From Chemical Imbalance to Metabolic Breakthrough: A New Path for Mental Health

Mark Hyman, MD

Dr. Mark Hyman is leading a health revolution—one focused on using food as medicine to support longevity, energy, mental clarity, happiness, and so much more. Mark Hyman, MD is a practicing family physician and an internationally recognized leader, speaker, educator, and advocate in the field of Functional Medicine. He is the founder and director of The UltraWellness Center, Founder and Senior Advisor for the Cleveland Clinic Center for Functional Medicine, a fifteen-time New York Times best-selling author, and Board President for Clinical Affairs for The Institute for Functional Medicine. He is the founder and chairman of the Food Fix Campaign, dedicated to transforming our food and agriculture system through policy.

He is a co-founder and the Chief Medical Officer of Function Health. He is the host of one of the leading health podcasts, The Dr. Hyman Show with 150+ million downloads. Dr. Hyman is a regular medical contributor to several television shows and networks, including CBS This Morning, Today, Good Morning America, The View, Fox, and CNN.

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Full Transcript

Automatically generated. Please forgive any typos or errors in the following transcript. It was generated by a third party and has not been subsequently reviewed by our team.

Dr. Mark Hyman
You know, I wanted to drive home is that you really are dealing with some of the underlying biology of the inflammation in the brain. Whether it's autism or Alzheimer's or ADD or depression or schizophrenia, if you biopsy the brains, they're all inflamed.

Before we jump into today's episode, I want to share a few ways you can go deeper on your health journey. While I wish I could work with everyone one on one, there just isn't enough time in the day. So I built several tools to help you take control of your health. If you're looking for guidance, education, and community, check out my private membership, the HymanHive, for live Q and As, exclusive content, and direct connection. For real time lab testing and personalized insights into your biology, visit Function Health.

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Dr. Chris Palmer
No one knows what causes mental illness. What we know are risk factors. So some people are passionate about one risk factor over another. So some people will say mental illnesses are chemical imbalances. And so the obvious treatment is a chemical to rebalance your chemicals.

Another common paradigm is stress and trauma. And there's no doubt that trauma and neglect abuse in childhood can cause mental disorders, not only in childhood, but all throughout life. And other people talk about hormones. All of the risk factors end up getting lumped into what we call the biopsychosocial model, which says there are biological, psychological, social factors. They all come together to results in mental illness.

And this applies to all mental disorders, even something like schizophrenia and bipolar disorder. Even though most people think of those as biological disorders, psychological and social factors play a role. But the real answer is nobody knows how they all fit together. And I think that speaks to one of the reasons why these disorders are so hard to treat right now is because we don't know really what we're doing. We don't know what we're treating.

We see symptoms, we see risk factors, but we don't know how they all fit together, and we don't know what the underlying, pathology is.

Dr. Mark Hyman
That's right. Mean, you hit it because when I went through psychiatric training as a doctor and as a family doctor, which I went through a number of rotations, I was like, Wow, this is really odd. All we're doing is describing symptoms. We're not talking about the cause. What's the cause and what's the why?

You know, it's basically a phenomenological description of symptoms and tells you nothing about the reason. And it's very circular, say, Oh, it's a chemical imbalance. Well, okay, what causes that chemical imbalance in the first place? And and in my career, I have really had the most extraordinary discoveries as a clinician, because I'm not a researcher. Well, at Cleveland Clinic, we do research and I'm involved with that, but I'm not, you know, a traditionally trained researcher.

And I just kinda was shocked to see when and I think the same thing happened to you when we get into the story. When you start to treat patients in a different way through diet and lifestyle, some of the root causes, and they get better, you're like, Holy cow, what is going on here? How could this happen? And how come I never learned about this in medical school? And then you go down the rabbit hole and, you know, once you see it, you can't unsee it.

And so tell us about how you discovered, as a traditionally trained psychiatrist at Harvard and McLean's, which is, you know, one of the top psychiatric hospitals in the world, how you kind of flipped your view and came up with this model of brain energy, is this new book that you put out, which is really extraordinary and everybody should get it. It's really out now, and it's really an important book in psychiatry, especially coming from someone in your position.

Dr. Chris Palmer
Thank you. I think the real turning point for me was, it started probably twenty years ago with my own health. You know, I had metabolic syndrome when I was in my 20s. I ended up changing my diet to a low carbohydrate diet, getting rid of a lot of processed foods, lot of sugars, other things. And I noticed a significant change in my mood and energy state.

And I began thinking, maybe this could be helpful for people with treatment resistant depression. And so probably eighteen years ago, I started using dietary interventions in people with treatment resistant depression, and sure enough, had some luck. But for the most part, I wasn't really blown away from with that because it's depression and, you know, yeah, eating a better diet, maybe some people feel better. Just didn't seem like it was as mind blowing to me as what happened to me in 2016. So, 2016, I have a patient, he'd been a patient of mine for eight years, diagnosed with what's called schizoaffective disorder, which is a cross between schizophrenia and bipolar disorder.

And he was absolutely disabled and miserable and tormented by his illness. He had hallucinations, delusions every day of his life, absolutely tormented by them, could barely leave his house, was chronically paranoid, convinced that people were trying to hurt him. So that's why he stayed home. It was just safer. He couldn't ride on a bus because he was convinced that everybody there was reading his thoughts and trying to hurt him.

And this man had tried pretty much all of our standard numerous antipsychotic medications, mood stabilizers, antidepressants, stimulants, everything else, and nothing was working. And for the most part, he's not unusual. That is the standard of care in our field. Tragically. Most people with that diagnosis are like that, they don't get that much better.

Dr. Mark Hyman
Ever, right? Is how they have You to live their whole just kind of give them medication and of manage their symptoms. It's basically, you know, the anti psychotics like Thorazine, now they have better versions of it, but essentially it's not much has changed since the 60s when they just used what we call them major tranquilizers, we just sedate them so they're not, you know, like, kind of going nuts.

Dr. Chris Palmer
So they're not causing trouble. And to be fair, it's better than putting them in jail. It's better than letting them die. It certainly does not restore people's health and it does not restore people's lives. And, there is no doubt every clinician in this field and every patient and family member who know anyone with these types of disorders know that we have a long way to go and we need better solutions.

So anyway, he asks for my help to lose weight. And so I'm pretty familiar with low carbohydrate ketogenic diets. He had already tried like three or four other types of weight loss methods without success. So we decided to try a ketogenic diet for weight loss. And at that point, even though I'd been using it in people with depression, I had no notion whatsoever that this would help his chronic psychotic disorder.

Those are very different things in my mind, completely different illnesses. And within two weeks, not only would they start losing weight, but I noticed this antidepressant effect. And in him, it was pretty remarkable. He didn't look so sedated anymore. He was making more conversation, making better eye contact in a way that I'd never really experienced with him.

Then I thought to myself, wow, that's really interesting. Here's this antidepressant effect that I've seen before. That's really remarkable. And it's great that he's losing weight and feeling better. But he was still psychotic.

He was still delusional, still hallucinating. Was probably about six to eight weeks later that he just spontaneously said, You know those voices that I hear all the time? I'm like, Yeah, I know about them. I think they're going away. I think they're getting better.

And the really striking thing to me was, you know, shortly after he said that, a week or two after he said that, he said, You know how I always thought that there were all these rich families conspiring against me, that they had targeted me and that they were were tormenting me on purpose? I'm like, oh, yeah, I know about that. Are we gonna talk about that? I'm thinking to myself, are we gonna talk about that again for the millionth time?

