Inflammation in Depression:
What We Know&
What Can We Do About it?
Rakesh Jain, MD, MPH
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In Psychiatry, Inflammation Is An Important Contributory to Suffering
Chang CK, et al. PLoS One. 2011;6:e19590.
MDDUK Pop.
Annual mortality risk (%) by age groups and diagnoses of mental illness, compared to England and Wales population in 2008.
Life expectancy was reduced by 10.6 years for males and 7.2 years in females with MDD compared with UK population.
No. of AdverseChildhood Experiences
Stud
y M
embe
rs w
ith th
e Co
nditi
on (%
)
70
60
50
40
30
20
10
Panel 1: Major Depression
Panel 3: Clustering of Metabolic Risk
Markers
0 (n=502)
1 (n=253)
≥2 (n=98)
32-year Prospective Study
Panel 1: z=4.94, p<0.001; hsCRP level >3 mg/L . Panel 2: z=3.24, p=0.001; clustering of metabolic risk markers. Panel 3: z=4.58, p<0.001; and ≥1 age-related disease risks. Panel 4: z=5.66, p<0.001.
Panel 2:hsCRP >3 mg/L
0Panel 4:
≥1 Disease Risk
Childhood Adversity Represents a Risk for Adulthood Disease
CRP=C-reactive protein; hsCRP=High-sensitivity C-reactive protein level. Danese A, et al. Arch Pediatr Adolesc Med. 2009;163:1135–1143.
Mean hs-CRP values in patients with current major depression vs. non-depressed subjects
Raison et al, in preparation
0
0.1
0.2
0.3
0.4
0.5
MDDcurrent
No MDD
hs-C
RP
(m
g/d
l)
n=38 n=461t=2.04, p=0.04Z=2.48, p=0.01
Patients With MDD Who Did Not Respond to Antidepressants Had Higher Inflammatory
Cytokine Levels
p=0.01p=0.004
24 healthy controls and 28 patients with depression (HAMD17 >20) after 6 weeks of SSRI treatment and 16 euthymic patients (previously resistant to SSRIs) currently successfully treated with an SNRI
or an addition of lithium to SSRI treatment.HAM-D=Hamilton depression score; MDD=Major depressive disorder; SNRI=Serotonin–norepinephrine reuptake inhibitor; SSRI=Selective serotonin reuptake inhibitor; TNF=Tumor necrosis factor.
O’Brien SM, et al. J Psychiatr Res. 2007;41:326–331.
Controls ControlsDepressed DepressedEuthymic Euthymic
TNF- IL-6
TN
F-
(pg/
ml)
IL-6
(pg/
ml)
O’Brian Study Conclusions -
“Suppression of pro-inflammatory cytokines
does not occur in depressed patients who fail to respond to SSRIs and is
necessary for clinical recovery”O’Brien SM, et al. J Psychiatr Res. 2007;41:326–331.
Why does psychosocial stress induce
inflammation?
From an Evolutionary Perspective Stress is…..
Hunting and being hunted….
The struggle for dominance and sexual access
From an Evolutionary Perspective Stress is…..
Danger Circuits
PVN:CRFAVP
LOCUS CERULEUS:Norepinephrine (NE)
PITUITARY:ACTH
ADRENAL:Cortisol
ADRENAL:NE, Epi
HPA Axis ANS
FLIGHT RESPONSE:Production, mobilization, and direction
of energy. Shut down of all nonessential bodily, vegetative,
functions. Narrowing of attentional focus to perceived danger.
INNATE IMMUNE RESPONSE:Activation of systemic
inflammatory response to prime the immune system for tissue
damage from danger situation
“Stress perception by the brain may serve as an early warning signal” to activate the immune system in preparation for a markedly increased likelihood of subsequent infection.”
Firdaus Dhabhar
Innate Acquired
Cells phagocytes (macrophages, neutrophils, natural killer cells) lymphocytes (B and T cells)
Recognition
Pathogen-associated molecular patterns (PAMPS) recognized by pattern recognition
receptors ( PRRs). PAMPs are essential polysaccharides and polynucleotides that differ little from one pathogen to another but are not found in the host. Receptor
structure is coded in the germline.
B and T cell receptors have very narrow specificity; i.e., recognize a particular epitope. Most epitopes are derived from proteins and
reflect the individuality of the pathogen. Receptor structure is a function of rearranging
genes.
