Section of Perinatal Psychiatry

Carmine M. Pariante, MD, MRCPsych, PhD Professor of Biological Psychiatry Institute of Psychiatry, King’s College London

Depression and Inflammation

Serotonin – 5HT pathways in the brain

Metabolic syndrome, inflammation and HPA axis Metabolic syndrome

Inflammation

Stress

HYPOTHALAMUS-PITUITARY-ADRENAL AXIS

STRESS CRF

Cytokines IL-1, IL-6, TNF

+

ACTH +

SNS

Immune System

Catecholamines

Adrenal Glands

Cortisol

Infection, Inflammation

Cortisol pl (nmol/L)

Plasma Cortisol in Depressed Patients and Controls 450 400 350 300 250 200 150 100 50 0

*

controls patients

Carvalho et al., 2007

Plasma IL-6 in Depressed Patients and Controls 3.5

IL-6 pl (pg/mL)

3.0

*

controls patients

2.5 2.0 1.5 1.0 0.5 0.0

Carvalho et al., 2007

Stress and Inflammation

Inflammation

Stress

STRESS Glucocorticoid Resistance

X

X

X

Salivary Cortisol suppression by Dexamethasone (0.5 mg) in Controls

nmol/L

Placebo

Dexamethasone

9 8 7 6 5 4 3 2 1 0 9

10

11

12

13

14

15

16

17

22

Time of the Day

Juruena et al. 2006

Salivary Cortisol suppression by Dexamethasone (0.5 mg) in Depressed Patients

nmol/L

Placebo

Dexamethasone

16 14 12 10 8 6 4 2 0 9

10

11

12

13

14

15

16

17

22

Time of Day

Juruena et al. 2006

STRESS CRF

Cytokines IL-1, IL-6, TNF

+

ACTH +

SNS

Immune System

Catecholamines

Adrenal Glands

Cortisol

Glucocorticoid Resistance

Infection, Inflammation

Mood disorder patients have reduced GR function IL-6 (% LPS-stimulated levels)

A)

B)

100

100

75

75

50

50

25

25

0

controls patients

0 -10

-9

-8

-7

-6

Dexamethasone [M]

-5

-4

-10

-9

-8

-7

-6

-5

-4

Cortisol [M]

GR function – % Glucocorticoid inhibition of LPS-induced IL-6 levels Carvalho et al., 2009

Stress and Inflammation

Inflammation

Stress

GENDEP study MRC SGDP Centre

Genome-based therapeutic drugs for depression A MULTICENTRE EUROPEAN STUDY

An 18-centre Integrated Project in PGx funded by the European Commission, 2004 to present

IL-1β, MIF and TNF-α levels as predicting the treatment outcome (predictor)

2

**

2

**

2

1.5

1.5

1.5

1

1

1

0.5

0.5

0.5

0

0

0

IL-1beta expression Non responders

MIF expression Responders

**

TNF-alpha expression

IL-1β, MIF and TNF-α levels as predicting the treatment outcome (predictor) Linear regression analyses to evaluate the contribution of each cytokine in predicting the treatment outcome

Stress and Inflammation

Inflammation

Stress

MALTREATMENT AND ADULT INFLAMMATION

Danese A et al, PNAS 2007, 104:1319-24

CHILD STRESS vs ADULT STRESS *

Child stress (N=56)

Adult+Child stress (N=27)

30 20 10 0

Adult hsCRP > 3 mg/L (%)

40

50

*

No stress (N=673)

Adult stress (N=109)

Danese A et al, Arch Gen Psychiatry 2008, 65: 409-15

CHILD STRESS ONLY CRP values in maltreated children

Danese A et al, Mol Psychiatry 2010

Stress and Inflammation

Inflammation

Stress

Proinflammatory Cytokines Induce Sickness Behaviour • Fatigue • Loss of appetite • Sleep disturbance • Social withdrawal • Decreased libido • Depressed mood • General malaise • Aches and pains

0

10

20

30

40

50

DEPRESSSION PROGRESSIVELY WORSENS DURING IFN-ALPHA AND RIBAVIRIN TREATMENT

0

10

20

30

40

50

week bdi

Linear prediction

Maddock et al., 2005

50

100

150

ANXIETY PROGRESSIVELY INCREASES DURING TREATMENT

0

10

20

30

40

50

week stai

Linear prediction

Maddock et al., 2005

5

10

15

20

25

30

FATIGUE INCREASES UP TO 8 WEEKS AND REMAINS SEVERE UNTIL THE END

0

10

20

30

40

50

week fat

Linear prediction

Maddock et al., 2005

0

100

200

300

QUALITY OF LIFE IS SUBSTANTIALLY REDUCED DURING TREATMENT

0

10

20

30

40

50

week qol

Linear prediction

Maddock et al., 2005

Serotonin – 5HT pathways in the brain

Effect Size of Depression

IFN-alpha-Induced Depression in Those With the “Short” Serotonin Transporter Polymorphism