Dr. Mark Hyman
And,

Dr. Chris Palmer
and he says, I don't think that's true anymore. I as I think about it, as I say it out loud, it sounds kind of crazy now. And, like, I don't think that's really happening and maybe it never was. And maybe I really do have schizophrenia, like everybody's been saying all along. And, and maybe it's getting better.

And so that man went on to lose 150 pounds, and he's kept it off to this day. He was his life in many ways was transformed. He was able to move out of his father's home. He was able to participate in school again and complete a certificate program. He was actually able to get up in front of a live audience and perform improv.

And this was a man that couldn't be on a bus. He couldn't go to a movie theater because he was terrified that people were out to get him. And, and that completely transformed everything I knew, because I was initially just in disbelief, like this can't be happening.

Dr. Mark Hyman
Don't confuse me with facts my mind's made up. Must be a spontaneous remission, right?

Dr. Chris Palmer
Exactly.

Dr. Mark Hyman
Maybe he never really had schizophrenia.

Dr. Chris Palmer
It was interesting because I actually, he was working with a psychologist as well and his father is very involved in his care. I had to ask both of them several times, Like, you seeing what I'm seeing? I'm having a hard time believing what I'm seeing. But he is dramatically transforming in ways that I've never seen with other people. And am I am I kind of seeing something that's not there?

Am I going crazy? Like what is happening here? And they were all like, absolutely, it's happening. So I ended up doing a pretty quick literature search. And, you know, at that point I only knew keto and low carb diets as weight loss interventions.

I also knew that they helped with diabetes, but I had no idea that the ketogenic diet had been used for one hundred years in the treatment of epilepsy.

Dr. Mark Hyman
Yeah, for sure.

Dr. Chris Palmer
I didn't know that at the time. Once I realized that, I

Dr. Mark Hyman
quickly You know why? Because we don't really learn anything about nutrition in medical school.

Dr. Chris Palmer
Exactly. No. And it

Dr. Mark Hyman
Because nutrition has nothing to do with disease, of course. Right?

Dr. Chris Palmer
Exactly. And the the tragic part about that in particular, now that I am kind of an expert on the ketogenic diet for mental illness, The tragic part about that is this is an evidence based treatment. We have two Cochrane reviews that demonstrate that we've had more than enough research, clinical trials demonstrating that the ketogenic diet can stop seizures even when pills and surgery don't.

Dr. Mark Hyman
Yes.

Dr. Chris Palmer
We have more than enough evidence on this.

Dr. Mark Hyman
That's the last resort is diet. After all the drugs and surgery don't work, then we try diet.

Dr. Chris Palmer
Yeah. Yeah. Then let's try diet. Even yeah. Even though because I mean

Dr. Mark Hyman
diet could be dangerous. You might, you know

Dr. Chris Palmer
Yeah. They they might end up losing weight. We we wouldn't want that. So once I realized that, I started using this intervention in many other patients, and it was not across the board, it was not a miracle cure for everyone, I will fully state that and disclose Yeah,

Ian Campbell
yeah, yeah.

Dr. Chris Palmer
But it was dramatically effective and sometimes even more effective for other patients that I used it with. And I was putting what I always thought of as chronic mental disorders, schizophrenia, bipolar disorder and others into full complete remission, sometimes getting people off all their meds, and they were remaining in remission for years. And I ended up getting connected with other patients who had found their way to this intervention, either through other clinicians or on their own. And some of these patients, the most striking case was somebody who had been in remission for, at the time was about twelve years. And, she was 70 years old and suffered from schizophrenia for fifty three Wow.

Her schizophrenia went into full complete remission off all medications for twelve years. And those things don't happen in psychiatry right now.

Dr. Mark Hyman
Mean, Chris, what you're saying is basically the world is not flat. You know, like, you're like Christopher Columbus and everybody else is actually saying the world is flat because it looks flat. We have these diseases, they don't go away, they're chronic, there's no cure for them. And and it's it's remarkable when you start to see it in a sense. It's like you're saying, I I I it's like saying, well, I saw someone who's fully autistic and now they're not.

That that's the level of drama of this case. It's it's and I've seen the same thing over and over and over again for decades because by doing functional medicine, you just get to the root cause. And the thing that, know, I wanna drive home is that you really are dealing with some of the underlying biology of the inflammation in the brain. And whether it's autism or Alzheimer's or ADD or depression or schizophrenia, if you biopsy the brains, they're all inflamed. Now the causes can be different, that's why the ketogenic might work for some, not others.

Maybe another person might have another issue. They may have, for example, heavy metals or a toxin that's causing a problem, and if you don't deal with that, then it is the single biggest cause of disability and cost. I think I read a study recently that $95,000,000,000,000 are gonna be spent over the next thirty five years on chronic illness, and a lot of that, the majority of that is for the disability that goes associated with depression and mental illness. Not necessarily being in the hospital and the loss of productivity to society. Like you said, this guy was just sitting at home, couldn't do anything.

Now he's a productive member of society. What is the cost of that? So let let's talk about what it taught you about the biology of the brain because you were trained as a psychiatrist, you didn't learn much about that other than the the neurochemistry of neurotransmitters and using psychiatric drugs which modulate neurotransmitters, which is good, but you probably didn't learn that much about how to address toxins or the gut microbiome or diet or, you know, nutritional deficiencies or hormonal imbalances or any of that. So so how how did you begin to unpack that? And and what was the what is the the view that you have now that you wrote about in your book, Brain Energy, that talks about the biology of what goes wrong.

Because once you understand that, then you have a roadmap which allows you to actually create a treatment plan that can work and be reproducible.

Dr. Chris Palmer
Yes. And I think And by

Dr. Mark Hyman
the way, before I let you go on, I just want to point out that ketogenic diets also work in autism, in Alzheimer's, and in many in epilepsy, and I've seen this also in schizophrenic patients, so it's really powerful.

Dr. Chris Palmer
It is. I just want to highlight, even though the disorders you just mentioned are all very serious disorders, and I was talking about schizophrenia a little bit ago, I want to just highlight one of the things you said, depression is the leading cause of disability. So this, you know, most people think of depression as a fairly straightforward illness, and we have tons of antidepressants and we've got psychotherapy and we've even got shock treatments and we've got so many treatments available, they have to be effective, right? Well, actually wrong. The majority of people with depression, bread and butter depression, are not getting better with our current treatments.

And it's not because they're not getting treatment, it's because our treatments fail to work for far too many of them. And so I think that, you know, it was really interesting because the way that I went about unpacking all of this was, you know, I started with the neurology literature and because this is an anti seizure treatment and we use anti seizure treatments in psychiatry every day in tens of millions of people. And so that was really low hanging fruit. And it was a great resource to tap into because we've got one hundred years of clinical and neuroscience evidence on the ketogenic diet and what is it doing to the brain. And so I could tap into that and lo and behold, sure enough, the ketogenic diet rebalances neurotransmitter imbalances, it, decreases brain inflammation.

It changes the gut microbiome in beneficial ways. Know, improves Gets

Dr. Mark Hyman
people off gluten.

Dr. Chris Palmer
Yes, it gets people off gluten. It gets people off lots of other toxic, foods, probably. It improves insulin, signaling and insulin resistance in most people. And so it has a wide range of effects. But still, this is where the field of psychiatry is.

