The Dr. Hyman Show - From Chemical Imbalance to Metabolic Breakthrough: A New Path for Mental Health

Episode Date: September 15, 2025

Many psychiatric labels—like bipolar disorder and schizophrenia—can obscure underlying biology, and symptom checklists often fail to explain or heal what’s really going on. Emerging evidence reframes mental illness as a problem of brain energy, mitochondria, and inflammation—shaped by insulin signaling, circadian rhythm disruption, the gut–brain axis, toxins, infections, and nutrient status. Metabolic interventions such as ketogenic nutrition, already established for epilepsy, show promise for rebalancing neurotransmitters, lowering neuroinflammation, and improving overall brain function. With depression now a leading cause of disability, shifting from “manage the symptoms” to “fix the biology” could dramatically improve outcomes where standard drugs fall short. In this episode, Dr. Christopher Palmer, Dr. Todd LePine, Dr. Iain Campbell and I explore how rethinking mental illness as a metabolic and inflammatory disorder of the brain—rather than just a chemical imbalance—could transform the treatment and prevention of conditions like depression, bipolar disorder, and schizophrenia. Dr. Chris Palmer is a psychiatrist and researcher working at the interface of metabolism and mental health. He is the Director of the Department of Postgraduate and Continuing Education at McLean Hospital and an Assistant Professor of Psychiatry at Harvard Medical School. For over 25 years, he has held leadership roles in psychiatric education, conducted research, and worked with people who have treatment-resistant mental illnesses. He has been pioneering the use of the medical ketogenic diet in the treatment of psychiatric disorders - conducting research in this area, treating patients, writing, and speaking around the world on this topic. More broadly, he is interested in the roles of metabolism and metabolic interventions on brain health. Dr. Todd LePine graduated from Dartmouth Medical School and is Board Certified in Internal Medicine, specializing in Integrative Functional Medicine. He is an Institute for Functional Medicine Certified Practitioner. Prior to joining The UltraWellness Center, he worked as a physician at Canyon Ranch in Lenox, MA, for 10 years. Dr. LePine’s focus at The UltraWellness Center is to help his patients achieve optimal health and vitality by restoring the natural balance to both the mind and the body. His areas of interest include optimal aging, bio-detoxification, functional gastrointestinal health, systemic inflammation, autoimmune disorders, and the neurobiology of mood and cognitive disorders.  Dr. lain Campbell is the first academic research fellow to specialise in Metabolic Psychiatry as the Baszucki Research Fellow in Metabolic Psychiatry at the University of Edinburgh. He has a PhD in Global Health from the University of Edinburgh and is a principal investigator on a pilot trial of a ketogenic diet for bipolar disorder. He is a workstream lead and co-investigator on the first publicly funded research hub for Metabolic Psychiatry, the UKRI Medical Research Council Hub for Metabolic Psychiatry at the University of Edinburgh. His research in metabolic psychiatry has been published in Nature press journals Molecular Psychiatry and Translational Psychiatry and presented at Mayo Clinic Grand Rounds and The Royal College of Psychiatrists International Congress.  This episode is brought to you by BIOptimizers. Head to bioptimizers.com/hyman and use code HYMAN to save 15%. Full-length episodes can be found here:A Harvard Psychiatrist Rethinks Mental Health As A Metabolic Disease Is Brain Inflammation The Cause of Depression, Dementia, ADD, And Autism? A Functional Medicine Approach To Neuroinflammation Is Bipolar Disorder Really a Diet Problem?

Coming up on this episode of the Dr. Hyman Show. 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. And whether it's autism or Alzheimer's or ADD or depression or schizophrenia, if you biopsy the brains, they're all inflamed. If you're feeling stressed, anxious, or having trouble sleeping, it's not always about willpower or mindset. It could be a mineral deficiency.

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illness um what we know are risk factors so 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. You know, 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. other, you know, so 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. That's right. I mean, you hit on 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? 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 in my career, I have really had the most extraordinary discoveries as a clinician because I'm not a researcher. Well, my Cleveland Clinic, we do research and I'm involved with that, but I'm not a traditionally trained researcher. And I just kind of was shocked to see when, and I think the same thing happened to you, when you 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 can I ever learn about this in medical school?

