Psychoneuroimmunology: Mood Disorders

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Psychoneuroimmunology: Mood DisordersPart 2 In PNI Series

September 2019 MRC2.PSY.D.00061


Provide a rationale for the focus on inflammation as a contributory component in the underlying pathophysiology of mood disorders

Elucidate the key mediators and processes underlying neuroinflammation in mood disorders

Outline potential causes and consequences of neuroinflammation in mood disorders

Discuss potential treatment modalities targeting neuroinflammation specific to mood disorders

Objectives

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INFLAMMATORY RESPONSE

IN THE BRAIN


Key Players Underlying Neuroinflammation1-8

4

1. Bilbo SD et al. J Neuroimmune Pharmacol. 2012;7(1):24-41. 2. Turner et al. 2014 Biochemica et Biophysica Acta 1843:2563-2582. 3. Miller AH & Raison C 2016 NATURE REVIEWS IMMUNOLOGY 16:22-34.. 4. Haroonet al. 2017 Neuropsychopharmacology REVIEWS 42:193–215. 5. Ferger AI et al. J Neuroinflammation. 2010;7:45. 6. Jones KA & Thomsen C. Mol Cell Neurosci. 2013 Mar;53:52-62. 7. Najjar S et al. J Neuroinflammation. 2013;10:43. 8. Kim HW et al. Neurobiol Dis. 2010;37(3):596-603.

Component Role/Contribution

Glial Cells Microglia; astrocytes; oligodendrocytes

Cytokines Immune/inflammatory molecules

Glutamate Excitotoxicity

Mitochondria/Oxidative Stress Cellular damage

HPA Axis Chronic stress

S100B & Arachidonic Acid Effector molecules in inflammatory pathways


Basics: Mood Disorders & Inflammation

Relationship between mental health and inflammation was first noted in 1887 by Julius Wagner-Jauregg of the University of Vienna, Austria1

Inflammation is associated with mood disorders and “Sickness Behavior”1,2

Positive, bi-directional, association between inflammation & mood disorders2

Several hypotheses postulated and likely interact, involving:1

Cytokines Glia activation Impaired neuroplasticity1/circuitry3

Treatment success is impacted:1

Inflammatory cytokines can sabotage and circumvent mechanisms of action of conventional antidepressant medication4

5

1. Rosenblat et al. Progress in Neuro-Psychopharmacology & Biological Psychiatry 2014; 53:23–34..2. Wager-Smith, K. Markou, A. Neurosci Biobehav Rev. 2011; 35(3): 742-764.3. Felger Molecular Psychiatry 2018; 1-19. 4. Raison et al. JAMA Psych 2013; 70(1): 31–41.


Inflammatory Cytokines & Neurotransmitters

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1. Van den Ameele et al., Frontiers in Psychiatry 2018; 9:250:1-9.

Inflammatory Cytokines:i.e., IFN-γ, TNF-α,…

Indoleamine 2,3, oxygenase 1 (IDO-1)

Tryptophan Kynurenine

Kynurenic Acid(KYNA)

3-hydroxykynurenine(3-HK)

Quinolinic Acid(QUIN) Cytotoxicity &

Neuroactivity

Guanosine triphosphate cyclohydroxylase 1(GTP-CH1)

NH2PPPNeopterin

BH4

THPAH

DopamineNorepinephrine

Epinephrine

L-DOPA

PhenylalanineTyrosine

TPH

Tryptophan

Serotonin

IFN-γ=interferon gammaTNF-α=tumor necrosis factor alphaNH2PPP=dihydroneopterin triphosphatePAH=phenylalanine hydroxylaseBH4=tetrahydrobipterinTH=tyrosine hydroxylaseTPH=tryptophan hydroxylaseL-DOPA=L-3,4-dihydroxyphenylalanine

Reduced Neurotrophic Factors(BDNF, GDNF)


Major Depressive Disorder“Depression leaves it’s fingerprint in microscopic domains”

-Vladimir Maletic


Glutamate/CRP Correlation in MDD

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1. Felger, et al, Molecular Psychiatry 2018; epub doi: 10.1038/s41380-018-0096-3.2. Haroon et al, Molecular Psychiatry 2016;21:1351-1357.

