Mood and the Inflamed BrainEdward Bullmore

A4M Brain Health Summit

26 June, 2021

Ed BullmoreDisclosures

Sources of Research Support

• Medical Research Council

• Wellcome Trust

• National Institute for Health Research

• National Institutes of Health, Graduate Partnership Program

• GSK, Janssen, Lundbeck, Pfizer

Employment

• Paid EmploymentUniversity of Cambridge(GSK, 0.5 FTE, 2005-2019)

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

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

Cambridgeshire & Peterborough NHS Foundation Trust

• Honorary RolesTreasurer, Academy of Medical Sciences

• RoyaltiesShort Books, London and overseas publishers of “The Inflamed Mind”

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“We could be on the cusp of a revolution. It won’t be televised. And I might be wrong. But I think it has already begun.”

Mrs P – a patient with arthritis is depressed

“Well, you would be, wouldn’t you?”

Depressive symptoms are commonly “comorbid” with inflammatory disorders

Wittenberg et al (2019) Molecular Psychiatry

SF36 mental health questionnaire data on 10,743 patients in anti-inflammatory drug trials for physical health disorders

The 400 year‐old roots of the split between body and mind in western medicine

Descartes (1637) Treatise on Human Nature

BBB – blood brain barrier – a Berlin wall in the brain

Dualist sting in the tail of DSMDiagnostic classification for major depressive disorder (MDD)

Inclusion criteria:Five or more of nine symptoms, including at least one of two “core” symptoms, representing a change in function, and causing significant distress or impairment, for at least two weeks:

1. Depressed mood2. Loss of pleasure3. Change in weight or appetite (up or down)4. Change in sleep (insomnia or hypersomnia)5. Psychomotor retardation or agitation6. Loss of energy or fatigue7. Worthlessness or guilt8. Impaired concentration or decisiveness9. Suicidal ideation or attempts

Exclusion criterion: Symptoms must not be attributable to a substance or medical condition

DSM5 (2013) American Psychiatric Association

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

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 (2019) British Journal Psychiatry

Controls TreatmentResponsive

MDD

TreatmentResistant

MDD

UntreatedMDD

• In medicine, causality implies therapeutic tractability: do anti-inflammatory interventions have anti-depressant effects?

The question(s) of causality: what is the evidence that inflammation can cause depression?

• Causes precede effects: does inflammation precede or anticipate depression?

• Causes are mechanistically linked to effects: how can inflammation of the body be mechanistically linked to disorders of the mind?

• In biology, natural selection of DNA is ultimately causal: is there an evolutionary theory for inflamed depression, and is there any genetic evidence for it?

• Causes have causes: what are the causes of inflammation that cause depression, and are any of them known risk factors for depression?

•First inflammation then depressive symptoms, over a range of time scales

• Days: typhoid vaccination induces 24-48 hours of “feeling down” for many people

• Weeks: interferon treatment for hepatitis is complicated by MDD several weeks later in about 40% of patients

• Years: low grade inflammation in population cohorts predicts greater risk of depression 10 years later

Inflammation can precede depression, so could be causal

Harrison et al (2009) Biological PsychiatryPariante et al (1999) The LancetKhandaker et al (2013) JAMA Psychiatry

The BBB - like the wall in Berlin – is not what it was in the ‘80s

Bullmore (2018) The Inflamed Mind

Inflammation and the human brain: correlational and experimental studies

Kraynak et al (2019) Neuroscience & Biobehavioral ReviewsHarrison et al (2009) Biological Psychiatry

Inflammation-related changes in fMRI activation are meta-analytically robust24 studies, N=457

Kitzbichler, Harrison et al (2021) unpublished data

CRP-related changes in brain structure are co-located with depression-related changes in functional connectivity

Human brain biomarkers of inflamed depresssion are in short supply

Schubert et al (2021) Biological Psychiatry: Cognitive Neuroscience & NeuroimagingZimmer et al (2014) J Neuroinflammation

Positron Emission Tomography, [11C]-PK11195CSF sampling for cells, protein, single cell gene expression in cerebrospinal fluid from spinal tap•poor tolerability in depression 

PET imaging of radioactive ligand binding to molecular targets in the brain’s immune system•available ligands are not immune‐specific

Organoids of neuronal and glial cells•maybe one day?

What causes the inflammation that causes depression?

• There are many bodily factors that could drive low‐grade inflammation

• Obesity, gut microbiome, chronic peri‐odontitis• Menopause• Age, winter…

• There are also many social stresses that could cause  inflammation

• Bereavement, caring, childhood adversity, public speaking…

Flaming stressed

Bellingrath et al (2012) Biol Psychology

Burnt out teacher

Resilient teacher

Time (mins)

Cytokine level in the blood

Immune memories of childhood maltreatment

Danese et al (2012) Archives of Pediatric & Adolescent Medicine

Stress, inflammation and depressionan artist’s impression

Helena Maxwell (2018)

Weber, Godbout & Sheridan (2017) Neuropsychopharm Rev

Stress, inflammation and depressiona neuroimmunological model

Why does inflammation cause depression?