And then you go on 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, which 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. Thank you.

I think the real turning point for me was it started probably 20 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, a 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. So probably 18 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 with that because it's depression.

And, you know, yeah, eating a better diet, maybe some people feel better. It 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 with, you know, 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 treatments, 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. It's most people with that diagnosis are like that.

They don't get that much better. Ever, right? It just is how they have to live their whole lives. You just kind of give them medication and kind of manage your symptoms. It's basically, you know, the antipsychotics like Thorazine. Now they have better versions of it. But essentially, it's not much has changed since the 60s when they just, we call them major tranquilize. just sedate them so they're not, you know, like kind of going nuts.

So they're not causing trouble. And, you know, and to be fair, it's better than putting them in jail. It's better than letting them die. But 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. 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 decide 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 did he 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. And 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. It was probably about six to eight weeks later that he just spontaneously said, you know, there's 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 tormenting me on purpose? I'm like, oh, yeah, I know about that. Are we going to talk about that? I'm thinking to myself, are we going to talk about that again for the millionth time? 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 maybe it's getting better. And so that man went on to lose 150 pounds, and he's kept it off to this day. 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. couldn't go to a movie theater because he was terrified that people were out to get him. And that completely transformed everything I knew because I was initially just in disbelief. Like, this can't be happening. Yeah. Don't confuse me with the facts. My mind's made up.

It must be spontaneous remission, right? Exactly. Maybe he never really had schizophrenia, you know. It was interesting because I actually. He was working with a psychologist as well, and his father is very involved in his care. And I had to ask both of them several times, like, are you seeing what I'm seeing? I'm having a hard time believing what I'm seeing. He is dramatically transforming in ways that I've never seen with other people.

And 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 it with diabetes. But I had no idea that they, you know, the ketogenic diet had been used for 100 years in the treatment of epilepsy.

Yeah, for sure. And I didn't know that at the time. And so once I realized that, I quickly. Why? Because we don't really learn anything about nutrition medical school. Exactly. No. Because nutrition has nothing to do with disease, of course, right? Exactly. And the tragic part about that in particular, now that I am kind of an expert on the keogenic 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 have had more than enough research, clinical trials,

demonstrating that the ketogenic diet can stop seizures, even when pills and surgery don't. Yes. We have more than enough evidence on this. Yeah, the last resort is diet. After all the drugs and surgery don't work, then we try diet. Yeah. Then let's try diet, even though.

Because, I mean, diet could be dangerous. You might, you know. Yeah, they might end up losing weight. We wouldn't want that. But so once I realized that I started using this intervention in many other patients, and, you know, it was not across the board. It was not a miracle cure for everyone. I will fully state that and disclose that. Yeah.

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, you know, the most striking case was somebody who had been in remission for, you know, at the time was about 12 years. And she was 70 years old. It suffered from schizophrenia for 53 years. And her schizophrenia went into full complete remission off all

medications for 12 years. And those things don't happen in psychiatry right now. I mean, Chris, what you're saying is basically the world is not flat. 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 it's remarkable when you start to see it.

And essentially, it's like you're saying, well, it's like saying, well, I saw someone who's fully autistic and now they're not. That's the level of drama of this case. 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, you know, I want to 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 toxin that's causing a problem. them and if you don't deal with that then maybe they tune all day every day in their tuna fish sandwiches that's their diet at home but but you know we have to kind of get to the root cause but when you start to sort of broaden your net and look at the the uh the overlying framework you're really dealing with this this brain inflammation and and what you're saying is so revolutionary because when you look at the economics and the disability of mental illness it far surpasses any other illness, heart disease, cancer, diabetes, Alzheimer's, it is the single biggest cause of disability and costs. I think I read a study recently that $95 trillion are going to be spent

over the next 35 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. It's 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? Magnesium is like the body's natural chill switch. It helps regulate stress, sleep, mood, and more. But most people are deficient.