25-45% of patients with MDD have High CRP1

High CRP in MDD is correlated with CSF cytokines and symptomatology1


Concentrationr2=0.4058

Guiltr2=0.6711

Sadnessr2=0.5139

Self-esteemr2=0.735

Suicidal thoughtsr2=0.7785

Tirednessr2=0.566

Inflammatory cytokine elevation in MDD

9

IL-6 plasma levels correlate with Symptom severity in MDD1

Correlations of IL-6 level with guilt, self-esteem, and suicidal thoughts remained significant after Bonferroni correction. IL-6=Interleukin-6; MDD=Major depressive disorder.

2.0

1.5

IL-1β

(pg/

ml)

1.0

0.5

0.0 Healthy controls

Depressedpatients

CSF IL-1ß levels in depressed patients and healthy controls.Means B SD. CSF IL-1ß levels are higher in depressed patients. ANOVA test: df = 1,20; F = 19.8; p < 0.0002

IL-1β elevated in CSF in MDD2

1. Alesci, S et al, J Clin Endocrinol Metab 2005; 90(5):2522-2530. (Left)2. Levine, et al, Neuropsychobiology, 1999;40:171-176. (Right)


Elevation of Inflammatory Cytokines in CSF May Alter 5-HT and Dopamine Metabolism1

• Inflammatory cytokines and monoamine metabolites were compared in 63 suicide attempters and 47 healthy controls

• MADRS scores correlated significantly with CSF IL-6 levels• IL-6 and TNF-a correlated with CSF 5-HIAA and HVA• Higher cytokine levels were associated with increased suicidality

1. Lindqvist D et al. Biol Psychiatry. 2009;66(3):287-292.

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IL-6

(log

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5-HIAA (log n)100 300 500

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HVA (log n)CSF = cerebrospinal fluid; 5-HT = 5-hydroxytryptamine; IL = interleukin; TNF = tumor necrosis factor; HIAA = hydroxyindoleacetic acid; HVA = homovanillic acid; log n=natural logarithim); Pearsons’s r=0.45, p<.001

10


Treatment response to antidepressants may be related to inflammatory markers

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1. Uher R, et al. Am J Psychiatry, 2014; 171: 1278-1286.2. Yoshimura R, et.al. Progress in Neuro-Psychopharmacology & Biological Psychiatry 2009; 33:722–726.

HC= healthy controls (n=30)Responsive = SSRI/SNRI responsive (n=31)Refractory = SSRI/SNRI refractory (n=20)

Higher plasma IL-6 levels may predict treatment

refractoriness2

C-Reactive Protein (CRP) level may predict response

to antidepressant treatment 1

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Antidepressant Response in MDD and BMI

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1. Kloiber et al, Biological Psychiatry, 2007;62:321-326.

Subjects with MDD and high BMI exhibit slower clinical response to antidepressant treatment1


Depression & Obesity/Metabolic Syndrome Depression and Obesity share key biological pathways

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1. Milaneschi et al., Molecular Psychiatry 2019; 24:18–33.

Depression and Obesity

Early Life Stress

Genetics

Chronic Stress

Infection

Genetics

Unhealthy microbiome

Poor Diet

Sedentary Lifestyle

Genetics

HPA Dysregulation

Leptin/Insulin Dysregulation

Inflamm

ation

Altered Brain

activity for Mood and Food


Bipolar Disorder


Neuroinflammation in Bipolar Disorder

1. O’Brien et al., J Affect Disord 2006; 90(2-3):263-7. 2. Brietzke et al., Journal of Affective Disorders 2009; 116:214–217.3. Soderlund et al., J Psychiatry Neurosci. 2011; 36(2):114-8.4. Sayana et al., J Affect Dis 2017; 92:160-182.5. Rege & Hodgkinson Aust N Z J Psychiatry. 2013; 47(12):1136-51.6. Muneer Clinical Psychopharmacology and Neuroscience 2016; 14(2):117-130. 7. Muneer Psychiatry Investig 2016;13(1):18-33. 8. Kauer-Sant’Anna et al., International Journal of Neuropsychopharmacolog. 2009; 12:447–458.

