depression: scope and consequences common fatal disabling...the emerging role of the immune system...
TRANSCRIPT
The Emerging Role of the Immune System in Depression - Andrew H. Miller, MD
Sunday, September 22, 2019
1
Cytokines Sing the Blues
Andrew H. Miller, M.D.Professor of Psychiatry and
Behavioral Sciences Emory University School of Medicine
Atlanta, GA USA
The emerging role of the immune system in depression and other psychiatric disorders
Nothing to Disclose
Depression: Scope and Consequences
Fatal Disabling Common
25 million adultsin US
Leading cause ofdisability worldwide
(years lived with disability)40,000 US adults10th leading
cause of death
The Emerging Role of the Immune System in Depression - Andrew H. Miller, MD
Sunday, September 22, 2019
2
Depression: Scope and Consequences
Need for new conceptual frameworks and targets to improve treatment outcome especially in patients with treatment resistance
Treatment Resistance
1/3 of all depressed adults are non-responsive to conventional treatments
Inflammation: A Common Mechanism of Disease Insight of the Decade (Science, 2010)
Inflammation is the body’s natural response to infection and wounding, but when chronic, inflammation can affect many parts of the body including the brain and behavior.
The Emerging Role of the Immune System in Depression - Andrew H. Miller, MD
Sunday, September 22, 2019
3
Patients with depression exhibit all the cardinal features of a chronic inflammatory response. increased inflammatory cytokines (IL-6 and TNF-alpha most reliable) increased acute phase reactants [C-reactive protein (CRP) most reliable] increased chemokines and cellular adhesion molecules increased inflammation in the brain
Data that Indicates Inflammation Plays a Role in Depression
Administration of inflammatory cytokines/stimuli causes depressive symptoms. neurotransmitters neurocircuits
Increased inflammatory markers are associated with treatment resistanceand poor response to SSRIs and SNRIs
Inhibition of inflammation reduces depressive symptoms. autoimmune and inflammatory disorders limited data demonstrating anti-inflammatory drugs treat depression in
otherwise healthy individuals
Administration of inflammatory cytokines/stimuli causes depressive symptoms. neurotransmitters neurocircuits
Increased inflammatory markers are associated with treatment resistanceand poor response to SSRIs and SNRIs
Inhibition of inflammation reduces depressive symptoms. autoimmune and inflammatory disorders limited data demonstrating anti-inflammatory drugs treat depression in
otherwise healthy individuals
Number of Failed Treatment Trials and Inflammatory Markers in Patients with Major Depression
Haroon et al, Psychoneuroendocrinology, 95:43-49, 2018.al,
The Emerging Role of the Immune System in Depression - Andrew H. Miller, MD
Sunday, September 22, 2019
4
Depression is not an Inflammatory Disorder
Musselman et al. Am J Psychiatry, 158:1252-1257, 2001.
Plasma IL-6 in Depressed Patients with and without Cancer
The Emerging Role of the Immune System in Depression - Andrew H. Miller, MD
Sunday, September 22, 2019
5
Mood Disorders - Depression/Bipolar DisorderAnxiety Disorders - PTSD, GAD, OCD, Panic DisorderSchizophreniaNeurodegenerative Disorders - Alzheimer’s Disease, Parkinson’s Disease, HIV Medical Illnesses – Cancer, Autoimmune/ Inflammatory Disorders, Cardiovascular Disease
1. Inflammation is only increased in a subgroup of depressed patients.
2. Inflammation is also increased in multiple other disorders in association behavioral symptoms.
• Inflammation effects on behavior are not about any specific disorder (transdiagnostic)
• Inflammation is about effects on specific neurotransmitter systems, neurocircuits and related symptoms across disorders
Where Does Chronic Inflammation Come From?
Obesity Chronic StressDysbiosis
Chronic Illness
Chronic Infections Medical Treatments
The Emerging Role of the Immune System in Depression - Andrew H. Miller, MD
Sunday, September 22, 2019
6
Mechanisms by whichInflammation Affects
the Brain and Behavior
Raison & Miller, Nat Rev Immunol, 16:22-34, 2016.