And most supplements don't give you the full spectrum. That's why I recommend magnesium breakthrough. The only formula with all seven forms of magnesium. Feel calmer, sleep better, and give your body what it's missing. Bioptimizers has increased their discount for my audience. Go to bioptimizers.com slash hymen and use code Hyman to get 15% off your order today. So 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, and then 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 how did you begin to say, unpack that? And what is 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.

Yes. And by the way, before I let you go on, I just want to point out that the ketogenic ties also work in autism and Alzheimer's and in many, in avi epilepsy, and I've seen this also in schizophrenic patients. So it's really powerful. It is. I just want to highlight, even though, you know, 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 is 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 and 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 100 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.

It, you know, improves people off gluten. 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 because 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 going to buy this and this miraculous treatment that I am seeing in front of my eyes is going to go wasted. And so I kind of felt like I'm an academic. No, you might not. You might lose your job. Yeah, I did worry about that many times. I mean, you probably wouldn't go to jail like Galileo, but you might lose your job.

I worried about that. The good news now is that I have the full support and endorsement of McLean Hospital, actually. Amazing. That's unbelievable. They are very enthusiastic and supportive of this. So 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. That's awesome.

So the way that I ended up coming to the science is I ended up focusing on mitochondria and mitochondrial function and more broadly what we call metabolism. And so I came at the science from that point. 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 So functional medicine has been doing this for decades, and yet I was holed up in my, you know, Harvard position and evidence-based medicine.

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 where this parliaments. 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. It's quite extraordinary. And, you know, I don't if you're aware of this, but right at Harvard, there is Umanadu, who has a whole department of nutritional psychiatry talking about the microbiome and the brain. And it's another physician

who's been on my podcast as 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 a lot of literature now that supports this notion. So when I look at sort of the mitochondria, it's really about metabolism and energy. And 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 is a psychiatrist, sort of neurologist, sorry, a neurologist. And I think she's also, works about it in psychiatry, I might be wrong, who wasn't 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 on a car accident or something. These brains are just full of inflammatory cells and the immune cells, the white blood cells called the glia.

And she also called what they have, a metabolic encephalopathy. She said that autism is just not a brain disorder. it's a systemic disorder that affects the brain. And it's what I hear you saying, that psychiatric illness, for the most part, is a systemic disorder that affects the brain. And the causes can be many. Like it could be your diet, it could be your microbiome.

But I was with the gentleman this weekend whose family, who's a Hungarian Jew, whose family was killed in the Holocaust. He says, I know 150 members of my family were killed in the Holocaust and everybody's name. And I've lived in a constant state of trauma and stressed my whole life. And, you know, I was like, wow, this is the epigenetics of this.

And 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 9-11, where they saw women who were pregnant when 9-11 happened, their children 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. And 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 it creates so much suffering. And so, you know, what you're talking about is really a revolution. 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. The 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.

And so in many ways, the reason that I became ridiculously excited about this theory is because it is a way to connect all of the dots, the bio-psychosocial models of mental illness. It is a way to connect all of them. So mitochondria are instrumental in neurotransmitter function, neurotransmitter 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 these questions, but wait, this can't, it can't be this simple. Like, this is too simple. There's no way 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. that should be true or this issue. And at the end of the day, everything in my mind seems to converge on these issues. 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. 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. Gleal 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, you know, 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, people who have depression have a higher risk for dementia. So it's not just about a serotonin deficiency. And it's just like cholesterol is not, you know, 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 neuroinflammation 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 have had pandas, which is the pediatric autoimmune neurop psychiatric 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 ticks, these OCD type behaviors, and et cetera. And these things are driven by neural inflammation. The original description was that

