INFLAMMATION AND

MENTAL HEALTH
Moderator Presenter
Surg Capt Rohith R Pisharody Sqn Ldr Santosh T S
Senior Advisor, HoD Psychiatry JR-3 Psychiatry

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 Overview
• Objectives
• History
• Inflammation: Friend and Foe
• Immune cross-talk between the brain and the periphery
• Immune system, Stress and Depression
• Role in other Psychiatry illnesses
• Gut brain axis
• Therapeutic Implications
• Future directions
• Take home message
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 Objectives
• Understanding the immune system
• Key components of neuroinflammation
• How peripheral and central inflammation effect psychiatric
illnesses
• Potential implications

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 History
• 1890s - William Osler – “sick behavior” in animals
• 1920s- Karl Menninger – influenza – psychosis
• 1970s- “Neuroinflammation”coined by R. Ader and N. Cohen
• 1980s- Moritz Tramer – Schizophrenia – winter/spring months
• Late 19th and early 20th centuries - psychotic symptoms in
advanced neurosyphilis

Konsman, Jan Pieter (March 2019). "Inflammation and Depression: A Nervous Plea for Psychiatry to Not Become Immune to
Interpretation". Pharmaceuticals.
Pariante, C. M. (2015). "Psychoneuroimmunology or Immunopsychiatry”. The Lancet Psychiatry. (3): 197–199. 4
 What is Inflammation
• Local accumulation of plasma proteins, white blood cells, fluid due
to physical injury, infection or local immune response.
• Acute inflammation: early and transient episodes
• Chronic inflammation: persistent infection or auto immune disease

Functions
• Deliver effector molecules and cells to injury site
• Prevent spread of infection
• Repair tissue damage
From Stress to Inflammation and Major Depressive Disorder: A Social Signal Transduction Theory of Depression George M. Slavich and Michael R. Irwin 2014
American Psychological Association 0033-2909/14 5
 The immune system - An overview
Innate Immunity Adaptive immunity

Non specific Specific to antigen

Immediate response Lag time from exposure to response
Limited immunological memory Long term immunological memory

Humoral
Cellular Humoral Cellular
Complement
Dendritic cells Antibodies T cells
Cytokines
Macrophages Cytokines B cells
Acute Phase
NK Cells
proteins
Kroken RA, Sommer IE, Steen VM, Dieset I and Johnsen E (2019) Constructing the Immune Signature of Schizophrenia for Clinical Use and Research; An
Integrative Review Translating Descriptives Into Diagnostics. Front. Psychiatry 9:753. doi: 10.3389/fpsyt.2018.00753 6
 Types of inflammation

• Acute response to injury

Peripheral • Aids in repair and resolution of injury/trauma
• Can stimulate behavioural changes in the brain

• Chronic glial activation (microglia and

Central/ astrocytes)
Neuroinflammation • Pro inflammatory mediators (cytokines,
chemokines)
• Neural dysconnectivity

From Stress to Inflammation and Major Depressive Disorder: A Social Signal Transduction Theory of Depression George M. Slavich and Michael R. Irwin 2014
American Psychological Association 0033-2909/14 7
 Inflammation: Friend and Foe

Furman, D. et al. Expression of specific inflammasome gene modules stratifies older individuals into two extreme clinical and immunological states. Nat.
Med. 23, 174–184 (2017).
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 Components of a typical inflammatory response

DAMPs- Heat Shock Protein, HMGB-1

PAMPs- LPS, Peptidoglycans

TLRs, complement, B/T cells

Cytokines, Chemokines

TARGET TISSUES

Inflammation in psychiatric disorders: what comes first? Moises E. Bauer and Antonio L. Teixeira, Ann. N.Y. Acad. Sci. 0 (2018) 1–11 C 2018 New York Academy
of Sciences. 9
Immune dysfunction in Neuropsychiatric disorders
PERIPHERAL
MOLECULAR CELLULAR
BLOOD
• Expression & • Monocytes • Pro inflammatory
polymorphism of • T and B Cells cytokines
IL-6, 1, TNF • Chemokines
• Activation of • Acute phase
intracellular proteins
pathways • Oxidative stress
(MAPK, NF-KB) markers
• Activation of • Autoantibodies
sensors(TLRs,
Inflammasome)

