Inflammation & Depression-Hunter

Question 1

What are the arguments in favor of the relationship b/w inflammation & depression?

Answer 1

• *1/3 people w/ depression have higher levels of inflammatory markers. CRP & cytokines: TNFalpha, IL-1, IL-6
• *level of inflammation mild compared to autoimmune or infectious, but similar to cardiovascular disease, stroke, diabetes
• *CRP & IL-1beta serve as biomarkers for risk & prognostic indicators of inflammation

Question 2

What are the weaknesses of this argument?

Answer 2

• *can’t intimately link depression & inflammation. Plenty of patients with depression prob don’t show inflammation.
• *mainly a genetic & environmental issues
• *other mental illnesses, like schizophrenia also show inflammation, not specific for depression

Question 3

Give another argument in favor.

Answer 3

• *depression occurs 5-10X higher rate in those with known inflammatory diseases
• *peripheral inflammation: psoriasis, RA, IBD
• *CNS inflammation: MS

Question 4

How do you use this in clinical practice?

Answer 4

Patient with MS seems depressed. They have higher risks of depression & suicide. Consider SSRI & psychotherapy.

Question 5

Another pro argument related to cytokine storm.

Answer 5

Chronic Hep C treated with IFNalpha & IL-2. Can create a cytokine storm. More prone to depression (30%).

Question 6

Describe how anti-inflammatory treatments have been associated with antidepressant effects.

Answer 6

• *Crohn’s disease received relief from depression w/ treatment with infliximab (anti TNF alpha).
• *55% of patients with psoriasis & depression treated with etanercept (TNFa receptor) effect equivalent to using antidepressants.

Question 7

Use anti-inflammatory w/ antidepressant?

Answer 7

perhaps

celecoxib (COX 2 inhibitor) added to SNRI improve depressive symptoms

Question 8

What happens to inflammation when you take anti-depressants?

Answer 8

people who had taken antidepressants had decreased levels of IL-1beta & IL-6
perhaps these antidepressants block the effect of inflammatory cytokines in the brain

Question 9

What are the conclusions of all this?

Answer 9

inflammation could be a precipitating or perpetuating factor for depression in those that are genetically susceptible.
could use inflammatory mediators as biomarkers to determine treatment plan
anti-inflammatory drugs may be helpful in treatment.

Question 10

Are there cytokines in the brain?

Answer 10

yes, produced in the brain by neurons, microglia, and astrocytes. These cells also have cytokine receptors.
Additionally, peripheral cytokines can signal brain.

Question 11

What are the 4 mechanisms by which peripheral cytokines signal the brain?

Answer 11

1. neural pathway
2. humoral pathway
3. cytokine transporters
4. secretion of secondary messengers

Question 12

What is the neural pathway for peripheral cytokines?

Answer 12

peripheral cytokines trigger sensory afferents of cranial nerves (vagal, glossopharyngeal).
they transmit signals to the brain.

Question 13

What is the humoral pathway for peripheral cytokines?

Answer 13

volume diffusion of cytokines thru leaky circumventricular organs, lie outside of BBB

Question 14

What is the pathway for cytokine transporters to get peripheral cytokines into the brain?

Answer 14

saturable cytokine transporters in the BBB

Question 15

What is the secondary messenger pathway to get peripheral cytokines to affect the brain?

Answer 15

cells of the BBB respond to peripheral cytokines by secreting secondary messengers (PGE2 & NO)
Remember: PGE2 causes fever!

Question 16

Why are cytokines implicated in depression?

Answer 16

b/c they affect the production, metabolism & reuptake of monoamine neurotransmitters
they also reduce BDNF which lessens neural plasticity

Question 17

What is the relationship b/w cytokines & cortisol?

Answer 17

with the release of cytokines you sometimes get CRH & cortisol release. This is anti-inflammatory & can combat negative effects of cytokines.
Sometimes people have glucocorticoid resistance, however, and the inflammatory cytokines get outta control!

Question 18

Explain how infection or tissue damage could theoretically lead to depression.

Answer 18

Damage sensed by PAMPs & DAMPs binding to pattern recognition receptors. 
This stimulates NFkappaB.
Proinflammatory cytokines are released. 
Affect the brain.
Exert their effects.

Question 19

Explain how stress could cause depression.

Answer 19

activate sympathetic neurons & inhibit parasympathetic neurons.
symp neurons synapse on macrophages & release NE. Stimulates NFKB.
Proinflammatory cytokines released.
Get into the brain.
Exert their effects.

Question 20

What’s the deal with glucocorticoid resistance?

Answer 20

activation of mitogen activated protein kinase pathways inhibits the function of glucocorticoid receptors
no negative feedback.
no opposition to pro-inflammatory pathway
perhaps more susceptibility to depression from inflammation.

Question 21

T/F 1/3 people have non-homeostatic responses to inflammation. Inflammatory stimulus-depressive symptoms.

Answer 21

True.