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ESPECIALLY BUGGED BY STRESS:SOCIAL ADVERSITY, MICROBES AND IMMUNITYIN THE DEVELOPMENT AND TREATMENT OF DEPRESSION

Charles L. Raison, M.D.Barry and Janet Lang Associate ProfessorOf Integrative Mental HealthUniversity of ArizonaTucson, AZ

Disclosure Statement

In the previous 12 months, Dr. Raison has served as a consultant for Bristol Myers Squibb and Pamlab and has developed and delivered disease‐state promotional talks for Pamlab Hedisease state promotional talks for Pamlab. He serves on the steering committee for CME LLC and receives grant support from the National Center for Complementary and Alternative Medicine (NCCAM).

What Are the Most Depressing Things in the World?

• Getting sick • Circumstances that evoke a perception of loss

– Not just any loss but especially:• Being rejected in important relationshipsBeing rejected in important relationships• Losing anything or anyone upon which (or whom) one’s self‐esteem is dependent

• Being defeated in any type of agonistic encounter• Losing the esteem of self or others through being put‐down, shamed, exposed

• Failing to achieve personally important life goals• Feeling trapped in one’s circumstances without the power to escape

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Nothing in Biology Makes Sense Except i h i h f l iin the Light of Evolution

Theodosius Dobzhansky

The Threat to Overall Fitness Model of Depressive Pathogenesis (TOF)

1. The perception of reduced overall personal evolutionary fitness should promote the development of major depression (MDD).development of major depression (MDD). 

2. Environmental conditions should be depressogenic to the degree that they are likely to induce a perception of reduced overall personal evolutionary fitness.

Components of Overall Evolutionary Fitness

Personal survivaluntil completion of childrearing

Maximal offspring who themselves 

reproduce maximally 

Reproductive success ofgenetically‐related

individuals

OVERALL EVOLUTIONARY FITNESS

Natural Selection Sexual Selection Kin Selection

Reproductive Success

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Proximate Mechanisms Evolved to Serve Ultimate Goals

The Tragedy of Environmental Mismatch

TOF, More Exactly

Environmental circumstances should be depressogenic to the degree that they reliably induce a perception that one is blocked from access to, or successful utilization of, , ,proximate mechanisms that—while consciously desired for their own sake—enhanced overall evolutionary fitness by enhancing survival, personal reproductive success and success of one’s genes in related individuals.

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An Immediate Problem with TOF

Which Picture Bothers You More?

TOF, Even More Exactly

Environmental circumstances should be depressogenic to the degree that they reliably induce a perception that one is blocked from access to, or successful utilization of, , ,proximate mechanisms that—while consciously desired for their own sake—enhanced overall evolutionary fitness inancestral environments by enhancing survival, personal reproductive success and success of one’s genes in related individuals.

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AFFILIATION

HEALTH AGENCY

AFFILIATION

HEALTH AGENCYSickness

Inflammation

Social Isolation

Rejection

Intimate Hostility

DefeatEntrapmentInflammation Entrapment

AFFILIATION

HEALTH AGENCY

How do we know that we have failed, or are at risk for failing, toaccomplish proximate mechanisms that enhanced overallfitness in ancestral environments?

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SightSoundSmellTouchColdHeatTaste

EXTERNALWORLD

INTERNALWORLD

Visceral conditionImmune signaling

Intrapsychic ConflictRumination

Default Mode Dysregulation

Therapeutic Implications of TOF

Manipulating internal CNS processes or peripheral sensory signaling pathways to produce emotionally “real” cognitions that one is in a situation likely to maximize overallis in a situation likely to maximize overall evolutionary fitness via success at proximal mechanisms should produce antidepressant effects.

Intrapsychic ConflictRumination

Default Mode Dysregulation

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?SightSoundSmellTouchColdHeatTaste

EXTERNALWORLD

INTERNALWORLD

Visceral conditionImmune signaling

?

Beauty in Nature May Have Antidepressant Properties

30

25

15

25.37

25.24

23.7

25.05

24.38

22.31

24.53

22.48

16.87

23.33

20.32

***

* P<0.007; **P<0.048.

ery‐AsbergRating 

ale Score

Mean (SD), paired t‐test

Kim W et al. Psychiatry Investig. 2009;6(4):245‐254.

10

5

0Week 1  Week 2 Week 3  Week 4

11.83

Controls

Hospital

Forest

MDD Remission Rates:

CBT in Forest = 61%

CBT in Hospital = 21%

Controls = 5%

Salivary Cortisol (µg/dL) Before the 4 week program After the 4 week program t P

Forest group 0.113 (0.053) 0.082 (0.044) 2.97 0.008

Hospital group 0.125 (0.052) 0.132 (0.057) ‐1.62 0.121

Controls 0.137 (0.100) 0.148 (0.106) ‐1.31 0.206

Montgome

Sca

Prior to the 20th Century nearly everyone who ever lived died from infection.

In most places and times, 50% of individuals died by age 15, largely from infection.

