Inflammation in Depression Flashcards
What is inflammation?
inflammation is a normal component of immune function
inflammation results from disruption of homeostasis due to infection, damage, or stress
promotes tissue healing and recovery of homeostasis
characteristic redness, swelling (edema), warmth, pain sensitization
What is innate immunity?
innate immune system recognizes pathogen- and damage-associated patterns
innate immune cells release factors that initiate inflammatory cascades
nitric oxide and reactive oxygen species - toxic “respiratory burst” to injure pathogens, signal immune response
prostaglandins and thromboxanes - local inflammation (vasodilation and pain stimulation)
cytokines (tumor necrosis factor (TNF), interleukins (IL)) - systematic inflammatory response
chemokines (monocyte chemotaxis protein (MCP-1)) - recruit cells of the adaptive immune system
What is immune “privilege”?
the CNS is isolated from the systemic immune system by the blood-brain barrier
endothelial cells in the vasculature form tight junctions
astrocyte end-feet form a second layer on the parenchymal surface of vessels
innate immunity in the CNS is provided by glial cells: microglia, astrocytes
What are the immune cells of the CNS?
glial cells comprise 50% of the cells in the brain
long held (simple) view that glia provide structure and support to the neurons: regulate homeostasis, regulate synaptic plasticity, regulate neurogenesis, guide and regulate development, regulate activity-dependent refinement
microglia and astrocytes comprise the innate immune system of the CNS
What are microglia?
primary immune cells
derived from early embryonic hematopoietic progenitors
surveillance of the CNS - sample the entire volume every ~2 hours
express pattern recognition receptors
mount the foreign body response to pathogens or damage
How are microglia versatile and multifunctional?
traditional roles as immune cells of the CNS
increasing identification of developmental roles
unique new proposed functions in synaptic plasticity, adult neurogenesis, circuit refinement, cell survival, etc
How do microglia retain a history of activation?
microglia retain a “history” of activation that can modify future responses to disturbance of homeostasis, and have been implicated in numerous neurogenerative disorders
once the microglia cell is activated, the cause of activation is unresolved so it stays primed and becomes hyper-activated
What are astrocytes?
define the blood brain barrier: regulate intake of nutrients and oxygen
regulate blood flow in the brain
form extensive signaling networks: coupled with electrical synapses - gap junctions
regulate synaptic functions and contribute to plasticity: glutamate and GABA recycling
astrocytes are activated secondarily to microglia and can function as antigen-presenting cells
What is the historical relationship between inflammation and psychiatric diseases?
the relationship between mental health and inflammation was first postulated by Wagner-Jauregg from 1887
extensively studied dementia paralytica, a psychosis resulting from neurosyphilis infection
inflammation as an etiologic factor in psychiatric disorders largely forgotten with the invention of neuroleptics, TCA and MAOI antidepressants
What is the relationship between inflammation in depression?
some early evidence comes from high rates of depression in medical illness
depression is the most common morbidity after ischemic stroke
depression is the most common psychiatric comorbidity of medical illness: elevated rates among patients with coronary heart disease, chronic pain, cancer, diabetes
elevated rates with chronic inflammatory diseases: autoimmune, inflammatory bowel disease, rheumatoid arthritis, asthma, allergies
What is the relationship between inflammation and comorbid/secondary depression?
much debate over phenomenology of psychiatric comorbidities: “feeling bad” about having chronic illness
depression severity does not correlate with expected outcome: positive prognosis does not relieve patients depression
depression is increased in relatively benign inflammatory diseases: allergies, asthma can have relatively low impact
What is the clinical evidence for the relationship between inflammation and depression?
evidence for inflammation has been measured in depressed patients using biomarkers (blood or CSF)
biomarkers are significantly increased in depression: strongest effects seen with CRP, TNFalpha, and IL-6
biomarkers correlate with severity of depression: suggested as a state marker for depressive episodes, some studies show decreased biomarkers with antidepressant treatment
What is the cytokine hypothesis of depression?
the contribution of inflammation to depression has been distilled down to the effects of acute or chronic cytokine elevation
acute elevation of cytokines proposed to cause depression in medical illness
chronic elevation of cytokines proposed to have a causal role in depressive disorders
the cytokine hypothesis integrates preceding hypotheses of mood disorders
a prediction of the hypothesis is that inducing a pro-inflammatory state in healthy controls would lead to mood symptoms
What is sterile inflammation in clinical populations and how does it relate to depression?
treatment for hepatitis C virus (HCV) includes immune booting treatments
HCV is treated with interferon-alpha (IFN-alpha): this treatment is associated with development of depressive symptoms
cancer patients receiving immune boosters develop depressive symptoms
observations of immune therapeutics allows investigation into immune activation in healthy controls: chronic disease remains a confound in both HCV and cancer treatments
sterile inflammation is induced in healthy subjects using cytokines or pathogen-derived molecules
What is sickness behavior?
set of depressive behaviors develop on induction of sterile inflammation
depressed mood, anhedonia, social withdrawal, anxiety, appetite changes, fatigue, sleep disturbance, decreased cognitive functions
sickness behaviors correlate with induction of IL-6 and TNFalpha
proposed to be an adaptive phenotype to prioritize recovery from infection: suggest depression is a maladaptive expression of sickness behavior
What is immune communication with the CNS?
peripheral cytokines interact with the CNS through a number of routes
act directly on the brain regions with porous BBB (hypothalamus, brainstem nuclei)
signal through vagus nerve or through indirect mechanisms (physiological)
significant convergent effects on the HPA axis
What is the monoamine hypothesis model of depression?
depression results from a specific deficit in the monoamine neurotransmitters e.g. 5-HT, norepinephrine, and/or dopamine
What is the HPA axis hypothesis model of depression?
depression results from elevated cortisol due to dysregulation of the HPA axis
What is the neurogenesis hypothesis model of depression?
depression results from impaired neurogenesis in the adult brain
What are the strengths of the HPA axis hypothesis model of depression?
