Treating the Inflamed Mind

Ed Bullmore

Management of Depression: Guidelines and beyondGeneral Medical Council, London

17 September, 2018

Ed BullmoreDisclosures

Sources of Research Support

• Medical Research Council

• Wellcome Trust

• National Institute for Health Research

• National Institutes of Health, Graduate Partnership Program

Employment

• Paid EmploymentUniversity of Cambridge (50% FTE)GlaxoSmithKline (50% FTE)

• Editorial Roles Biological Psychiatry – Deputy EditorNetwork Neuroscience – Senior Editor

• National Health Service (HCP) RoleHon Consultant Psychiatrist and Director of R&D, Cambridgeshire & Peterborough NHS FT

• Stock Equity (>$10,000)GlaxoSmithKline

• Speaker’s BureauNone 

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Immuno-PsychiatryAiming to develop new therapeutics by a radical shift in focus from neuronal to immune targets

3Tracey (2002) “The inflammatory reflex” Nature

Classic neuronal target:Monoaminergic neurotransmission

Novel neuroimmune target:Vagal inflammatory reflex

Three “dumb” questions about immuno-psychiatry

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What is the reason to believe?• Rapidly advancing knowledge of how the nervous system

and the immune system interact functionally• Growing evidence base for immunological mechanisms of

mood, cognitive and behavioural disorders

How will it be different this time?• Peripherally accessible, mechanistically specific biomarkers• Harmonization with immuno programs could make

psychiatry R&D more cost-efficient

What would success look like?• Don’t expect new drugs to displace historical blockbusters

like SSRIs• 2nd line options for treatment resistant patients• Biologically or clinically stratified subgroups• Repurposed indications for drugs already marketed or in

development for inflammatory disorders

Depression and Inflammation citations 2004-2014 (PubMed)

Bullmore & Lynall (2014) Biological Psychiatry

Depression is robustly associated with increased peripheral IL6 and CRP

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Cumulative meta-analysis shows that, over the last 20 years, the evidence for increased peripheral IL6 in association with major depressive disorder has become a matter of fact

This is a moderately strong and robust association between MDD and IL6, overall d~0.54

There is equally strong evidence for an association between MDD and CRP, some evidence for association between MDD and TNF-, but no evidence for an association between MDD and IL1-

1995

2015

IL6, d ~ 0.5

CRP, d ~ 0.5 TNF-, d ~ 0.4 IL1-, d ~ 0.0

Happakoski et al (2015) Brain Behavior & Immunity

Inflammation anticipates depressive symptoms over a range of time scales

– Typhoid vaccination induces 24-48 hours of “feeling down” for most people

– Interferon treatment for hepatitis is complicated by MDD several weeks later in about 30% of patients

– Low grade inflammation in population cohorts predicts greater risk of depression up to 10 years later

Inflammation can precede depression, so it could be causal

Khandaker et al (2013) JAMA Psychiatry

Anti-inflammatory drugs are often anti-depressant

Wittenberg, Stylianou, Khan et al (2018) in review

Overall (7 MoA classes) d ~ 0.29

IL-6 (sirukumab and siltuximab, in RA) d ~ 0.80

IL-12/23 (ustekinumab, in psoriasis) d ~ 0.74

Mega-analysis of GSK and Janssen trials for non-psychiatric disorders

Anti-inflammatory treatment of major depressive disorder: without biomarkers we will fail

Improved depression

Higher baseline CRP

Raison et al (2013) JAMA PsychiatryLeday, Vertes et al (2013) Biological Psychiatry

How, exactly, does inflammation cause depression?Stress induces microglial activation and “immature” monocyte trafficking into CNS

Peripheral immune biomarkers could be coupled to central nervous and immune response to stress…the single biggest known risk for depression

Inflammatory gene expression Glucorticoid receptor function

Depression and peripheral innate immune gene expressionTwo whole blood microarray studies of depression

Leday, Vértes et al (2017) Biological Psychiatry

What is the cellular origin of transcriptional changes in whole blood samples from MDD case-control studies?

Leday, Vértes et al (2017) Biological Psychiatry

Innate immune genes over-expressed in MDD were characteristic of monocytes and other myeloid cells

Wellcome Trust Consortium forNeuroimmunology of Mood Disorders and Alzheimer’s Disease 

(NIMA)

NIMA consortium overview

P2X7 antagonist JNJ-54175446 for treatment resistant depression

CSF1R inhibitor JNJ-40346527 to reduce microglial activation in Alzheimer’s disease

Nature Medicine 2017

BIODEPA peripheral and neuroimaging biomarker discovery project in MDD

MDD unresponsive

to MA drugsN≈100

MDD responsive to MA drugs

N≈50

MDD untreated

by MA drugsN≈50

Healthy adultsN≥50

All primary cohort participants will have:• Interview including antidepressant history• Clinical symptom questionnaires• Peripheral immunophenotyping

(cytokines/cytometry), transcriptomics, ex vivo LPS.• Waking, midday and 20:00 salivary cortisol

High CRP (> 3 mg/L)

