our bodies suffer from it.

- Obviously it's good to develop healthy habits at a young age and make that a part of your daily routine, whether it be exercise, proper sleep, good diet.

But how do you encourage people who haven't done that over time to really begin to do so?

Somebody's watching right now, what do you say to them?

- I say there's no better time than now.

And if you can make that first step into an exercise program a little bit at a time, build it up, start small, build it up, add a little bit on so that you don't overwhelm yourself.

And when we overwhelm ourselves, what do we do?

We tend to quit.

So I think start today.

But also, don't feel bad if you're struggling with it.

It's hard.

It really is hard.

It takes sometimes a number of resets.

I'm a former smoker, for example.

It took me, I think, 20 times to actually quit smoking cigarettes and have it stick.

Integrating or implementing an exercise regimen into your lifestyle is similarly hard.

And if you're suffering from, for example, depression, it can be even more challenging.

So take a little step, start small, build up, do it today, don't wait.

- I think that's great answer and great advice.

And thank you for sharing your own experience with smoking.

And I'm happy that you stopped smoking.

That's one of the least healthy things we can do.

- It's terrible, terrible.

- One of the facts that I find fascinating that relates to this is that if a person has a heart attack, obviously you wanna control blood pressure, you wanna control cholesterol, et cetera, but untreated depression is actually the worst risk factor for a bad outcome subsequent to the heart attack.

And I'd like you to speak about that in the context of our conversation.

- Yeah.

I mean, that was one of the data points that drove a lot of our early studies.

I can tell you the... I can start with more of a philosophical perspective.

I think there's definitely behavioral outcomes related to depression that can increase your risk for cardiovascular disease, particularly in patients that have something called severe anhedonia, which is one of the key symptoms of depression.

And it's really one's kind of inability to experience things as pleasure, a loss of motivation for doing things.

And those symptoms can actually drive unhealthy habits.

So from a philosophical perspective, I think if we can treat those symptoms in the brain, then we can allow our ourselves to live and lead healthier lives.

But from a biological perspective, we've done a little bit of work in this space.

I'll caution you, a lot of the work is in preclinical models, so not in humans, but in rodents.

And what it looks like happens is that when you are chronically stressed... Of course we can't make a mouse depressed, but we can chronically stress a mouse.

What it does is it causes the immune system to start producing a particular type of inflammatory cell.

It's called a monocyte.

And those monocytes can pump out inflammatory molecules that can get into the bloodstream and ultimately they can go to any organ system, including the brain.

In the case of cardiovascular disease, particularly atherosclerotic cardiovascular disease, that leads to a heart attack, the plaque itself that resides in your blood vessel wall, those monocytes, those inflammatory immune cells, can penetrate those plaques, they can infiltrate those plaques and they can cause that plaque to rupture, causing additional cardiovascular events.

And so we think that that's the link between why an individual that has a heart attack and unresolved depression, or, i.e., stress, has an increased risk for mortality and other negative effects of that cardiovascular event.

- So a key take-home message, whether or not you have a heart attack or at risk for atherosclerotic heart disease or anything else, is if you have a depression, get treatment 'cause it affects other parts of the body.

- Absolutely.

And that goes for all of these comorbid illnesses that we've talked about today.

Cancer is another big one.

Untreated depression and cancer can have really deleterious effects.

- I wanna ask you to sort of project forward.

The institute just started.

Where do you see it going in 5, 10 years?

When we have a conversation at that point in time, what new things are you envisioning being able to share with us?

- I'm very hopeful that we will be moving towards immune modulatory therapeutics for treating mental illness.

There's a couple of trials that have been ongoing, some are ongoing right now in the institute, where we're using something called a monoclonal antibody.

I think probably folks are very familiar with monoclonal antibodies.

They became a popular treatment modality during COVID.

And what these antibodies do is that they kind of replicate our body's own host defense systems by scavenging up particular molecules, neutralizing them, and preventing them from acting deleteriously on a target organ.

So, for example, in our earliest work, we found that interleukin-6, it's an inflammatory cytokine that's produced by immune cells, is elevated in patients with depression.

We did a bunch of testing to show that it's linked causally to the expression of stress-relevant behaviors.

And we're now starting to dose our first patients here at Mount Sinai with monoclonal antibodies against components of the interleukin-signaling cascade.

My hope is that those therapeutics will develop to a point where they become part of the arsenal for treating this heterogeneous disease that we call depression.

- That is exciting.

And I think that this work is going to really have an impact on all of our health.

So, Scott, I wanna thank you for joining us today and for the work that you have done and continue to do in this important area.

Thank you.

- Thank you, Jeff.

I had a lot of fun.

Thanks for having me.

(gentle music) - We all experience stress, but if stress is resulting in depression, anxiety, insomnia, or other psychiatric symptoms or physical symptoms, don't suffer in silence, seek help.

Remember, with help, there is hope.

(gentle music) (gentle music continues) Do not suffer in silence.

With help, there is hope.

(gentle music) This program is brought to you in part by the American Psychiatric Association Foundation, the John & Polly Sparks Foundation and the WoodNext Foundation.

(gentle music) (gentle music continues) (gentle music continues) (gentle music continues) (gentle music continues) (gentle music continues) (gentle music continues) (gentle music continues) (gentle music continues) (gentle music fades)