Soluble mediators that
affect other cells
macrophage-derived cytokines, i.e., IL-1, IL-6, TNF-alpha, type I interferons
lymphocyte-derived cytokines, i.e., IL-2, IL-4, IL-5, IL-6, IL-10, IFN-gamma
Memory No memory of prior exposure Memory of prior exposure
Response Immediate Slow (3-5 days), needs time for clonal expansion
Epitope: A part of an antigen to which an antibody binds. Also called an antigenic determinant.
Divisions of the Immune System: Innate vs. Acquired
INNATE IMMUNITY ACQUIRED IMMUNITY
• Non-specific recognition of pathogens, tissue damage and danger signals
• Rapid (hours to days) imprecise, relatively metabolically cheap
• Contains threat but at the cost of generalized wear and tear on bodily tissues
• Activation promotes sickness and depressive symptoms
• Specific recognition of pathogens and danger signals
• Delayed (days to a week), precise, metabolically expensive
• Contains threat without appreciable damage to bodily tissues except in case of autoimmunity
• Activation resolves sickness and may protect against depression
Stress and inflammation in MDD
Raison et al, Arch Gen Psychiatry. 2010;67(12):1211-1224
A Psychosocial stress,social isolation, personality
factors
IL-1, TNF-, IL-6
IL-6
EuthymiaStress resilience
Major depression sickness behavior
G
Immunoregulation
k t
i H
PA
- a
xis
- c
IL-10, TGF-
NE
/-AR IL-1,
TNF-, IL-6
NF-B
ACh TLR
7nAChr
GR
Infection, tissue trauma, neoplasm Macrophage GCs
IL-10, TGF-
Glia-Neuron Interaction May Influence Neurotrophic Factors
5-HT=serotonin. BDNF=brain-derived neurotrophic factor. CNS=central nervous system. GLU=glutamate. IDO=indoleamine 2,3 dioxygenase. IFN=interferon. IL=interleukin. NMDA=N-methyl-D-aspartate. QUIN=quinolinic acid. RNS=reactive nitrogen species. ROS=reactive oxygen species. TNF=tumor necrosis factor. TRP=tryptophan. Miller AH, et al. Biol Psychiatry. 2009;65(9):732-741. Reprinted with permission from Elsevier Limited.
Inflammatory Markers Predict the Future Development of Depression
Pasco et al. Brit J Psychiatry 2010, 197:372-377.
In a cohort of 644 initially non-depressed females, 48 developed de novo MDD over an approximate 10 year follow up. Survival plot (Kaplan-Meier) showing the probability of remaining free of de novo major depressive disorder for women stratified into tertiles of hsCRP. The concentration of hsCRP in each tertile is: low, <1.12 mg/l; mid, 1.12-2.97 mg/l; and high, >2.97 mg.l.
Tertile 1 (low) 100 – Tertile 2 (medium) Tertile 3 (high)
98 –
96 –
Per
cent
94 –
92 –
90 –
0 3 4 6 8 10 Time, years
*Correlations of IL-6 level with guilt, self-esteem, and suicidal thoughts remained significant after Bonferroni correctionIL-6=Interleukin-6; MDD=Major depressive disorder; VAS=Visual analogue scale.
Alesci et al. J Clin Endocrinol Metab 2005;90(5):2522-30.
Comparison of 9 MDD patients with 9 matched healthy controls
Inflammatory Cytokine Levels May Be Associated With Symptom Severity in MDD Patients
Obesity and Depression: Another Modern Problem That is Increasing Risk for Depression
Relationship Between Obesity, Metabolic Syndrome and Depression
Association between the metabolic syndrome (MetS) and depression in each body massindex (BMI) category. Graph displays the odds ratio (OR) for depression after adjustment for age, gender, prior cardiovascular
disease, employment status, marital status, smoking status, dietary score, and physical activity. Obesity was defined as a BMI 30 and overweight status as a BMI between 25 and 30 kg/m2
Odd
s Ra
tio -
Dep
ress
ion
Skilton et al, 2007, Biol Psychiatry, 62(11): 1251-7.
MDD, Adiposity and Inflammatory Markers
Miller GE et al. Am J of Cardiol. 2002;90(12):1279-83
0.00
0.25
0.50
0.75
1.00
Low (BMI < 30) High (BMI > 30)
CR
P ±
SE
M (
mg
/L)
ADIPOSITY
C-Reactive Protein
50 MDD patients compared with 50 healthy matched controls
Weeks on IFN-alpha
Su
rviv
al Fre
e o
f M
ajo
r D
ep
ressio
n (
%)
0 2 4 6 8 10 120
20
40
60
80
100
Incidence of Major Depression During the First 12 weeks of IFN-alpha
Musselman et al., New England Journal of Medicine, 344:961-966, 2001.
