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

26:35And 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 be true. 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. Now, 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.

27:17And 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 micro glial 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.

27:55And 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.

28:42So 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.

29:26It'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 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 ticks, these OCD type behaviors, et cetera. And these things are driven by neuroinflammation. The original description was that it was due to a strep infection. And mothers and fathers know about that because when a kid gets a sore throat, to take them to the doctor, make sure they don't get a strep infection.

30:11And 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.

30:48Dr. Mark Hyman:Yeah, it's just such a remarkable, the research on the brain in the last decade and how it's revealed that all the conditions that we thought were maybe psychiatric are maybe more biological in the sense that they're disorders of brain immune function. 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, including lack of sleep, which is a big one. That's when it's really active. But 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, incurable conditions.

31:22Dr. Mark Hyman:And it's not often easy to find what the cause is. I had a patient the other day who had tics since he was a little boy. And it turned out he was really, they come 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 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.

31:59Dr. Mark Hyman:And usually that's sort of temporary. But these sort of chronic mood disorders are 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. 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 Ultramind Solution over a decade ago. And it's only increased in terms of the prevalence of these problems and the data linking inflammation and actually uncovering some of the causes of inflammation that are driving this.

32:34Dr. Mark Hyman: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 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.

33:08And 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 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.

33:45And, 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 unturned. 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 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.

34:36So it's a real, you know, you have to play detective is what is the key.

34:40Dr. Mark Hyman: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 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. I just recorded a podcast with Emmer 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.

35:14Dr. Mark Hyman: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, 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 inflame the brain. And then of course, there's infections that you were talking about, like viruses or tick infections and so forth.

35:55Dr. Mark Hyman:These all can be driving brain inflammation. So in functional medicine, what we do is we go, wait a minute, well, what is the story behind this person's particular illness? As you said, we 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 with some beautiful 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.

36:26And you were talking about the connection with the gut and there's really some fascinating stuff. When I was in training, we talked about Parkinson's and Parkinson's is the old person's disease. As you 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 with actually both bacteria and yeast. And there's a fascinating literature on the microbiome and the metabolites of the microbiome.

37:08And 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 what we call 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.

37:50And in fact, they're actually training dogs to sniff out Parkinson's.

37:54Dr. 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. I prescribe dogs all the time. It's one of my prescription. Absolutely. Yeah. 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 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.

38:37In 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, you know, when somebody has psychosis or a breakdown, if you will, they call that, you know, 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 spirochal 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 private practice today.

39:24It's just a condition which was readily treated, and it's pretty much gone, although there's still some occurrences of it. But syphilis is caused by a spirochetal 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 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.

40:12And 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 description.

40:33Dr. Mark Hyman:Yeah, I do answer that question. Yeah, I'm a psychoneuroimmunoendogutologist, and basically looking at the whole connection between the brain, the gut, the immune system, and all of the body, and 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 saw 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

41:12spirochetal infection. I also have 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 a 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 neuroinflammation that's driving their symptoms.

42:07Dr. Mark Hyman:Yeah, it's quite incredible. So I've had patients who have schizophrenia before or bipolar disease, and you think these problems are just so intractable and so difficult to treat, and they can be. but you know in fact the whole field of functional medicine came out of the field of psychiatry with abram hofer's discovery that you could treat schizophrenia you know using nutrients and helping to improve the biochemistry of the brain and then linus calling wrote his seminal paper orthomolecular psychiatry and science magazine in 1969 which talked about the perspective of how do you straighten molecules in other words how do you correct the imbalances or dysfunctions in your biochemistry.

42:47Dr. Mark Hyman: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, you know, many schizophrenic patients have high levels of, for example, gluten antibodies. About 20 % of schizophrenics have anti-gliden 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.

43:21Dr. Mark Hyman:So 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.

43:53Dr. Mark Hyman: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 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 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.

44:29And 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 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 did this whole genome-wide association studies of saying, well, what gene or what genes are associated with schizophrenia?

45:07And they did what's called a Manhattan plot. And on chromosome six, it sort of stood out like 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?

45:44And 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. Bone marrow transplant is basically giving you a new immune system. After he got the bone marrow transplant, guess what happened to his 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.

46:22I 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 got schizophrenia. He got schizophrenia. Wow.

