Coming to Our Senses: Implications of Embodiment for the Pathogenesis and Treatment of Major Depression Charles L. Raison, MD Associate Professor College.

Coming to Our Senses: Implications of Embodiment for the Pathogenesis and Treatment of Major Depression

Charles L. Raison, MDAssociate ProfessorCollege of Medicine

Barry and Janet Lang Associate Professor of Integrative Mental HealthCollege of Agriculture and Life Sciences

University of ArizonaTucson, AZ

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

National Institute of Mental Health

FAMILY

SOCIETY

ECOSHERE

BODY

“MICROBE-SPHERE”

ECOSHERE

Family Causality in Depression

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

Brown GW. Soc Psychiatry Psychiatr Epidemiol 1998;33:363-72

• 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 Disord 2011;129:275-81; Bandiera FC et al. Psychosom Med 2010;72:331; Lee KJ. BMJ Open 2014;4:e003734; Schoevers PJ et al. Acta Psychiatr Scand 2010;121:84-93; Lederbogen F et al. Nature 2011;474:498-501; Volk HE et al. Environ Health Perspect 2011;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?

And maybe treat it better?

4

0

6

8

10

12

14

16

18

20

22

0 1 2 3 4 5 6 7 8

Less

Dep

ress

ion

Time in Weeks

PlaceboActive antidepressant

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0

6

8

10

12

14

16

18

20

22

0 1 2 3 4 5 6 7 8

Less

Dep

ress

ion

Time in Weeks

PlaceboRon-responders receiving active drugResponders receiving active drug

Sight Sound

SmellTouch

Immune

CGI, Clinical Global Impression; INFLIX, infliximab; TRD, treatment-resistant depression.Raison CL et al. JAMA Psychiatry. 2013;70(1):31-41.

Evidence That Peripheral Treatments for MDD May Be Effective

Infliximab

Placebo

60

50

40

30

20

0

10

Med + Low High

Per

cen

t R

esp

on

der

s D

uri

ng

Stu

dy

Hs-CRP (tertiles)

Weeks4 123 101 62Baseline 8

Infusion Infusion Infusion

n=30

n=30INFLIX

(5 mg/kg)

PLACEBO

Randomization

Clinician-Administered Psychiatric Assessments (HAM-D, CGI)Adverse Events Evaluation

Blood Draw for Inflammatory Markers and Safety Labs

TRD Pts(n=60)

StratificationMale vs Female

CRP >2 vs CRP ≤2

30

25

20

15

10

0

5

4 12

Ad

jus

ted

Mea

n H

AM

-D-1

7

Weeks3 101 62Baseline 8

Infliximab

Placebo

Sight Sound

SmellTouch

Immune Temperature

PFC PAG

WBH

DRI DRLVAH/POA

Tb CoreImproved sleepInflammation

Depression

SweatingHeart rate var.Inflammation

5HT Cells Sweat Glands

LPB RPa

5HT, BDNF, NT-3in CNS

5HT, BDNF, NT-3

plasma

23 ○ C 37 ○ C0

30

40

50

60Sw

imm

ing

(%)

Swimming (%) 4020 30 50 7060

38.037.837.637.437.237.036.836.636.4

Post

Incu

batio

n T re

c (○ C

)

23 ○ C37 ○ C

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)

Whole Body Warming Alone

Aeskulap Clinic in Switzerland

First Open Trial of WBH

Pre-WBH Day 5-Post WBH

35

30

25

20

15

10

5

0

CES-

D D

epre

ssio

n Sc

ore Active Hyperthermia (N=15)

t[15] = 4.53 p < 0.001, effect size d = 1.13

Pre-WBH Day 5-Post WBH

37.4

37.3

37.2

37.1

37.0

36.9

36.8

36.7

Mea

n 24

-Hr B

ody

Tem

p.

t[5.5], df 6, p=0.002, effect size d = 2.1

Effect of WBH on Core Temperature

Hanusch et al. Am J Psychiatry 2013; 170: 802-4

Active Hyperthermia (N=7)