Inflammation Effects on the Brain
The Emerging Role of the Immune System in Depression - Andrew H. Miller, MD
Sunday, September 22, 2019
7
Therapeutic Targets to Address Inflammation Effects on the Brain
1. Inflammation2. Downstream effects of inflammation
on the brain (e.g. dopamine or glutamate)
Targeting Inflammation
The Emerging Role of the Immune System in Depression - Andrew H. Miller, MD
Sunday, September 22, 2019
8
TNF-alpha Blocker (Infliximab) to Treat Depressed Patients with Treatment Resistance
Biologics (monoclonal antibodies) are potent.
Biologic anti-TNF drugs have no off-target effects and limited drug-drug interactions
12 week randomized controlled trial in patients with treatment resistant depression (TRD)
Double-Blind, Parallel-Group, Randomized Design
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 ≤2Randomization
INFUSION INFUSIONINFUSION
TRD - Treatment Resistant Depression INFLIX – infliximab - Remicade©
The Emerging Role of the Immune System in Depression - Andrew H. Miller, MD
Sunday, September 22, 2019
9
Clinical Characteristics of Study Sample
Infiximab PlaceboBMI (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)
Raison et al., JAMA Psychiatry, 70:31, 2013
• ~50% of our TRD patients exhibited “high” inflammation according to CDC/AHA guidelines (CRP>3mg/L) - ~4.0 million depressed individuals in US
• ~1.5 million individuals have RA in US, ~1.5 million have IBD
•
Change in HAM-D-17 in Infliximab- versus Placebo-Treated TRD Patients
Significant interaction among treatment, time and log hs-CRP (t=2.65, df=302, p=0.01)Raison et al., JAMA Psychiatry, 70:31, 2013.
The Emerging Role of the Immune System in Depression - Andrew H. Miller, MD
Sunday, September 22, 2019
10
Change in HAM-D-17 Score from Baseline to Week 12 (Infliximab-Placebo) in TRD Patients
Subgrouped By Baseline Plasma CRP
Standardized Effect Size = 0.41 favoring infliximab at CRP>5mg/L
Percent Treatment Responders in Infliximab- Versus Placebo-Treated TRD Patients
with a Baseline CRP≤5mg/L or >5mg/L
Treatment Response (≥50 reduction in HAM-D-17 at any point during treatment)
62%
33%
50% 50%
57%
41%
Raison et al., JAMA Psychiatry, 70:31, 2013.
The Emerging Role of the Immune System in Depression - Andrew H. Miller, MD
Sunday, September 22, 2019
11
Symptoms Responsive to Infliximab and Placeboin TRD subjects with Baseline CRP>5
Raison et al., JAMA Psychiatry, 70:31, 2013.
Targeting Downstream Effectsof Inflammation on the Brain
The Emerging Role of the Immune System in Depression - Andrew H. Miller, MD
Sunday, September 22, 2019
12
Impact of IFN-alpha on Ventral Striatal Activation during a Hedonic Reward Task Using fMRI
Gambling Task
Win Lose
$17 $15
Reuter et al. Nat Neurosci. 8(2):147-8, 2005
Coronal View
Impact of IFN-alpha on Ventral Striatal Activation during a Hedonic Reward Task Using fMRI
Win versus Lose (n=28)
Capuron et al. , Arch Gen Psychiatry, 69:1044, 2012
ControlIFN-alpha
all p<0.01; CTL>IFN
The Emerging Role of the Immune System in Depression - Andrew H. Miller, MD
Sunday, September 22, 2019
13
all r>0.6, p<0.001
ControlIFN-alpha
Capuron et al. , Arch Gen Psychiatry, 69:1044, 2012.