46:41Dr. Mark Hyman:That's pretty amazing. That's pretty amazing. It is amazing. I was blown away by that. And I think that, you know, people who are doing, you know, 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. A metabolic psychiatry is 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 is a chemical imbalance, a neurotransmitter imbalance.

47:25But 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 a 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.

47:54but 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 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 um 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.

48:33So basically it's a metabolic problem.

48:36Dr. Mark Hyman:It's sort of like diabetes in the brain in a sense. 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 manifests as diabetes. For some people, it manifests as schizophrenia, as bipolar disease or as Alzheimer's, which they call type 3 diabetes.

49:14Dr. Mark Hyman:So it's the same fundamental problem of insulin resistance and insulin signaling and glucose metabolism that's disrupted that is you know can be caused by many factors yes but but you're you're basically talking about going upstream and dealing with the root causes yes of the problem insulin signaling 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 Signaling.

49:53And I point out in this paper that many of the major targets of lithium are part of the insulin signaling network.

49:59Dr. Mark Hyman:By the way, lithium is the drug that's used to treat open bipolar disease. You know, the PI cycle, GSK3, AKT, mTOR, 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 with energy metabolism. Since proposing this, there's been quite a number of studies on it. There was a study in Lancet Journal in neurobiology where Martin Alda, who developed the Alda scale for lithium, for example, and a team investigated this in what's, they make these kind of organoids.

50:34They're like mini brains. They derive from neurons from bipolar patients. and they found that that lithium was modulating this insulin signaling pathway but i think the kind of 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 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's this metabolic damage and dysfunction that can happen.

51:10And 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 that leads to diabetes and so forth. Powerade function and other things, yeah. So I think looking for better metabolic treatments is a really important area for psychiatry research.

51:30Dr. Mark Hyman:So we're kind of entering this new era 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 some of the diagnostic tools the blood biomarkers metabolomics functional mri imaging imaging you know i mean the thing about psychiatrists never do brain imaging it's kind of crazy when you think about it it's like but it's like you want to you don't want to look under the hood and see what's happening someone 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.

52:09Dr. Mark Hyman: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 the Diagnostic and Statistical Manual Version 5, because there's been one, two, three, four, five. And the latest version, and basically it's descriptive. Yes. It's a phenomenological description of these symptoms and if you fall into this category of these collective symptoms, you get this diagnosis. You get ADHD, you get bipolar disease and there's subcategories. Yes. Schizophrenia, depression, different kinds of depression and it's very, very detailed and it's like incredibly detailed about which type of each mental illness you can get, different kinds of anxiety disorders different kinds of bipolar different it's like yeah 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 under undertake to actually investigate these things we're never going to help address one of the biggest causes of suffering globally i mean And yes, obesity, diabetes, and heart disease, cancer are really the big killers.

53:36Dr. Mark Hyman:Yes. But when you look at them, there are also metabolic problems. Yes. And when you look at the amount of quality of life lost, we call it the quality adjusted life years or qualities. Yes. Basically, how many years have you lost to suffering, which you lost many years to suffering? When you take that number, depression 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 that 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?

54:25Dr. Mark Hyman: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 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?

55:04Dr. Mark Hyman: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 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 Buzuki, their son, received a diagnosis of bipolar disorder.

55:44And, 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 u.s 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 um 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, Denise Potter, a dietician, and experienced remission of his symptoms.

56:24And 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.

56:33Dr. Mark Hyman:And your father's a researcher as well. Yes. He worked in developing countries doing global health research throughout his career and he's always been interested in he's been uh 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 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 Buzicki 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 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 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.

57:41And 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 this really was how the field started through the support of the Buzickis 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 and um but it really came from just reaching a peak of suffering both their family journey our research journey my family and um and many others across the world shibani seti chris palmer that have 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 um so i totally agree the map is not matching the territory.

58:52And this is, we're all trying to reconfigure this.

58:55Dr. Mark Hyman:Yeah, I don't know if you just came up with that, but that was something my professor mentor, Dr. Sidney 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 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. and we have the wrong map across all of the chronic health diseases, not just psychiatric illness. And all these diseases of chronic suffering that humanity has got right now, which is globally just so incredible.

59:32Dr. Mark Hyman:And it's only in the last 150 years that we've really begun to see the explosion of these chronic illnesses. We now are beginning to finally understand them. And it seems to me like a new kind of golden era of medicine and also particularly psychiatry. Now, 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, you know, 50 years ago, like we've decoded our whole genome.