Blood and CSF samples indicate altered inflammatory cytokine profiles in individuals with bipolar disorder, namely increased pro-inflammatory cytokines, decreased anti-inflammatory cytokines and neurotrophic factors1-4, 7

~Alterations in cytokine profile and neurotrophic factors correlate with clinical severity and symptoms 7,8

Evidence suggests a link between acute mania and an increased pro-inflammatory state4

Research indicates stage/episode-related cytokine profiles that may be related to cognitive decline5

Elevated markers of oxidative stress and mitochondrial dysfunction5-6

Alterations in antioxidant levels may also be stage-dependent6

Several studies have found potential evidence for inflammatory marker & neurotrophic factor variations across the course of bipolar disorder7,8

Kauer-Sant’Anna and colleagues found higher levels of TNFα and IL-6 and lower levels of BDNF in late stage bipolar patients compared to controls and individuals in early stage of illness8


Inflammatory Signals in Bipolar Disorder

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A typical inflammatory response consists of 4 principal components:(1) Inducers: produced by tissue damage or bacterial translocation (i.e., leaky gut)/infection(2)Sensors: receptors expressed on immune cells(3)Mediators: cytokines that mediate function of target tissues(4)Target tissues: CNS and other organs

DAMPs=damage-associated molecular patterns; PAMPs=pathogen-associated molecular patterns; ccf nDNA=circulating cell-free nuclear deoxyribonucleic acid; HSP70=heat shock protein 70; ATP=; HMGB1=high mobility group box 1; sCD14=soluble CD14; TLRs=toll-like receptors; MAPK=mitogen-activated protein kinase; NF-κB=nuclear factor- κB; TNF=tumor necrosis factor; α=alpha; R=receptor; IL=interleukin1. Fries et al., Pharmacology, Biochemistry and Behavior 2019; 177:12-19.

1

2

3

4

Elevations in all of these have been in seen in bipolar patients, suggestive of chronic low-grade dysregulated immune activation


Inflammatory Signals in Bipolar Disorder (BD)

17

A typical inflammatory response consists of 4 principal components:(1) Inducers: produced by tissue damage or bacterial translocation (i.e., leaky gut)/infection(2)Sensors: receptors expressed on immune cells(3)Mediators: cytokines that mediate function of target tissues(4)Target tissues: CNS and other organs

DAMPs=damage-associated molecular patterns; PAMPs=pathogen-associated molecular patterns; ccf nDNA=circulating cell-free nuclear deoxyribonucleic acid; HSP70=heat shock protein 70; ATP=; HMGB1=high mobility group box 1; sCD14=soluble CD14; TLRs=toll-like receptors; MAPK=mitogen-activated protein kinase; NF-κB=nuclear factor- κB; TNF=tumor necrosis factor; α=alpha; R=receptor; IL=interleukin1. Fries et al., Pharmacology, Biochemistry and Behavior 2019; 177:12-19.


Neuroprogression & Staging in Bipolar Illness

Biological FindingsPro-Inflammatory cytokinesAnti-Inflammatory cytokinesNeurotrophinsOxidative StressLateral & 3rd ventricles

Clinical FindingsEpisode densityEpisode severityCognitive performanceAutonomySuicidality

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1. Muneer Clinical Psychopharmacology and Neuroscience 2016;14(2):117-130.

Staging

Biological/Clinical Findings

“Neuroprogression”

Mounting Allostatic Load contributes to vicious cycle of ‘wear & tear’ on brain and body


Inflammation & Neurocircuits

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1. Felger Current Neuropharmacology 2018; 16:533-558.