Similar Results with Endotoxin and Typhoid Vaccination(Eisenberger et al. Biol Psych, 68:748, 2010, Harrison et al. Biol Psych, 80:73, 2016)
MFI–Multidimentional Fatigue Inventory
IFN-alpha-Induced Decrease in Ventral Striatal Activationis Associated with Reduced Motivation
IFN-alpha and Dopamine Release in Striatum as measured by In Vivo Microdialysis in Rhesus Monkeys
K+ - voltage dependent DA release
Amphetamine (Amph) - stimulated DA release and inhibited DA reuptake
probe
The Emerging Role of the Immune System in Depression - Andrew H. Miller, MD
Sunday, September 22, 2019
14
IFN-alpha and Dopamine Release in Striatum as measured by In Vivo Microdialysis in Rhesus Monkeys
0
1
2
3
4
5
6
IFN-alphaSaline
0
1000
2000
3000
4000
IFN-alphaSaline
DA (nM) HVA (nM)
Baseline
Felger et al. , Neuropsychopharmacology, 38:2179-87,2013.
DA-dopamine, HVA-homovanillic acid
IFN-alpha and Dopamine Release in Striatum as measured by In Vivo Microdialysis in Rhesus Monkeys
- 20 0 20 40 60 80 100 120
Time (minutes)
0
20
40
60
80
100
120
140
160
180
200
220
K+ Amph
IFN- alphasaline
- 20 0 20 40 60 80 100 120
Time (minutes)
0
20
40
60
80
100
120
140
160
180
200
220
Dop
amin
e (n
M)
Stimulated via Reverse Microdialysis
Felger et al. , Neuropsychopharmacology, 38:2179-87,2013.
DA-dopamine, HVA-homovanillic acid
The Emerging Role of the Immune System in Depression - Andrew H. Miller, MD
Sunday, September 22, 2019
15
IL-6 (ip) Leads to an Acute Reduction in Nucleus Accumbens Dopamine as Measured by In Vivo Microdialysis in Rats
Yohn et al., Psychopharmacology, 233:3575-86, 2016.
IL-6 treatment decreases DA production in midbrain organoids
3D human brain organoids derived frominduced pluripotent stem cells (iPSCs)
Wen, Treadway, unpublished.
100
80
60
40
20
0
Det
ectio
n (n
A)
StandardsDay 84 midbrain organoidsDay 84 midbrain organoids + IL-6 (5ng/ml/24h)
5 10 15Elution Time (min)
PITX3 (green): DA neuronsTyrosine hydroxylase (red)
The Emerging Role of the Immune System in Depression - Andrew H. Miller, MD
Sunday, September 22, 2019
16
Stimulated DA Release
0
1.0
2.0
3.0
4.0
5.0
6.0BaselineIFN-alpha
0 20 40 60 80 100 120
Time (minutes)
L-DOPAAMPH
% b
asel
ine
nM D
A (x
1000
)
L-DOPA Reverses IFN-alpha-Induced Decrease in Stimulated Dopamine Release
Felger et al., Int J Neuropsychopharm, 2014.
L-DOPA administered via reverse in vivo microdialysisDOPAC - 3,4-Dihydroxyphenylacetic acid
Microglial Activation and Monocyte Trafficking to Brain during Immune Stimulation with IFN-alpha
IFN-alphatreated
Blood Vessels and Meninges- Striatum
Parenchymal Microglia-Globus Palidus
Control
100um 100um
100um 100um
100um
100um
Activated Microglia
Macrophages
Felger et al., unpublished data.
The Emerging Role of the Immune System in Depression - Andrew H. Miller, MD
Sunday, September 22, 2019
17
Chronic Social Defeat Leads to Increased Permeabilityof the Blood Brain Barrier to IL-6 in Nucleus Accumbens
Menard et al., Nat. Neurosci., 20: 1752–1760, 2017.
CTRL – controlSS – stress sensitiveRES – stress resilient
Do Inflammation Effects on Dopamine Affect Reward Circuitry in Patients with Major Depression?
Resting State Functional
Connectivity
The Emerging Role of the Immune System in Depression - Andrew H. Miller, MD
Sunday, September 22, 2019
18
Haber & Knutson, Neuropsychopharm., 2010.