Paroxetine Pretreatment Reduces the Incidence of Major Depression During the
First 12 weeks of IFN-alpha
00
20
40
60
80
100
2 4 6 8 10 12
Weeks on IFN-alpha
Su
rviv
al Fre
e o
f M
ajo
r D
ep
ressio
n (
%)
PlaceboParoxetine
Musselman et al., New England Journal of Medicine, 344:961-966, 2001.
The Trier Social Stress Test (TSST)
Psychological Stress, a Well-Known Precipitant of Depressive Illness, Induces an Inflammatory Response: A Possible Link
Between Stress, Depression and Illness
*-the majority of the depressed patients in this sample also endorsed significant early life stress as measured by the CTQ
Pace et al., Am J Psychiatry, 2006.
*Between group comparison, p < 0.05
+Within group comparison vs. 0 min time pt, p < 0.05
Major Depression (n = 14)
Pla
sm
a I
L-6
, p
g/
ml
0
1
2
3
4
5
6
-15 0 15 30
Control (n = 13)
TSST
*
Pla
sm
a I
L-6
, p
g/
ml
0
1
2
3
4
5
6
-15 0 15 30 45 60 75 90
Major Depression (n = 14)
Control (n = 13)
TSST Time (min)
*
+
+
++ +
*Between group comparison, p < 0.05
+Within group comparison vs. 0 min time pt, p < 0.05
+
*
80
90
120 130-15 0 15 45
TST
+
+
Double-Blind, Parallel-Group, Randomized Study of Peripheral Cytokine Antagonist
TRD Pts(N=60)
INFLIX(5mg/kg)
PLACEBO
Baseline Wk 1 Wk 2 Wk 3
N =30
N =30
Wk 4 Wk 6 Wk 10 Wk 12Wk 8
Clinician-Administered Psychiatric Assessments (HAM-D, CGI)Adverse Events Evaluation
Blood Draw for Inflammatory Markers and Safety Labs
StratificationMale vs Female
CRP >2 vs CRP ≤2
Randomization
INFUSION INFUSIONINFUSION
hs-CRP Tertiles:Low: 0-1.56 mg/LMedium: 1.56-5.12 mg/LHigh: >5.12 mg/L
End of Treatment HAM-D 50% Reduction in HAM-D 17
Baseline CRP Interacts with Group Assignment To Predict End of Treatment (12 Wks) HAM-D-17 score and Treatment
Response as defined by 50% reduction in HAM-D 17 at 12 Wks
Representative Changes from Baseline to End of Treatment in HAM-D 17 as a Function of Baseline hs-CRP
Symptoms Responsive to Infliximab and Placebo in TRD subjects with Baseline CRP >5 mg/L
Pathogen NeutralizationWound Healing
Behavioral ChangesReduced Activity
AnhedoniaFatigue
Depression
Protection fromAttack
Behavioral ChangesInsomnia
HyperarousalHypersensitivity
Anxiety
Neurobiological ChangesDecreased Dopamine and
Serotonin Neurotransmission
Neurobiological ChangesIncreased dACC activation
Increased Time AwakeDecreased Sleep Efficiency
INFLAMMATION
NEUROPSYCHIATRIC DISORDERS
Laying Low On the Look Out
StressInfectionInjury
Balancing Survival Priorities
Laying Low
Pathogen Neutralization
Wound Healing
Behavioral ChangesReduced Activity
AnhedoniaFatigue
Depression
On the Look Out
Protection from
Attack
Behavioral ChangesInsomnia
HyperarousalHypersensitivity
Anxiety
Neurobiological ChangesDecreased Dopamine and
Serotonin Neurotransmission
Neurobiological ChangesIncreased dACC activation
Increased Time AwakeDecreased Sleep Efficiency
INFLAMMATION
NEUROPSYCHIATRIC DISORDERS
Genetics Environment
StressInfectionInjury
Balancing Survival Priorities
Laying LowPathogen NeutralizationWound Healing
Behavioral ChangesReduced Activity
AnhedoniaFatigue
Depression
On the Look OutProtection fromAttack
Behavioral ChangesInsomnia
HyperarousalHypersensitivity
AnxietyNeurobiological ChangesDecreased Dopamine and
Serotonin Neurotransmission
Neurobiological ChangesIncreased dACC activation
Increased Time AwakeDecreased Sleep Efficiency
StressInfectionInjury
INFLAMMATION
NEUROPSYCHIATRIC DISORDERS
Genetics Environment
Balancing Survival Priorities
Lessons From Inflammation: Treatment
Neurobiology of Exercise – A Complex Cascade
Dishman RK et al. (2006), Obesity 14(3):345-356; VTA = ventral tegmental area; ROS = reactive oxygen species; WAT = white adipose tissue; NFKB = nuclear factor kappa B; ANS = autonomic nervous system ; CVD = cardiovascular disease
