mm038-day2-1515-nemeroffneurosciencecme.com/pdf/mm038-day2-1515-nemeroff.pdf · 2012. 10. 22. ·...

10/19/12

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Depression and Inflammation: The Interplay With Autoimmune Disease

Charles B. Nemeroff, MD, PhD Leonard M. Miller School of Medicine University of Miami Miami, FL

Charles B. Nemeroff, MD, PhD

●  Research/Grants: Agency for Healthcare Research and Quality (AHRQ); National Institutes of Health (NIH)

●  Consultant: Eli Lilly and Company; Shire Pharmaceuticals Inc.; SK Pharma; Roche; Takeda Pharmaceuticals North America, Inc.; Xhale, Inc.

●  Stockholder: CeNeRx BioPharma; NovaDel Pharma, Inc.; PharmaNeuroBoost, Revaax Pharmaceuticals LLC; Xhale, Inc.

●  Other Financial Interest: CeNeRx BioPharma; PharmaNeuroBoost ●  Patents: Method and devices for transdermal delivery of lithium

(US 6,375,990B1) Method of assessing antidepressant drug therapy via transport inhibition of monoamine neurotransmitters by ex vivo assay (US 7,148,027B2)

●  Scientific Advisory Boards: American Foundation for Suicide Prevention (AFSP); Anxiety Disorders Association of America (ADAA); CeNeRx BioPharma; National Alliance for Research on Schizophrenia and Depression (NARSAD); PharmaNeuroBoost; Xhale, Inc.; Skyland Trail; AstraZeneca Pharmaceuticals (2009)

●  Board of Directors: American Foundation for Suicide Prevention (AFSP); Gratitude America; Mt. Cook Pharma. Inc. (2010); NovaDel Pharma, Inc. (2011); Skyland Trail

Disclosures

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Learning Objective

Recognize the interplay of inflammation and depression and use this knowledge to accurately and consistently assess patients with inflammatory disease for depression

Proinflammatory Cytokines Play a Central Role in Classic Autoimmune Conditions

●  Rheumatoid arthritis ●  Inflammatory bowel disease ●  Multiple sclerosis ●  Psoriasis ●  Ankylosing spondylitis But also: ●  Coronary artery disease ●  Diabetes and the metabolic syndrome ●  Cancer ●  Alzheimer’s disease

Major Clinical Disorders Associated with Inflammation ●  Cardiovascular disease ●  Inflammatory markers (CRP/IL-6) are potent predictors

of disease outcome; involvement of inflammation in plaque formation and cardiac irritability

●  Diabetes/metabolic syndrome/obesity ● High correlation between insulin resistance and IL-6

and other inflammatory markers ●  Cancer ● Activation of inflammatory signaling pathways

(e.g., NF-kB) implicated as a fundamental mechanism of carcinogenesis and chemotherapy resistance

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Immune- Based

Diseases

Depression/ Sickness Behavior

Stress, Depression

Inflammation/ Immune Activation (e.g. secondary to infection, trauma, surgery, radiation, chemotherapy, stress, etc.)

CNS IMMUNE SYSTEM

Endocrine System

Cytokines

(e.g. IFN-alpha, IL-1, IL-6, TNF-alpha)

Miller AH, et al. Biol Psychiatry. 2009;65(9):732-741.

Major Depressive Disorder and Systemic Illnesses

●  Patients with MDD have a doubling of mortality and coronary artery disease at any age, independent of smoking, hypertension, and other risk factors for poor health1

●  20% to 25% premenopausal patients with MDD have premature osteopenia and osteoporosis

●  MDD is associated with an ~ 2-fold increase in the risk for Type II diabetes

1. Wulsin LR. Harv Rev Psychiatry. 2004;12(2):79-93. PMID: 15204803

Is Major Depressive Disorder a Pro-Inflammatory State?

