coming to our senses: implications of embodiment for the pathogenesis and treatment of major...
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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
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“Through research we know that mental disorders are brain disorders.”
National Institute of Mental Health
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FAMILY
SOCIETY
ECOSHERE
BODY
“MICROBE-SPHERE”
ECOSHERE
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Family Causality in Depression
Weissman MM et al. JAMA 2006;295:1389-98
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Brown GW. Soc Psychiatry Psychiatr Epidemiol 1998;33:363-72
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• 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
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If factors outside the brain are associated with depression, might
they also treat it?
And maybe treat it better?
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4
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Time in Weeks
PlaceboActive antidepressant
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Less
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ress
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Time in Weeks
PlaceboRon-responders receiving active drugResponders receiving active drug
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Sight Sound
SmellTouch
Immune
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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
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Sight Sound
SmellTouch
Immune Temperature
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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
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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
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Aeskulap Clinic in Switzerland
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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
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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)
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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)
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.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)
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WBH at the University of Arizona
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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
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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
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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
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The “Vatman” Approach
Sight Sound
SmellTouch
Immune
The “Let Evolution Do Someof the Hard Work” Approach
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CAUSE
RISK FACTORS
ILLNESS
STRESS
INFLAMMATION
POLLLUTION
DIET
ACTIVITY
LEVEL ISOLA
TION
SOCI
AL C
ONFLIC
T
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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
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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
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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
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CAUSES
ILLNESS
STRESS
INFLAMMATION
POLLLUTION
DIET
ACTIVITY
LEVEL ISOLA
TION
SOCI
AL C
ONFLIC
T
NL EVOLVEDRESPONSE
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In Conclusion
Don’t overestimate
the brain…..