Inflammation in psychiatric disorders: what comes first? Moises E. Bauer and Antonio L. Teixeira, Ann. N.Y. Acad. Sci. 0 (2018) 1–11 C 2018 New York Academy
of Sciences. 10
 Stress and Inflammation

Inflammation in psychiatric disorders: what comes first? Moises E. Bauer and Antonio L. Teixeira, Ann. N.Y. Acad. Sci. 0 (2018) 1–11 C 2018 New York Academy
of Sciences.
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 Immuno-Psychiatry model – Stress and Inflammation

• HPA Axis
• Autonomic Nervous System
• Changes in neurotransmitter
metabolism

Jones, Brett D. M.; Daskalakis, Zafiris J.; Carvalho, Andre F.; Strawbridge, Rebecca; Young, Allan H.; Mulsant, Benoit H.; Husain, M. Ishrat (July
2020). "Inflammation as a treatment target in mood disorders: review". BJPsych Open. 12
 Stress and Cortisol

FIGHT OR FLIGHT

From Stress to Inflammation and Major Depressive Disorder: A Social Signal Transduction Theory of Depression George M. Slavich and Michael R. Irwin 2014
American Psychological Association 0033-2909/14
Inflammation in psychiatric disorders: what comes first? Moises E. Bauer and Antonio L. Teixeira, Ann. N.Y. Acad. Sci. 0 (2018) 1–11 C 2018 New York Academy 13
of Sciences.
 Social signal transduction theory

From Stress to Inflammation and Major Depressive Disorder: A Social Signal Transduction Theory of Depression George M. Slavich and Michael R. Irwin 2014
American Psychological Association 0033-2909/14 14
 Inflammation and depression
INFLAMMATION

DECREASED INCREASED
DECREASED
NEUROTRASMITTER GLUTAMATE
NEUROGENESIS
METABOLISM EXCITOTOXICITY

ALTERED
NEUROCIRCUITRY

DEPRESSION

The Neuroinflammation Perspective of Depression: Reuniting the Outstanding Mechanisms of the Pathophysiology Article in Bulletin of Clinical
Psychopharmacology · June 2016
Haroon E, Raison CL, Miller AH. Psychoneuroimmunology meets neuropsychopharmacology: translational implications of the impact of inflammation on 15
behavior. Neuropsychopharmacology. 2012 Jan;37(1):137-62.
 IL-18
IFN Symptoms of Depression
ALPHA

Th1 Th17
CRP DOPAMINE IL-6,17
IL-1,6 SEROTONIN Motivation microbiome
Microbiome Sadness Sociability
Appetite
IL-1,6
Worthlessness GLUTAMATE CRP
TNF R2 Suicidal Mood
ideations Sleep Ifn
Aggression disturbance IL-1,6
PMA TNF
IL-2,6,8 Anhedonia
Fatigue
TNF
VEGF IL-6, 1
Anxiety Difficulty in IL-6,17 IL-6,1
concentration CRP Ifn
Th17 TNF
Kynurenine TLR2/4 CRP Th17
pathway IL-17 TLR3
TNF
NOREPINEPHRINE
CCL2
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The Bidirectional Relationship of Depression and Inflammation: Double Trouble Ele´ onore Beurel Neuron 107, July 22, 2020
 Childhood to adulthood

GENETIC FACTORS
CHRONIC
INFLAMMATION
PERSONALITY TRAITS ANXIETY
PERCEPTION OF SOCIAL THREAT
MILD INFLAMMATION

SOCIO-
ENVIRONMENTAL ANXIETY
DEPRESSION

From Stress to Inflammation and Major Depressive Disorder: A Social Signal Transduction Theory of Depression George M. Slavich and Michael R. Irwin 2014
American Psychological Association 0033-2909/14 17
 Bipolar Affective Disorder
Psychopathology

Network balancing alterations

NT signalling changes

Limbic network damage

Immune dysregulation

A unified model of the pathophysiology of bipolar disorder Paola Magioncalda. Molecular Psychiatry March 2021
 of 11

