Dr. Charles Raison on Depression, the Immune-Brain Interface & Whole-Body Hyperthermia

Posted on March 19th 2018 (9 months)

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. He also examines the physical and behavioral effects of compassion training on the brain, inflammatory processes, and behavior as well as the effect of heat stress as a potentially therapeutic intervention major depressive disorder.

Whole-body hyperthermia as a treatment for major depression.

"Thermal regulation is one of the royal roads into human consciousness in ways that are really profound." - Dr. Charles Raison Click To Tweet

Dr. Raison and his colleagues have demonstrated some promising evidence that a technique called whole-body hyperthermia has the potential for real-world clinical efficacy as a tool in the fight against major depression.

In Dr. Raison’s randomized, double-blind study published in JAMA in 2016, it was shown that a single session of whole-body hyperthermia (core body temperature was elevated to 38.5 C) produced a significant antidepressant effect in people with major depressive disorder compared to those who received a sham control. The improvements were apparent within a week of treatment and persisted for six weeks after treatment.

But what is responsible for this antidepressant effect? In a previous episode of the podcast, we learned that sauna use seems to share many qualities of exercise, including improvements in arterial compliance, elevations in heart rate that reach levels you might see in aerobic exercise. Moreover, sauna use has been shown to be associated with reductions in heart-related mortality, dementia and more. The impact of heat stress on the behavior of our immune system through transient alterations in the cytokines expressed by our tissues may be one more area where we can see some overlap.

The relationship between inflammation and depression.

"People that have higher levels of inflammation and are depressed have different functional connectivity in their brains than people that have lower levels." - Dr. Charles Raison Click To Tweet

Dr. Raison, as well as others, have found that inflammatory mediators such as IL-6 and C-Reactive protein (CRP) are higher in depressed individuals independent of other health factors like obesity and can independently predict the subsequent development of depression over a decade or more.

Moreover, the fact that chronic inflammation might not only be predictive but also induce depression is suggested by studies where injection with pro-inflammatory cytokines such as IFN-alpha have been shown to cause depressive symptoms in people. In fact, at high IFN-alpha doses, fully 50% of patients without depression will meet criteria for major depressive disorder within three months. Read Dr. Raison's review on some of this phenomena.

Recently, however, IL-6 has begun to be shown to have a slightly more nuanced role in a variety of ways. IL-6, while often associated with chronic inflammation and its associated diseases, as well as being an important part of the acute phase response to infection, can also be potently activated by exercise, even being necessary to confer some of the benefits of exercise such as improved insulin sensitivity.

In the context of exercise, IL-6 can serve an anti-inflammatory role through rapid activation of a well-known anti-inflammatory cytokine known as IL-10. It is, perhaps, for this reason, that Dr. Raison calls IL-6 Janus-faced (having two sharply contrasting characteristics).

In much the same way exercise activates IL-6, so too does heat stress. Perhaps more surprising, however, is that, according to Dr. Raison, his group found that the amount that IL-6 went up during the whole-body hyperthermia was predictive of the strength of the antidepressant effect a week later.

As Dr. Raison explains in this episode, there may be a few good reasons why this transient "hit" of inflammation that we see from things like exercise and whole-body hyperthermia may actually be helpful for depression, but one that stands out from the conversation is this: rather than the diminished neurotrophic support we see with chronic inflammation, shorter bursts of smaller or more transient inflammation seem to have beneficial neurotrophic effects.

Summary of discussion

In this nearly 2-hour episode, we discuss...