Inflammation is the primary bodily sense bywhich the brain comes to know it is infectedor in significant danger for infection. Becauseinfection has been the leading cause of early mortality during human evolution, and because early mortality strongly reduces overall fitness,inflammation should produce depression

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InflammationInflammation

MacrophageTNF, IL‐1, IL‐6 IFN‐alpha

Chemokines

Stromalcell

Endothelial cell

Adhesion molecules

Leukocyte Diapedesis

Local

NF‐κB

Local Effects‐ Increased vascular permeability‐ Vasodilation ‐ Chemokine production‐ Expression of adhesion molecules‐ Pain

TumorRuborCalorDolor

Acute Phase Response‐ C‐reactive protein‐ serum amyloid A‐ haptoglobin‐ alpha 1‐antichymotrypsin

Effects on Liver

Toll‐like receptors (TLRs)

TNFIL‐1IL‐6IFN‐alpha

Systemic

Effects on Brain‐ Fever‐ Fatigue‐ Anorexia‐ Anhedonia‐ Altered sleep

Sickness behavior/depression

14

12

10

8DRS SCORE

IFN‐ALPHA, n=23

Inflammation Causes Depression

8

6

4

2

0

0 4 8 12

WEEKS

MEA

N M

AD IFN ALPHA, n 23

HCV CONTROL, n =14 

Raison et al. Mol Psychiatry 2010 May;15(5):535‐47

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ree of 

ssion (%)

60

80

100

Chronic Cytokine Exposure Induces MDD

Weeks on IFN‐alpha

Survival Fr

Major Depres

0 2 4 6 8 10 120

20

40

60

Placebo

Paroxetine

Musselman. N Engl J Med. 2001;344:961.

One of the reasons inflammation induces depression is to isolate individuals 

Visual Perception of Sickness Increases Immune Activity

Schaller et al. Psychol Sci 2010: Epub

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An Inflammatory Stimulus induces Feelings of Social Isolation

Eisenberger et al. BBI 2010; 24: 558‐63

Inflammation Activates Brain Regions that Mediate Feelings of Social Disconnection

Inagaki et al. Neuroimage 2012; 59: 3222‐26

Brain Responses to Peer Rejection Correlate with Inflammatory Responses to Stress

Slavich et al. PNAS 2010; 107: 14817‐22

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Mild Increases in Peripheral InflammationInterfere with the Placebo Response

50% Reduction in HAM‐D 17

hs‐CRP Tertiles:Low: 0‐1.56 mg/LMedium: 1.56‐5.12 mg/LHigh: >5.12 mg/L

Raison et al, submitted

Why Social Isolation?

In ancestral environments, social isolation:o Protected group members with whom one shared genes from infection

o Protected the sick individual from co infectiono Protected the sick individual from co‐infection with other types of pathogens

o Protected the sick individual from exposure to pathogens from members of out‐groups against which he/she would have reduced resistance

We Need To Expand the Family System

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Only one out ofevery ten cellsin our body aremammalian ….

Fumagalli et al.PLoS Genet 2011; Epub

Pathogen Infection Promotes Depressive Symptoms

Hickie et al. BMJ 2006; Epub

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Food Poisoning Predicts Future Development of Other Diseases

Clark et al. BMJ 2010; Epub

ELS Promotes Lifelong Inflammation and Accounts for Inflammation in MDD

Danese et al., PNAS 2007;104:1319-24Danese et al., Arch Gen Psychiatry 2008;65:409-16

Prospectively assessed maltreatment in childhoodpredicted increased markers of inflammation in adulthood independently of other factors known toincrease inflammation. In this population, MDD wasassociated with increased inflammatory markers, butthis association was accounted for by the increasedchildhood maltreatment in depressed population.

Microbial Exposure Early in Life Reduces Inflammatory Tone

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THE OLD FRIENDSTHE OLD FRIENDS

Gut FloraGut Flora

Saprophytic Saprophytic MycobacteriaMycobacteria

Rook, Raison and Lowry. Microbiologist ; Sept. 2011: 32‐36

Gut FloraGut Flora

HelminthsHelminths

Chronic Treatment with M vaccae  Reduces IL‐4 and TNF‐alpha

M Vaccae and SurvivalIn Patients with LungAdenocarcinomaStanford et al. Eur J Cancer 2008; 44: 224‐7

Potential Health BenefitsOf the “Old Friends”:Mycobacterium vaccae

CHEMO+

M VACCAE

CHEMOALONE

Dlugovitzky et al. Respiratory Medicine 2006; 100: 1079‐87

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Probiotics Reduce Negative Emotionality in Healthy Volunteers

Messaoudi et al. Brit J Nutr 2011; 105: 775‐64

Immunity is More Like a Conversation or Battle than a Rigid Physiological System: Pathogen Manipulation

Klein. Physiol Behav 2003;79:441‐9

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Sociality Before Sickness Sets In: An Example of Pathogen Manipulation?