5-HT - serotonin; ACC - anterior cingulate cortex; BH4 - tetrahydrobiopterin; DA - dopamine; Glu - glutamate; NLRP3 - NACHT domain- leucine-rich repeat- and pyrin domain-containing protein 3; I - imaging; IDO – indoleamine 2,3 dioxygenase; MR – magnetic resonance; NE -norepinephrine; NO-nitric oxide; NOS-nitric oxide synthase; NSAIDS-nonsteroidal anti-inflammatory drugs; PFC - prefrontal cortex; PHA – phenylalanine hydroxylase; ROS -reactive oxygen species; TH – tyrosine hydroxylase; Trp – tryptophan.


Inflammation & Cognition

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1. Fourrier et al., CNS Spectrums 2019; 24:4-15.

A wide and redundant range of cognitive impairments are reported in psychiatric disorders, including mood disorders, that strongly impair quality of life and recovery, and suggest a possible contributory role for inflammation


Inflammation & Cognition

21

1. Fourrier et al., CNS Spectrums 2019; 24:4-15.

A wide and redundant range of cognitive impairments are reported in psychiatric disorders, including mood disorders, that strongly impair quality of life and recovery, and suggest a possible contributory role for inflammation


Microbiome, Gut-Brain Axis, & Mood Disorders

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1. Morris et al., Australian & New Zealand Journal of Psychiatry 2018; 52(10) 924–948.

Neuropathology

Pre- & Probiotics?

Neurotransmitter & Modulator

Enteric Nervous System

InflammatoryCytokines

Immune System

Neuroanatomical Pathwayof

Gut-Brain Axis

HPA Axis Intestinal Mucosal Barrier& Blood Brain Barrier

Microbiota &Microbial

Metabolites

Zonulin?


Bipolar Disorder, a multi-system inflammatory disorder?

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1. Leboyer et al., Journal of Affective Disorders 2012; 141:1–10.

Sleep & Circadian Dysfunction

AutoimmuneDisorder

Stress Retrovirus

Genetic RiskFactors

EnvironmentalRisk Factors

Brain & Peripheral Immuno-Inflammation

OxidativeStress

ApoptosisCell Damage

Bipolar Disorder

Cerebrovascular Disease

Cardiovascular Disease

Obesity

DiabetesHypertension


Potential Anti-Inflammatory Treatment Approaches


Pharmacologic Anti-Inflammatory Treatments

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)• Most frequently investigated type of anti-inflammatory drug in clinical trials2

• Meta-analysis of 14 clinical trials suggested that NSAIDs in general promote improved antidepressant effects compared to placebo2

• Efficacy data of NSAIDs for specific depressive symptoms is lacking, despite evidence for symptom efficacy in other mental illnesses2

Selective COX-2 Inhibitors Thought to have larger anti-inflammatory and anti-depressant effects than other

NSAIDs2

Efficacy observed in symptoms of MDD and bipolar disorder1

Non-selective COX Inhibitors Readily available and inexpensive2

No randomized controlled trials as adjunctive treatments2

Monotherapy trials have shown mixed results2

Two trials observed the attenuation of antidepressant effects of SSRIs1

A retrospective chart analysis of 5,145 patients showed a statistically significant reduction in the relative risk of clinical deterioration in patients with bipolar disorder on a low-dose non-selective COX inhibitor and a mood stabilizer3

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1. Najjar S et al. J Neuroinflammation. 2013;10:43. 2. Kohler O et al., Curr Neuropharm, 2016; 14:732-742. 3. Rosenblat JD et al., Bipolar Dis. 2016; 18: 89-101.



Cytokine Inhibitors• Cytokine inhibitors have direct anti-inflammatory effects1

• Four monotherapy trials have shown borderline significance towards a better anti-depressant effect than placebo1

• Anti-TNF drugs are the most commonly studied anti-cytokine treatments2

– As a group, anti-TNF therapies show a statistically significant anti-depressant effect– There is some evidence to suggest that the antidepressant effect of these treatments

increases with depression severity May not efficiently enter brain, but efficacy may be mediated by targeting peripheral

inflammation3

Tetracycline Antibiotics Readily cross into the brain from periphery1

Can potentially exert anti-depressant effects through neuroprotective activity, including increased neurogenesis and antioxidation, anti-glutamate excitotoxicity, and down-regulation of pro-inflammatory agents1

Significant improvement in depressive and bipolar symptoms observed in small trials.1,4

Ongoing clinical trials1

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1. Kohler O et al., Curr Neuropharm, 2016. 2. Kappleman N et al., Mol Psych; 2018; 23:335–343. 3. Haroon E et al. Neuropsychopharmacology. 2012;37(1):137-62. 4. Savitz JB et al., Trans Psych. 2018;8-27.



