Metabolism, Mitochondria & Bipolar Disorder - Chris Palmer MD

one of the big points that I want to make is a lot of us here are talking about this as an emerging field a new field I don't at all see it that way this is about connecting the dots of mental illness this field dates back at least a century and a half we have an abundance of evidence of metabolic abnormalities in the brains of people with mental disorders and I am going to review just a tiny snapshot of some of that but I want to start with a big picture question what causes mental illness right now our field is clear and unequivocal in its answer no one knows all we know are risk factors and to date nobody has been able to synthesize all of them and put them together in a coherent way what are the risk factors it's the biopsychosocial model there are biological factors psychological factors and social factors that all come together to result in mental illness now although most people think about mental disorders some of them are biological disorders bipolar disorders schizophrenia those are biological and then there are other ones that are social or psychological like anxiety or depression but in fact those distinctions are not true biological psychological and social affect all mental disorders including schizophrenia and bipolar disorder including anxiety and depression and I've been asking the question for years could metabolism play a role but that begs the question what is metabolism so although a lot of people have simplistic thoughts about metabolism metabolism is burning calories metabolism is about metabolic syndrome it's about obesity diabetes and cardiovascular disease I take a much broader perspective that is not metabolism those are parts of metabolism but metabolism a simplistic definition living organisms take food they convert it into energy and building blocks used to maintain or grow cells metabolism also includes the appropriate management of waste products in fact metabolism is fundamental to the definition of all living organisms so in a way of course mental disorders are related to metabolism everything is and this graphic that you see is just one representation of the various metabolic pathways in the human body the circle that you see is the Krebs citric acid cycle I'm also going to be talking about mitochondria so what are mitochondria although most people know the definition the PowerHouse of the cell the reality is research over the last 20 30 years suggests something far greater mitochondria are so much more than powerhouses although Powerhouse function is important they are critical players in what I would call metabolism there are hundreds or thousands of them in each cell they are highly dynamic they move around cells they fuse with each other they butt off from each other they are involved in numerous cellular processes including calcium regulation the epigenetic control of our nuclear DNA steroid hormone synthesis and many other functions so we're going to be talking about mitochondrial dysfunction because that's the buzzword these days mitochondrial dysfunction so what is mitochondrial dysfunction I will argue that based on the numerous roles of mitochondria this is actually difficult to Define it's difficult to measure so the most common way to measure it is called oxidative stress or reactive oxygen species terms most people have heard of and so this dates back to 1956 when Dr Denham Harmon proposed the free radical Theory of Aging and what is aging aging is about metabolic disorders aging is about obesity diabetes cardiovascular disease cancer and Alzheimer's disease and what causes those diseases he proposed free radicals in 1972 he amended this hypothesis recognizing that mitochondria were critical to this process of free radical production and in fact the theory goes that mitochondria or dysfunctioning mitochondria produce free radicals those free radicals turn around and damage the mitochondria themselves they can result in mitochondrial DNA mutations that causes more dysfunction in the mitochondria which causes more free radicals and it's a vicious cycle that results in what we call illness or aging and death but it turns out that this theory is not so accurate because free radicals actually serve a very critically important role in the human body so here's just a timeline of some of the metabolic and mitochondrial hypotheses of bipolar disorder there were many to pick and choose from so in 1879 Sir Henry modsley quoted diabetes is a disease that shows itself in families in which Insanity prevails insanity is schizophrenia and bipolar disorder from the 1930s to the 1950s the most widely used treatment in the field of Psychiatry for mood and psychotic disorders with something called insulin comatherapy now I am not advocating for the return of insulin comotherapy but you're going to hear from additional researchers insulins making a comeback in the mental health field this is nothing new let's be humble about what we're doing nothing new they knew about insulin 100 years ago in the 1950s abnormalities in metabolic markers were first identified in patients with bipolar disorder and schizophrenia abnormalities and lactate 70 years ago in the 1990s functional neuroimaging studies began and we have a plethora of data showing metabolic abnormalities or metabolic differences in the brains of people with mental disorders so those researchers are going to say metabolic Psychiatry where have you been we have been measuring metabolism in the brain for decades wake up welcome to the party that led to the first hypothesis the mitochondrial hypothesis of bipolar disorder proposed by Cato and Cato in 2000. that was quickly followed by researchers at our own McLean Hospital I look at Virginia who identified mitochondrial Gene differences in patients with bipolar disorder and in normal controls that same year other researchers identified differences in lactate metabolism in the brains of patients with bipolar disorder compared to healthy controls and since that time there has been an explosion of research on the mitochondrial and metabolic hypothesis of bipolar disorder and also schizophrenia I will walk you through just a couple of examples of that but wait bipolar disorder is genetic it's genes right it runs in families well in fact there are genetic disorders called mitochondrial diseases in which people have genetic mutations in proteins that code for mitochondria themselves 16 to 21 of those patients have bipolar disorder which is an approximately 20-fold increase