Mental illness and inflammation Flashcards
Evidence linking depression to inflammation
Bonnacorso 2002 - Treatment of Hep C patients with interferon alpha increases risk of depression. It was later found that one in four patients treated with IFN gets depression, and prophylactic treatment with antidepressants reduces this risk. IFN treatment increases cytokines.
Pace et al 2006 - increased stress-induced inflammatory response in men with major depression (mononuclear blood cell pathways activated by lab stress such as giving a speech)
Maes et al 2001 - the post-partum inflammatory response is amplified in women who’ve had previous depression, suggesting depression sensitises immune system
Maes et al 1995 - increased blood IL-6 in MDD
Miller et al 2011 - increased blood IL-6, IFNgamma and TNF alpha. Decreased IL-10.
Ramirez et al 2015 - imipramine blocks social avoidance behaviour and decreases microglia IL-6 in rats exposed to stress
Carvalho et al 2013 - antidepressant resistance is associated with immune activation
Kohler et al 2014 - meta-analysis showing NSAIDs, alone or as an adjunct to antidepressants, may be effective at treating depression
Evidence linking psychosis to inflammation
Drexhage et al 2010 - innate immune system and T cell activation in schizophrenia and bipolar disorder
Miller et al 2012 REVIEW - prenatal immune activation or inflammation increases risk of schizophrenia.
Increased IL-2, 6 and 8 in schizophrenic patients’ serum and IL-1B in CSF
Jian et al - GWAS has shown MHC markers associated with schizophrenia. Interestingly, some in non-coding region!
Khandaker 2014 - people with atopic disorders more likely to have experienced psychosis
Increased Chlamydophila in frontal lobes found on post-mortem. These bacteria reside in microglia and hence may disturb signalling.
Herpes Simplex encephalitis can present as psychosis
Benros et al 2011 - 30-year study found autoimmune diseases and severe infections were risk factors for schizophrenia. Risk of schizophrenia in autoimmune disease patients increased linearly with episodes of severe infection
Autoimmune encephalitis.
Towards a mechanism
Khandaker et al 2014 - influenza in 1st and 2nd trimester and toxoplasmosis in 3rd trimester increase risk of psychosis in offspring. Increased maternal TNFalpha (Buka) and IL-8 (Brown) and CRP (Canetta)
Increased IL-6 at 9 years predicts depression and psychosis at 18, and persistent symptoms between 12 and 19 years. Avon Longitudinal Study of Parents and Children n=5000.
In animals, injection of IL-6 or LPS induces schizophrenia-related phenotypes
Cytokines can diffuse across the BBB, so tell brain about peripheral inflammation, by activating microglia
Dysbiosis
Disrupted microbiome is found in schizophrenia. It increases gut permeability, as indicated by markers like CD14, which reports bacterial translocation. This causes repetitive low-level inflammatory response, which causes production of autoantibodies.
Borre 2015 - normal gut microbiota are required for normal brain development.
O’neill et al 2016 - found a weak association between C-section birth and psychosis
Shaw 2010 - increased Clostridium metabolite in urine of schizophrenic patients. Clostridium is characteristic of gut microbiome from C-section.
So maybe the gut microbiome is establised pre- and perinatally, is persistent, and communicates with the brain in its development and later, to activate microglia and cause schizophrenia?
Toxoplasmosis has been linked to schizophrenia, and decreases gut microbiota diversity.
Olanzapine (atypical antipsychotic) decreases gut biodiversity in the rat, more in female than in male. Metabolic side-effects of antipsychotics are more common in women than men. Antibiotics can reverse these metabolic side-effects. So maybe they’re mediated by gut flora alterations.
Autoimmunity
Up to 50% of autoimmune disorder patients show depression-like symptoms
Benros et al 2013 - depression risk correlates linearly with number of hospital contacts with infections in autoimmune disorder patients
Benros et al 2011 - 30-year study found autoimmune diseases and severe infections were risk factors for schizophrenia. Risk of schizophrenia in autoimmune disease patients increased linearly with episodes of severe infection
Autoimmune encephalitis.
Schizophrenic patients have threefold to fourfold higher anti-gliadine autoantibodies, have more antibodies against hypothalamus and hippocampus, and are three times more likely to have high levels of anti-NMDAR. This links with glutamate hypothesis of schizophrenia.
Microglia hypothesis
Bilbo and Schwartz - microglia hypothesis - prenatal infection leaves microglia in permanent activated/primed state, then adult challenge causes exaggerated response and perhaps neuronal apoptosis.
Steiner et al 2006 - elevated microglial density in anterior cingulate cortex and mediodorsal thalamus of schizophrenic patients who committed suicide during a psychotic episode
Investigating causality
Khandaker et al 2017 - Using ALSPAC cohort again, looked at the minor allele of IL-6R, which is anti-inflammatory. If inflammation is involved, then a downstream regulator should also be associated with the illness. Found that having A/C genotype increased serum IL-6 a bit, C/C some more. A/C genotype had no effect on serum CRP, but C/C genotype decreased it a lot.
A/C genotype has the lowest risk of psychotic disorder, A/A had the highest risk of depression. C/C had the lowest risk of depression and the lowest risk of psychosis. So having two copies of the minor allele is protective.
IL-6R minor allele was not associated with any of the common risk factors for inflammation, depression or psychosis.
Kappelman et al 2011 - anti-cytokine drugs (e.g. for rheumatoid arthritis) improve depression symptoms. Anti-depressant effect is not correlated with improvement in physical symptoms though.
