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

Inflammation and Depression

• Dr. Charles Raison: Professor at the School of Human Ecology, University of Wisconsin Madison
• Founding director of the Center for Compassion Studies, University of Arizona
• Research on the effects of inflammation on the development of depression
• Whole body hyperthermia as a treatment for major depressive disorders

Role of Inflammation in Depression

• Link between the brain and the immune system discovered in the 1980s
• Inflammatory markers (cytokines) found to be elevated in depressed people
• Exposure to inflammatory chemicals increases the likelihood of developing depression
• Interferon alpha: a chemical that turns on inflammation and can cause depression when used as a treatment for hepatitis C
• Chronic inflammatory activation can induce changes in the brain and body that increase the risk of depression

Evolutionary Advantage of Inflammation-​​Induced Depression

• Human depression may have evolved out of sickness
• Significant overlap between symptoms of sickness and depression
• Depressed people have chronic elevations in body temperature (hyperthermia)
• Depression is associated with shunting iron and zinc, raising body temperature
• Inflammation and sickness reactions may have evolved as a strategy for pathogen defense
• Stress as a reliable indicator of increased risk of wounding and infection
• Inflammation induces sickness, which shares many characteristics with depression

Genetic Factors in Depression and Inflammation

• Depression is a polygenic disorder, making it difficult to find genes reliably associated with it
• Single nucleotide polymorphisms (SNPs) in genes with known functional capacity may provide anti-​​pathogen benefits

• MTHFR gene involved in folate metabolism has a form that is a depression risk factor
  Immunology, Inflammation, and Depression

• Inflammation may be linked to depression 
  • Pro-​​inflammatory genes may increase survival in high pathogen areas but increase risk of depression in low pathogen areas
  • Inflammatory activation and depression may have evolutionary origins
• Obesity and inflammation 
  • Obese individuals often have higher markers of inflammation and are more likely to be depressed
  • Weight loss may improve mood and decrease inflammation
• Administering pro-​​inflammatory cytokines (e.g., interferon-​​alpha) can cause depressive symptoms 
  • Inflammatory mediators can cross the blood-​​brain barrier and disrupt neurotransmitters
  • Inflammatory cells can enter the brain
• Endotoxin and typhoid studies 
  • Typhoid injections can cause feelings of social isolation and dysphoria, as well as changes in brain function related to depression
  • Endotoxin injections can cause similar effects, especially in women
  • Counter data: endotoxin injections in severely depressed patients produced a powerful antidepressant response
• Animal studies
  • Blocking inflammation before stress exposure can prevent apoptosis and downstream behavioral effects in rodents
  • Stimulating inflammation after stress exposure can produce an antidepressant response
• Cytokines (e.g., TNF, IL‑1 beta, IL‑6) can have neurotrophic effects at lower levels in the brain, possibly due to evolutionary processes TNF knockout mice have difficulty navigating, suggesting that lower levels of these mediators may be beneficial in the CNS. Inflammation in the CNS can have trophic effects, targeting areas like the cingulate cortex and dopamine areas in the ventral striatum. This may be an evolutionary mechanism to reduce the risk of pathogen manipulation. Microorganisms can change behavior in ways that benefit their survival and reproduction. 
• Inflammation is elevated in depression, but only in a certain way. There is a subgroup of depressed people with elevated inflammation, and they have different functional connectivity in their brains than those with lower levels. These subgroups also have different responses to immune agents. It is possible that some depressed people might benefit from a hit of inflammation, such as through exercise or hyperthermia. 
• Exercise has been shown to be as potent as some antidepressants in treating depression. It elevates inflammatory processes acutely, followed by a more powerful anti-​​inflammatory and antioxidant response. Exercise can also affect the inflammatory response induced postprandially (after eating). Eating can cause a mild fever, known as diet-​​induced thermogenesis, which may have antibiotic effects. Fasting has a powerful anti-​​inflammatory effect, reducing gene expression for the NLRP3 inflammasome. 
• Whole body hyperthermia has been used to treat major depressive disorder, with a single bout having a lasting effect for six weeks. This treatment is similar to using a sauna, but with a more controlled and intense heat. Hyperthermia raises the core body temperature to 38.5°C (101°F), which is extremely hot and can cause significant discomfort. Some researchers are also studying the effects of hot yoga on inflammation and depression.
  Hot Yoga, Sauna, and Hypothermia as Antidepressant Strategies
• Hot yoga elevates core body temperature, similar to hypothermia treatment 
  • Many people find hot yoga to be an effective antidepressant strategy
• Sauna usage also elevates core body temperature 
  • Personal anecdote: Sauna usage helped cope with graduate school stress
  • Possible mechanism: Heat stress increases beta-​​endorphins and dinorphin, which may sensitize mu-​​opioid receptors to endorphins
• Hypothermia treatment has shown antidepressant effects 
  • Increases levels of interleukin‑6 (IL‑6), an inflammatory cytokine
  • Higher IL‑6 levels correlated with reduced depression symptoms a week later
  • Acute mood elevation also correlated with increased IL‑6 levels

