Inflammation in Depression

Question 1

What is inflammation?

Answer 1

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

Question 2

What is innate immunity?

Answer 2

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

Question 3

What is immune “privilege”?

Answer 3

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

Question 4

What are the immune cells of the CNS?

Answer 4

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

Question 5

What are microglia?

Answer 5

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

Question 6

How are microglia versatile and multifunctional?

Answer 6

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

Question 7

How do microglia retain a history of activation?

Answer 7

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

Question 8

What are astrocytes?

Answer 8

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

Question 9

What is the historical relationship between inflammation and psychiatric diseases?

Answer 9

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

Question 10

What is the relationship between inflammation in depression?

Answer 10

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

Question 11

What is the relationship between inflammation and comorbid/secondary depression?

Answer 11

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

Question 12

What is the clinical evidence for the relationship between inflammation and depression?

Answer 12

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

Question 13

What is the cytokine hypothesis of depression?

Answer 13

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

Question 14

What is sterile inflammation in clinical populations and how does it relate to depression?

Answer 14

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

Question 15

What is sickness behavior?

Answer 15

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

Question 16

What is immune communication with the CNS?

Answer 16

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

Question 17

What is the monoamine hypothesis model of depression?

Answer 17

depression results from a specific deficit in the monoamine neurotransmitters e.g. 5-HT, norepinephrine, and/or dopamine

Question 18

What is the HPA axis hypothesis model of depression?

Answer 18

depression results from elevated cortisol due to dysregulation of the HPA axis

Question 19

What is the neurogenesis hypothesis model of depression?

Answer 19

depression results from impaired neurogenesis in the adult brain

Question 20

What are the strengths of the HPA axis hypothesis model of depression?

Answer 20

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

Question 21

What are the limitations of the HPA axis hypothesis model of depression?

Answer 21

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

Question 22

What is the monoamine hypothesis based on?

Answer 22

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

Question 23

What are the strengths of the monoamine hypothesis?

Answer 23

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

Question 24

What are the limitations of the monoamine hypothesis?

Answer 24

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

Question 25

What is the relationship between inflammation and monoamines?

Answer 25

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

Question 26

What is the neurogenesis hypothesis?

Answer 26

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

Question 27

What are the limitations of the neurogenesis hypothesis?

Answer 27

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

Question 28

What is the relationship between inflammation and the neurogenesis hypothesis?

Answer 28

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

Question 29

What are microglial roles in depression?

Answer 29

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

Question 30

What are the anti-inflammatory effects on depression?

Answer 30

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

Question 31

What are the clinical observations of the anti-inflammatory effects on depression?

Answer 31

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

Question 32

What are the limitations of the anti-inflammatory effects on depression?

Answer 32

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