Pathways of the Reward Circuit
Does Inflammation Disrupt Connectivity in Dopamine-Related Reward Circuits in Depression?
vmPFC - ventromedial prefrontal cortex VS – ventral striatum
C-Reactive Protein (CRP) is a Marker of Endogenous Systemic Inflammation
*American Heart Association/ Centers for Disease Prevention and Control (2003)
The Emerging Role of the Immune System in Depression - Andrew H. Miller, MD
Sunday, September 22, 2019
19
y=8
Inflammation Decreases Functional Connectivity in Reward Circuits
during Resting State fMRI
Felger et al., Molecular Psychiatry, 21:1358, 2016. vmPFC - ventromedial prefrontal cortex
vmPFC
iVS – inferior ventral striatum
Inflammation Affects Behavior (Anhedonia and Psychomotor Speed) in Depression by
Decreasing Connectivity in Reward Circulits
Felger et al., Molecular Psychiatry, 21:1358, 2016.
Similar findings with measures of psychomotor activity
vmPFC - ventromedial prefrontal cortexiVS – inferior ventral striatum
The Emerging Role of the Immune System in Depression - Andrew H. Miller, MD
Sunday, September 22, 2019
20
Inflammation is associated with decreased corticostriatal connectivity which is associated with Effort-Based motivation in women with breast cancer
-0.2
0
0.2
0.4
0.6
r=-0.55, df=14, p=0.027
0 2 4 6 8
-0.4
Plasma CRP (mg/L)
dcP
to v
mPF
C F
unct
iona
lC
onne
ctiv
ity (Z
-sco
re)
Left dcP
dcP to vmPFC FunctionalConnectivity (Z-score)
20
40
60
80
0
-0.2 0.0 0.2 0.4
% H
igh
Effo
rt C
hoic
es o
n EE
fRT
r=0.67, df=8, p=0.034
vmPFC - ventromedial prefrontalcortex
dcP – dorsal caudal putamen
Felger, Treadway in preparation.
Inflammation-Related Decreases in VS to vmPFC Connectivity Can be Reversed with L-DOPA
iVS to vmPFC Left iVS
Y=8
vmPFC
X=0L-DOPA/carbidopa
100-250/25 mg (Sinemet)
vmPFC - ventromedial prefrontal cortexiVS – inferior ventral striatum
Felger et al., unpublished data.
The Emerging Role of the Immune System in Depression - Andrew H. Miller, MD
Sunday, September 22, 2019
21
Patients with high inflammation may preferentially respond to
dopaminergic medications
BupropionStimulantsMonoamine oxidase inhibitorsDopamine agonists
- pramipexole- L-DOPA- aripiprazole
Dopamine is a Target
Summary1. Inflammation affects specific neurotransmitters
and neurocircuits that can serve as targets of treatment, dopamine (and glutamate) as well as inflammation itself being especially attractive targets.
2. Patients with increased inflammation can readily be identified, allowing focused treatment and prevention on specific subgroups.
3. Precision medicine is possible for behavioral complications of inflammation.
The Emerging Role of the Immune System in Depression - Andrew H. Miller, MD
Sunday, September 22, 2019
22
Acknowledgements
Animal Studies:Jennifer C. Felger, Ph.D.Carla HernandezMar Sanchez, Ph.D.Amanda Freedman, Ph.D.David B. Rye, M.D., Ph.D.
Laboratory Studies:Evanthia WommackThaddeus W.W. Pace, Ph.D.Fang Hu, Ph.D.Gerald Vogt, Ph.D.
Clinical Studies:Ebrahim Haroon, M.D.Jennifer C. Felger, Ph.D.Michael T. Treadway, Ph.D.Canhua Xiao, Ph.D.Mylin A. Torres, M.D.Charles L. Raison, M.D.Lucile Capuron, Ph.D.Bobbi J. Woolwine, MSWCharles B. Nemeroff, M.D., Ph.D.Dominique L. Musselman, M.D.Giuseppe Pagnoni, Ph.D.
Support- National Institutes of Health, NARSAD, CDC, American Cancer Foundation, and the DANA Foundation