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Charles L. Raison, MD Associate Professor College of Medicine

Coming to Our Senses: Implications of Embodiment for the Pathogenesis and Treatment of Major Depression. Charles L. Raison, MD Associate Professor College of Medicine Barry and Janet Lang Associate Professor of Integrative Mental Health College of Agriculture and Life Sciences

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Charles L. Raison, MD Associate Professor College of Medicine

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  1. Coming to Our Senses: Implications of Embodiment for the Pathogenesis and Treatment of Major Depression Charles L. Raison, MD Associate Professor College of Medicine Barry and Janet Lang Associate Professor of Integrative Mental Health College of Agriculture and Life Sciences University of Arizona Tucson, AZ

  2. “Through research we know that mental disorders are brain disorders.” National Institute of Mental Health

  3. ECOSHERE SOCIETY FAMILY BODY “MICROBE-SPHERE” ECOSHERE

  4. Family Causality in Depression Weissman MM et al. JAMA 2006;295:1389-98

  5. Brown GW. Soc Psychiatry PsychiatrEpidemiol1998;33:363-72

  6. In animal models air pollution impairs cognition provokes depressive-like behavior, increases inflammation and reduces dendritic branching in the hippocampus. In humans air pollution has been repeatedly associated with increased suicide attempts and completions. Overall environmental risks (pollution, sunspots, temperature, etc.) reported to account for 34% of variance in suicide. • Secondhand smoke exposure repeatedly associated with depression in children and adults • Multiple studies show that people living in rural areas have lower rates of MDD than those living in urban areas. Urban upbringing associated with increased anterior cingulate responses to social stress. Current city living associated with increased amygdala response to social stress • Individuals living near freeways in utero or at delivery are 86% and 122% more likely to develop autism, respectively • Presence of lithium in drinking water reduces rates of completed suicide Postolache TT et al. Mol Psychiatry 2005;10: 232-8; Fonken LK et al. Mol Psychiatry 2011, 1-11; Szszkowicz M et al. Environ Health Insights 2010;15:79-86; Kim C et al. Am J Psychiatry 2010;167:1100-7; Yang AC et al. J Affect Disord2011;129:275-81; Bandiera FC et al. Psychosom Med 2010;72:331; Lee KJ. BMJ Open 2014;4:e003734; Schoevers PJ et al. ActaPsychiatrScand 2010;121:84-93; Lederbogen F et al. Nature 2011;474:498-501; Volk HE et al. Environ Health Perspect2011;119:873-7; Kapusta ND et al. Brit J Psychiatry 2011;198:346-50

  7. If factors outside the brain are associated with depression, might they also treat it? And maybe treat it better?

  8. 22 20 18 16 Less Depression 14 12 10 8 Placebo 6 Active antidepressant 4 0 0 1 2 3 4 5 6 7 8 Time in Weeks

  9. 22 20 18 16 Less Depression 14 12 10 8 Placebo 6 Ron-responders receiving active drug 4 Responders receiving active drug 0 0 1 2 3 4 5 6 7 8 Time in Weeks

  10. Sight Sound Touch Smell Immune

  11. Evidence That Peripheral Treatments for MDD May Be Effective Weeks Baseline 1 2 3 4 6 8 10 12 Infliximab TRD Pts(n=60) INFLIX(5 mg/kg) n=30 Placebo StratificationMale vs FemaleCRP >2 vs CRP ≤2 Randomization 60 n=30 PLACEBO Infusion Infusion Infusion 50 Clinician-Administered Psychiatric Assessments (HAM-D, CGI)Adverse Events EvaluationBlood Draw for Inflammatory Markers and Safety Labs 40 30 25 Percent Responders During Study 30 20 20 Adjusted Mean HAM-D-17 15 10 Infliximab 10 5 Placebo 0 0 Baseline 1 2 3 4 6 8 10 12 Med + Low High Weeks Hs-CRP (tertiles) CGI, Clinical Global Impression; INFLIX, infliximab; TRD, treatment-resistant depression. Raison CL et al. JAMA Psychiatry. 2013;70(1):31-41.

  12. Sight Sound Touch Smell Immune Temperature

  13. Depression PAG 5HT, BDNF, NT-3 in CNS AH/ POA DRI DRLV PFC Tb Core Improved sleep Inflammation LPB RPa Sweating Heart rate var. Inflammation 5HT, BDNF, NT-3 plasma WBH Sweat Glands 5HT Cells

  14. 38.0 60 Thirty-two adolescent male Wistar rats were randomized to one of 4 conditions: 3 injections of citalopram (5 mg/kg) or vehicle and pre-FST incubation at an ambient temperature of 23 or 37○C (WBW condition). Results indicated that in SSRI- and vehicle-treated groups combined, pre-exposure to the warm condition demonstrated antidepressant properties as measured by increased time swimming (F[1,27]=11.56, p=0.002) and reduced time spent immobile (F[1,27]=4.993, p =0.034). Although underpowered to examine direct effects of WBW, a trend was observed for vehicle-treated rats pre-incubated at 37○C to demonstrate increased swimming behavior compared to those pre-incubated at 23○C (t(14)=-1.7 p=0.11) 37 ○ C 37.8 23 ○ C 37.6 50 37.4 Post Incubation Trec (○C) Swimming (%) 37.2 40 37.0 36.8 30 Whole Body Warming Alone 36.6 0 36.4 23 ○ C 37 ○ C 20 30 40 50 60 70 Swimming (%)