1:00:10Dr. Mark Hyman: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 seven 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 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?

1:00:50Dr. Mark Hyman:And what does that tell us about what's happening energetically in the brain? You know, Suzanne Goh 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. He treated those kids with mitochondrial therapies and they work. 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 disorder. I have anxiety, or I have depression, or I have, you know, you name it, OCD. Do these share common things? Does this apply also to those from your perspective?

1:01:23I think bipolar disorder is an extreme version. You know, it's 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 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 in many different types of people i could share some of what the history of the 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 um psychiatrist called Amel Kreplin.

1:02:05In 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.

1:02:38And 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.

1:03:09And he said that the most striking disorders in manic deprefts 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, he said, in many of my patients, I saw mooniness set 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 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.

1:03:52So 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 hospitalisations, it occurs at the spring equinox, at the autumn equinox. And conversely, depression happens in the winter.

1:04:25so 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 kind of seeing is a male crippling was describing the seasonal variation of energy and metabolism related to circadian function and if you look at um you know the natural world this is a part of the natural world humans for 95 percent 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 and 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.

1:05:07There's extreme examples in the natural world. Exactly, yeah. And so the extreme examples in the natural world are hibernation torpor in the winter and migration hypermetabolic behaviours 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.

1:05:54A 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, you know, we're talking about insulin signaling and in the winter, many species suppress their insulin signaling and glucose metabolism. They go into metabolic depression. Like bears, they hibernate. Yeah.

1:06:14Dr. Mark Hyman:And they gain all their 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 an 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.

1:06:50Dr. Mark Hyman: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.

1:07:25And there's a really interesting analogy in the natural world called a Zagunru, which is a thing that Johan Andreas Neumann 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 behaviour so 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.

1:08:13Dr. 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. 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. Amil Kreplin, who was considered the founder of modern psychiatry, in 1921 he wrote books describing this biological basis of mental illness.

1:08:53But there was a kind of split in psychiatry where Amil 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 issues with your mother and so forth. You're laying on the couch for five days a week for 20 years and you might feel better. Yeah, exactly. You might feel better. Yes.

1:09:14Dr. Mark Hyman:Now you're sort of 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 psychological in nature, or maybe it was a chemical imbalance. And I mean, the chemical imbalance idea wasn't exactly wrong. It is biochemical, but it's just they were looking at the wrong thing. I was like serotonin, it's dopamine, it's this and that. And I think 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.

1:09:46Dr. Mark Hyman: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 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 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.

1:10:39And so I think that 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.

1:10:51Dr. Mark Hyman:I mean, when you look at the literature, there's interesting genes that affect mental health, like methylation genes, which involves how we kind of transfer 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 detoxification and to regulating oxidative stress and inflammation. I mean, what's really interesting that it's 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.

1:11:28Dr. Mark Hyman:It can't handle the environmental toxins that we're exposed to. It can't handle the various kinds of stressors. And so we kind of break down. And there's 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, 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 wanted to ask you which circadian genes have been noted that you're interested in. There's something called clock genes and ARNTL or ARNTL genes.

1:12:04Dr. Mark Hyman:These are genes that just affect circadian rhythm. They affect our biology in ways that affect mood disruption if their circadian rhythm is 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 chronopsychiatry research led by Professor Daniel Smith in Edinburgh. And the central focus of chronopsychiatry 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 in the suprachiasmatic nucleus of the brain, which is kind of like a clock system in the brain.

1:12:44And 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

1:13:11Dr. Mark Hyman: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 guests' opinions.

1:13:45Dr. Mark Hyman:Neither myself nor the podcast endorses the views or statements of my guests. This podcast is for educational purposes only and is not a substitute for professional care by a doctor or other qualified medical professional. This podcast is provided with the understanding that it does not constitute medical or other professional advice or services. If you're looking for help in your journey, please seek out a qualified medical practitioner. And if you're looking for a functional medicine practitioner, visit my clinic, the Ultra wellness center at ultrawellnesscenter.com and request to become a patient.

1:14:15Dr. Mark Hyman:It's important to have someone in your corner who is a trained, licensed healthcare practitioner and can help you make changes, especially when it comes to your health. This podcast is free as part of my mission to bring practical ways of improving health to the public. So I'd like to express gratitude to sponsors that made today's podcast possible. Thanks so much again for listening.