it was due to a strep infection. And, you know, 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've focused on strep being important because a strep infection can cause rheumatic heart disease. A strep infection can cause glomeral anopritis. 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 infections, 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. Yeah, it's just so remarkable the research on the brain 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 their disorders of brain immune function and and you mentioned the glial cells which 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 which is a big one that's when it's really active but i i know i've seen in my practice that focusing on brain inflammation has led to the most miraculous cures for all sorts of, quote, and curable conditions. And it's not often easy to find what the causes. They're not a patient 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 been 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 30 or 40 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 you see, that's sort of temporary. But the sort of chronic mood disorders are often related to brain inflammation. And they've even talked about using drugs for rheumatoor arthritis for depression to kind of shut off the inflammation of the brain. I 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 ultra-mind solution over a decade ago and it's only you know increased in terms of the 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'll get 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? Well, that's where 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 did their patient, when did the patient 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 that can trigger inflammation. And that's where you really

have to play medical detective. And, you know, sometimes you're going to find it on the first time. Sometimes you're not. It might take you, you know, a lot of uncovering, you know, lifting up stones, leaving no stone unturn. And that's where a functional medicine approach where, you know, we do a lot of advanced testing to look for, you know, not necessarily an infection per se. It's not like you have a fever and you're, 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. You know, it's a real, you know, you have to play detective is what is the key. I mean, and the key things, you know, really drive the problems are 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, you know, 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.

And I just recorded a podcast with Emmerin Mayer for the doctor's pharmacy. And he's all about the gut immune connection and how it affects the brain and 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-down 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 microbiomes role, toxins, 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, when we do is we go, wait a minute, well, what is the story behind? behind this person's particular illness. As you said, we've gone into a deep history. And if we don't do that, we will miss often the real keys

to figure out the root cause of their problems. And that's really what's so beautiful of functional medicines. We have a set of tools and a set of therapies that 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. Absolutely.

And you were talking about, you know, the 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 you get, as you get older, you slow down. And part of that slowing down is Parkinson's-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 with actually both bacteria and yeast. And there's a fascinating. literature on the 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 and the yeast actually do a metabolism of those foods, and will produce these chemicals, which are we call the metabolome or the gut micrometabolone.

And those metabolites in some people can affect the brain. And so in an 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. 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. I prescribe dogs all the time. It's like, it's one of my, I found my prescription, absolutely, yeah. It's interesting, the body knows. And I, you know, I think maybe we can just sort of share as a way of illustrating the power of address the inflammation on the brain with some cases. I have a bunch of cases from autism and Alzheimer's, but it would be good to get sort of a sense for, From your experience, what are the things that show up and how did you treat it and what happened? Well, you know, 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, you know, when somebody has psychosis or a breakdown, if you will, they call that a psychotic break or a manic break. or whatever you want to call that. And we've had a couple of recent cases where the patient's underlying trigger was Lyme disease, which is a spyrical condition. And I 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 as 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 spiro, or is caused by a spirochetal bacteria, and that's the same thing as Lyme disease. And Lyme disease is the great mimicor, and it also can cause dementia and psychosis. So that's one of the conditions that trigger neuroinflammation. And then also, there was a recent case of Bartonella also causing neuropsychiatric. conditions and a diagnosis of schizophrenia. So it's really a fascinating, fascinating field.

And the problem is, 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, you know, quite fascinating to me. And I, you know, people, always ask me, you know, what kind of doctor are you? And I have my own, my own description. Yeah, I'm a psycho-neuroimmuno-endogutologist and 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. So what happened? You said this patient with schizophrenia, right, and you found the tick infections. What happened then? 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 mycoplasm 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 a fascinating thing. And one of the tests that you can do that can check for this, it's a, it's not a common test.

And I don't know if you've done this, Mark, is the NMA 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 neuroinflammation that's driving their symptoms.

Yeah, it's quite incredible. So I've had patients who have schizophrenia before or bipolar disease, and, you know, you think these problems are just so intractable and so difficult to treat. And that can be. But, you know, in fact, the whole field of, functional medicine came out of the field of psychiatry with Abram-Hoffer's discovery that you could treat

schizophrenia, you know, using nutrients and helping to improve the biochemistry of the brain. And then Linus Pauline wrote his seminal paper, orthomolecular psychiatry in Science Magazine in 1969, which talked about the perspective of how do you straighten molecules. So those, how do you correct the imbalances or dysfunctions in your biochemistry? That's called orthomolecular, which means to straighten. and that has really led to the whole field of functional medicine and we then to 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 20% of schizophrenics have any gliding