In individuals receiving an influenza vaccine, social contacts were significantlyincreased in the 48 hours after the injection when compared to either pre‐injection or follow‐up periods. Importantly, the period when sociality was maximally increased following vaccine coincides with the period of greatestvirus shedding and hence infectivity during naturalistic influenza infection.

Reiber et al. Ann Epidemiol 2010;20:729‐33

Meta-Analysis of Studies Suggesting Toxoplasma gondii Might Promote Schizophrenia

d

1Previous StudiesWende 1956Caglieris 1958Cook Derrick 1961Yegerov 1962Berengo 1966Garrido & Redondo 1968Cui 1984Lu 1990Zhang 1994Wang 1995Lian 1996Li 1999Mia & Ding 1999Gu 2001Yolken 2001Lu 2002Torrey & Yolken 2003Leweke 2004Gallo 2005

Group

Combined

1 Previous Studies

2 New Studies

Torrey EF et al. Schizophr Bull. 2012;38(3):642-647.

Le

ge

nd

Schwarz 2005Dickerson 2005Wang 2006Tankuksel 2010Ave

2 New StudiesZhu 2003Xu 2005El Sahn 2005Sun 2005Cetinkaya 2007Hinze-Selch 2007Tamer 2008Dogruman-Al 2009Sarael-Sahnesaraei 2009Yuksel 2010Daryani 2010Hamidinejat 2010Liu 2011Tedla 2011Alvarado-Esquival 2011Ave

Total

Odds Ratio0.1 1 10 100

Beyond Serotonin: IDO, Inflammation, and the Metabolism of Tryptophan

IDOCytokines

Tryptophan KynurenineBlood brain barrier

Astrocyte Microglia

Peripheral macrophage

3-HAO, 3-hydroxy-anthranilic acid oxygenase; IDO, indoleamine-2,3-dioxygenase; KAT-II, kynurenineaminotransferase-II; KMO, kynurenine-3-monooxygenase.Haroon E et al. Neuropsychopharmacology. 2012;37(1):137-162.

Astrocyte MicrogliaKynurenine

KAT II KMO3-HAO

Kynurenicacid

α7nAChR blockadeGlutamate releaseDopamine release

NMDA receptor activationLipid peroxidation

Cognitive dysfunction ExcitotoxicityOxidative stress

Neurodegeneration

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Chronic Inflammation Increases Schizophrenia-Relevant Kynurenine

Metabolites in Spinal Fluid

e (

12

we

ek

s) 20

30

Control IFN-alpha Control IFN-alpha

***

***

40

50

30

20

10

0

150

100

50

0

CS

F K

YN

, n

M

CS

F Q

UIN

, n

M

KA, kynurenic acid; KYN, kynurenine; MADRS, Montgomery-Asberg Depression Rating Scale; QUIN, quinolinic acid; TRP, tryptophan.*P<0.05; **P<0.01; ***P<0.001 using Wilcoxon Rank Sum test.Raison CL et al. Mol Psychiatry. 2010;15(4):393-403.

20 30 40 50 60 70 80

CSF QUIN, nM

MA

DR

S S

co

re10

0Control IFN-alpha Control IFN-alpha

*8

6

4

2

CS

F K

YN

, n

M

3

2

1

0

CS

F T

RP

, u

M

Evidence for Increased Kynurenic Acid in Brains of Individuals With Schizophrenia

150

125

100

75

50

Kynurenine

nM

******3.5

4.5

4.0

3.0

2.5

2.0

1.5

Kynurenic Acid

nM

****

ole

s/m

g p

rote

in

Kynurenic AcidP=0.058 **

12.5

10.0

7.5

5.0

3.0

1 0

4.0

2.0

Tryptophan

μM

Linderholm KR et al. Schizophr Bull. 2012;38(3):426-432; Sathyasaikumar KV et al. Schizophr Bull. 2011;37(6):1147-1156.

**P<0.01, ***P<0.001

25

0.0

1.0

0.5

0.0

*P<0.05

Squares, controls; triangles, participants with schizophrenia.

Pm 2.5

0.0

BA 9 BA 10

1.0

0.0

Controls, n=29Patients with schizophrenia, n=16

IDO Activation Protects Against Micro-Organisms Implicated in Schizophrenia

100

80

60

**

va

l

6000

4000

*

ysts

0 15 30 45 60 75 90 105

**P<0.0001; *P<0.03.Divanovic S et al. J Infect Dis. 2012;205(1):152-161.

60

40

20

0

Time After Infection, d

% S

urv

iv 4000

2000Bra

in C

y

Control 1-MT

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But IDO Activation Increases Disease Risk from Other Pathogens

5

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*P<0.05; **P<0.01; ***P<0.005.Divanovic S et al. J Infect Dis. 2012;205(1):152-161.

0 1 2 3 4 5 6 7 8 9 10 11 12Time After Infection, wk Time After Infection, wk

P 1 3 5 7 9 12

Schizophrenia Should Increase the Risk for Leishmaniasis

Schulenburg et al. Phil Trans R Soc B 2009; 364: 3-14

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