It's like all of these different things. And so I went on a deeper search for how do these connect?

Dr. Mark Hyman
Because

Dr. Chris Palmer
at first I started off with a mission to how am I going to convince other mental health clinicians to use the ketogenic diet for serious mental disorders? Because nobody's going to believe this. They're just not going to believe it Unless I can present a clear and plausible mechanism of action based on science, nobody's gonna buy this. And this miraculous treatment that I am seeing in front of my eyes is gonna go wasted. And I so I kind of felt like I'm an academic scientist.

Dr. Mark Hyman
Lose your job. Yeah.

Dr. Chris Palmer
That I I did worry about that many times.

Dr. Mark Hyman
Probably wouldn't go to jail like Galileo, but you might lose your job.

Dr. Chris Palmer
I worried about that. The good news now is that I have the full support and endorsement of, McLean Hospital, actually.

Dr. Mark Hyman
Amazing. That's unbelievable.

Dr. Chris Palmer
They are very enthusiastic and supportive of this.

Dr. Mark Hyman
I was like, when I heard about what you're doing, I just said the happy dance. I was like, and I've been telling everybody, I'm like, wow, finally, somebody's getting it where it counts.

Dr. Chris Palmer
That's awesome. So the way that I ended up coming to the sciences, I ended up focusing on mitochondria and mitochondrial function, and more broadly what we call metabolism. And, and so I came at the science from that perspective and ultimately viewing mental disorders as metabolic disorders of the brain. And that in order to understand metabolism, you have to understand mitochondria. But in fact, you have to understand everything that you have known about for decades, functional medicine, how it's all interconnected, how diet, toxins, hormones, the gut, stress, all of that come together to result in illness.

So functional medicine has been doing this for decades, and yet I was holed up in my Harvard position and, evidence based medicine and, and so we didn't learn a lot about functional medicine and certainly functional medicine protocols are not being used, in psychiatric hospitals. For the most part around the world, most psychiatric hospitals are not using these protocols or this paradigm. And so, But at the end of the day, even looking at mental disorders as metabolic disorders, which revolve quite a bit around mitochondria and mitochondrial function, I ended up coming to the same conclusions that you did.

Dr. Mark Hyman
It's quite extraordinary, and I don't know if you're aware of this, but right at Harvard there is Uma Naidu who has a whole Department of Nutritional Psychiatry talking about the microbiome and the brain. There's another physician who's been on my podcast at Stanford, they have a Department of Metabolic Psychiatry. So it's starting to happen, and more and more psychiatrists are becoming aware of the data, because there is data, there's lot of literature now that supports this notion. So when I look at sort of the mitochondria, it's really about, you know, and energy, and so I'd like you to sort of unpack how that actually connects to psychiatric diseases, because, you know, I first heard this concept when I talked to Martha Herbert, who's a psychiatrist, sort of neurologist, right, a neurologist, and I think she also works around psychiatry, I might be wrong, who was treating autism. And she was doing brain scans on these autistic kids.

She saw their brains were swollen and inflamed on biopsies with these kids got killed in a crack or something, and see these brains are just full of inflammatory cells, the immune cells, white blood cells called the glia. And she also called what they have a metabolic encephalopathy. She said that that autism is just not a brain disorder, it's a systemic disorder that affects the brain. And and it it's what I hear you saying, that psychiatric illness, for the most part, is a a systemic disorder that affects the brain. Now and the causes can be many, like it could be, like, your diet, it could be your microbiome, but I I was with a gentleman this weekend whose family it was a Hungarian Jew whose family was killed in the Holocaust.

He says, I I know a 150 members of my family were killed in the Holocaust. I know everybody's name, I've lived in a constant state of trauma and stress my whole life, and, you know, I was like, wow, this is the epigenetics of this. Scientific American just came out with a paper, not a paper, but an article sort of documenting some of the research in New York after nineeleven where they saw women who were pregnant when nine eleven happened, their children were were incredibly affected by the stress and trauma that happened to the mothers when they were pregnant and was registered in gene expression patterns and epigenetics and in cortisol levels and cortisol receptor function, I was like, Wow, this is the data is really coming along in this. So there's a lot of things that can affect it, but often, you know, the psychiatric problems are so misdiagnosed and mistreated, honestly, and creates so much suffering. And so, you know, what you're talking about is really a revolution.

Dr. Chris Palmer
It is. It certainly was for me, and it certainly is for psychiatrists that I speak with. I don't think they've really considered this. Reason that I am so passionate about mitochondria in particular is because they actually are responsible for much more than just energy production. So most people know mitochondria as the powerhouse of the cell, and so they create ATP, which is our energy source.

And there's no doubt they do that and they are instrumental in that role, and without that we would not live. But they actually do so much more than that. So they are primary regulators of hormones, for instance, key hormones like cortisol, estrogen, testosterone, progesterone, and others, that the production of those hormones actually begins inside mitochondria. And as those hormones travel through the body and influence cells throughout your body, the primary influence ends up converging on mitochondria. So, in many ways, the reason that I became like ridiculously excited about this theory is because it is a way to connect all of the dots, the biopsychosocial models of mental illness, it is a way to connect all of them.

So mitochondria are instrumental in neurotransmitter function, production, the release of neurotransmitters, the influence of neurotransmitters, they play a significant and powerful role in inflammation. But inflammation in turn affects mitochondria. And so it all, at least in my mind, once I started diving deeper, I was kind of flooded with all of these questions, but wait, this can't, it can't be this simple. Like this, is too simple. There's no way that this complex issue and the complexity of psychiatry and the brain, there's no way it can end up being this simple.

And, you know, for the last five years, I have tormented myself in some ways with questions like, if this is really true, then this should be true, or that should be true, or this should.

Ian Campbell
Yeah.

Dr. Chris Palmer
And at the end of the day, everything in my mind seems to converge on these issues.

Dr. Todd LePine
The brain actually is not so much about the neuron, but it's about what I call the dark matter of the brain. In physics, we know about dark matter. Most of the universe is actually dark matter. We can't really see it and it's not there. And regular conventional medicine entirely misses the dark matter of the brain, which is really related to the glial cells.

And this is really important. A lot of people have probably never heard of glial cells. Glial cells actually come from the Latin term meaning glue. So it's the cells that hold the brain together. Only about 10% of the brain are composed of neurons and about 90% of the other cells in the brain are the glial cells.

And the very important part of the brain that's related to neuroinflammation are what are called the microglial cells. And a lot of doctors probably forgot about this. They learned it in medical school and promptly forgot about it. But the microglial cells are the immune system part of the brain. And this is the part of the brain that gets activated under exposure to a bacteria, a fungi, a virus, or some type of pathogenic organism, or some type of foreign molecule.

And when the brain gets activated via the microglial system, that causes neuroinflammation. And neuroinflammation is incredibly important. I mean, a lot of the things that we see in our day to day practice, you mentioned it, depression. Depression is not about serotonin. Yes, serotonin is an important neurotransmitter, but a large part of depression is actually related to neuroinflammation.

In fact, studies have shown that people who have depression have a higher risk for dementia. So it's not just about a serotonin deficiency. It's just like cholesterol is not, that's not the big thing about heart disease. Heart disease is about inflammation. Neuroinflammation is about inflammation.

It's not just about these single molecules like cholesterol and serotonin. So it's really important to look at the whole big picture and how that relates to conditions that we see all the time. Things like Alzheimer's disease, things like ALS, things like multiple sclerosis, things like even schizophrenia. And actually I'll talk about some interesting vignettes about how schizophrenia is actually tied in with the neural inflammation in the immune system. It's really quite fascinating stuff.

