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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

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


Through research w e k now that mental d isorders are brain d isorders

“Through research we know that mental disorders are brain disorders.”

National Institute of Mental Health


Charles l raison md associate professor college of medicine

ECOSHERE

SOCIETY

FAMILY

BODY

“MICROBE-SPHERE”

ECOSHERE


Family causality in depression

Family Causality in Depression

Weissman MM et al. JAMA 2006;295:1389-98


Charles l raison md associate professor college of medicine

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


Charles l raison md associate professor college of medicine

  • 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


If factors outside the brain are associated with depression might they also treat it

If factors outside the brain are associated with depression, might they also treat it?

And maybe treat it better?


Charles l raison md associate professor college of medicine

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


Charles l raison md associate professor college of medicine

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


Charles l raison md associate professor college of medicine

Sight

Sound

Touch

Smell

Immune


Evidence that peripheral treatments for mdd may b e effective

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.


Charles l raison md associate professor college of medicine

Sight

Sound

Touch

Smell

Immune

Temperature


Charles l raison md associate professor college of medicine

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


Charles l raison md associate professor college of medicine

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 (%)


Aeskulap clinic in switzerland

Aeskulap Clinic in Switzerland


First open trial of wbh

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


Effect of wbh on core temperature

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


Temperature predicts ad response

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


Temperature and mood after wbh

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)


Wbh at the university of arizona

WBH at the University of Arizona


Day 3 and day 7 wbh vs sham

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


Hamd wbh vs sham at 1 week

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


Hamd wbh vs sham to week 4

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


Charles l raison md associate professor college of medicine

Sight

Sound

Touch

Smell

Immune

The “Let Evolution Do Some

of the Hard Work” Approach

The “Vatman” Approach


Charles l raison md associate professor college of medicine

RISK FACTORS

INFLAMMATION

STRESS

ILLNESS

CAUSE

DIET

POLLLUTION

ISOLATION

SOCIAL CONFLICT

ACTIVITY

LEVEL


Charles l raison md associate professor college of medicine

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


The impact of blocking inflammation in the body

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.


The brain scan can never settle causality

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


Charles l raison md associate professor college of medicine

CAUSES

INFLAMMATION

STRESS

ILLNESS

NL EVOLVED

RESPONSE

DIET

POLLLUTION

ISOLATION

SOCIAL CONFLICT

ACTIVITY

LEVEL


Charles l raison md associate professor college of medicine

In Conclusion

Don’t overestimate

the brain…..


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