Inflammation and schizophrenia

Genetic and epigenetic factors Abnormal allostasis
MHC locus/complement C4 Infection
Cytokine genes Psychosocial stress
Tissue injury

Peripheral inflammation
Cellular activation, monocytes
Acute cytokine production
Acute phase response

Central inflammation

Evaluating the Hypothesis That Schizophrenia Is an Inflammatory Disorder Brian J. Miller, M.D., Ph.D. et al Focus 2020; 18:391–401 20
 Contd…
Inc Cytokines IDO pathway Microglial activation
Kynurenic acid Quinolinic acid

Abnormal neurodevelopment
White matter pathology Neurotransmitter abnormalities
Brain dysconnectivity Dopamine
Impaired neurogenesis Glutamate
Hippocampal volume loss Acetylcholine

Positive symptoms
Mood symptoms
Negative symptoms
Cognitive symptoms

Evaluating the Hypothesis That Schizophrenia Is an Inflammatory Disorder Brian J. Miller, M.D., Ph.D. et al Focus 2020; 18:391–401
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 Schizophrenia
• Infectious agents (viruses), may underlie some cases of schizophrenia.

• Evidences include:
(1) an excess number of patient births in the late winter and early spring.
(2) an association between exposure to viral epidemics in utero and the
later development of schizophrenia,
(3) a higher prevalence of schizophrenia in crowded urban areas .

Kroken RA, Sommer IE, Steen VM, Dieset I and Johnsen E (2019) Constructing the Immune Signature of Schizophrenia for Clinical Use and Research; An
Integrative Review Translating Descriptives Into Diagnostics. Front. Psychiatry 9:753. 22
 Substance Use Disorder
BRAIN
HMGB1- TLR4
HMGB1 and
NF-KB
TLR4
CYTOKINES

LIVER TNF
ALPHA

LEAKY GUT

LPS
STOMACH Ethanol (EtOH)
EtOH releases HMGB1 and TLR4
signals

Koob GF, Volkow ND. Neurobiology of addiction: a neurocircuitry analysis. Lancet Psychiatry. 2016 Aug;3(8):760-773. 24
 Neuro Degenerative Disorders
NEUROINFLAMMATION

NF KB

Cytokines

Hippocampal Substantia Nigra

neurons neurons

Alpha Synuclein
Tau polymers
polymers

Neuroinflammation as a Common Feature of Neurodegenerative Disorders Leonardo Guzman-Martinez Frontiers in Pharmacology, September 2019 25
 Contd…
Neurodegeneration DEMENTIA

Neuroinflammation Oxidative Amyloid Tau

Stress accumulation hyperphosphorylation

Pro inflammatory
Cytokines
DM T2

Chronic
Inflammation Obesity Insulin
Resistance

Inflammation: Major denominator of obesity, Type 2 diabetes and Alzheimer's disease-like pathology? Article in Clinical Science · March 2020
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 Other Disorders

• PANDAS
• PTSD
• OCD
• ASD
• Chronic Fatigue Syndrome

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 Gut Brain Axis

Brain–gut–microbiota axis in depression: A historical overview and future directions Lijia Chang et al. Brain Research Bulletin 182 (2022) 44–56 28
 Targeting the brain–gut–microbiota for
depression

• Diet – Mediterranean, SCFA

• Psychobiotics
• Faecal Microbiota Transplantation
• Antidepressants – Fluoxetine, Ketamine

Brain–gut–microbiota axis in depression: A historical overview and future directions Lijia Chang et al. Brain Research Bulletin 182 (2022) 44–56
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Saturated fatty acids and Neuroinflammation

Melo HM, Santos LE and Ferreira ST (2019) Diet-Derived Fatty Acids, Brain Inflammation, and Mental Health. Front. Neurosci. 13:265. 30
 C - Reactive Protein (CRP)
• Marker of memory and visuospatial impairment in the elderly
• Cerebral microstructural disintegration, affecting frontal lobe
pathways
• High CRP levels - biomarker for worse prognosis in schizophrenia
• Benefit from immunomodulatory drugs