Understanding the Role of Inflammatory Cytokines

• Infection activates pro-​​inflammatory cytokines interleukin‑1 beta (IL-​​1β) and tumor necrosis factor (TNF)
  • These cytokines activate interleukin‑6 (IL‑6), which is consistently elevated in depression
  • Elevated IL‑6 levels are associated with increased risk of heart attacks, strokes, cancer, and hippocampal shrinkage
• Exercise activates IL‑6 without activating IL-​​1β or TNF 
  • IL‑6 has both pro-​​inflammatory and anti-​​inflammatory effects
  • Exercise-​​induced IL‑6 activates interleukin-​​10 (IL-​​10), a powerful anti-​​inflammatory cytokine
• Hypothermia treatment also increases IL‑6 levels without activating IL-​​1β or TNF 
  • Similar immune response to exercise

Opposite Approaches to Antidepressant Effects

• FDA approval expected for a novel antidepressant that antagonizes kappa opioid receptors 
  • Opposite effect of heat stress, which stimulates kappa receptors
• Salvinorin A, a kappa agonist, has potential antidepressant effects at lower doses 
  • Example of opposite approaches producing similar outcomes (antidromia)

Hypothermia Treatment Study

• Challenge: Creating a placebo for hypothermia treatment 
  • Used fake infrared lights, heating coils, and a fan to mimic real treatment
  • Over 70% of participants receiving fake treatment believed they received real treatment
• Results: Real heat treatment group showed significant increase in IL‑6 levels 
  • No change in immune measures for the placebo group
  • Higher IL‑6 levels correlated with reduced depression symptoms and increased happiness
  • Suggests heat is the key factor in the antidepressant effect
    Effects of Inflammation on Depression and the Role of IL‑6

• IL‑6 is activated by immune cells, fat cells, and muscle cells

• In the context of exercise, IL‑6 is a myokine and plays a key role in exercise’s ability to induce insulin sensitivity
• Blocking IL‑6 in a rodent that exercises blocks all the beneficial metabolic effects
• Inflammation can affect serotonin metabolism by activating an enzyme called indoleamine 2,3‑dioxygenase (IDO)
  • IDO shunts tryptophan away from serotonin production and into kynurenine production
  • Kynurenine can form neurotoxic quinolinic acid, which is associated with depression

Exercise and its Effects on Tryptophan, Kynurenine, and Depression

• Exercise causes branched-​​chain amino acids (BCAAs) to be taken up into muscle cells, allowing more tryptophan to enter the brain and produce serotonin
• Exercise also causes muscle cells to take up kynurenine, preventing the formation of neurotoxic quinolinic acid
• These mechanisms suggest that exercise can help alleviate depression by increasing serotonin production and reducing neurotoxicity from quinolinic acid

Thermoregulation and Depression

• Depressed people often have impaired thermoregulation and struggle to cool off
• Hyperthermia treatment can induce hypothermia, which may help recalibrate and strengthen anti-​​inflammatory pathways in the brain and body
• This hormetic effect may contribute to the antidepressant effects of hyperthermia treatment

Schizophrenia and Thermoregulation

• Schizophrenics also have significant thermoregulatory challenges
• They may experience worse symptoms with either heat or cold, depending on the individual

Inflammation, Serotonin, and Kynurenine Pathway

• Chronic inflammation can cause tryptophan to be converted into kynurenine instead of serotonin
• Kynurenine can form neurotoxic quinolinic acid, which is associated with depression