And then there's the other thing I don't see children, but PANDAS. I'm sure you have probably cases of patients who had PANDAS, which is the pediatric autoimmune neuropsychiatric disorders relate to strep infections. And this can be a devastating clinical scenario where all of a sudden this young boy or girl starts getting these strange neurological type behaviors, these tics, these OCD type behaviors, And these things are driven by neuroinflammation. The original description was that it was due to a strep infection. Mothers and fathers know about that because when a kid gets a sore throat, they take them to the doctor, make sure they don't get a strep infection.

And typically we focused on strep being important because a strep infection can cause rheumatic heart disease. A strep infection can cause glomerulonephritis. That's why we're so on top of strep infections. But what doctors are missing, and even a lot of mainstream pediatricians are missing, is that those strep infection, not only can they cause molecular mimicry where the molecules, when they're attacking the strep bacteria, what they'll do is those antibodies will actually start attacking the brain. And that's where we end up with these, conditions like PANDAS.

Dr. Mark Hyman
Yeah, it's just so remarkable that the research on the brain in the last decade and how it's revealed that all the conditions that we thought were maybe psychiatric or maybe more biological in the sense that they're disorders of brain immune function. And and you mentioned the glial cells, is the brain's immune system that cleans things up. But there's so many things that screw it up and including lack of sleep, is a big one, that's when it's really active. I know I've seen in my practice focusing on brain inflammation has led to the most miraculous cures for all sorts of quote incurable conditions. And it's not often easy to find what the cause is.

And I had a patient the other day who had tics since he was a little boy, and it turned out he was really, they came on after he had really bad series of strep infections. And I think to my mind, he hasn't even thought of having PANDAS, but he might have an sort of this low grade inflammatory response from the strep that's been going on for thirty or forty years, but nobody picked it up. So we see all this kind of stuff, whether it's depression. And depression, you know, depression, you think, oh, that's a mood disorder. Well, yeah, it is a mood disorder.

And sometimes it's because, you know, you have a loss or some tragedy in your life. And usually that's sort of temporary, but these sort of chronic mood disorders often related to brain inflammation. And they've even talked about using drugs for rheumatoid arthritis for depression to kind of shut off the inflammation of the brain. Think that's a bad idea. But, you know, what's causing all this brain inflammation that's leading to this sort of rampant epidemic of brain diseases?

I wrote a lot about this in the Ultramind Solution over a decade ago, and it's only, you know, increased in terms of the prevalence of these problems and the data linking inflammation and and actually uncovering some of the causes of inflammation that are driving this. Can you talk about like what, you know, from a traditional perspective, what we do is we give you medications, we're getting antidepressants, and we're not actually giving anti inflammatories for Alzheimer's, although they tried giving people like Advil and see what happens, but it didn't work. So what is like the approach we take to finding out what the causes are?

Dr. Todd LePine
Well, that's where you really have to take time. And as you well know, we do a deep dive in listening to the history. And I think that's one of the things that probably distinguishes us when we do functional medicine is we have the time and we take the time to actually listen and listen to the patient's story. And there's a saying in medicine, if you listen long enough, the patient will tell you what the problem is, but you have to allow the patient to talk and you have to be able to listen and piece together the puzzle. So it's really about mapping out the timeline of when the patient's symptoms start, how old were they, what was happening around that time.

Did they get a vaccination? Did they take an antibiotic? Were they bitten by a tick? Were they exposed to some kind of a toxin? Did they have dental work?

I mean, there's all different kinds of things that can trigger inflammation. And that's where you really have to play medical detective. And sometimes you're going to find it on the first time, sometimes you're not. It might take you a lot of uncovering, lifting up stones, leaving no stone unturned. And that's where a functional medicine approach where we do a lot of advanced testing to look for not necessarily an infection per se.

It's not like you have a fever and you're sick, but what we would call a stealth infection, where you have a bacteria or a virus or an atypical bacteria present in the body that is causing this immune activation. And in the process of the immune activation, the brain gets inflamed and then can manifest as having a whole bunch of different types of neuropsychiatric conditions or potentially even memory issues or motor conditions or other neurological conditions like multiple sclerosis. So it's a real, you have to play detective is what is the case.

Dr. Mark Hyman
It is, mean, and the key things, you know, really drive the problems or the usual things we see that drive inflammation in general, whether it's autoimmune disease or anything else, you know, it's toxins. So it could be all the environmental toxins. We see this in Parkinson's, with pesticides and chemicals. We see evidence of heavy metals playing a role in many of these brain disorders that drives inflammation as well as toxicity. We see the microbiome playing a huge role.

Just recorded a podcast with Emory and Mayer for the doctor's pharmacy, and he's all about the gut immune connection and how it affects the brain, the gut brain connection. And he's written a lot about the biology of this. This is not some abstract idea. It's something that's really becoming fleshed out in literature and that people are coming to grips with as a force to be reckoned with in terms of the brain. And so we have to understand the microbiome's role, foods.

For example, gluten can be very inflammatory for the brain for many, many people, because it produces both inflammatory antibodies that affect the immune system and autoimmune disease, but also it can be a direct irritant in terms of the proteins that get digested and that flame the brain. And then of course there's infections that you were talking about, like viruses or tick infections and so forth. These all can be driving brain inflammation. So in functional medicine, what we do is we go, wait a minute, what is the story behind this person's particular illness? And as you said, go into a deep history.

And if we don't do that, we will miss often the real keys to figuring out the root cause of their problems. And that's really what's so beautiful about functional medicine is we have a set of tools a set of therapies that'll help allow us to one identify the causes and two to actually treat them directly. And it's pretty exciting because we do see a lot of changes from people's health.

Dr. Todd LePine
And you were talking about, you know, connection with the gut and there's really some fascinating stuff. You know, when I was in training, you know, we talked about Parkinson's and Parkinson's is the old, old person's disease. As get older, you slow down. And part of that slowing down is Parkinson like features. But what we're finding out is that Parkinson's is a spectrum illness and there is a big connection between patients who have Parkinson's and gut disruptions, leaky gut, gut dysbiosis without actually both bacteria and yeast.

And there's a fascinating literature on microbiome and the metabolites of the microbiome. And there's a woman whose husband has Parkinson's. And believe it or not, she actually diagnosed his Parkinson's by how he smelled, which is to say that when you eat certain food, the bacteria in the yeast actually do a metabolism of those foods and will produce these chemicals, which are called the metabolome or the gut micro metabolome. And those metabolites in some people can affect the brain. And so in essence, you can sort of sniff out Parkinson's.

And she actually did that. She actually could, she sensed that there was something going on with him and then had him examined and he was then diagnosed with Parkinson's. And in fact, they're actually training dogs to sniff out Parkinson's.

Dr. Mark Hyman
Dogs can tell you if you're going to have a seizure or if you have a low blood sugar or if you have Parkinson's or cancer, it's pretty fascinating.

Dr. Todd LePine
Prescribe dogs all the time. It's one of my prescription pad. Absolutely. Yeah.

Dr. Mark Hyman
Well, it's interesting. The body knows. And I think maybe we can just sort of share as a way of illustrating the power of addressing inflammation on the brain with some cases. I have a bunch of cases from autism and Alzheimer's, but it'd be good to get sort of a sense from your experience. What the things that show up and how did you treat it and what happened?