Evidence for an Immune Role on Cognition in Schizophrenia: A Systematic Review Rafael Ribeiro-Santosa et al . Current Neuropharmacology, 2014, 12, 273-280
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Therapeutic Implications

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 Therapeutic targets
• Cytokines (IL-1, IL-6, TNF)
• Cytokine signalling pathways (NF- KB, COX)
Immunologic • Chemokines (C-C family)
• T cells (Th17, T reg)

• IDO and its metabolites

Neurotransmitter • BH4 (Tetrahydrobiopterin)

• Glucocorticoid receptor
Neuroendocrine • Protein Kinase A

Neuropsychopharmacology. 2012 Jan; 37(1): 137–162.

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 Contd…

Immune targets for therapeutic development in depression: towards precision medicine Wayne C. Drevets et al. Nature Reviews | Drug Discovery Reviews
volume 21 | March 2022 34
 Contd…

Immune targets for therapeutic development in depression: towards precision medicine Wayne C. Drevets et al. Nature Reviews | Drug Discovery Reviews
volume 21 | March 2022 35
 Contd…

Immune targets for therapeutic development in depression: towards precision medicine Wayne C. Drevets et al. Nature Reviews | Drug Discovery Reviews
volume 21 | March 2022 36
 Contd…
ANTI-INFLAMMATORY DRUGS

NSAIDs Aspirin/acetyl-salicylic acid

Celecoxib

Steroids Prednisolone

NOVEL BIOLOGICALS—MONOCLONAL ANTIBODIES AGAINST

CYTOKINES/CYTOKINE RECEPTORS/CELL ADHESION MOLECULES
Tocilizumab
Siltuximab
Natalizumab
Infliximab
Adalimumab

Kroken RA, Sommer IE, Steen VM, Dieset I and Johnsen E (2019) Constructing the Immune Signature of Schizophrenia for Clinical Use and Research; An
Integrative Review Translating Descriptives Into Diagnostics. Front. Psychiatry 9:753. doi: 10.3389/fpsyt.2018.00753 37
 Contd…
MISCELLANEOUS DRUGS WITH ANTI-INFLAMMATORY ACTION
N-acetylcysteine
Erythropoetin
Pioglitazone
Simvastatin/ Atorvastatin
Pravastatin
Minocycline
Estrogens
Omega-3 fatty acids
Dehydroepiandrosterone (DHEA)
Pregnenolone
L-theanine
Kroken RA, Sommer IE, Steen VM, Dieset I and Johnsen E (2019) Constructing the Immune Signature of Schizophrenia for Clinical Use and Research; An
Integrative Review Translating Descriptives Into Diagnostics. Front. Psychiatry 9:753. 38
 Role of Ketamine
• Anti depressant
• Anti inflammatory

Targeting inflammation in depression: Ketamine as an anti-inflammatory antidepressant in psychiatric emergency, Naghmeh Nikkheslat. Brain, Behavior, &
Immunity - Health 18 (2021) 39
 Psychedelics
• Ayahuasca - N,N-Dimethyltryptamine (DMT)
- 5-Methoxy-N,N-dimethyltryptamine
• Psilocybin (magic mushroom)
• Lysergic Acid Diethylamide (LSD)
• 3,4-Methylenedioxymethamphetamine (MDMA)
• 2,5-Dimethoxy-4-iodoamphetamine
• Ketamine

Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanisms, Antonio Inserra et al, Pharmacol Rev 73:202–277, January
2021 40
 Future directions
• Transfer of research from phenomenology to pathology
• Inflammatory and non-inflammatory groups- immunoneuropsychiatry
• Potential of genetic and epigenetic research
• New classificatory system
• Inflammatory markers as objective investigation tools
• Use of portable devices to track immune changes

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 Summary
• Stress- key role in psychiatric illness by activating immune response
• Update contemporary theories of depression with information about biological
mechanisms
• Targeting inflammatory markers in treatment resistant depression and psychotic
disorders
• Targeting the brain–gut–microbiota axis as new modality of treatment
• Importance of lifestyle modification

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THANK YOU

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