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Macrophage

Local

Systemic

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

Effects on Brain -  Fever -  Fatigue -  Anorexia -  Anhedonia -  Altered sleep Acute Phase Response - C-reactive protein

- Serum amyloid A - Haptoglobin - Alpha 1-antichymotrypsin

Effects on Liver

Chemokines

Stromal cell

Endothelial cell

TNF, IL-1, IL-6 IFN-alpha

Adhesion molecules

Leukocyte Diapedesis

Toll-like receptors

(TLRs) Pathogen

(e.g. bacteria), Cellular Debris

TNF IL-1 IL-6 IFN-alpha

NF-κB

sickness behavior/ depression

tumor rubor calor dolor

Conservation of energy resources to promote increased metabolic demands of fighting

infection and mounting a fever

Innate Immunity/Inflammation

Basis for the Hypothesis that Inflammation and an Activated Innate Immune Response May Play a Role in Depression ●  Patients with depression

(both medically ill and medically healthy) have been found to exhibit all the cardinal features of inflammation ●  Increased plasma and CSF

concentrations of innate immune cytokines (IL-6 most reliable)

●  Increased acute phase reactants (CRP most reliable)

●  Increased chemokines ●  Increased cellular adhesion

molecules

●  In the majority of studies, inflammatory markers decrease with successful antidepressant therapy (“state marker”)

●  Depressed patients with increased inflammatory markers are more likely to be treatment resistant In our study, ●  2/3 with “high” inflammation

according to CDC/AHA guidelines with CRP > 3mg/L - ~5 million depressed individuals in US

●  1/3 with CRP > 5mg/L ~3 million depressed individuals in US

Depression is Associated with Elevated Body Temperature in Medically Healthy Patients

Szuba, et al. Biol Psychiatry. 1998.

36.4

36.8

37.2

37.6

7:00 AM 3:00 PM 11:00 PM 6:00 AM Time

Tem

p (o

C)

Depression No Depression

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IL-6 Concentrations In Patients With Depression And Cancer

* Depressed CA Patients with highest IL-6 plasma concentrations (H = 13.9, df = 3, p = .003) Musselman DL, et al. Am J Psychiatry. 2001:158(8):1252-1257.

Pla

sma

IL-6

Con

cent

ratio

n (p

g/m

l)

700

600

500

400

300

200

100

0 Healthy Controls (n = 10)

Depressed Controls (n = 12)

Cancer Patients (n = 13)

Depressed Cancer

Patients* (n = 8)

Study Group*

Basis for the Hypothesis that Inflammation May Play a Role in Depression ●  Positive correlation between depressive symptom severity

and innate immune cytokines ●  Elevated innate immune cytokines predict poor response to

antidepressant therapies and are elevated in patients with treatment resistance. Cytokine gene polymorphisms (IL-1, TNF) predict antidepressant treatment response

●  Administration of innate immune cytokines, especially IL-1, TNF-alpha, and IL-6, as well as IFN-alpha, produce behavioral changes in laboratory animals and humans that resemble major depression

●  Inhibition of cytokine signaling has been found to alleviate depressive and anxiety behaviors in patients with inflammatory disorders and in laboratory animals

Basis for the Hypothesis that Proinflammatory Cytokines Play a Role in Depression and Depressive Symptoms ● Cytokines released peripherally have access to

the brain ● Passage through leaky regions in the BBB ● Active transport ● Transmission through afferent nerve fibers (vagus)

● There is a cytokine network in the CNS ● Glia (microglia) and neurons express/produce

cytokines and express cytokine receptors

● Cytokines have effects on neurotransmitter turnover, neuroendocrine function, and behavior (sickness behavior)

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Childhood Abuse = Unhealed Wounds

McCauley J, et al. JAMA. 1997;277(17):1362-1368. PMID: 9134941.

Less More

More

Psychological Problems

Physical Symptoms

(such as depression

anxiety, somatization, low

self esteem, substance abuse, suicide attempts)

(such as back pain, headaches, pelvic pain, abdominal symptoms, etc.)

