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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
Raison, et al. Arch Gen Psychiatry. 2012; 3:1-11. PMID: 22945416.
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
Raison, et al. Arch Gen Psychiatry. 2012; 3:1-11. PMID: 22945416.
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Double-Blind, Parallel-Group, Randomized Design
Raison, et al. Arch Gen Psychiatry. 2012; 3:1-11. PMID: 22945416.
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
Raison, et al. Arch Gen Psychiatry. 2012; 3:1-11. PMID: 22945416.
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
Raison, et al. Arch Gen Psychiatry. 2012; 3:1-11. PMID: 22945416.
Clinical Characteristics of Study Sample (cont’d.)
Raison, et al. Arch Gen Psychiatry. 2012; 3:1-11. PMID: 22945416.
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)
Raison, et al. Arch Gen Psychiatry. 2012; 3:1-11. PMID: 22945416.
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
Raison, et al. Arch Gen Psychiatry. 2012; 3:1-11. PMID: 22945416.
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
Raison, et al. Arch Gen Psychiatry. 2012; 3:1-11. PMID: 22945416.
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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