antibodies in their bloodstream when you take the gluten away they 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 of 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 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. That's what's so exciting when we see in 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 and understanding the connection between the brain and some of these systemic processes. Yeah, absolutely. And when you take a schizophrenic and you, you look at them with a PET scan, the positive emission tomography, what you'll see is their brain

lights up. And that's because their microglia, which is their 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. And this mark is, I'm going to mention this because when I was, I actually do, I've done some lectures for American Academy of anti-aging medicine on neuroinformation. 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 did 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 the, you know, the empire state building. And 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. And 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, you know, why did this happen? And the two case reports were this. And this tells you, you know, 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. The bone marrow transplant is basically giving you a new immune system. After he got the bone marrow transplant, guess what happened to was refractory schizophrenia. It was gone. What happened? 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 he caught he got schizophrenia he gets schizophrenia wow that's pretty amazing that's pretty amazing yeah it is amazing i was blown

away by that and i think that you know in you know people who are doing i'm you know i'm a clinician i'm seeing patients but the those those case reports are really really seminal to change how we think about how we see these conditions a metabolic psychiatry is uh essentially a proposal that I know you've recognized for a long time, but that 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 as a chemical imbalance and neurotransmitter imbalance. But one of the ways I think about this when you hear this as a patient is, it's 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 want to look for like what is causing this to happen more fundamentally. And the 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 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 the air conditioning.

You 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 gas of neurotransmission and so forth. 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 Yes. Energy factories in your cells to take oxygen and food and combust them to turn into ATP or energy. Yes.

And if there's an energy crisis because you can't make it because there's basically bad energy. Yes. you're going to have a whole set of downstream symptoms and problems as a result of that. And for some people it manifests as diabetes, for some people it manifests as schizophrenia for some of bipolar disease or as Alzheimer's, which they call type 3 diabetes. So it's the same fundamental problem of insulin resistance and singling and glucose metabolism that's disrupted that can be caused by many factors.

Yes. But you're basically talking about going upstream and dealing with the root causes of the problem. Insulin is a particularly interesting example because 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 signalling. And I point out in this paper that many of the major targets of lithium are part of the insulin signaling network. By the way, lithium is the drug that's used to treat and bipolar disease. You know, the PI cycle, G-SK-3, AKT, M-T, M-Tor,

these are all parts of the insulin signaling network. For those in English, those are the biochemical pathways that relate to your blood sugar and insulin control that we have many redundancies in, and there are many of those pathways that get interrupted by problems in the energy metabolism. Since proposing this, there's been quite a number of studies on it. There was a study in Lancet Journal in your biology

where Martin Alda, who developed the Aldo Scale for lithium, for example, and a team investigated this in what's, they make these kind of organoids. 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 they kind of, what we might be starting to discover is that we're kind of obtrusely or like I say, bluntly addressing some of these metabolic pathways through various forms of treatment.

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

is a really important area for psychiatry research. 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 and the genetics and the diagnostic tools, the blood biomarkers, metabolomics, functional MRI imaging, imaging.

You know, the thing about psychiatrists never do brain imaging It's kind of crazy when you think about it. It's like, you don't want to look under the hood and see what's happening. Someone said that modern medicine 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-5, which means a diagnostic and statistical manual version 5. Yes. Because there's been one, two, three, four, five. Yes. And the latest version, and basically, it's descriptive. Yes. It just, it's a phenomenological description of these symptoms. And if you, you fall into this category of these collective symptoms, you get this diagnosis.

You get ADHD. You get bipolar disease, and there's subcategories. is schizophrenia, depression, different kinds of depression. And it's very, very detailed. And it's like, incredibly, like, detailed about which type of each mental illness. You can get different kinds of anxiety disorders, different kinds of bipolar, different. 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. Yes. And unless we take seriously this fact and take. Seriously, the research that we need to undertake to actually investigate these cases, 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. Yes. But when you look at them, there are also metabolic problems.