  15. Aeskulap Clinic in Switzerland

  16. First Open Trial of WBH 35 30 25 20 CES-D Depression Score 15 Active Hyperthermia (N=15) 10 5 t[15] = 4.53 p < 0.001, effect size d = 1.13 0 Pre-WBH Day 5-Post WBH

  17. Effect of WBH on Core Temperature 37.4 37.3 37.2 37.1 Mean 24-Hr Body Temp. 37.0 36.9 Active Hyperthermia (N=7) 36.8 t[5.5], df 6, p=0.002, effect size d = 2.1 36.7 Pre-WBH Day 5-Post WBH Hanusch et al. Am J Psychiatry 2013; 170: 802-4

  18. Temperature Predicts AD Response 37.8 37.6 37.4 Pre-WBH Core Body Temp. 37.2 37.0 Active Hyperthermia (N=12) 36.8 r=0.62, df=9, p=0.043 -24 -20 -16 -12 -8 -4 0 Change in CES-D Depression Score

  19. Temperature and Mood After WBH 40 35 30 25 Δ CES-D Score 20 15 10 Active Hyperthermia (N=7) 5 0 r=0.73, df=4, p=0.06 0 .05 .1 .15 .2 .25 .3 .35 .4 .45 .5 Δ Mean Tb Core (○C)

  20. WBH at the University of Arizona

  21. Day 3 and Day 7 WBH vs. Sham Sham Hyperthermia (n=6) 50 Hyperthermia (n=7) 45 40 35 IDS-SR DEPRESSION Score 30 25 20 15 Day 7 Pre-TX Day 1 Day 3 Day 2 DAY 3 WBH vs. SHAM: ANCOVA B1= -13.18, p = 0.06; effect size d = 1.28 DAY 7 WBH vs. SHAM: ANCOVA B1 = -12.26, p=0.1; effect size d= 1.07

  22. HAMD: WBH vs. Sham at 1 Week Sham Hyperthermia (n=6) Hyperthermia (n=7) 25 20 HDRS-17 Score 15 ANCOVA B1 = -7.65, p=0.03; effect size d = 1.68 10 WK 1 Post-RX Pre-RX 5 of 6 SHAM thought they received active WBH; 6 of 7 active WBH thought they received active WBH

  23. HAMD WBH vs. Sham to Week 4 Sham Hyperthermia (n=6) 25 Hyperthermia (n=7) ANCOVA B1 = -6.8, p = 0.1; effect size d = 1.30 20 HDRS-17 Score 15 10 5 Pre-TX Week 1 Week 2 Week 4

  24. Sight Sound Touch Smell Immune The “Let Evolution Do Some of the Hard Work” Approach The “Vatman” Approach

  25. RISK FACTORS INFLAMMATION STRESS ILLNESS CAUSE DIET POLLLUTION ISOLATION SOCIAL CONFLICT ACTIVITY LEVEL

  26. Inflammation Causes Depression 14 12 10 IFN-ALPHA, n=23 8 MEAN MADRS SCORE HCV CONTROL, n =14 6 4 2 0 0 4 8 12 WEEKS Raison et al. Mol Psychiatry2010 May;15(5):535-47

  27. The Impact of Blocking Inflammation in the Body Weeks Baseline 1 2 3 4 6 8 10 12 Infliximab TRD Pts(n=60) INFLIX(5 mg/kg) n=30 Placebo StratificationMale vs FemaleCRP >2 vs CRP ≤2 Randomization 60 n=30 PLACEBO Infusion Infusion Infusion 50 Clinician-Administered Psychiatric Assessments (HAM-D, CGI)Adverse Events EvaluationBlood Draw for Inflammatory Markers and Safety Labs 40 30 25 Percent Responders During Study 30 20 20 Adjusted Mean HAM-D-17 15 10 Infliximab 10 5 Placebo 0 0 Baseline 1 2 3 4 6 8 10 12 Med + Low High Weeks Hs-CRP (tertiles) CGI, Clinical Global Impression; INFLIX, infliximab; TRD, treatment-resistant depression. Raison CL et al. JAMA Psychiatry. 2013;70(1):31-41.

  28. The Brain Scan Can Never Settle Causality MAJOR DEPRESSION BRAIN EFFECTS OF INFLAMMATION Hamilton JP et al. Am J Psychiatry 2012;169:693-703; Capuron L et al. Biol Psychiatry 2005; 58: 190-996

  29. CAUSES INFLAMMATION STRESS ILLNESS NL EVOLVED RESPONSE DIET POLLLUTION ISOLATION SOCIAL CONFLICT ACTIVITY LEVEL

  30. In Conclusion Don’t overestimate the brain…..

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