• Exercise can help alleviate this by causing muscle cells to take up kynurenine, preventing the formation of quinolinic acid and increasing serotonin production in the brain
  Exercise, Heat, and Depression

• Exercise has various mechanisms that positively affect depression 
  • Hormetic effect
  • Increased serotonin
  • Hypothermic effect
  • Anti-​​inflammatory effect
• Heat exposure (e.g., hot yoga, sauna, hot bath, steam shower) also has positive effects on depression

Heat Shock Proteins

• Study on heat shock protein 105 in mice 
  • Mice with increased heat shock protein 105 were protected from depressive symptoms after stress tests
  • Correlated with an increase in brain-​​derived neurotrophic factor in a specific brain region
• Heat shock proteins may contribute to the release of IL‑6 from muscles, which could drive secondary immune effects

Ancient Practices for Well-being

• Ancient practices discovered across human history for healing and spiritual purposes may have biologic and behavioral effects relevant for depression
• Modern world has disrupted many of these practices, leading to disorientation and potential depressive problems
• Examples of ancient practices: 
  • Heat exposure (e.g., sweat lodges, hot baths) — widespread across cultures
  • Fasting — powerful anti-​​inflammatory and mood-​​elevating effects
  • Running — used in various cultures to induce powerful spiritual states

Running and Spiritual States

• Many cultures use intense running as a way to induce spiritual states 
  • Native American communities
  • Tibetan Buddhism
  • Japanese Zen — extreme running protocol believed to induce transcendent states
• Running to the point of exhaustion is considered one of the natural states closest to the mind of a Buddha in Tibetan Buddhist texts

• Rapid shifts in autonomic nervous system functioning, such as those experienced during running, may be related to transcendent states
  Evolution of Human Brains and Long Distance Running

• Human brains may have evolved in response to long distance running

• Humans are the best thermoregulators in the animal world 
  • Can outrun any animal for 100 miles in a hot environment
• Human foot evolved before the human brain 
  • Remarkably evolved for running
• Theory: humans developed large brains due to ability to stand upright and thermoregulate 
  • Allowed for better cooling and energy utilization

Persistence Hunting

• Humans can outrun animals by keeping them at a pace where they have to gallop 
  • Animals can’t cool off while galloping, leading to heat stroke and death
• Example: David Attenborough documented San Bushmen running an eland to death

Psychedelics and Altered States of Consciousness

• Humans and other mammals are drawn to substances that induce altered states of consciousness
• Ancient practices that induce heightened states of awareness may have evolved from survival strategies
• Examples: exercise, dancing, and psychedelic substances

Shamanistic Cultures and Psychedelic Experiences

• In shamanistic cultures, psychedelic experiences often occur at puberty 
  • Aim to identify a spirit guide for a lifetime
• Examples: Yolkits in Central California used ant bites to induce psychedelic experiences
• Ancient Greek Eleusinian Mysteries may have involved psychedelic substances

Psychedelics as Treatment for Depression

• Studies show that a single exposure to psilocybin (found in magic mushrooms) can induce powerful antidepressant responses lasting six months or longer
• Mystical experiences seem to be important for the antidepressant effect
• Studies also show changes in the Default Mode Network, which is involved in rumination

Inflammation and Rumination

• Inflammation may drive rumination 
  • Inflammatory molecules change the brain’s rumination center (dorsal anterior cingulate)
• Rumination is a significant part of depression

Meditation and Mystical Experiences

• Overlap between meditative states and mystical experiences
• Mystical experiences are the common denominator between meditation and psychedelic experiences

• Both meditation and psychedelics can induce transformative experiences that can help with depression and anxiety
  Meditation and Brain Changes

• Long-​​term meditators show changes in brain volume and activity

• Studies show that novices can achieve similar brain changes with 8 weeks of intensive meditation
• Compassion meditation and mindfulness meditation can have positive effects on the brain
• Richie Davidson’s research at the University of Wisconsin shows that meditation can have significant benefits for mental health

Running as Meditation

• Both running and traditional meditation can have similar calming effects on the brain
• Running can help reduce anxiety and improve mood

