Download ISAD Berlin - April 29, 2014 - EMGO Institute for Health and Care

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Innate immune response
in depression and anxiety
Nicole Vogelzangs a
Johannes H Smit a, Sabine Bahn b, Brenda W Penninx a
a
Psychiatry & EMGO+ Institute
VU university medical center & GGZ inGeest
Amsterdam
[email protected]
[email protected]
b
Institute of Biotechnology, University of Cambridge, Cambridge, United Kingdom
Meta-analyses:
inflammation in depression
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# studies
Effect size /
Mean Difference
CRP
49
0.15
IL-6
61
0.25
IL-1
14
0.35
TNF-α
13
3.97 pg/ml
Marker
Howren et al. Psychosomatic Medicine, 2009
Dowlati et al. Biological Psychiatry, 2010
Confirmed by:
Hiles et al. Brain, Behavior, and Immunity, 2012
Liu et al. J Affective Disorders, 2012
ISAD Berlin - April 29, 2014
Inflammation in anxiety
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Some studies suggest increased
inflammation in anxiety:
- anxiety symptoms 1,2
- post traumatic stress disorder 3,4
- panic disorder 5,6
- generalized anxiety disorder 5,7
1. Pitsavos et al. Atherosclerosis, 2006
2. Liukkonen et al., Eur Psychiatry, 2011
3. Gill et al., Perspect Psychiatr Care, 2009
4. Spitzer et al., J Psychiatr Res, 2010
5. Vogelzangs et al., Transl Psychiatry, 2013
6. Hoge et al., Depress Anxiety, 2009
7. Bankier et al., Eur Heart J, 2008
ISAD Berlin - April 29, 2014
But, …
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Meta-analyses show large heterogeneity
+
Basal circulating inflammation levels:
- low levels
- circadian rhythmicity
- high inter-individual variability
=> Stimulate the immune system to assess the maximal production
capacity of cytokines = innate immune response
- higher levels, less variable
- mimics natural environment more closely
- under strong genetic control
=> Take depressive and anxiety characteristics into account
ISAD Berlin - April 29, 2014
Questions
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 Is the innate immune response increased in depression and anxiety?
 Is innate immune response associated with depressive and anxiety
characteristics?
 Severity?
 Duration?
 Ag of onset?
 Comorbidity?
 Cognitive vs. somatic symptoms?
ISAD Berlin - April 29, 2014
Netherlands Study of Depression and Anxiety
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Design
• Naturalistic cohort study
• Assessments at baseline and after 1, 2, 4 and 8 years.
www.nesda.nl
Sample
• 2,981 subjects (1979 F, 1002 M), 18-65 years (mean age: 42y)
recruited in community, primary care and specialized mental
health care to reflect total range of psychopathology
• Includes healthy controls and both remitted and current
depressed and/or anxiety disorder patients
Penninx et al. Int J Meth Psychiatric Res 2008
ISAD Berlin - April 29, 2014
Depressive and anxiety
disorders and characteristics
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Depressive / Anxiety disorder diagnosis
Major Depressive Disorder, Dysthymia
Generalized anxiety, Social phobia, Panic disorder, Agoraphobia
CIDI interview, DSM-IV based, current recency (6 months)
Severity
Inventory of Depressive Symptoms (IDS)
Beck Anxiety Inventory (BAI)
Cognitive vs. symptoms taken from IDS and BAI
Comorbidity Depression only, anxiety only, depression + anxiety
Duration
% of time affected in past 4 years, life chart
Age of onset in years (derived from CIDI)
ISAD Berlin - April 29, 2014
Innate immune response
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Ex vivo whole blood stimulation by addition of lipopolysaccharide (LPS)
Multi-analyte profiling of plasma using Human CytokineMAP A v 1.0
(Myriad RBM, Austin, TX)
N=1241 with available data on LPS-stimulated cytokines
LPS-stimulated cytokines
• Interferon (IFN)-γ
• IL-2, IL-4, IL-6, IL-8, IL-10, IL-18
• Monocyte chemotactic protein (MCP)-1
• Macrophage inflammatory protein (MIP)-1α, MIP-1β
• Matrix metalloproteinase (MMP)-2
