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.

http://www.getzoned.com.au/images/product_book_the_anti_inflammation_zone_full_size.jpg

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

Rakesh Jain:

JainTexas@gmail.com

Come see Us in Texas

Mi Case, Su Casa !