compared to the normal population three high-risk genes for bipolar disorder include ant1 disc 1 and just this year just a month or so ago acap 11. and what do these genes do they actually all play a role in mitochondrial function and Metabolism there's a stem cell model researchers took fibroblasts from bipolar patients and healthy controls and reprogram them into neurons what they found is that the neurons from the bipolar patients had mitochondrial dysfunction or abnormalities and they were hyper-excitable among the bipolar patients who responded to lithium the lithium in the petri dish stopped that hyper-excitability in those cells there's another study mitochondrial changes in the phases of bipolar disorder so you know where we measure mitochondria is important and different cells have different levels of mitochondrial fund they actually have different mitochondria they have different levels of mitochondria and different levels of mitochondrial function but a common metric is to look at mitochondrial DNA copy number and or function in white blood cells and this research group looked at the three phases of bipolar disorder manic depressed and euthymic and they found that on average patients had decreased mitochondrial DNA copy number in the phases of illness which then normalized in the euthanic phase and that as patients got more and more ill the DNA mitochondrial DNA copy number declined and in fact there's vasic dysregulation of mitochondria and bipolar disorder there are many lines of evidence to support this including PET Imaging of brain glucose metabolism calcium regulation levels of dopamine and glutamate activity so what causes mitochondrial dysfunction the real answer is numerous things the good news is a lot of these things are things you've all heard about they're all risk factors for mental disorders or the exacerbation of mental disorders I'll briefly just mention two so this all of this research that I mentioned has not been lost on the research Community the explosion of research of antioxidants and anti-inflammatory agents for metabolic and mental disorders is all based on the mitochondrial hypothesis of bipolar disorder make no mistake this is nothing new we are coming up with a new not even a new treatment because it's actually 100 year old treatment we're talking about a ketogenic diet 100 year old treatment but we're talking about a new application that builds on a tremendous amount of science so levels of inflammation are higher in patients with bipolar disorder and I'll cut to the chase numerous anti-inflammatory agents and antioxidants have been studied and at best they have statistically significant differences but they are not clinically meaningful differences they do not change people's lives insulin resistant we've all heard about insulin resistance insulin resistance causes mitochondrial dysfunction and then we come to the ketogenic diet so what is the ketogenic diet doing I know some many of you could give five day conferences on this topic what is the ketogenic diet doing it's doing lots of things it's changing neurotransmitters ION channel regulation levels of inflammation the gut microbiome blah blah blah but I am going to focus right here it induces mitochondrial biogenesis it induces mitophagy so we are healing mitochondria and we are changing metabolism when people are on a ketogenic diet so what are some of the challenges of advancing this work and I am only going to map out the academic challenges there are many political challenges reimbursement challenges and others involved in this the academic challenges of advancing this work the reality is mitochondrial dysfunction has been found in everything else it's been found in obesity cardiovascular disease Alzheimer's disease Parkinson's disease cancer aging so in order to really explain the mitochondrial theory of bipolar disorder we have to be able to explain the mitochondrial Theory of Everything mitochondrial function is difficult to measure can be different in different cells and it often changes due to these factors listed there are heterogeneous symptoms in people with the exact same mitochondrial mutations so you can have two people from the same family exact same mitochondria mutation one can have bipolar disorder the other may not and people with the exact same symptoms bipolar disorder may have very different mitochondrial or metabolic abnormalities or findings the biggest challenge to this work make no mistake is that many of our current treatments cause mitochondrial dysfunction they cause metabolic abnormalities and so on the on on the surface for most clinicians and researchers if you're saying metabolism or mitochondrial dysfunction causes mental illness why the hell would our treatments work you have to be wrong and you better dare not say that our treatments might actually be causing harm because then you would be a dangerous quack if we get past that then we have a multi-billion dollar pharmaceutical industry who will not want a paradigm shift but the reality is two leading researchers two leading researchers who have committed their careers to the mitochondrial hypothesis bipolar disorder here are two quotes from Cato the original proposer even if we say that mitochondria and calcium signaling are involved in bipolar disorder it's no different from saying that cells are involved in bipolar disorder because most cells have mitochondria and calcium signaling plays a role in everything so what are we really saying another person who will go unnamed that is a leader in this field we need a supercomputer that can analyze Chaos Theory to figure this out and with that said I will audaciously or stupidly share with you that I believe the dots do connect in very clear and plausible ways and that once the dots are connected in these clear and plausible ways we can actually make accurate predictions about a wide variety of things that we already know to be true in the mental health field and I do believe that the metabolic and mitochondrial hypothesis a bipolar disorder which I am calling the brain energy theory in my book has the potential to transform our field thank you [Applause]

Channel: Metabolic Mind

Views: 25,599

Keywords: metabolic psychiatry, keto, ketogenic diet, keto for mental health, nutritional psychiatry, mental health, mental illness, bipolar, schizophrenia, depression, alternative psychiatry, metabolic health, mitochondria, brain energy, chris palmer, dr chris palmer

Id: qV1bD_bGLnI

Length: 13min 58sec (838 seconds)

Published: Wed Nov 30 2022