Found My Fitness with Dr. Rhonda Patrick – Dr. Charles Raison on Depression, the Immune-Brain Interface & Whole-Body Hyperthermia

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  • Real clinical depression can have a biological cause that science is showing to be linked to the behavior of the immune system and its interaction with the brain
  • Charles Raison, M.D. is a professor at the School of Human Ecology at the University of Wisconsin-Madison and Founding Director of the Center for Compassion Studies in the College of Social and Behavioral Sciences at the University of Arizona.
    • Dr. Raison’s research focuses on inflammation and the development of depression in response to illness and stress.
  • Check out Charles’ book –  The New Mind-Body Science of Depression
What role does inflammation play in depression?
  • The brain and the immune system are linked
  • Inflammatory markers (like cytokines) are elevated in depressed people
    • If you have episodes of inflammation earlier in life, an autoimmune condition, or a bad infection, you’re significantly more likely to develop major depression
    • “There’s something about chronic inflammatory activation that induces changes in the brain and body that tee you up for depression”
The Evolutionary Benefit of Depression
  • There’s evidence that suggests depression may have evolved out of sickness
  • There’s many overlapping symptoms of sickness and depression
    • For example, both sick and depressed people have elevations in their core body temperature
    • Iron levels are also low in sick and depressed people
      • Our iron levels drop when we’re sick because intracellular bacteria need the iron more than you do
  • When we get sick, many things that happen protect us from pathogens
    • Hyperthermia (increase in core body temperature) – ramps up immune functioning
      • Microorganisms tend to “unwind” at higher temperatures and thus aren’t as harmful
  • In summary – depression evolved out of sickness as a strategy for pathogen defense
    • Inflammation induces sickness
    • We know sickness and depression share a lot in common
    • Anything that signals a need for increased inflammation, activates a suite of behaviors that over time, involves into depression
  • Genes found to be depression risk factors seem to have anti-pathogen effects
  • Many factors in the modern world are pro-inflammatory and are also associated with depression (obesity, sedentary lifestyle, diet etc.)
    • Rates of depression may have risen because of this
  • “There is a direct link between depression and increased survival from infection”
Is inflammation driving depression?
  • Studies show that the link between obesity and behavioral cognitive problems are mediated by increased inflammation
  • The heavier you are, especially around the mid section, the more likely you are to be depressed
    • Fat cells are big producers of inflammatory markers
  • In studies, introducing pro inflammatory cytokines (ex: interferon alpha) directly into the body, can cause people to immediately have depressive symptoms
  • Aerobic and strength training exercise can serve as potent forms of antidepressants
    • Exercise elevates inflammatory processes acutely
    • Then there’s an anti-inflammatory response, that is much more powerful than the initial stressor that occurred
  • When you get sick, two primary pro-inflammatory cytokines are activated – Interlukin one beta (IL-1B) and Tumor necrosis factor alpha (TNFa)
    • IL-1 activates another cytokine called interleukin 6, or IL-6
      • IL-6 is a “bad guy” – it’s most consistently elevated in depressed people
      • High IL-6 levels are associated with heart attacks, stroke, and cancer
      • IL-1 also activates IL-10, which is anti-inflammatory
    • Exercise activates IL-6 (also IL-10) like crazy, but doesn’t activate IL-1 or TNFa – this same thing happens in hyperthermia treatments (like using the sauna)
      • IL-6 plays a key role in exercise’s ability to induce insulin sensitivity
      • If you block IL-6, you block the beneficial metabolic effects of exercise
        • So by exercising, and taking a nonsteroidal anti-inflammatory agent afterwards, you block the effects of IL-6
        • There’s been studies showing taking high dose antioxidants (like vitamin C) suppressed the insulin sensitivity effects of exercise, possibly by suppressing IL-6
  • When you exercise, IL-6 rises briefly, but over time your base levels will drop
Food and Depression
  • One of the major risk factors for chronic low-grade activity of the immune system is frequent and abundant food intake
    • Postprandial inflammation (inflammation after you eat) increases with meal size, and meal frequency
    • Food is a foreign substance and can be hard on the gut – the gut barrier is compromised with every meal, you’re releasing a little bit of endotoxin into the blood stream because your immune system is activated
  • Every time you eat, your body temperature elevates
    • Hyperthermia has antibiotic effects – think in terms of evolution, when we didn’t know how safe our food was
  • Fasting has powerful anti-inflammatory effects
    • One study looked at the effects of a 24 hour fast on the NLRP3 inflammasome (activates inflammation)
      • It was found that the gene expression for that complex is dramatically reduced
      • When you eat again, it rises, and thus inflammation rises
Using Whole Body Hyperthermia to Treat Major Depressive Disorder
  • Check out Charles’ paperWhole-body hyperthermia for the treatment of major depression
  • Similar to using a sauna or doing hot yoga
    • “A lot of people are hooked on hot yoga, and I’m convinced, because it’s an anti-depressive strategy”
    • A hot bath might even work
    • In the study people were treated to a core body temperature of around 100F
  • Rhonda has noticed sauna use lowers her anxiety and increases her ability to deal with stress
    • Heat stress causes the release of beta-endorphins in the brain (same with exercise)