Dr. Todd LePine
Well, I've had a whole variety of cases. In fact, a couple of cases that we've had at the clinic where we had some patients who presented to psychiatric hospitals. And when it came out, when somebody has psychosis or a breakdown, if you will, they call that psychotic break or a manic break or whatever you want to call that. We've had a couple of recent cases where the patient's underlying trigger was Lyme disease, which is a spirochic condition. And always remember, this is something that I really like to emphasize to my patients is that way back when doctors used to treat syphilis we don't have a lot of syphilis in a private practice today.

It's just it's a condition which was readily treated and it's pretty much gone, although there's still some recurrences of it. But syphilis was caused by a spirochetal bacteria, bacteria, and that's the same thing as Lyme disease. And Lyme disease is the great mimicker, and it also can cause dementia and psychosis. So that's one of the conditions that trigger neuroinflammation. And then also, was a recent case of Bartonella also causing neuropsychiatric conditions and a diagnosis of schizophrenia.

So it's really a fascinating field. And the problem is that psychiatrists are not trained to think this way. And neurologists are not trained to step over into psychiatry. So they're like, they're two different fields, but they're really the same field. So it's neuropsychiatry.

This is an area that is actually really quite fascinating to me. People always ask me, what kind of doctor are you? And I have my own

Dr. Mark Hyman
description. Yeah, I do answer that question.

Dr. Todd LePine
Yeah, I'm a psycho neuro immuno endo gutologist basically looking at the whole connection between the brain, the gut, the immune system and all of the body when it's all sort of interconnected. And it's really, really fascinating and you can really help these people who are having significant conditions.

Dr. Mark Hyman
So what happened? You saw this patient with schizophrenia, right? And you found the tick infections. What happened then?

Dr. Todd LePine
We're able to get their symptoms down by treating the underlying cause, which is the underlying spirochetal infection. I also had another patient who had a mycoplasma infection. And it's actually known in the literature. Mycoplasma is an atypical bacteria and it's another infection which can cause the brain to be on fire. So it's a really fascinating thing.

And one of the tests that you can do that can check for this, it's not a common test. I don't know if you've done this, Mark, is the NMDA receptor antibody testing. This is looking at the parts of the brain that are stimulatory. And this is something that any doctor who has a patient who has gone, quote unquote, crazy or had a psychotic break, they should have an NMDA receptor antibody test. Because if you have this, it tells you that there is some type of neuro inflammation that's driving their symptoms.

Dr. Mark Hyman
Yeah, it's quite incredible. So I've had patients who had schizophrenia before or bipolar disease. And you think these problems are just so intractable and so difficult to treat. And can be. You know, in fact, the whole field of functional medicine came out of the field of psychiatry with Abraham Hoffer's discovery that you could treat schizophrenia you know, using nutrients and helping to improve the biochemistry of the brain.

And then Linus Pauling wrote his seminal paper, Orthomolecular Psychiatry and Science Magazine in 1969, talked about the perspective of how do you straighten molecules. In other words, how do you correct the imbalances or dysfunctions in your biochemistry? It's called orthomolecular, which means to straighten. And that has really led to the whole field of functional medicine. And we then sort of expand on that with our understanding of the role of inflammation in the brain.

And I, and I, you know, many schizophrenic patients have high levels of, for example, gluten antibodies. About twenty percent of schizophrenics have antiglide antibodies in their bloodstream. When you take the gluten away, do better. That causes brain inflammation. And when you do autopsy studies on people with Alzheimer's or autism or schizophrenia or depression, you find that their brains are inflamed.

So, you know, when you start to think about that, it's like, wait a minute, we are treating this completely incorrectly. And this is what was classical traditional medicine. You treat the symptoms, not the cause. And functional medicine is really about the cause and why, not just what disease you have, but why do you have it? And in the case of these brain disorders, it's often not obvious and the problem may be far away from the brain.

It might be in the gut or it might be in your diet or it might be a toxin or it might be an infection or it might be mold and it might be all sorts of things that we are kind of missing the boat on. And so we have this potential to sort of rethink our whole approach to brain science. This is so exciting when we see the work of guys like Dale Bredesen or others and nutritional psychiatrists like those at Harvard and metabolic psychiatrists at Stanford. They're doing work in this field, understanding the connection between the brain and some of these systemic processes.

Dr. Todd LePine
Yeah, absolutely. And when you take a schizophrenic and you look at them with a PET scan, the positive mission tomography, what you'll see is their brain lights up. And that's because their microglia, which is the immune cells in the brain are literally on fire. And unless you actually treat that, a schizophrenic is at high risk for developing dementia down the road because their fire is not being put out. This mark is I'm going to mention this because when I was I actually have done some lectures for American Academy of Anti Aging Medicine on neuroinflammation.

And in the process of preparing for that, I came up against some really fascinating things. One is that when you look at the genetics of schizophrenia, there's they needed this whole genome wide association studies of saying, well, what gene or what genes are associated with schizophrenia? And they did what's called a Manhattan plot. And on chromosome six, it sort of stood out like Empire State Building. What they found out is that on chromosome six, chromosome six is highly involved with the immune system.

So that tells us that a lot of patients who have schizophrenia have an issue on chromosome six related to the immune system. And what I'm going to tell you next is absolutely positively fascinating, this sort of blew me away. There were two case reports. And remember, case reports are just like a doctor observing, Okay, this is interesting. Look what happened.

Why did this happen? And the two case reports were this. And this tells you how the immune system is intimately involved in schizophrenia. One is a patient had refractory schizophrenia and developed some type of cancer and needed a bone marrow transplant. The refractory patient with schizophrenia got a bone marrow transplant.

A bone marrow transplant is basically giving you a new immune system. After he got the bone marrow transplant, guess what happened? It was refractory schizophrenia. It was gone.

Dr. Mark Hyman
What happened?

Dr. Todd LePine
Gone. Wow. It completely cleared up because it changed his immune response to whatever it was responding to. I don't know. But his refractory schizophrenia went away.

On the flip side, there was another gentleman who also needed a bone marrow transplant. He got his bone marrow from his brother who had schizophrenia. Guess what happened to him? Got schizophrenia? Got He got schizophrenia.

It goes both ways.

Dr. Mark Hyman
That's pretty amazing. That's pretty amazing. Yeah, that's pretty

Dr. Todd LePine
is amazing. I was blown away by that. And I think that people who are doing I'm a clinician. I'm seeing patients. But those case reports are really, really seminal to change how we think about how we see these conditions.

Ian Campbell
Metabolic psychiatry is essentially a proposal that I know you've recognized for a long time, but there's an energy disruption, a metabolic disruption, that underlies psychiatric conditions. And this metabolic disruption, this energy disruption affects the brain. And for many people, like, we've described, they've been told this is a chemical imbalance, a neurotransmitter imbalance. But one one of the ways I think about this when you hear this as a patient is is like if you imagine you were driving down the highway and the car is filling up with smoke. There's clearly an emergency happening.

But the way you address that is not necessarily to change the air conditioning. You know? You wanna look for, like, what is causing this to happen more fundamentally.

Dr. Mark Hyman
And the

Ian Campbell
neurotransmitter explanation feels as a patient and someone living with the condition to many of us, like, you know, we're trying to adjust the air conditioning when there's something much more fundamentally wrong with our engine system. But if you address the the fundamental disruption, which is the engine is on fire, you know, your metabolism is not working, the energy production is not working. It fixes all the downstream problems. You don't have to mix with the air conditioning. Don't have to worry about smoke.