0-4-8-12-16-20Change in CES-D Depression Score

Pre-

WBH

Cor

e Bo

dy T

emp. 37.8

37.6

37.4

37.2

36.8

37.0

-24

Temperature Predicts AD Response

r=0.62, df=9, p=0.043

Active Hyperthermia (N=12)

.15 .2 .25 .35 .45.4 .5.05 .10 .3

40353025201510

50

Δ Mean Tb Core (○C)

Δ C

ES

-D S

core

Temperature and Mood After WBH

r=0.73, df=4, p=0.06

Active Hyperthermia (N=7)

WBH at the University of Arizona

IDS-

SR D

EPRE

SSIO

N S

core

5045403530252015

Pre-TX Day 1 Day 2 Day 3 Day 7

Hyperthermia (n=7)Sham Hyperthermia (n=6)

Day 3 and Day 7 WBH vs. Sham

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

25

20

15

10Pre-RX WK 1 Post-RX

HD

RS-1

7 Sc

ore

Hyperthermia (n=7)Sham Hyperthermia (n=6)

HAMD: WBH vs. Sham at 1 Week

ANCOVA B1 = -7.65, p=0.03; effect size d = 1.68

5 of 6 SHAM thought they received active WBH; 6 of 7 active WBH thought they received active WBH

Pre-TX Week 1 Week 2 Week 4

25

20

15

10

5

HD

RS-1

7 Sc

ore

Hyperthermia (n=7)Sham Hyperthermia (n=6)

HAMD WBH vs. Sham to Week 4

ANCOVA B1 = -6.8, p = 0.1; effect size d = 1.30

The “Vatman” Approach

Sight Sound

SmellTouch

Immune

The “Let Evolution Do Someof the Hard Work” Approach

CAUSE

RISK FACTORS

ILLNESS

STRESS

INFLAMMATION

POLLLUTION

DIET

ACTIVITY

LEVEL ISOLA

TION

SOCI

AL C

ONFLIC

T

14

12

10

8

6

4

2

0

0 4 8 12WEEKS

MEA

N M

ADRS

SCO

RE

IFN-ALPHA, n=23

HCV CONTROL, n =14

Inflammation Causes Depression

Raison et al. Mol Psychiatry 2010 May;15(5):535-47

CGI, Clinical Global Impression; INFLIX, infliximab; TRD, treatment-resistant depression.Raison CL et al. JAMA Psychiatry. 2013;70(1):31-41.

The Impact of Blocking Inflammation in the Body

Infliximab

Placebo

60

50

40

30

20

0

10

Med + Low High

Per

cen

t R

esp

on

der

s D

uri

ng

Stu

dy

Hs-CRP (tertiles)

Weeks4 123 101 62Baseline 8

Infusion Infusion Infusion

n=30

n=30INFLIX

(5 mg/kg)

PLACEBO

Randomization

Clinician-Administered Psychiatric Assessments (HAM-D, CGI)Adverse Events Evaluation

Blood Draw for Inflammatory Markers and Safety Labs

TRD Pts(n=60)

StratificationMale vs Female

CRP >2 vs CRP ≤2

30

25

20

15

10

0

5

4 12

Ad

jus

ted

Mea

n H

AM

-D-1

7

Weeks3 101 62Baseline 8

Infliximab

Placebo

The Brain Scan Can Never Settle Causality

Hamilton JP et al. Am J Psychiatry 2012;169:693-703; Capuron L et al. Biol Psychiatry 2005; 58: 190-996

MAJOR DEPRESSION BRAIN EFFECTS OF INFLAMMATION

CAUSES

ILLNESS

STRESS

INFLAMMATION

POLLLUTION

DIET

ACTIVITY

LEVEL ISOLA

TION

SOCI

AL C

ONFLIC

T

NL EVOLVEDRESPONSE

In Conclusion

Don’t overestimate

the brain…..