Other Treatments:• N-acetyl cysteine• Coenzyme Q10• Steroids• Neurosteroids• Melatonin• Polyunsaturated Fatty Acids• Vitamin D• Thiazolidinedione-type Anti-Diabetic

27

1. Najjar S et al. J Neuroinflammation. 2013;10:43. 2. Wager-Smith K, Markou A. Neurosci Biobehav Rev. 2011; 35(3):742-64. 3. Berk M et al. Neurosci Biobehav Rev. 2011; 35(3):804-17. 4. Kohler O et al., JAMA Psych 2014; 71(12):1381-1391. 5. Savitz JB et al. Trans Psych 2018; 8(27) 1-11.


Anti-inflammatory Treatment Timing and Duration

• Need to weigh risk/benefit of exposure to anti-inflammatory agents due to incidence of side effects with prolonged use

• Timing and duration of treatment has not been extensively studied

• Current studies suggest that limited use during the acute phase of the mood episode is sufficient to confer efficacy and minimize risk of side effects

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1. Kohler et al., Curr Neuropharm. 2016; 14:732-742.


Non-pharmacologic Anti-Inflammatory Interventions1-12

Caloric Restriction/Intermittent Fasting Cognitive Behavioral Therapy Enhanced Nutrition Exercise Increased Socialization Meditation/Mindfulness Phytoncides Probiotics/Prebiotics/Synbiotics Sleep

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1. Gonzalez et al., Oral Dis. 2012; 18(1): 16–31.2. Lopresti Australian & New Zealand Journal of Psychiatry, 2017; 51(6) 565–582.3. Casas et al. Endocrine, Metabolic & Immune Disorders - Drug Targets. 2014; 14:245-25.4. Woods et al., Aging and Disease. 2012; ( 3):1:131-140.5. Kennedy et al., Journal of Alzheimer’s Disease 2017; 55:1–18.

6. Lacey et al., Psychoneuroendocrinology 2014; 50, 85-94.7. Yang et al., Soc Sci Med. 2014; 107: 124–135.8. Kok et al., Psychological Science 2013;24(7) 1123–1132.9. Rosenkranz et al., Psychoneuroendocrinology. 2016; 68: 117–125.10. Plaza-Diaz et al., Nutrients 2017; 9, 55.11. Irwin et al., Biol Psychiatry. 2016; 1; 80(1): 40–52.12. Kuo Front Psych 2015; 6 (1093): 1-8.


Summary: Neurobiology & Inflammation Across Psychiatric Disorders

ELA = early-life-adversity.

1. Maletic V & Raison CL. Front Psych 2014. 5 (98)1-24.

Neuropsychiatric Symptoms♦ Emotional♦ Cognitive♦ Behavioral♦ Physical

Systemic Manifestations

“Network” Level: Dysregulation of Neural Circuitry♦ Functional Changes♦ Structural Changes

Neuroendocrine, Autonomic, and

Immune Dysregulation

Cellular and Subcellular Level Impact on:

♦ Intracellular Signaling♦ Gene Transcription♦ Neurotrophic Support

Epigenome

Epigenetic Modulation

Genetic Epistasis

ELA

Stress

Etiology Pathophysiology Clinical Presentation

D E V E L O P M E N T


Questions?

Thank You!!

© 2019 Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, MD Lundbeck, LLC.


Psychoneuroimmunology: Mood Disorders

Part 2 in PNI Series

September 2019 MRC2.PSY.D.00061

Psychoneuroimmunology: Mood Disorders

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