You don't have to you know, all the things that can go wrong can stem from this, like, more fundamental disruption. And so this is what people such as yourself, Chris Palmer, are proposing this kind of energy disruption is the root cause of mental illness. And I think this really resonates with the patient community because it feels much closer to what we're experiencing, fixing this kind of engine versus trying to, adjust, you know, very specific aspects of neurotransmission and so forth.

Dr. Mark Hyman
So basically it's a metabolic problem. It's sort of like diabetes in the brain in a sense. Like it's a and the brain is the source of, you know, so many mitochondria. It's got more mitochondria per cell than any other organ in the body. And mitochondria are the little energy factories in your cells that take oxygen and food and combust them to turn into ATP or energy.

And if there's an energy crisis because you can't make it because there's basically bad energy, you're going to have a whole set of downstream symptoms and problems as a result of that. And for some people it might manifest as diabetes, for some people it manifests as schizophrenia, bipolar disease, or as Alzheimer's, which they call type three diabetes. So it's the same fundamental problem of insulin resistance and insulin signaling and glucose metabolism that's disrupted that can be caused by many factors.

Ian Campbell
Yes.

Dr. Mark Hyman
But but you're you're basically talking about going upstream and dealing with the root causes Yes. Of the problem.

Ian Campbell
Insulin signaling is a particularly interesting example because I I think some of the ways we're trying to treat mental health conditions at the moment are kind of, obtusely or bluntly addressing these pathways, but they're not giving a full holistic benefit to the metabolic problem that's underlying the condition. So I have a paper in Nature Journal Translational Psychiatry called Lithium and Insulin Signaling. Yeah. And I point out in this paper that many of the major targets of lithium are part of the insulin signaling network.

Dr. Mark Hyman
By the way, lithium is the drug that's used to treat often bipolar disease.

Ian Campbell
You know, the PI cycle, GSK3, AKT, mTOR, these are all parts of the insulin signaling network.

Dr. Mark Hyman
For for those in English, those are the biochemical pathways that relate to your blood sugar and insulin control that that we have many redundancies in, and and there are many of those pathways that get interrupted by Yes. Problems with energy metabolism.

Ian Campbell
Since proposing this, there's been quite a number of studies on it. There was a study in journal in neurobiology where Martin Aldo, who developed the Aldo scale for lithium, for example, and a team investigated this in was they make these kinda organized. They're like mini brains they derive from neurons from bipolar patients. And they found that lithium was modulating this insulin signaling pathway. But I think what we might be starting to discover is that we're kind of obtusely or, like I say, bluntly addressing some of these metabolic pathways through various forms of treatment.

For example, suppressing metabolism so heavily that someone can't go manic, but they also put on 40 or 50 pounds of weight and have diabetes. So it's like you're stopping the acute mania, which can save someone's life in hospital. But in the long run, there's this metabolic damage and dysfunction that can happen. And there's other medications like lithium, which I think address aspects of insulin signaling that can be, in the short term, helpful for someone, but in the long term can lead to damage, at least, you know, diabetes and so forth.

Dr. Mark Hyman
Boweloid function and other things.

Ian Campbell
So I think looking for better metabolic treatments is a really important area for psychiatry research.

Dr. Mark Hyman
So we're kind of entering this new year of psychiatry and sadly it's not getting to patients who need it most. Before we kind of dive into the biology, I want to really get into the biology of what's happening in the genetics and some of the diagnostic tools, the blood biomarkers, metabolomics, functional MRI imaging, imaging. You know, the thing about psychiatrists never do brain imaging is kind of crazy when you think about it. It's like, but

Ian Campbell
it's like, want to, well, you don't want to look under the hood and see what's happening.

Dr. Mark Hyman
Someone once said that modern medicine is, is like trying to diagnose what's wrong with your car by listening to the noises it makes, you know, instead of lifting up the hood and looking underneath the hood. But before we get into that, I want to sort of touch on, I think something that's really quite important, which is the field of psychiatry has classically been about this diagnostic manual called DSM five, which means the Diagnostic and Statistical Manual version five.

Ian Campbell
Yes. Has there

Dr. Mark Hyman
been one, two, three, four, five? Yes. And the latest version and basically it's descriptive.

Ian Campbell
Yes.

Dr. Mark Hyman
It just, it's a phenomenological description of these symptoms. And if you, you've, you fall into this category of these collective symptoms, you get this diagnosis, you had ADHD, you get bipolar disease, and there's subcategories, schizophrenia, depression, different kinds of depression. It's very, very detailed. And it's like family like detailed about which type of each mental illness. Can get different kinds of anxiety disorders, different kinds of bipolar, different kinds.

It's like, and it's fundamentally really flawed because, to kind of get back to your earlier point, there's fundamental underlying biological mechanisms that are causing people to suffer with these problems. And unless we take seriously this fact and take seriously the research that we need to undertake to actually investigate these things, we're never going to help address one of the biggest causes of suffering globally. I mean, yes, obesity, diabetes, and heart disease, cancer are really the big killers. But when you look at them, they're also metabolic problems. And when you look at the amount of quality of life loss, call it the quality adjusted life years or qualities, basically how many years have you lost to suffering, which you lost many years suffering.

When you take that number, you know, and psychiatric illness far exceeds everything else. And so this is like a global crisis and I don't see really, except at the margins, a lot of work being done around this. You mentioned the Brzezinski group, which is a group sort of helped fund a lot of this work. Only because of luck did someone who was very wealthy, have a kid who was bipolar, who went keto, who got better, who said, what's going on here? Let me start throwing millions and millions of dollars at funding this research because it's not happening from the academic medical centers really much.

It's not happening from NIH very much. It's like maybe a little here and there and it's starting to change. But I think we have this really fundamental diagnostic flaw. And I think what's really exciting to me is that it's not just me and my little clinic treating patients, seeing these things. It's now academic scientists starting to kind of dig in and see these problems.

So what are the kind of novel and emerging diagnostic tools that we are using to start to map out what is going on with these people. And by the way, the whole idea that there's like one cause of depression or one cause of bipolar disease or one cause of schizophrenia or one cause of autism or whatever it is kind of misses the fact that we're all unique and different and that different people have different combinations of things that need to be treated. And so while they have some common themes, you need to sort of look at the underlying individuality of each person and begin to understand how to unravel that accordion knot.

Ian Campbell
So I mean, I can answer from a researcher perspective and a patient perspective. As you mentioned, the Bizicki family who are funding metabolic psychiatry research and Matt Bizicki, their son, received a diagnosis of bipolar disorder. And he had really incredibly severe symptoms. He was hospitalized many times, went through and their family really went through many treatments, like over 30 treatments, having full access to The US health care system. And even being able to try every treatment available, nothing was helping his symptoms, even as people who had ability to do that.

So you can imagine what it's like for homeless people, for example, people that you know, it's very difficult for people, even if you can try everything, to have any effective treatment in treatment resistant patients. And eventually, he, went on a ketogenic diet with, Chris Palmer, a Denise Potter dietitian, and experienced remission of his symptoms. And in a kind of parallel journey, my father and I were researching this and trying to understand how do we get research to happen to address this. And we we kind of

Dr. Mark Hyman
And your father's a researcher as well.

