Inflammation and depression - Hunter Flashcards
What was the macrophage theory of depression postulated by Smith et al?
- depression is caused by inflammation and the acute phase response including activity of TNF-a, IL-1B and IL-6
- cytokines gain access to the brain and cause hyperactivity of the hypothalamic-pituitary-adrenal axis, disturbed serotonin metabolism and neurovegative symptoms
What are neurovegative symptoms?
- sleep disturbances
- decreased appetite
- decreases energy
What evidence did the psychiatric community want to see before embracing the macrophage theory of depression?
- evidence that the stimulation of inflammation increases the risk for depression
- evidence that attenuation of inflammation decreases the rate of depression
- a biological link between cytokines and depression
More recently, some research has argued in favor of the inflammation-depression link. Describe the findings.
- approx. 1/3 of people with depression have higher levels of inflammatory markers in their sera compared with non-depressed
- these increases are more modest than in autoimmune or infectious diseases, but similar to levels documented in other diseases where inflammation if implicated - such as cardiovascular disease, stroke and diabetes
- the most replicated finding pertain to raised CRP and IL-1B confirmed by 2 recent meta-analyses. These cytokines may serve as biomarkers for risk or prognostic indicators
What inflammatory markers have been found to be higher in depressed people?
- C-reactive protein
- TNF-a
- IL-1B
- il-6
What is a weakness in the argument that inflammation causes depression?
- inflammation is neither necessary nor sufficient to be the SOLE cause of depression
- the data support inflammation as a feature of depression in a subset of patients. There is considerable evidence for genetic and environmental susceptibility factors for depression
- immune/inflammatory disruption has been found in a number of other neuropsychiatric conditions, including schizophrenia, so its not specific for depression.
Describe the findings associated with the link between those with known inflammatory disease and depression.
- depression occurs at a 5-10 times higher rate in those with known inflammatory diseases
- the association (15% rate of depression) is seen in peripheral inflammation, in diseases such as psoriasis, RA, and IBD.
- depression is also common in diseases of the CNS such as MS, with a lifetime prevalence of around 50% and rates of suicide up to 15%.
- however, even cancer, stroke, CAD, and epilepsy patients (non-inflammatory etiopathology) are at risk for depression
Describe the link between patients treated with inflammatory cytokines and depression.
- patients treated with inflammatory cytokines have a high rate of depression
- IFN-a and IL-2 are used as immunotherapy in chronic hepatitis C and cancer (they create a cytokine storm)
- those who undergo this treatment are more prone to develop depression
- a recent meta-analysis found that the prevalence of IFN-a induced depression in Hep. C patients was 30%
Describe the link between anti-inflammatory treatments and antidepressant effects.
- it has been found that people with Crohn’s disease and depression had significant remission from depression after treatment with infliximab (a anti-TNF-a antibody)
- 55% of patients with psoriasis and depression who were treated with etancercept (a soluble TNF-a receptor) showed improved Beck’s depression inventory scores, with an effect size comparable with antidepressants (improved independent of improvement in psoriasis).
- it has been shown that celecoxib (COX-2 inhibitor) added to reboxetine (selective NE reuptake inhibitor) improved depressive symptoms more than reboxetine alone.
Describe the link between treatment with anti-depressants, inflammatory mediators and depression.
- treatment with anti-depressants causes decreased inflammatory mediators in those with depression
- a meta-analysis found that IL-1B and IL-6 levels (but not TNF-a) decreases in response to therapy, along with a deduction in depressive symptoms
- the response was found to be specific for SSRI’s
- the findings propose the possibility that inflammatory cytokines contribute to depressive symptoms and that antidepressants block the effect of inflammatory cytokines in the brain
What are the main conclusions regarding the humans studies that have been done on depression and inflammation?
- data suggests that inflammation is associated with depression
- inflammation may play a role only in a subset of genetically susceptible individuals
- inflammation may not only act a s a precipitating factor that pushes a person into depression, but also as a perpetuation factor that may pose an obstacle to recovery
- inflammatory mediators may be potential biomarkers, aiding diagnosis or even helping to predict prognosis
- treatment with anti-inflammatory drugs has promise in some patients with depression
Describe the association between cytokines and cytokine receptors in the brain.
- cytokines are produced in the brain and extort an effect there
- cytokines are produced by neurons, microglia, and astrocytes
- these same cell types have numerous cytokine receptors
- peripheral cytokines can signal the brain through at least four mechanisms
Describe the neural pathway of cytokine signaling to the brain.
Cytokines produced in the periphery trigger sensory afferents of cranial nerves (vagus glossopharyngeal nerves) that transmit signals to the brain.
Describe one humoral pathway of cytokine signaling to the brain.
Cytokines diffuse from ‘leaky’ circumventricular organs outside the BBB into the brain.
Describe another humoral pathway of cytokine signaling to the brain.
Cytokines get into the brain via saturable cytokine transporters in the BBB.