And when you look at the amount of quality of life loss, we call it the quality-adjusted life years or qualities, basically how many years have you lost to suffering, which you lost many years to suffering. When you take that number, you know, depression and psychiatric illness far exceeds everything else. Yes. 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 Brizinski group, which is a group of that sort of help 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, 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, it 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 and not. So, I mean, I can answer it from a researcher perspective and a patient perspective. As you mentioned, the Buzuki family who are funding metabolic psychiatry research and Matt Buziki, their son, received a diagnosis of bipolar disorder and you know he had really incredibly severe symptoms he was hospitalized many times went through and their family really went through you know

many treatments like over 30 treatments having full access to the US healthcare 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 and treatment-resistant patients. And eventually he went on a ketogenic diet with Chris Palmer, 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 kind of... And your father's a researcher as well. Yes. He worked in developing countries doing global health research throughout its career, and he's always been interested in, he's been a, 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 their research this. I had to work a day job for many years to support my research. I was turned down from 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 Piziki, because I put up a, one of the few things I could do the time was put up a YouTube video of a, I put up this 45-minute YouTube video describing some of the things you're describing about the frustration with diagnosis. And, and I think what we both recognized for me the 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 were being given aren't the map is not matching the territory yeah we're trying to describe this complex biology yeah but the the the maps were 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 um Jan Buzicki and Dave Vizuki funded our pilot study at Edinburgh and this was after about six years of trying to find support for this. And this really was how the field started through the support of the

Buzikis putting investment because of their son's journey. And so I really find that remarkable how much they've got sort of in the trenches with patients and said, we're going to make this happen. We're going to 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 Jenny, my family, and many others across the world, Chibanii, Chris Palmer, that I've been working in this field for a long time, Georgia Eid, treating patients, and everyone's sort of realizing we have to fix this.

This can't continue. So I totally agree the map is not matching the territory, and this is, we're all trying to reconfigure this. Yeah, I don't know if you just came up with that, but that was something my professor, mentor, Dr. Cindy Baker, taught us, which is that we're given the wrong map for the territory of illness we're in. Yes, yeah, absolutely. And 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 going to help you. Yes, absolutely, yes. You know, and I think that's what we have in medicine. We have the wrong map. And across all of the chronic health diseases,

not just psychiatric illness. And all these diseases have chronic, chronic suffering that humanity has got right now, which is globally just so incredible. And it's only in the last 150 years, we really began to see the explosion of these chronic illnesses, you know, we now are beginning to finally understand them. And it seems to be like a new kind of golden era of medicine

and also particularly psychiatry. You know, I want to sort of get into the weeds a little bit because I think, you know, as people listening, I 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 or I have the pressure, 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, you know, 50 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 5 to 7 million 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 MRI imaging, which is basically now 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 Goe from Harvard Oxford trained physician, pediatric neurologist, has done a lot of an autism and also found it to be a mitochondrial energy deficit. that you treated those kids with mitochondrial therapies and then they work. Yeah, yeah.

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

I think bipolar disorder is an extreme version, you know, it's in 1% 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, you know, 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 and many different types of people. I could share some of what the history of the biomarkers and the ways people have conceptualized bipolar 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 Kreplen.

In 1921, he published a paper called manic depression of insanity. 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. And what do you mean by metabolic disorder? 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 the most striking disorders in manic depresses of 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 said in many of my patients i saw mooniness set in in the autumn and pass over 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 in many other conditions, schizophrenia and so forth, have this kind of 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 in

energy. So if you speak to bipolar patients in the spring, they have this huge surge of energy and activity, 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 photo period, 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 photo period is that's lowest. So what we're kind of seeing is a male Krippelin 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 the same amount of food, right? Yeah, exactly, yeah. And so the extreme examples in the natural water 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 used throughout the year could be completely

