Inflammation & Depression-Hunter Flashcards
What are the arguments in favor of the relationship b/w inflammation & depression?
- *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
What are the weaknesses of this argument?
- *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
Give another argument in favor.
- *depression occurs 5-10X higher rate in those with known inflammatory diseases
- *peripheral inflammation: psoriasis, RA, IBD
- *CNS inflammation: MS
How do you use this in clinical practice?
Patient with MS seems depressed. They have higher risks of depression & suicide. Consider SSRI & psychotherapy.
Another pro argument related to cytokine storm.
Chronic Hep C treated with IFNalpha & IL-2. Can create a cytokine storm. More prone to depression (30%).
Describe how anti-inflammatory treatments have been associated with antidepressant effects.
- *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.
Use anti-inflammatory w/ antidepressant?
perhaps
celecoxib (COX 2 inhibitor) added to SNRI improve depressive symptoms
What happens to inflammation when you take anti-depressants?
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
What are the conclusions of all this?
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.
Are there cytokines in the brain?
yes, produced in the brain by neurons, microglia, and astrocytes. These cells also have cytokine receptors.
Additionally, peripheral cytokines can signal brain.
What are the 4 mechanisms by which peripheral cytokines signal the brain?
- neural pathway
- humoral pathway
- cytokine transporters
- secretion of secondary messengers
What is the neural pathway for peripheral cytokines?
peripheral cytokines trigger sensory afferents of cranial nerves (vagal, glossopharyngeal).
they transmit signals to the brain.
What is the humoral pathway for peripheral cytokines?
volume diffusion of cytokines thru leaky circumventricular organs, lie outside of BBB
What is the pathway for cytokine transporters to get peripheral cytokines into the brain?
saturable cytokine transporters in the BBB
What is the secondary messenger pathway to get peripheral cytokines to affect the brain?
cells of the BBB respond to peripheral cytokines by secreting secondary messengers (PGE2 & NO)
Remember: PGE2 causes fever!
Why are cytokines implicated in depression?
b/c they affect the production, metabolism & reuptake of monoamine neurotransmitters
they also reduce BDNF which lessens neural plasticity
What is the relationship b/w cytokines & cortisol?
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!
Explain how infection or tissue damage could theoretically lead to depression.
Damage sensed by PAMPs & DAMPs binding to pattern recognition receptors. This stimulates NFkappaB. Proinflammatory cytokines are released. Affect the brain. Exert their effects.
Explain how stress could cause depression.
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.
What’s the deal with glucocorticoid resistance?
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.
T/F 1/3 people have non-homeostatic responses to inflammation. Inflammatory stimulus-depressive symptoms.
True.