=

Women who experienced no abuse

Women who experienced childhood

abuse

Women experiencing

current abuse

Women who have experienced childhood

abuse and are experiencing current abuse

Chronic Pelvic Pain, Fatigue, and Physical Symptoms

Pre

vale

nce

of C

PP

(%)

0 20 40 60 80 100

Controls ELS ELS/PTSD

*

Acyclic Chronic Pelvic Pain

Loss of Energy/Fatigue

Pre

vale

nce

of F

atig

ue (%

)

0 20 40 60 80 100

Controls ELS ELS/PTSD

*

Dotted bar: Loss of energy Filled bar: Tired all the time

Number of Symptoms in the Past Month 0 5 10 15 20 25 30

General Dermatological Visual Audio/Olfactoric MTN Cardiological Endocrinological Orthopedical Gastrointestinal Neurological OB-GYN/Urological

*

General Health Checklist

ELS/PTSD ELS Controls

Patients with Major Depression Exhibit an Exaggerated Inflammatory Response to Stress A Possible Link Between Stress, Depression, and Illness

Pla

sma

IL-6

, pg/

ml

0

1

2

3

4

5

6

-15 0 15 30

Major Depression (n = 14)

Control (n = 13)

TSST

*

*Between group comparison, p < 0.05 +Within group comparison vs. 0 min time pt, p < 0.05

Pla

sma

IL-6

, pg/

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)

*

+

+

+ + +

NF-

kB D

NA

-bin

ding

(%

of b

asel

ine)

+

*

80

90

100

110

120

130

-15 0 15 30 45 60 75 90

TSST Time (Min)

+ *

+

Major Depression (n = 10) Control (n = 16)

* Between group comparison, p < .05 + Within group comparison vs. 0 min time pt, p < .05 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;163(9):1630-1633. PMID: 16946190.

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Childhood Maltreatment Predicts Adult Inflammation in a Life-Course Study

●  The life-course association between childhood maltreatment and adult inflammation was examined in a birth cohort followed to age 32 years as part of the Dunedin Multidisciplinary Health and Development Study

●  Maltreated children showed a significant and graded increase in the risk for clinically relevant C-reactive protein levels, 20 years later

●  The association between maltreatment and adult inflammation also generalizes to fibrinogen and white blood cell count

●  Childhood maltreatment is a previously undescribed, independent, and preventable risk factor for inflammation in adulthood

Danese A, et al. Proc Natl Acad Sci USA. 2007;104(4):1319-1324. PMID: 17229839.

The Association of Childhood Maltreatment with Biomarkers of Inflammation

Danese A, et al. Proc Natl Acad Sci U S A. 2007;104(4):1319-1324. PMID: 17229839.

Questions

● Do proinflammatory cytokines, and therefore, the immune system contribute to the pathophysiology of major depression in the medically ill?

● What mechanisms are involved? ● What are the treatment implications?

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Interferon-Alpha as a Model System to Study Cytokine-Induced Depression

● Antiviral/antiproliferative cytokine used to treat viral infections and cancer ● Potent inducer of innate immune

response including innate immune cytokines (especially IL-6) ● Potent inducer of behavioral toxicity

including symptoms of major depression in humans and non-human primates

IFN-Alpha-Induced Behavioral Symptoms in Patients with Malignant Melanoma

Capuron L, et al. Neuropsychopharmacology. 2002;26(5):643-652. PMID: 11927189.

Placebo-treated patients (%) experiencing moderate-to-severe intensity in the listed symptom during IFN-alpha therapy

Randomized, Double-Blind

Treatment (N = 40)

Parox

etine

x 2 W

eeks

Placebo

x 2 Weeks

IV IFN-α x 4 Weeks

20 x 106 U/m2

SQ IFN-α up to

48 Weeks 10 x 106 U/m2

Paroxetine Arm

20-40 mg

Placebo Arm

Week 0 Week 4 Week 8 Week 12

High-Dose Interferon in Malignant Melanoma Paroxetine Pretreatment

Musselman DL, et al. N Engl J Med. 2001;344(13):961-966. PMID: 11274622.

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Incidence of Major Depression During the First 12 weeks of IFN-alpha

Musselman DL, et al. N Engl J Med. 2001;344(13):961-966. PMID: 11274622 .