  • The reason we may have evolved an immune-mediated depressive response in the first place, a hypothesis Dr. Raison calls the "Pathogen Host Defense" theory of depression or "PATHOS-D." Read Dr. Raison’s paper on PATHOS-D.
  • How depression as a disease may be subdivided based on the involvement of chronic inflammation.
  • The changes in functional brain connectivity that are associated with the high inflammation subtype of depression.
  • The place inflammation may have in the treatment for depression, even among members of the low inflammation subgroup.
  • How inflammation can play a somewhat double role where on the one hand immune cells can release beneficial growth factors in response to stimulation from cytokines, but on the other hand, how this response can become reduced from excessive and chronic stimulation over time.
  • Ways to naturally elicit a transient but potentially beneficial "hit" of inflammatory cytokines.
  • How higher eating frequency may help promote a low-grade inflammation due to a postprandial inflammatory response.
  • The potentially therapeutic effects of whole-body hyperthermia for major depressive disorder.
  • The physiological similarity of hot yoga with whole-body hyperthermia from the standpoint of potentially therapeutically boosting body temperature.
  • Some of the short-term endocrine changes that happen during heat stress, especially related to the opioid pathway, which may help account for some of the anti-depressant phenomena associated with whole-body hyperthermia.
  • The role of an important cytokine known as IL-6 in depression and how this cytokine which fluctuates during activities such as exercise and whole-body hyperthermia also exhibits anti-inflammatory properties through another cytokine called IL-10.
  • How the anti-depressant effects of whole-body hyperthermia may actually intimately depend on the spike in IL-6.
  • The role IL-6 plays as a myokine by conferring beneficial metabolic adaptations in response to exercise, including increased insulin sensitivity.
  • How taking an NSAID or even certain antioxidants like vitamin C and vitamin E at the wrong time can diminish some of the benefits of exercise, such as satellite cell migration and improved insulin sensitivity.
  • Heat stress as a means to sensitize pathways important to thermoregulatory cooling that also affect brain regions implicated in the regulation of mood.
  • The thermoregulatory dysregulation found in other relevant psychiatric conditions outside of depression, such as schizophrenia.
  • An evolutionary-biological explanation for why chronic inflammation shunts tryptophan, an important precursor of serotonin, into a neurotoxic pathway that produces a substance called kynurenine, which can become a neurotoxic NMDA agonist known as quinolinic acid that is powerfully associated with depression.
  • How kynurenine can then go on to become a metabolite known as quinolinic acid which is powerfully associated with depression.
  • How our muscles actually help us shift the metabolism of kynurenine away from quinolinic acid when we exercise, particularly if that exercise is endurance exercise.
  • Some of the preliminary evidence that increased expression of a certain heat shock protein in the brain may influence behavior by protecting against stress-induced depression.
  • The biological wisdom that may be embedded in traditional spiritual practices when it comes to keeping depression at bay… especially the use of phasic high-heat, often for healing or transcendent purposes, but also potentially other practices like fasting and ultra long distance running.
  • The role that heat tolerance played as a unique human adaptation enabling persistence hunting in early humans. Watch a video of persistence hunting.
  • The staggering lengths that some indigenous tribes went through to induce a classical psychedelic-like experience as a rite of passage, including subjecting themselves to extensive bites or consuming them for their venom.
  • Some of the growing body of literature surrounding the effects of psychedelic-occasioned mystical experiences for depression, end-of-life anxiety among cancer patients, and even as an aid in smoking cessation.
  • The ability of meditation to induce real changes in the gray matter of the brain and some of the interesting evidence showing that the effects of meditation can begin to build and show up in as little as 8-weeks.
  • The place that some of these lifestyle interventions or hacks may increasingly have in clinical practices for the management of mood disorders.
  • The dilemma clinicians face in figuring out which of their patients, around a quarter of the depressed population, will actually be made worse by the current standard of care SSRIs.
  • The possibility that antidepressants, by being a type of so-called "unearned grace," may prevent enduring behavioral changes and create a type of long-term reliance and potentially increased vulnerability.
  • Dr. Raison’s perspective on so-called ancient wisdom traditions that may offer broad transformative value for creating states of mind that may be inimical to depression.
  • The role bright light therapy may have in the amelioration of a variety of depressive disorders and how our modern relationships with screens that increase our light at night and office environments that reduce our light during the day may disrupt our natural biological rhythms to our detriment.

People mentioned

Learn more about Dr. Charles Raison

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