Transcript Document

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 we know that
mental disorders are brain disorders.”
National Institute of Mental Health
ECOSHERE
SOCIETY
FAMILY
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;167:11007; 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?
Less Depression
22
20
18
16
14
12
10
8
6
4
Placebo
Active antidepressant
0
0
1
2
3
4
5
Time in Weeks
6
7
8
Less Depression
22
20
18
16
14
12
10
8
6
4
Placebo
Ron-responders receiving active drug
Responders receiving active drug
0
0
1
2
3
4
5
Time in Weeks
6
7
8
Sight
Sound
Touch
Smell
Immune
Evidence That Peripheral Treatments for MDD May Be
Effective
Weeks
Baseline 1
INFLIX
(5 mg/kg) n=30
TRD Pts
(n=60)
Stratification
2
3
4
6
8
10
12
Placebo
Randomization
PLACEBO
60
n=30
Infusion
Infusion
Infusion
Clinician-Administered Psychiatric Assessments (HAM-D, CGI)
Adverse Events Evaluation
Blood Draw for Inflammatory Markers and Safety Labs
30
25
20
15
10
Infliximab
5
Placebo
0
Percent Responders During Study
Male vs Female
CRP >2 vs CRP ≤2
Adjusted Mean HAM-D-17
Infliximab
50
40
30
20
10
0
Baseline 1
2
3
4
Weeks
6
8
10
12
Med + Low
High
Hs-CRP (tertiles)
CGI, Clinical Global Impression; INFLIX, infliximab; TRD, treatment-resistant depression.
Raison CL et al. JAMA Psychiatry. 2013;70(1):31-41.
Sight
Sound
Touch
Smell
Immune
Temperature
Depression
PFC
AH/
POA
DRI
PAG
DRLV
5HT, BDNF, NT-3
in CNS
RPa
Sweating
Heart rate var.
Inflammation
Tb Core
Improved sleep
Inflammation
LPB
5HT, BDNF,
NT-3
plasma
5HT Cells
Sweat Glands
Post Incubation Trec (○C)
Swimming (%)
60
50
40
30
0
23 ○ C
37 ○ C
Whole Body Warming Alone
38.0
37.8
37.6
37.4
37.2
37.0
36.8
36.6
36.4
37 ○ C
23 ○ C
20
30
40
50
60
70
Swimming (%)
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, preexposure 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)
Aeskulap Clinic in Switzerland
First Open Trial of WBH
CES-D Depression Score
35
Active Hyperthermia (N=15)
30
25
20
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
Mean 24-Hr Body Temp.
37.4
Active Hyperthermia (N=7)
37.3
37.2
37.1
37.0
36.9
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
Pre-WBH Core Body Temp.
Temperature Predicts AD Response
37.8
Active Hyperthermia (N=12)
37.6
37.4
37.2
37.0
36.8
r=0.62, df=9, p=0.043
-24 -20 -16 -12 -8 -4
0
Change in CES-D Depression Score
Δ CES-D Score
Temperature and Mood After WBH
40
35
30
25
20
15
10
5
0
Active Hyperthermia (N=7)
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
IDS-SR DEPRESSION Score
Day 3 and Day 7 WBH vs. Sham
Sham Hyperthermia (n=6)
Hyperthermia (n=7)
50
45
40
35
30
25
20
15
Pre-TX Day 1
Day 2
Day 3
Day 7
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
Sham Hyperthermia (n=6)
Hyperthermia (n=7)
HDRS-17 Score
25
20
15
10
ANCOVA B1 = -7.65, p=0.03; effect size d = 1.68
Pre-RX
WK 1 Post-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
ANCOVA B1 = -6.8, p = 0.1; effect size d = 1.30
HDRS-17 Score
25
20
15
10
Sham Hyperthermia (n=6)
Hyperthermia (n=7)
5
Pre-TX
Week 1
Week 2
Week 4
Sight
Touch
Sound
Smell
Immune
The “Let Evolution Do Some
of the Hard Work” Approach
The “Vatman” Approach
RISK FACTORS
CAUSE
Inflammation Causes Depression
MEAN MADRS SCORE
14
12
10
8
IFN-ALPHA, n=23
6
HCV CONTROL, n =14
4
2
0
0
4
8
12
WEEKS
Raison et al. Mol Psychiatry 2010 May;15(5):535-47
The Impact of Blocking Inflammation in the Body
Weeks
Baseline 1
INFLIX
(5 mg/kg) n=30
TRD Pts
(n=60)
Stratification
2
3
4
6
8
10
12
Placebo
Randomization
PLACEBO
60
n=30
Infusion
Infusion
Infusion
Clinician-Administered Psychiatric Assessments (HAM-D, CGI)
Adverse Events Evaluation
Blood Draw for Inflammatory Markers and Safety Labs
30
25
20
15
10
Infliximab
5
Placebo
0
Percent Responders During Study
Male vs Female
CRP >2 vs CRP ≤2
Adjusted Mean HAM-D-17
Infliximab
50
40
30
20
10
0
Baseline 1
2
3
4
Weeks
6
8
10
12
Med + Low
High
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
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
CAUSES
NL EVOLVED
RESPONSE
In Conclusion
Don’t overestimate
the brain…..