Function DiseaseStructure
Executive ControlsPrefrontal & Cingulate Cortex
Emotional ControlsAmygdala, Prefrontal Cortex
External InputVisual
OlfactoryAcoustic
GustatorySomatosensory
ANS&
Endocrine
Systems
DA↓
Parkinson’s Disease
↑ROS
Alzheimer’s Dementia
Schizophrenia
Depression
Sleep Disorders
Obesity
Diabetes
CVD
Immune Disorder
IBD, Constipation Colon Cancer
Learning & Memory
Immune Control
Gastrointestinal Control
MuscleCardiovascular ConsequencesMetabolic ConsequencesLiver, WAT, Pancreas
Thermal Consequences
Behavior•Social•Sexual•Coping•Addictive•Escape•Fight & Flight•Stress•Sleep•IngestiveMotor Controls
Motor CortexStriatum, Brainstem, Cerebellum, Spinal
Cord
Motivational ControlsReward, Wanting, SelectionHypothalamus, Accumbens, VTA
Cognitive ControlsHippocampus, Cortex
Neural
Primary Afferents
“Exercise”
Internal Feedback
“Consequences of exercise”
Humoral
Factors
CNS
Energy Balance
RepairPlasticityProtection
NeurogenesisTranscription
NA, 5-HT,GABA,
Glutamate, Glycine
BDNF/TrkBERK/CREB
NFKB
Are Cytokines Pro-inflammatory in Adipose Tissues and Anti-inflammatory
in Skeletal Muscles?
Rosa Neto JC et al. Eur J Appl Physiol. 2009;106(5):697-704.
Adipose tissue Muscle tissue
C = controls
ED = immediately after exercise
E2 = 2 hrs after exercise
E6 = 6 hrs after exercise
Exercise – Effects on Immune System, Skeletal System, Adipose tissue and Brain
Pedersen BK, Febbraio MA. Physiol Rev. 2008;88:1379-1406.
Exercise And Cytokines – Exercise’s Modulating Effects
Smits HH, et al. Clin Exp Immunology. 1998;111:463-468.
Blood was obtained 40 minutes before, and 20 minutes after single bout of exercise
*, **, *** p <.05
9 athletes, oarsmen, single session exercise till exhaustion, 15-20 minutes
Before exercise
After exercise
Practicing Mindfulness
“If your attention wanders a hundred times, simply bring it back a hundred
times.”
(Present Moment)
(Attention)
(Nonjudgmental)
Mind on chosen target
Attention wanders
Observe wandering, begin again
50 healthy women (mean age=41.32, range=30-65), 25 novices and 25 experts, were exposed to each of the conditions (yoga, movement control, and passive-video control) during 3 separate visits.
Autonomic Nervous System and Inflammatory Responses, Stress, and Meditation
Kiecolt-Glaser JK et al. Psychosom Med. 201;72(2):113-121.
Antidepressants and Inflammation• TCAs and SSRIs inhibit proinflammatory cytokine production from
monocytes and lymphocytes• PDE4 inhibitors (i.e. rolipram) are antidepressants in humans. These
agents increase c-AMP signaling, suppress in vivo and in vitro TNF-alpha production and block autoimmune encephalomyelitis, a rodent model for multiple sclerosis
• Chronic, but not acute, antidepressant administration attenuates in vivo cytokine responses to immune challenge in rodents
• Fluoxetine and amitriptyline suppress NO and PGE release from LPS stimulated human cells in vitro
• Chronic SRI treatment lowered TNF-alpha/CRP levels in depressed humans
• Chronic ECT lowered TNF-alpha levels in severely depressed patients• Chronic antidepressant administration blocks behavioral effects of
proinflammatory cytokines in rodentsMaes, Adv Exp Med & Biol, 1999; Griswold et al. J Pharm & Exp Ther, 1998; Shen et al. Life Sciences, 1999; Yaron et al. Arth & Rheum 1999; Tuglu et al. Psychopharm 2003; Hestad et al. J ECT 2003; Yirmiya et al. Neuropsychopharm 2001.
0 1 2 3 4 5 610
15
20
25
30
Reboxetine and Celecoxib (n = 20)Reboxetine and Placebo (n = 20)
weeks
Esti
mat
ed m
argi
nal m
eans
Müller N et al, Molecular Psychiatry 2006;11:680–684
Comparison of HamD scores during therapy with celecoxib or placebo (ANOVA, estimated marginal means; advantage of celecoxib group: Greenhouse–Geisser-corrected F= 3.220; df 2.434; P= 0.035) *Pp0.05.