*

SS & SL LL

0.5

-0.5

0

4

8

12

24

Week

Bull et al., Mol. Psychiatry, 2009

IFN-alpha-Induced Fatigue in Those With the “Short” Serotonin Transporter Polymorphism Serotonin Genotype and Fatigue Symptoms Fatigue Effect Size

1.5

SS & SL LL

1.0 0.5 0.0

-0.5

0

4

8

12

24

Week

Bull et al., 2009

Effect Size of Depression

IFN-alpha-Induced Depression In Those With the “High IL-6” Polymorphism 1.0

*

GG & GC CC

0.5

0.0

-0.5

0

4

8

12

24

Week

Bull et al., Mol. Psychiatry, 2009

IFN-alpha-Induced Fatigue In Those With the “High IL-6” Polymorphism IL-6 Genotype and Fatigue Symptoms Effect Size of Fatigue

1.5

GG & GC CC

1.0 0.5 0.0

-0.5

0

4

8

12

24

Week

Bull et al., 2009

At Follow-Up the Cohort’s Depression Had Not Improved, Remaining Significantly Worse than Base Line 14 12

P = 0.1

10 8

P = 0.026

6 4

M ean BDI Score

2 0 Base Line

End of Follow Up Treatment Bull et al., unpublished

Kynurenine pathway

KMO KAT Neuroprotective KYNU

Neurotoxic NMDA receptor agonist

IDO: indolamine-2,3-dioxygenase KAT: kynurenine amino transferase

KMO: kynurenine 3-hydroxylase KYNU: kynureninase

GXG Interaction in IFN-alpha-Induced Depression: Subjects with the “High IL-6” Polymorphism

ffect of Serotonin Genotype on Depression in Non-Protective I Group 1.5

SS & SL LL

Effect Size

1.0 0.5 0.0

-0.5 -1.0

0

4

8

12

24

Week

Bull et al., Mol. Psychiatry, 2009

GXG Interaction in IFN-alpha-Induced Depression: Subjects with the “Low IL-6” Polymorphism

fect of Serotonin Genotype on Depression in Protective IL-6 Gro 1.5

SS & SL LL

Effect Size

1.0 0.5 0.0

-0.5 -1.0

0

4

8

Week

12

24

Bull et al., Mol. Psychiatry, 2009

IFN-alpha-Induced Depression and Genes Regulating PUFAs Metabolism PUFAs

PLA2

EPA

DHA

AA

COX2 Cytokines PGs

Depression Progressively Worsens During Ifn-alpha And Ribavirin Treatment Percentage of IFN-induced depression

30% 25% 20% 15% 10% 5% 0% 00

22

44

68

10 8

12 10

16 12

24 16

Week of IFN treatment Su et al., Biol. Psychiatry, 2010

IFN-alpha-Induced Depression and Genes Regulating PUFAs Metabolism Percentage of Depressed

60 50 40

* At Risk Gen. Non At Risk

30

*

20

*

10 0 PLA2

COX2

PLA2+COX2

G/G at BanI polymorphism of cPLA2 gene A/G at COX-2 rs4648308 Su et al., Biol. Psychiatry, 2010

IFN-alpha-Induced Depression and Genes Regulating PUFAs Metabolism 4.00

DHA level (%)

* 3.50

3.00 0

2

4

8

12

24

Weeks of IFN therapy the higher risk group

the lower risk group

Su et al., Biol. Psychiatry, 2010

IFN-alpha-Induced Depression and Genes Regulating PUFAs Metabolism 0.875

EPA level (%)

0.850

0.825

*

0.800

0.775

0.750 0

2

4

8

12

24

Weeks of IFN therapy the higher risk group

the lower risk group

Su et al., Biol. Psychiatry, 2010

Stress and Inflammation

Inflammation

Stress

The Model • Investigate changes in neuronal differentiation Proliferation 3d

Hoechst

Differentiation 7d

Dcx

Dcx & MAP2 immunocytochemis try

Hoechst

MAP2

STRESS CRF

Cytokines IL-1, IL-6, TNF

+

ACTH +

SNS

Immune System

Catecholamines

Adrenal Glands

Cortisol

Glucocorticoid Resistance

Infection, Inflammation

Section of Perinatal Psychiatry