N≈45

Low CRP(≤ 3 mg/L)

N≈45

Healthy adultsN≥45

All secondary cohort participants will have:• sMRI/fMRI and 1 or 2 additional CNS measures

• [11C]-PK11195 PET • CSF sampling

Stratified by blood CRP levels

Stratified by anti-depressant exposure &

response

Secondary Clinical CohortAdult MDD, sub-sampled from

primary cohort, N≤100

Primary Clinical CohortAdult MDD, 25-50 yrs,

sampled from NHS services, N ≤ 200

113

BIODEP primary cohortPeripheral immunophenotyping protocol

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1 x SST tube

PAXgene RNA tubeStraight into ‐80 freezer

Whole blood transcriptomics

Cytokine analysis

6 x 9ml EDTA tubes PBMCs

1 x PPT tube 

1 x SST tube1 x PPT tube 1 x 9ml EDTA tubes

Transcriptomics

Primary cohort

Cytokine analysis

Immunophenotyping

PAXgene RNA tubeWhole blood transcriptomics

PBMCs

Transcriptomics

Immunophenotyping

Secondary cohort

Pool and centrifuge over histopaque to obtain 

PBMCs

Centrifuge to separate 

serum/plasma

CRP is increased in treatment resistant depression Associated with BMI, fatigue, anxiety and childhood adversity

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Clinical profile accounted for about 35% of the variation in CRP

• Body mass index (BMI)

• Sleep and vitality symptoms of depression• Psychomotor retardation • Middle insomnia • Not being able to work

• Anxiety symptoms• Feeling insecure • Feeling anxious

• Childhood adversity• Feeling unloved • Wanting to change one’s family

(Partial least squares analysis)

Chamberlain et al (2018) British Journal Psychiatry

Serum cytokines and chemokines are abnormal in MDDBut often low levels at or beyond the limit of MSD multiplex assay resolution

Cavanagh, Vértes et al, BIODEP, unpublished data, 2017

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PLS

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PLS

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-2 -1 0 1 2 3 4BMI (residuals)

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PLS

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R=0.44P<0.0001

R=0.21P=0.001

P=4.1e-05 P=0.0007

Controls Patients Controls Patients

– There is evidence for significant case-control differences in a set of measurements of serum cytokines, chemokine and CRP

– MDD associated with relatively increased:

• IL6, IL12, MDC, CRP• MCP1, MCP4, MIP1b

- Increased IL6, IL12, MDC and CRP also positively correlated with BMI (obesity) and CTQ (childhood trauma questionnaire)

- Many cytokine measurements were at or below the LLOQ of the multiplex assay

- Partial least squares was used to explore and simplify the relationships between MDD and multiple, correlated biomarkers

Treatment resistant MDD, compared to responsive MDD, over-expresses inflammatory genes, and under-expresses the GR gene, in blood cells

Con Resp Resist Untreat

Con Resp Resist Untreat

Con Resp Resist Untreat

Con Resp Resist Untreat

• Con, N=35 • MDD Resp, N=35• MDD Resist, N=55• MDD Untreat, N=35

Cattaneo, Pariante et al (2018) BIODEP Primary Cohort, qPCR analysis whole blood, unpublished data

Peripheral CRP is associated with structural and functional MRI changes in brain reward circuitry

19Harrison, Kitzbichler et al, BIODEP, unpublished data, 2017Felger et al (2017) Molecular Psychiatry

CRP is associated with micro-structural MRI change in ventral striatum

Functional connectivity of ventral striatum and orbitofrontal cortex is associated with CRP

What’s the big picture?Stress induces microglial activation and “immature” monocyte trafficking into CNS

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Compatible with increased monocyte chemoattractantproteins in BIODEP

Compatible with increased IL1- and decreased GR expression in whole blood in BIODEP

Compatible with myeloid origin of microarray profile in Janssen/GSK study

Biomarker Gaps

- Direct evidence for microglial activation

- TSPO PET has limited sensitivity and specificity for microglial activation

- CSF proteomicsandcytometry may be limited by patient acceptability

- Further evidence for monocyte mobilisation and trafficking

- Stronger genetic evidence for inflamed depression

Weber, Godbout & Sheridan (2017) Neuropsychopharmacology Reviews

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WGAS risk genes for major depressive disorder are enriched for immune function

Olfactomedin 4

Controls gastric mucosal inflammatory response to H pylori infection

Wray et al (2017) bioRxiv

Conclusions

– Inflammation can cause depression, and there are plausible biological mechanisms

– Peripheral immune biomarkers (transcripts) of inflammatory and glucorticoid pathways are associated with MDD, especially treatment resistant depression

– Future work will focus on– Brain inflammation biomarker development– Genetic validation of immune targets for depression– Animal models of immune mechanisms for stress-related effects on depressive behaviours– Providing definitive, direct test of anti-depressant efficacy of anti-inflammatory drugs in MDD

– Anti-inflammatory drugs could have anti-depressant effects – with the right targets and biomarkers - there is an opportunity to make much-needed therapeutic progress