Anti-inflammatory Add on Therapy – Preliminary Data looks Promising
BT - before Treatment
AT - after treatment
Hamilton Depression Rating Scale – scores before and after treatment
Interleukin-12 (IL-12) levels
Interleukin-4 (IL-4) levels
BT AT
40
35
30
25
20
15
10
5
0
30
25
20
15
10
5
0BT AT
9876543210
BT AT
IL-1
2 (
pg
/ml)
HD
RS
IL-4
(p
g/m
l)
Anti-depressant Treatment and Effects on Pro- & Anti-inflammatory Cytokines
Sutcigil L, et.al. Clinical and Developmental Immunology.2007.
To Summarize the Complex Issue
CNS INFLAMMATION
MedicalIllness
(e.g. CVD, diabetes,cancer)
BehavioralMorbidity
(depression, fatigue, cognitive dysfunction
and pain)
EndocrineSystem
Stress/Depression
Cytokines(e.g. IFN-alpha, IL-1,
IL-6, TNF-alpha)
Immune Activation(e.g. secondary to infection,
autoimmunity, cancer, surgery,radiation, chemotherapy
tissue damage or destruction)
A Clinician’s Integrative View of “Mind-Body” Disruptions in Psychiatric Mood Disorders
Adapted from Goldstein BI, et al. J Clin Psychiatry. 2009;70(8):1078-1090.Adapted from Szelényi J, Vizi ES. Ann N Y Acad Sci. 2007;1113:311-324.
Pain
Neuropsychological impairmentNeurodegeneration
Mood disorders
Sleep disorders
Osteoporosis
Obesity, insulin and lipid
abnormalities
Coronary artery disease
Substance misuse
Inflammation
Inflammatory and Neurodegenerative (I&ND) Hypothesis of Depression
Maes M, et.al Metab Brain Dis. 2009;24:27-53
GENETIC PREDISPOSITION IN ANY OF THE BIOMARKERS
Leaky Gut Lower DPP IV
Lower n-3 status
Decreased neurogenesis
BDNF, FGF, NCAM
Neurodegeneration and cell death in
hippocampus
O&NS damage tofunctional peptides
and membrane fatty acid
Internal stressors - postnatal - inflammation(CHD, MS, IBD,
RA, IMD)
External stressors (psycho-social)
cytokines and intracellular
inflammation
ACUTE PHASE RESPONSEin the LIVER
Lower tryptophan +changes in 5HT1A
and 5-HT2 receptors
IDO inductionTRYCATs
O&NS
Increased HPA -axis activity
andGR
downregulation
Depressionsymptoms, recurrence,treatment resistance,
bipolar illness
CHD = coronary heart disease; MS = multiple sclerosis; IBD = irritable bowel disease; RA = rheumatoid arthritis; IMD = immunodeficiency; DPP = dipeptidyl peptidase; IDO = indoleamine 2,3-dioxygenase; TRYCATs = tryptophan catabolites ; O&NS = oxidative & nitrosative stress; GR = glucocorticoid receptor ; FGF= fibroblast growth factor; NCAM = neural cell adhesion molecule
● Loss of pleasure*● Loss of appetite*● Weight loss*● Cognitive disturbance*● Decreased sexual energy*● Fatigue*● Physical slowness*● Sleep disturbance*● Social isolation*● Increased pain* ● Fever *● Sad mood†● Suicidal ideation†● Worthlessness/guilt†
● Loss of pleasure*● Loss of appetite*● Weight loss* ● Cognitive disturbance*● Decreased sexual energy*● Fatigue*● Physical slowness*● Sleep disturbance*● Social isolation*● Increased pain complaints*● Increased body temperature *● Sad mood†● Suicidal ideation†● Worthlessness/guilt†
Inflammation Induced“Sickness”
“Real” Depression
Raison et al. Biol Psychiatry 2003
Stress/depression increases the risk of the following:
• Coronary artery disease, heart attacks, sudden cardiac death
• Obesity, diabetes
• Alzheimer’s disease
• Developing a cold upon virus exposure
• Progression of HIV disease
• Progression of cancer
• Poor response to vaccination
In Conclusion - Lessons From Inflammation Research
INFLAMMATION increases the risk of the following:
• DEPRESSION
Treatment Implications:
Mind-Body Approach for Patients may be our best tool
Treatment / s ??
Understanding