• Ultimately the answer must come back to Darwin• Depressive behaviour is, or was, invoked by the immune system to help us survive

Miller & Raison (2016) Nature Reviews ImmunologyWray et al (2018) Nature Genetics

Olfactomedin 4: in mice, a gene which regulates the immune response of the stomach to infection

GWAS of MDD (2018), 44 SNPs 

Polygenic risk score for major depressive disorder was significantly associated with blood CRP concentration

Pitharouli et al (2018) American J Psychiatry

Anti-inflammatory drugs are often anti-depressant for “co-morbid” depression, measured as a secondary endpoint in large RCTs

Wittenberg, Stylianou, Khan et al (2019) Molecular Psychiatry

Overall (7 mechanisms of action) d ~ 0.29

Anti- IL-6 (sirukumab and siltuximab) d ~ 0.80

Anti-IL-12/23 (ustekinumab) d ~ 0.74

Anti-inflammatory drug trials for MDD will have to be biomarker-guided

Improved depression

Higher baseline CRP

Raison et al (2013) JAMA Psychiatry

What does a good biomarker look like?

• Biologically as close and specific to the target (molecule) as possible

• Acceptable to patients, accessible and affordable to investigators

• Reliable, replicable and robustly associated with (a subgroup of) depression

Increased neutrophils and CD4+ T cells are correlated with clinical symptoms and inflammatory proteins in MDD

Lynall et al (2020) Biological Psychiatry

• Case‐control design• Absolute cell counts from 

venous blood in 14 cell classes

• N=206 MDD cases• N=77 healthy controls

• Correlation matrix thresholded at FDR 5%

Cell counts can be used to define an inflamed subgroup of MDD casescontrolling for age, sex, BMI, tobacco, recent infection

Lynall et al (2020) Biological Psychiatry

Meta-analysis of whole genome transcriptional studies of whole blood samples in case-control studies of MDD

• 4 independent primary studies• N = 1,552 MDD cases and 947 healthy controls• 325 genes differentially expressed with FDR 5%• Genes coded for a significantly interactive protein network and

were enriched for myeloid leukocyte functions

Wittenberg et al (2020) in review

ATP: a phase 2 clinical trial of a P2X7 antagonist for stratified MDD

The Target

• P2X7 is a ligand-gated ion channel, expressed abundantly on the surface of microglia, that is activated by supra-physiological levels of ATP produced during pathology

• In CNS, P2X7 signaling mediates neuroinflammation; antagonism of P2X7 produces efficacy in models of anhedonia (Bhattacharya et al., 2018)

• P2X7 antagonism could have anti-depressant efficacy by uncoupling stress from adverse brain changes caused by microglial release of IL1-

The Drug

• JNJ-54175446 is a novel P2X7 antagonist with high selectivity, high CNS penetration and good safety and tolerability profile from previous clinical trials (Letavic et al., 2017; Timmers et al., accepted)

IL1 release from microglia has toxic effects on local neurons causing depressive symptoms

Vagal Inflammatory Reflex

Interventions for inflamed depression need not be drugs

Tracey (2009) Nat Rev Immunol

Anti-inflammatory interventions might not be relevant only for depression

St George-Hyslop et al (2012) New England Journal of Medicine

Frau Auguste D (1850‐1906)

What is long COVID?

NICE guidance, published Dec 2020https://www.nice.org.uk/guidance/NG188

What does this mean for depressive symptoms after SARS-CoV2 infection?

Bullmore (2018) The Inflamed Mind

SARS-CoV2 can elicit a pro-inflammatory “cytokine storm”, with myeloid cell hyper-activation and lymphopenia

Keyhanian et al (2021) J Neuroimmunology

Innate immune response Adaptive immune response

SARS-CoV2 can invade the nervous system and/or elicit a local immune response in the brain

Matschke et al (2020) Lancet NeurologySong et al (2021) Cell Reports Medicine

Microglial proliferation Cross‐reactive anti‐SARS‐CoV‐2 antibodies

Post-COVID mental health seems to be part of a protean, systemic disorder;and brain MRI changes are associated with inflammation

58 post-hospitalised COVID patients30 age, sex, BMI-matched controls

Raman (2021) EClinicalMedicine

• In medicine, causality implies therapeutic tractability: do anti-inflammatory interventions have anti-depressant effects? Circumstantially yes, but needs more purposive testing, for long COVID as well as other inflammation-associated forms of depression

“The” question of causality: what is the evidence that inflammation can cause depression?

• Causes precede effects: does inflammation precede or anticipate depression? Yes, it can

• Causes are mechanistically linked to effects: how can inflammation of the body be mechanistically linked to disorders of the mind? Structural and functional MRI, PET

• In biology, natural selection of DNA is ultimately causal: is there an evolutionary theory for inflamed depression, and is there any genetic evidence for it? Rapidly increasing genetic support

• Causes have causes: what are the causes of inflammation that cause depression, and are any of them known risk factors for depression? Social stress and childhood adversity