Ian Campbell
Yes. He worked in developing countries doing global health research throughout his career, and he's always been interested in he's been a he he basically saved my life by helping me through bipolar disorder throughout my life. He's a really remarkable person. And so we really were trying from the research side to understand this, and Matt and his family from the patient side were trying to understand this. And it was very hard to get any funding to understand or research this.

I I I had to work at a day job for many years to support my research. I I was turned down for every fellowship, every grant, every possible way of doing this, and I was publishing papers, but there was no interest in it. And so eventually, I met Jan and Matt Pizicki because I put up a one of the few things I could do at the time was put up a YouTube video of a I put up this forty five minute YouTube video describing some of the things you're describing about the frustration with diagnosis. And And I think what we both recognised from either side was that we've been given this label that's bipolar disorder, but underlying that is a biological condition that is running that we don't fully understand, and the explanations we're being given aren't the map is not matching the territory. We're trying to describe this complex biology, but the maps we're being given for that don't fit the territory accurately.

And so this was the genesis of this research, was from the patient side, from research side. Jan Buzicki and Dave Buzicki funded our pilot study at Edinburgh. And this was after about six years of trying to find support for this. And and this really was how the field started through the support of the Buzicki's investment because of their son's journey. And so I I really, find that remarkable how much they've, got sort of in the trenches with patients and said, we're gonna make this happen.

We're gonna find out what's going on here. And that is an incredibly fortunate thing to have in the world because there's not a lot of mainstream support for these ideas. But it really came from just reaching a peak of suffering, both their family journey, our research journey, my family, and and many others across the world, Shibani Sethi, Chris Palmer that have been working in this field for a long time, Georgia Eid, treating patients, and everyone sort of realizing we have to fix this. This can't continue. So I I totally agree.

The map is not matching the territory, and this is we're all trying to to reconfigure this.

Dr. Mark Hyman
Yeah. Don't if you just came up with that, but that was something my professor mentor, doctor Sydney Baker, taught us, which is that we're given the wrong map for the territory of illness we're in. Yeah. You know? And it was something I often talk about with functional medicine is a different map.

Yes. So how do you if you're given a map for, you know, London and you're in New Delhi, it's not gonna help you. Yes. Yes. You know?

And I think that's what we have in medicine. We have the wrong map across all of the chronic health diseases, not just psychiatric illness. All of these diseases have chronic suffering that humanity has got right now, which is globally just so incredible. It's only in the last one hundred and fifty years that we've really begun to see the explosion of these chronic illnesses. Know, we now begin to finally understand them.

And it seems to me like a new kind of golden era of medicine and also particularly psychiatry. I want to sort of get into the weeds a little bit because I think, you know, as people listening often say, you know, just because you know the name of your disease, it doesn't mean you know what's wrong with you. Because you can say, well, I have bipolar, I have depression, but like what is unique to you? How do we sort of start to think differently about diagnosing people and using our existing tools, which we didn't even have necessarily fifty years ago? Like we've decoded our whole genome.

What does that tell us about our mental health issues? And so I think we have this moment where we can start to interrogate people's biology in ways we never had the capacity before. We can do your whole genome. We can see all your 20,000 genes, but we can see your five to 7,000,000 variations in that genetic code. We can look at your metabolome, which is thousands and tens of thousands of metabolites.

We can look at blood biomarkers. We can look at your microbiome, which plays a big role in mental health. You can look at your entire profile of, of, MRI imaging, which is basically allowing us to look at functional capacity, not just structurally. Do you have a tumor, but like what's your brain doing in a functional way and what does that tell us about what's happening energetically in the brain? You know, Suzanne Go from Harvard Oxford trained physician, pediatric neurologist has done a lot of work on autism and also found it to be a mitochondrial energy deficit and treated those kids with mitochondrial therapies and then they work.

Ian Campbell
Yeah. Yeah.

Dr. Mark Hyman
You know, so I guess the question I have for you, Ian is, is before we dive into the details of the, of the biology is people say, well, I don't have bipolar, I have anxiety or I have depression or I have, you you know, name it, OCD. Do these share common things? I mean, this apply also to those from your perspective?

Ian Campbell
I think, bipolar disorder is an extreme, version that, you know, is in one, two percent of the population, but I think it indicates an underlying dynamic that's present in many people. And perhaps by understanding the extreme case, it could be helpful to people who are experiencing lesser symptoms, seasonal affective disorder, depression, anxiety. Bipolar has very severe swings to mania and depression. But I think these happen in a lower level in a different way in many different types of people. I I could share some of what the history of the the biomarkers and the ways people have conceptualized bipolar and and then bring it around to how this might apply to other people.

If you look before the age of psychopharmacology, there was this psychiatrist called Emil Kripplin in 1921. He published a paper called Manic Depressive Insanity, and and he was considered the founder of modern psychiatry. And all he did was observe his patients very closely and try to understand really what is their condition by asking what are they really experiencing. And this was long before we conceptualized this as neurotransmitters and different types of treatment. He was really just looking at what patients are experiencing, which is my interest as a patient as well.

And he noted kind of three core features that were particularly notable about bipolar disorder. And, again, I think these relate to many conditions. And he said there's a metabolic disturbance. He said, all my observations indicate that in bipolar manic depressive insanity patients, metabolic disorders must take place. And then he noticed this

Dr. Mark Hyman
And what do you mean by metabolic disorder?

Ian Campbell
So he would track their body weight, and he would track lots of different metabolic measures that were available at the time. And you can see in this manuscript in 1921, he's drawing diagrams, really detailed diagrams of body weight and how it changes with mood and symptoms. And so he said there's something metabolic about this illness. And then the second thing he said was that there's circadian and sleep disruption, and he said that the most striking disorders in a manic depressive insanity are the disorders of sleep and general nourishment. And then the third thing he pointed out was that there was seasonal variation of symptoms.

So he said he describes it kind of poetically. He said, in many of my patients, I saw Munina set in in the autumn and Passover in the spring when the sap shoots in the trees. And he was describing that there's a seasonal variation to this condition, and seasonal affective disorder and many other conditions, schizophrenia and so forth, have this seasonal variation. And so he was taking these as three core aspects of bipolar disorder. And then from there, the reason I think this is interesting is because the seasonal variation of symptoms in bipolar is a seasonal variation energy.

So if you speak to bipolar patients in the spring, they have this huge surge of energy and activity. They're they want to move. They want to go out. They want to exercise, start new projects. This kind of mania really comes on strongly in the spring.

But it also occurs in the autumn, and this is because the the photoperiod, the length of daylight changes very rapidly at these times. It's called the equinox, the spring equinox, the autumn equinox. And if you look at systematic review of when mania occurs in patients by hospitalizations, it occurs at the spring equinox, at the autumn equinox. And conversely, depression happens in the winter. So the the same systematic review highlights winter depression, and it occurs around the weeks of the winter solstice when photoperiod is at its lowest.

So what we're kinda seeing is a male cripple was describing the seasonal variation of energy and metabolism related to circadian function. And if you look at, you know, the natural world, this is a part of the natural world. Humans for 95% of our time on Earth, were living in a natural daylight cycle seasonal variation, and it was essential for survival to be able to allocate your energy, optimally. So in the spring when there was opportunities for hunting, reproduction, so forth, it would make sense to have a surge of energy. And in the winter, it made sense to conserve energy because there's not the same opportunities available.

There's extreme examples in Or the

Dr. Mark Hyman
the same amount of food, right?