HPA axis is plastic to known risks: early childhood trauma, chronic stress
polymorphisms associated with HPA function predict response to antidepressants
HPA axis function is normalized by antidepressant treatment
What are the limitations of the HPA axis hypothesis model of depression?
significant proportion of patients have normal HPA function: ~50% exhibit elevated cortisol
cortisol is not a reliable state marker of depression: changes in cortisol often do not correlate with symptom severity
What is the monoamine hypothesis based on?
based on the observation that drugs affecting monoamine levels are anti-depressant: specific emphasis on 5-HT and norepinephrine
key hypothesis driving pharmaceutical development
MAOI - inhibit monoamine metabolism
TCA - inhibit monoamine reuptake
SSRI & SNRI - selective inhibitors of 5-HT and/or NE reuptake
What are the strengths of the monoamine hypothesis?
deficits in 5-HT systems are observed in depression
acute tryptophan depletion induces rapid, transient depression in healthy volunteers: tryptophan depletion causes 5-Ht depletion
monoaminergic systems are involved in many aspects of mood: extensive involvement in the limbic system
What are the limitations of the monoamine hypothesis?
time discrepancy between monoamine and therapeutic effects: monoamine normalize within hours-days, mood effects are seen in 2-3 weeks
some drugs that decrease monoamines are effective antidepressants
cocaine and amphetamines - potent monoamine reuptake inhibitors - are not effective antidepressants
What is the relationship between inflammation and monoamines?
peripheral inflammation activates glia
microglia induce expression of indolamine-2, 3-dioxygenase (IDO)
IDO catabolizes tryptophan to the kynurenine pathway
cytokines also induce catabolism of 5-HT to 5-hydroxindoleacetic acid (5-HIAA)
cumulative result is 5-HT depletion
cytokines increase trafficking of 5-HT transporters
increased rate of 5-HT clearance from synapse
What is the neurogenesis hypothesis?
impaired neurogenesis leads to development of depressive symptoms
stressors capable of triggering depression inhibit neurogenesis in animal models
neurogenesis is stimulated by antidepressant treatment: time required for neurogenesis would explain the therapeutic delay
behavioral responses to antidepressants are diminished by blocking neurogenesis
What are the limitations of the neurogenesis hypothesis?
some regions of the brain highly involved in depression show no signs of adult neurogenesis
especially prefrontal cortex - highly involved in emotional and cognitive changes in depression
neurogenesis is well demonstrated in animal models but haven’t been able to see it in humans
“depressive” behaviors in animal models are at best a proxy
very difficult to examine in the depressed human brain
limits generalizability of results
What is the relationship between inflammation and the neurogenesis hypothesis?
elevated cytokine levels: decrease trophic support to neurons, reduce neurogenesis, increase oxidative stress, disrupt neuron-glia interactions
animal studies show stress or cytokine administration decrease social function: correlates with decreased neurogenesis, administration of an IL-1 receptor antagonist blocks both effects
products of IDO - kynureine and quinolinic acid are gliotoxic and neurotoxic: gliotoxicity reduces astrocyte regulation of glutamate
quinolinic acid is an NMDA receptor agonist: can exacerbate glutamatergic excitotoxicity
What are microglial roles in depression?
pathological stress or peripheral inflammation can activate CNS resident microglia: increased microglial secretion of cytokines
activation of microglia results in excessive synaptic pruning: glial release of cytokines can trigger neuronal apoptosis
glial activation inhibits neurogenesis
collective effects may contribute to pathologic cell death and resultant behavioral/cognitive dysfunction
What are the anti-inflammatory effects on depression?
anti-inflammatory treatments in medical co-morbidities of depression have antidepressant effects
retrospective studies show depressed patients co-administering acetylsalicylic acid (ASA, Aspirin) had higher rates of emission
clinical trials have demonstrated efficacy of celecoxib (selective COX-2 inhibitor) and minocycline (antibiotic with anti-inflammatory effects) as effective adjunctive therapeutics with antidepressant therapy
What are the clinical observations of the anti-inflammatory effects on depression?
circumin, a plant phenol isolated from turmeric is an anti-inflammatory used in complementary medicine
anti-inflammatory and anti-oxidant effects in models of Alzheimer’s, PD. cardiovascular disease
preclinical work shows decreased cytokines, stabilized HPA activity, decreased oxidative stress, and improved mood behaviors in animal models
omega-3 polyunsaturated fatty acid are anti-inflammatory by competition for COX enzymes
What are the limitations of the anti-inflammatory effects on depression?
inflammation not observed in all depressed patients: some show decreased cytokines
monoamine oxidase inhibitors (e.g., phenylzine) are poor anti-inflammatories: some studies show increased cytokine release with phenylzine treatment
much is derived from animal model work: generalizability