Weeks on IFN-alpha

Sur

viva

l Fre

e of

M

ajor

Dep

ress

ion

(%)

0 2 4 6 8 10 12 0

20

40

60

80

100

n = 20

Paroxetine Pre-treatment Reduces the Incidence of Major Depression During the First 12 weeks of High Dose IFN-alpha for Malignant Melanoma

Musselman DL, et al. N Engl J Med. 2001;344(13):961-966. PMID: 11274622.

Weeks on IFN-alpha

Sur

viva

l Fre

e of

M

ajor

Dep

ress

ion

(%)

0 2 4 6 8 10 12 0

20

40

60

80

100

Placebo (n = 20) Paroxetine (n = 18)

TRP Serotonin IDO

Kynurenine

Quinolinic Acid

IFN-alpha/ Cytokines

ACTH

CRH

Adrenal Gland IFN-alpha/ cytokines Cortisol

IFN-alpha-induced Depression is Associated with Exaggerated HPA Activation

Depression/ Sickness Behavior

IDO – indolamine 2,3 dioxygenase

Capuron L, et al. Mol Psychiatry. 2002;7:468-473. PMID: 12082564.

IFN-alpha-induced Depression is Associated with Tryptophan (TRP) Depletion

Capuron L, et al. Am J Psychiatry. 2003;160:1342-1345. PMID: 12832253.

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“Huddler” “Non- Huddler”

0

50

100

150

200

250

AC

TH (p

g/m

l)

*

* p < .01

Taken from Taken from KalinKalin, N.H., , N.H., 1985 [12]1985 [12]Taken from Taken from KalinKalin, N.H., , N.H., 1985 [12]1985 [12]

ICV CRH sc IFN-alpha

(20 million units/m2) Maximal ACTH response to IFN-alpha in “huddlers” vs. “non-huddlers”

Huddling: a fetal-like self-enclosed position with head at or below shoulders.

IFN-alpha-induced Depressive-like Behavior (“Huddling”) is Associated with Exaggerated HPA Activation in Monkeys

McKinney WT Jr., et al. Dis Nerv Syst. 1971;32(11):735-741. PMID: 5002259 . Kalin NH, et al. Life Sci. 1985;36(12):1135-1140. PMID: 2984495.

IFN-alpha Effects on Basal Ganglia Function Correlate with Fatigue

Capuron L, et al. Neuropsychopharmacology. 2007;32(11):2384-2392. PMID: 17327884.

IFN-alpha IL-6 dopamine

r = -0.43, p < .05

0 1 2 3 4 5 6

CSF IL-6 (pg/ml)

0

10

20

30

40

50

60

70

80

90

100

CS

F H

VA (n

g/m

l)

0 10 20 30 40 50 60 70 80 90 100

Fatigue (Total Score)

0

10

20

30

40

50

60

70

80

90

100

CS

F H

VA (n

g/m

l)

r = -0.43, p < .05

HVA fatigue

CSF Homovanillic Acid (HVA), the Major Metabolite of Dopamine, Correlates with Fatigue and CSF IL-6 in IFN-alpha-treated Patients

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Prevalence of Moderate/Severe Depressive Symptoms During Treatment with Pegylated IFN-alpha

Raison CL, et al. J Clin Psychiatry. 2005;66(1):41-48. PMID: 15669887.

----- Exponential Trend Line p < .001 (Cochran-Armitage Trend Test)

% o

f Pat

ient

s w

ith S

DS

In

dex ≥

60

0

5

10

15

20

25

30

Baseline Week 4 Week 8 Week 12 Week 24

* *

*

*

* Significantly different from baseline (p < .05)

Rates of Depression Are Uniformly Elevated in Inflammatory Conditions ● Depressive syndromes are a risk factor

for the development of CAD, metabolic syndrome, cancer

● Depression increases morbidity in all inflammatory conditions and has been repeatedly shown to increase risk of mortality in context of CAD and cancer (and its treatment)

Raison, Capuron, Miller. Trends in Immunology. 2006;227:24-31. PMID: 16316783.