dysregulated by artificial light conditions, metabolic factors, diet, and so forth. I think that, you know, we're talking about insulin signalling, and in the winter, many species suppress their insulin signaling and glucose metabolism. They go into metabolic depression. Like bears, they hibernate. Yeah. And they gain all the weight in the fall, and then they live off the fat in the winter, right? Yeah, and 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 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. M-Tor, AMPK, Sertunes, A-K-T, 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 disregulating. The light bulb in the advent of... Refined sugars and starches led to a big host of chronic disease problems, including mental health. A really great example I could share is, so I mentioned Matt Buzuki, and 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 photo period, changing length of daylight at the spring equinox. And it's really notable, you know, 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 as a gun room,

which is, I think that Johann Andreas Norman noted, in animals in captivity, many, particularly migratory birds, for example, around the spring equinox become hypermetabolic. They start trying to bang their head off the side of the cage. They're staying up all night. Their circadian rhythm is suppressed. They're having insomnia. 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 think these are just analogies from the natural world. Of course, they're not directly related. But I think there is clear evolutionary mechanisms, circadian and metabolic mechanisms that are active in bipolar and across some of these psychiatric conditions

that we need to explore. Historically, mentalness has really been about philosophy and religion and just psychological explanations, which don't actually fit the current understanding of mental health issues. 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, you know, this kind of Cartesian idea that the body and the brain are separate has really informed a lot of psychiatric practice.

Amel Kreplen, who was considered the founder of modern psychiatry. In 1921, he wrote books describing this biological basis of mental illness. But there was a kind of split in psychiatry where Emil Krippin 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. Just laying the couch for five days a week for 20 years and you might feel better. Yes. You might feel better. Yes.

Now you're sort of getting into the biology a little bit. And so you came 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 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. It was like serotonin and 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, you know, genetic profiles we do in our clinic at the ultra-wleness center, look at the risk factors for psychiatric disease. Can you talk about some of those genetics? Bipolar disorder and many psychiatric conditions are quite polygenic, which means that there's not any kind 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 think where it gets interesting is the gene environment interaction.

You know, maybe there's an evolutionary, many people have hypothesized as an evolutionary purpose for things like bipolar, it stays at 1 or 2% in the population consistently. You know, why would this be conserved in humans? Why wouldn't it be selected out of the gene pool? And many people have said 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. And so 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 of genes. Many, many combinations of genes. Yeah. I mean, when you look at the literature, there's an interesting genes that affect mental health, like methylation genes, which involve how we kind of transfer a carbon and 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 do.

detoxification and to regulating oxidative stress and inflammation. I mean, and what's really interesting 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't handle the environmental toxins that were exposed to. It can't handle the various kinds of stressors. And so we kind of break down.

And there's, you know, and like genes like MTA. far in COMT that you can measure now that can tell you what's going on. There's genes that relate to serotonin metabolism, 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 surrogate stuff. I don't know if you want to say something about the genetics. I want to ask you to which circadian genes have been noted that you're interested in.

It's something called clock genes and ART, ARNTL or ARN-TL are genes. These are genes that just affect circadian rhythm. They affect, you know, our biology. ways that affect mood disruption if there's circadian rhythms disrupted. That's really interesting. Because half of my research is on, well, the majority of my research is on metabolic psychiatry, but we also have a lot of chrono-psychiatry research led by Professor Daniel Smith in Edinburgh.

And the central focus of chronic psychiatry research is the things you're mentioning, clock B-MAL-1, per cry. And these are your circadian regulators. And they basically take signals from the environment, the light, and they convert this the super-chaismatic 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 downregulate 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 kind of conserve and utilize energy accordingly. So I think these make sense in terms of an energy metabolic disorder. If you love this podcast, please share it with someone else you think would also enjoy it. You can find me on all social media channels at Dr. Mark Hyman. Please reach out.

I'd love to hear your comments and questions. Don't forget to rate, review, and subscribe to the Dr. Hyman show wherever you get your podcasts. And don't forget to check out my YouTube channel at Dr. Mark Hyman for video versions of this podcast and more. Thank you so much again for tuning in. We'll see you next time on the Dr. Hyman show. This podcast is separate from my clinical practice at the Ultra Wellness Center, my work at Cleveland Clinic, and Function Health, where I am chief medical officer. This podcast represents my opinions and my guest's opinions.

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