• TNF-α, TNF-β
LPS-stimulated index: sum of all standardized LPS-stimulated markers
ISAD Berlin - April 29, 2014
Baseline characteristics
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Women, %
Age (yrs)
Education (yrs)
Current smoker, %
Alcohol intake, %
None
Moderate
Heavy
Physical activity (MET-min)
BMI
# of chronic diseases
Anti-inflammatory med, %
No
Remitted
Current
dep/anx
dep/anx
dep/anx
n=297
n=251
n=694
62.0
66.9
66.9
42.2 (13.9) 45.9 (12.2) 41.9 (12.1)
13.1 (3.2) 12.8 (3.3) 11.7 (3.2)
23.6
34.3
43.9
21.2
66.7
12.1
4.0 (13.1)
25.2 (4.7)
0.5 (0.7)
2.0
21.9
65.7
12.4
3.7 (2.8)
26.2 (4.8)
0.6 (0.8)
8.4
ISAD Berlin - April 29, 2014
39.2
49.6
11.2
3.5 (3.1)
25.7 (5.2)
0.7 (1.0)
5.3
p
.30
<.001
<.001
<.001
<.001
.08
.06
<.001
.003
Immune response and depression/anxiety disorder
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Adjusted for sociodemographics
LPS index
IL-8
IL-18
Remitted disorder
OR
95%CI
p
1.08
0.87-1.34 .50
1.36
1.13-1.64 .001
1.15
0.95-1.39 .15
Current disorder
OR
95%CI
p
1.19 0.99-1.43 .06
1.35 1.16-1.59 <.001
1.22 1.04-1.43 .01
Adjusted for lifestyle and health factors
LPS index
IL-8
IL-18
Remitted disorder
OR
95%CI
p
1.02
0.82-1.28 .86
1.28
1.06-1.55 .01
1.15
0.95-1.39 .15
Current disorder
OR
95%CI
p
1.12 0.92-1.35 .27
1.25 1.06-1.48 .01
1.13 0.96-1.33 .14
ISAD Berlin - April 29, 2014
Immune response and depression/anxiety severity
Adjusted for sociodemographics
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IDS
IFN-γ
IL-2
IL-4
IL-6
IL-8
IL-10
IL-18
MCP-1
MIP-1α
MIP-1β
MMP2
TNF-α
TNF-β
LPS index
β
-.006
.017
.007
.054
.113
.078
.076
.134
.039
.073
.103
-.005
.069
.091
BAI
p
.87
.58
.81
.14
<.001
.03
.01
<.001
.26
.04
.001
.88
.03
.01
β
.047
.027
-.024
.107
.115
.106
.098
.140
.071
.103
.142
.034
.119
.127
ISAD Berlin - April 29, 2014
p
.16
.38
.40
.003
<.001
.003
.001
<.001
.04
.003
<.001
.32
<.001
<.001
Immune response and depression/anxiety severity
Adjusted for lifestyle and disease
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IDS
β
IFN-γ
IL-2
IL-4
IL-6
IL-8
IL-10
IL-18
MCP-1
MIP-1α
MIP-1β
MMP2
TNF-α
TNF-β
LPS index
BAI
p
β
p
.03
.03
.03
.07
.007
.35
.11
<.001
.002
.01
.069
.059
.029
.087
.02
.10
.32
.008
.028
.071
.42
.02
.077
.066
.078
.053
.088
.032
.055
.110
.042
.046
.16
.18
.094
.087
ISAD Berlin - April 29, 2014
Cognitive vs. somatic symptoms
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Duivis, Vogelzangs et al., PNEC, 2013:
Basal CRP, IL-6 and TNF-α are associated with somatic symptoms of IDS
and BAI, but NOT with cognitive symptoms of IDS and BAI
LPS index
IDS
BAI
β
p
β
p
Total
.091
.01
.127
<.001
Somatic
.094
.009
.131
<.001
Cognitive
.082
.03
.102
.005
Adjusted for sociodemographics
ISAD Berlin - April 29, 2014
Depressive and anxiety characteristics
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Within the subsample of current depressive/anxiety patients (N=694)
 Severity
=> replication of findings within total sample
 Duration
=> no association
 Age of onset
=> no association
 Comorbidity
=> no differences between pure depression, pure anxiety disorder and
comorbid depressive and anxiety disorder
ISAD Berlin - April 29, 2014
Conclusions
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 Innate immune response is increased in persons with higher levels of
depressive and in particular anxiety symptoms, even when taking lifestyle
and health factors into account.
 IL-8 production capacity is increased in both previously and currently
depressed an anxious persons => genetic vulnerability?
 No specific associations with duration, age of onset or comorbidity.
 Unlike basal inflammation levels, innate immune response is associated
with both somatic and cognitive depressive/anxiety symptoms.
=> Measuring innate immunity provides additional insight in immune
functioning in depression and anxiety.
ISAD Berlin - April 29, 2014
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Thank you for your attention!
ISAD Berlin - April 29, 2014