IFN-a

Translational Targets

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Inflammation and Treatment Resistance

Clinical Predictor of Antidepressant Non-Response

Relation to Inflammation

Obesity Dose response relationship between BMI and inflammatory markers

Early Life Stress Increased inflammation and inflammatory response to stress in individuals exposed to early life stress

Medical Illness Increased inflammatory markers in cancer and cardiovascular disease

Personality Disorders/Anxiety Increased inflammatory markers in patients with Anxiety Disorders, Borderline Personality Disorder and Neuroticism

Inflammation and Depression: The Perfect Storm Cytokines and Treatment Resistance

●  Cytokines reduce monoamine synthesis (IDO) and increase reuptake (p38 MAPK) ●  Conventional antidepressants act through increasing the availability of

monoamines (block reuptake)

●  Cytokines inhibit neurogenesis ●  Conventional antidepressants are less effective in the absence of

neurogenesis1

●  Cytokines impact glutamate metabolism ●  Conventional antidepressants target monoamines and do not act on

glutamate metabolism ●  Ketamine, a glutamate antagonist, is effective in treatment-resistant

depression2

IDO = indoleamine 2,3 dioxygenase; MAPK = mitogen activated protein kinase 1. Santarelli, et al. Science. 2003;301:805-809. PMID: 12907793. 2. aan het Rot M, et al. Biological Psychiatry. 2010;67:139-145. PMID: 19897179.

Improvement in symptoms of depression were not correlated with objective measures of skin clearance or joint pain

Etanercept and Clinical Outcomes, Fatigue, and Depression in Psoriasis Double-Blind Placebo-Controlled Randomized Phase III Trial

Tyring S, et al. Lancet. 2006;367(9504):29-35. PMID: 16399150.

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Testing the Cytokine Hypothesis of Depression

● Does blockade of inflammatory cytokines reverse depression in patients with treatment-resistant depression (TRD)?

Raison, et al. Arch Gen Psychiatry. 2012; 3:1-11. PMID: 22945416.

Goal: To Test the Cytokine Hypothesis of Depression in Patients with TRD TNF-alpha Antagonist ● Scientific Reasons ● TNF-alpha reliably elevated in MDD ● TNF-alpha and its soluble receptor correlates

with IFN-alpha-induced depression ● TNF-alpha antagonist improved depressed

mood in patients with inflammatory disorders ● TNF receptor KO mice exhibit

antidepressant-like response and decreased anxiety following immune stimulation


Goal: To Test the Cytokine Hypothesis of Depression in Patients with TRD (cont’d.)

TNF-alpha Antagonist ●  Infliximab* – monoclonal antibody directed at

TNF-alpha ● Used to treat autoimmune and inflammatory disorders

● Pharmacologic reasons ● Biologics (monoclonal antibodies) have no off-target

effects or drug-drug interactions (directly test the cytokine hypothesis of depression)

● Limited brain penetrance (central vs. peripheral effects) ● No compliance issues with infusions

*Off label use


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Double-Blind, Parallel-Group, Randomized Design


TRD Pts (N = 60)

INFLIX* (5mg/kg)

PLACEBO

Baseline

N = 30

N = 30

Wk 10

Wk 12

Clinician-Administered Psychiatric Assessments (HAM-D, CGI) Adverse Events Evaluation

Blood Draw for Inflammatory Markers and Safety Labs

Stratification Male vs. Female

CRP >2 vs. CRP ≤2

Randomization

INFUSION INFUSION INFUSION

Wk 8

Wk 6

Wk 4

Wk 3

Wk 2

Wk 1

*Off label use

Inclusion/Exclusion Criteria ●  Males/Females ages 25-60 ●  Medically Healthy (Normal PE and labs) ●  MDD or Bipolar depressed by SCID ●  QIDS-16 score ≥14 ●  On stable antidepressant regimen or off meds for

at least 4 weeks ●  No psychotic symptoms or hx of psychosis ●  No substance abuse X 6 months ●  Not suicidal ●  Non-pregnant on birth control


Infliximab* (n = 30) Placebo (n = 30) Age (yrs.) – mean (SD) 42.5 (8.2) 44.3 (9.4) Sex (female) – no. (%) 20 (66%) 20 (66%) Ethnic Origin - no. (%) Caucasian Black Other

23 (77%) 6 (20%) 1 (3%)

23 (77%) 5 (17%) 2 (6%)

Education (Highest Degree) – no. (%) Graduate Degree College Graduate Partial College High School Graduate

8 (27%)

13 (43%) 8 (27%) 1 (3%)

7 (23%)

13 (43%) 9 (30%) 1 (3%)

Unemployed – no. (%) 12 (40%) 12 (40%)

Demographic Characteristics of Study Sample

*Off label use Raison, et al. Arch Gen Psychiatry. 2012; 3:1-11. PMID: 22945416.