Depression and Antidepressants

• SSRIs are commonly prescribed for depression, but they may not be effective for everyone
• About 70% of people do better with antidepressants than with a placebo, while 25% do worse
• Antidepressants can be a helpful short-​​term solution, but they may not address the root causes of depression

Alternative Treatments for Depression

• Lifestyle interventions, such as weight loss, exercise, and meditation, can be effective for treating depression
• Whole-​​body hyperthermia, sauna, hot yoga, and hot baths may also have positive effects on mental health
• Psychedelics show promise for treating depression, but they are not yet legal for this purpose

The Future of Depression Treatment

• There is hope that the medical community will embrace alternative treatments for depression
• Treatment centers may begin to offer meditation, hot yoga, sauna, and other non-​​pharmaceutical interventions
• The goal is to find treatments that help patients become less dependent on external sources for their well-being

Antidepressant Dependency and Relapse

• Long-​​term use of antidepressants may lead to downregulation of serotonin receptors, making it difficult to stop taking the medication
• Relapse rates are high when antidepressants are stopped quickly, with 60–80% of patients relapsing within a month
• Placebo responses are more stable and long-​​lasting than antidepressant responses

Ancient Practices for Mental Health

• Ancient practices, such as meditation, may help protect against depression by promoting self-transformation
• These practices may not be as immediately effective as antidepressants, but they can help address the root causes of depression
• Overcoming patterns of behavior, thoughts, and feelings that contribute to depression is key to long-​​term mental health

Life as a Series of Challenges and Personal Transformation

• Life is a series of challenges to perfect the functioning of oneself 
• Ultimate antidepressant strategy: personal transformation 
• Dalai Lama example: transformed brain-​​body complex, making depression unlikely
• Combining standard pharmacology with personal transformation 
  • Antidepressants can be a tool for transformation or an excuse not to face life’s challenges

The Wild Five Program

• Developed by Rakesh and Sandra Jain
• Combines exercise, diet, sleep, social connectivity, and mindfulness
• User-​​friendly, doable, and provides feedback
• Results in significant improvements in well-​​being after 30 days
• Rakesh Jain: a psychiatric leader at the interface of pharma, now focusing on transformative wellness practices

Importance of Light Exposure and Circadian Rhythm

• Evolutionary mismatch: artificial lights, changed light exposure patterns
• Bright light exposure helps treat non-​​seasonal depression 
  • Affects cortisol and cytokine rhythms
• Humans evolved to function optimally with certain types of inputs (e.g., bright light in the morning, dark at night)
• Circadian rhythm regulated by light and food intake 
  • Cortisol affects 25% of the human genome, including genes involved in inflammation

Optimizing Light Exposure

• Philips Hue lights: adjustable color and brightness 
  • Blue light in the morning, red light at night
  • Helps with sleep onset and melatonin production
• Apps like Flux to reduce blue light on screens
• Importance of spending time outdoors for natural light exposure 
  • 30 minutes of bright light exposure in the morning
• Dark environments during sleep are crucial for optimal melatonin release
  Moon and Madness: Light and Manic Episodes
• Ancient belief: Moon associated with madness 
• Argument: Moon as a light source activated manic episodes due to sleep deprivation
• Example: Ancient Rome was pitch black at night without the moon

Darkness and its Effects

• London in the 1760s: pitch black, enabling illicit activities
• Tom Ware: studied the effects of darkness on bipolar patients
• Dark retreat: Tibetan Buddhist practice of complete darkness for 49 days 
  • Purpose: to recognize the world can arise from the creation of their mind

Circadian Rhythms and Bipolar Disorder

• Gene polymorphisms (SNPs) in Npass2 gene involved in circadian rhythm and susceptibility to bipolar disorder
• Bipolar disorder: response to the adversity of time 
  • Sensitive to fluctuations in circadian patterns
  • Manic episodes triggered by sleep deprivation
• Chronotherapy: therapeutic approach for bipolar disorder involving strict sleep schedules and caution with air travel 
  • Example: Increased risk of psychotic mania for travelers from America to Heathrow due to sleep deprivation

The New Mind-​​Body Science of Depression

• Book by Dr. Charles Raison and Vladimir Maletic
• Covers inflammation, evolutionary aspects, risk factors, and neurobiology of depression
• Includes case studies and discussion of hyperthermia treatment
• Available on Amazon and in some bookstores