Ian Campbell
Yeah, exactly. Yeah. And so the extreme examples in the natural world are hibernation torpor in the winter and, you know, migration, hypermetabolic behaviors in the spring. But these mechanisms, the circadian and metabolic mechanisms that do this energy modulation throughout the seasons are conserved in humans. I have a paper about this called Metabolic Plasticity, and I think that this is a metabolic energy and circadian regulation disorder.

And I think that what it is the underlying mechanisms, circadian and metabolic mechanisms, are sort of ancient preserved mechanisms of seasonal adaptation and metabolism. And so I think that I know you've talked about this yourself, these kind of, like, ancient survival mechanisms. They become dysregulated in our modern environment. A kind of mechanism that could give you optimal energy use throughout the year could be completely dysregulated by artificial light conditions, metabolic factors, diet, and so forth. I think that we're talking about insulin signaling, and in the winter, many species suppress their insulin signaling and glucose metabolism.

They go into metabolic depression.

Dr. Mark Hyman
Suppress Like bears, they hibernate. Yeah. And they gain all their weight in the fall, and then they live off the fat in the winter, right?

Ian Campbell
Yeah, they do two things. They suppress their circadian rhythm and they suppress their metabolism. And this is what happens in bipolar depression. Your circadian rhythm is suppressed, your metabolism depressed. Obviously, this is just analogy.

It's not a direct comparison. But the same mechanisms underlying these seasonal adaptations are conserved in humans. MTOR, AMPK, sirtuins, AKT, the insulin signaling network. There may be an evolutionary mismatch we're experiencing in some of these conditions where we have these ancient survival mechanisms that our modern world is heavily dysregulating.

Dr. Mark Hyman
The light bulb in the advent of refined sugars and starches led to a big a host big of chronic disease problems, including mental health.

Ian Campbell
A really great example I could share is, so I mentioned Matt Bazooki, and we have a we have a podcast where we interview patients about their symptoms. And many people have described to us, including himself, that this mania occurs around the time of the changing photoperiod, changing length of daylight at the spring equinox. And it's really notable, you know, it's it's at the spring equinox. Manic patients become hypermetabolic. They're going out trying to start new things, exercise, and so forth.

And there's a really interesting analogy in the natural world called a zagunru, which is, I think, that Johan Andreas Neumann noted. In animals in captivity, many, particularly my migrated birds, for example, around the spring equinox become hypermetabolic. They start trying to bang their head off the side of the cage. They're they're staying up all night. Their circadian rhythm is suppressed.

They're having insomnia. They're trying to they're getting this deep evolutionary impulse and drive that they can't express in the unnatural environment, and it's to migrate at the spring equinox. It happens also at the autumn equinox, this behavior. So I I think these are just analogies from the natural world. Of course, they're not directly related, but I think there's clear evolutionary mechanisms, circadian and metabolic mechanisms, that are active in bipolar and across some of these psychiatric conditions that we need to explore.

Dr. Mark Hyman
Historically, mental illness has really been about philosophy and religion and just psychological explanations, which don't actually fit the current understanding of mental health issues.

Ian Campbell
Yeah. And I think what you're saying about these philosophical assumptions about mental health, they really inform the treatment of patients and how they experience the condition. So this Cartesian idea that the body and the brain are separate has really informed a lot of psychiatric practice. Emil Kreplin, who was considered the founder of modern psychiatry, In 1921, he wrote books describing this biological basis of mental illness. But he there was a kind of split in psychiatry where Amel Kreplin was looking for what you're describing this biological basis, biomarkers.

But then other people like Freud were saying, no, it's to do with psychoanalysis, like you say, and, you know, issues with your mother and so forth.

Dr. Mark Hyman
You're just laying on the couch for five days a week for twenty years and you might feel better. You might feel better. Yes. Now you're getting into the biology a little bit. And so you get through the history of how we sort of began to observe these phenomena, but they were kind of neglected.

It was thought to be sort of psyche psychological in nature, or maybe it was a chemical imbalance. I mean, the chemical imbalance idea wasn't exactly wrong. It is biochemical, but it's just they were looking at the wrong thing. Was like serotonin, it's dopamine, it's this and that. And I think, you know, the genetics are really interesting around this and there's actually whole genetic profiles we do in our clinic at the Ultra Wellness Center look at the risk factors for psychiatric disease.

Can you talk about some of those genetics?

Ian Campbell
Bipolar disorder and many psychiatric conditions are quite polygenic, which means that there's not any of core gene that can be absolutely identified to cause this condition, like with rare genetic disorders. But there are a combination of genes that contribute to the condition. And I I think where it gets interesting is the gene environment interaction. You know, maybe there's an evolutionary many people have hypothesized there's an evolutionary purpose for things like bipolar. It stays at one or two percent in the population consistently.

You know, why would this be conserved in humans? Why wouldn't it be selected out of the the gene pool? And many people have said that maybe there was some adaptive advantage to this back in our evolutionary history when we're living in natural daylight, seasonal cycles. And to have this ability to upregulate your energy so much at times of opportunity and to heavily suppress it to conserve energy at times of disadvantage would have been a beneficial survival trait. Mhmm.

And so I I think that this you know, there might be evolutionary perspectives that can explain this genetic preservation of bipolar, but it's not one gene. It's a combination

Dr. Mark Hyman
Many, many combinations of genes. Yeah. I mean, when you look at the literature, there's some interesting genes that affect mental health, like methylation genes, which involve how we kind of transfer a carbon three hydrogen chemical group called methyl group, which is basically the currency of our biology. It's involved in everything from neurotransmitter formation to energy production, to detoxification, and to regulating, oxidative stress and inflammation. Mean, what's really interesting that is unifying a lot of these mental health issues and chronic disease in general is inflammation.

And so what happens is the brain gets inflamed and it gets inflamed because it can handle the load of, the stress from our diet in terms of processed refined carbs and sugars. It can handle the environmental toxins that we're exposed to. It can handle the various kinds of stressors. And so we kind of break down and there's, you know, and like genes like MTHFR and COMT that you can measure now that can tell you what's going on. There's genes that relate to serotonin metabolism to even to circadian rhythms and clocks and how those relate to mood disorders.

So I think those are really interesting. And there's like a lot of circuit stuff. I don't know if want to say something about the genetics.

Ian Campbell
Well, I wanted to ask you which circadian genes have been noted that you're interested

Dr. Mark Hyman
It's something called clock genes and ART, ARNTL or Arntel genes. These are genes that just affect circadian rhythm. They affect, you know, our our biology in ways that affect mood disruption if their circadian rhythm is disrupted.

Ian Campbell
So That's really interesting. Because the the half of my research is on well, the majority of my research is on metabolic psychiatry, but we also have a lot of chronopsychiatry research led by professor Daniel Smith in our Edinburgh. And the central focus of chronic psychiatry research is clot the things you're mentioning, clot, BMAL one, per cry. And these are your circadian regulators, and they basically take signals from the environment, the the light, and they convert this in the suprachiasmatic nucleus of the brain, which is kind of like a clock system in the brain, and they use that to regulate your metabolism. So this happens daily when you go to sleep.

These clock genes, tell your body it's time to down regulate metabolism and go to sleep, but it also happens seasonally. These clock genes tell your body about the changing light conditions, the changing length of daylight, and they then feed into your metabolic system to tell you whether to have more or less energy to conserve and, utilize energy accordingly. So I I think these make sense in terms of an energy metabolic disorder.

Dr. Mark Hyman
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