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Infiximab Placebo

Age of Onset of MDD (yrs.) – mean (SD) 19.1 (8.3) 18.9 (10.7)

Lifetime Episodes of MDD – no. (SD) 8.7 (24.8) 7.8 (24.8)

Duration of Current Episode (mos.) – mean (SD) 184.4 (148.8) 238.7 (165.25)

Antidepressant Trials in Current Episode – no. (SD) 4.6 (3.2) 3.7 (2.1)

MGH-S score – mean (SD) 7.73 (6.6) 6.1 (3.5)

Family History of MDD – no. (%) 27 (90%) 23 (77%)

Mood-Relevant Psychotropic Medication – no. (%) 16 (53%) 21 (70%)

Co-Morbid Medical Illness – no. (%) 13 (43%) 19 (63%)

Bipolar Disorder – no. (%) 3 (10%) 6 (20%)

Clinical Characteristics of Study Sample


Clinical Characteristics of Study Sample (cont’d.)


Infiximab Placebo

BMI (kg/m2) – mean (SD) 31.2 (6.9) 32.7 (8.0)

Baseline hs-CRP (mg/L) – mean (SD) 6.21 (9.1) 5.7 (8.1)

Baseline HAM-D 17 – mean (SD) 24.1 (4.0) 23.6 (3.8)

Baseline CGI-severity – mean (SD) 4.8 (0.59) 4.8 (0.81)

Change in HAM-D-17 in Infliximab* vs. Placebo-Treated TRD Patients

Significant interaction among treatment, time and log hs-CRP (t = 2.65, df = 302, p = .01)


LS Mean (SEM)

Change in HAM-

D-17 from Baseline

*Off label use

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Change in HAM-D-17 Score from Baseline to Week 12 (Infliximab*-Placebo) in TRD Patients Subgrouped By Baseline Plasma hs-CRP

*Off label use

Standardized Effect Size = 0.41 favoring infliximab at CRP > 5mg/L


Change in HAM-D-17 Scores from Baseline to Week 12 in Infliximab*- or Placebo-Treated TRD Patients with a Baseline CRP > 5 mg/L versus ≤ 5mg/L

*Off label use


A. CRP > 5mg/L B. CRP ≤ 5mg/L

Percent Treatment Responders in Infliximab*- vs. Placebo-Treated TRD Patients with a Baseline hs-CRP ≤ 5mg/L or >5mg/L

Treatment Response (≥ 50 reduction in HAM-D-17 at any point during treatment)

Raison, et al. Arch Gen Psychiatry. 2012; 3:1-11. PMID: 22945416. *Off label use

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Symptoms Responsive to Infliximab* and Placebo in TRD Subjects with Baseline hs-CRP>5

Raison, et al. Arch Gen Psychiatry. 2012; 3:1-11. PMID: 22945416. *Off label use

Hitting the Sweet Spot

Summary

● Depression is associated with evidence of increased inflammation, which in turn may contribute to the impact of depression on comorbid medical disorders

● Stress is capable of activating the inflammatory response (likely through SNS pathways)

● Activation of the inflammatory response can induce behavioral symptoms that overlap with MDD

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Summary (cont’d.)

● Cytokine (IFN-alpha)-induced depression appears to be mediated by alterations in serotonin metabolism, activation of CRH pathways, and alterations in basal ganglia circuitry

● Aggressive preventative treatment strategies can be used to limit depression in high-risk medically ill

● Treatments targeting the immune system may be relevant for the treatment of depression in both medically ill and medically healthy patients

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mm038-day2-1515-nemeroffneurosciencecme.com/pdf/mm038-day2-1515-nemeroff.pdf · 2012. 10. 22. ·...

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