    • Dynorphin is upregulated during heat stress to cool you down
      • Dynorphin is responsible for what one might call, a dizziness feeling, at the tail end of a sauna session – that feeling of “oh god, I have to get out”
      • Dynorphin binds to kapa opioid receptors in the brain
        • This causes a feedback response in other opioid receptors in the brain (mu opioid receptors) which bind to beta endorphins 
        • Once your are past the dizziness/dysphoric feeling from dynorphin release, you feel really good
          • Why? – More mu opioid receptors are binding to beta endorphins
          • This explains the lasting “feel good” effects from sauna use throughout the day, and allows you to feel the effects of beta endorphins even more
  • To reiterate the above – hyperthermia (and exercise) activates IL-6 (also IL-10) like crazy
    • Charles thinks the muscle cells are responsible for the increase in IL-6
    • In Charles’ study, the higher the IL-6 went up, the happier people felt a week later
    • The acute mood elevating effect, was also correlated with IL-6 levels – if you had a higher IL-6 response, you’d be happier at the end of the hyperthermic treatment
  • Neopterin – a chemical that’s really only made by activated immune cells (like monocytes)
    • Neopterin also went up after the hyperthermic treatment, correlating with IL-6
  • Charles has also found that the higher your core body temperature (and therefore, the more depressed you are), the better antidepressant effect of the hyperthermia treatment
    • A week later, the core body temperatures of depressed people were lowered
Kynurenine Pathway and Exercise
  • Exercise helps treat depression through this pathway
  • Kynurenine is a byproduct of tryptophan metabolism, when your immune system is activated in the case of chronic inflammation
    • You’re not converting tryptophan into serotonin, you’re converting it into kynuerenine
    • Kynurenine can form quinolinic acid and kynurenic acid
      • Kynurenic acid is a NMDA antogonist (it inhibits it’s effects)
      • Quinolinic acid is a NMDA agonist and causes neurotoxic effects – this has a powerful association with depression
    • KEY – when you exercise, muscle cells take up kynurenine, preventing the formation of quinolinic acid, and thus reducing depression
  • Chronic inflammation changes serotonin metabolism
    • Chronic inflammation activates an enzyme called indoleamine 2,3-dioxygenase
      • This enzyme takes tryptophan and shunts it away from serotonin, into kynurenine
      • Looking at the ratio of kynurenine to tryptophan tells how active this enzyme is, and thus how inflammed you are
We’re really just going back to our roots..
  • At one point, it was common to use exposure to high heat for healing purposes
    • Hot baths and sweat boxes were common
    • Why repeatedly expose yourself to miserably high temperatures? – Because that sort of periodic exposure induces profound states of positive well being that have antidepressive effects
  • Fasting
    • Many religions have fasting as a key element
    • Fasting has powerful anti-inflammatory and beneficial metabolic effects
    • Fasting is thought to have anti-depressive effects
  • Running
    • Many cultures use excessive running as a way to induce powerful spiritual states – it’s very common in Native American communities
    • Japanese Zen Buddhists have a very strict running protocol – at the end of it, people run more than 50 miles a day for 100 days straight
      • Only 48 people have successfully completed in since the 1850s
  • Psychedelics
    • Have been used repeatedly by humans all around the world for extended periods
    • Mammalian brains are drawn to altered states of consciousness
    • For more on psychedelics and depression check out these Podcast Notes 
Dealing with Depression
  • Antidepressants
    • 70% of people will do much better short term with an antidepressant than with a placebo
    • 25% of people, who are depressed, will do much worse with an antidepressant compared to a placebo
    • Clearly for some people, they work
    • “They are an unearned grace. They take you from a state where you feel horrible about yourself to super you. The problem – you’re only that person when you’re taking the antidepressant.”
    • There’s some data that suggests, the longer you take antidepressants, the more you rely on them
      • There’s some evidence showing a down regulation of serotonin receptors caused by frequent antidepressant use
  • Other ancient, aleternative practices (meditation, psychedelics)
    • What they do – set you on a path so you can begin to transform yourself, in ways that will protect you from depression
  • “Life is a like a series of challenges to perfect the functioning of who you are”
    • If you do that, that is the ultimate antidepressant strategy
    • Compared to antidepressants, Charles thinks the alternative strategies are more likely to drive you in this direction.
    • “When they work, you make yourself more resilient, and you begin to develop perspectives that line up very strongly with many ancient traditions about the truth of what it means to be alive in this particular universe.”
    • Many people take antidepressants as an excuse not to face what’s going on in their life
Artificial Light
  • Until fairly recently on the scale of human life, mornings were light, and nights were very dark
    • Artificial light has changed this
      • We have a need to be competitive, so we feel the need to stay up late working in front of computer screens
  • Bright light exposure has been known to treat people with both seasonal and non-seasonal depressive disorder
    • Go outside in the morning to get bright light, even on a cloudy day
  • Artificial light can change cortisol levels – a hormone that can change the expression of 25% of the human genome, many of those genes involved in inflammation
  • Rhonda has Philips Hue light bulbs in every room of her house


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