Inflammation and depression

The immune system and inflammation in particular play a key role  in psychiatric disorders such as bipolar disorder, anxiety disorders, personality disorders, schizophrenia and depression.

Inflammation is thought to start in the periphery and spread to the brain. This allows us to use peripheral markers of inflammation in the blood stream such as CRP, ESR, TNF, IL-1β and IL-6. Having measured these we can then use a treatment to see which inflammatory marker predicts response to which treatment. 

Not only is there considerable variability within the depressed population but we do not know the percentage of patients in whom inflammation plays a role. It is felt that inflammation is not the prime cause of depression but that it can have a compounding effect. 

Not all of these markers are readily available in clinics and hospitals but if proven to be desirable they could be made available. 

It is recognised that different areas of the brain can become inflamed possibly reflecting genetic variations causing different symptoms and generating the various diagnoses including bipolar disorder, anxiety disorders, personality disorders, schizophrenia and depression. It is not known whether the inflammation has started in the brain or started in the periphery and spread to the brain. 

Positron emission tomography (PET scanning) has been used in depressed patients to identify activated microglia reflected by upregulation of the translocator protein (TSPO). 1 It is not yet clear whether these are activated in response to normal regulatory  and protective work or activated by inflammation. This means that PET is not ready to be used in regular clinical practice for the diagnosis or management of depression. 

Greater inflammatory responses to stress as reflected by salivary concentrations of soluble TNF receptor 2 have also been correlated with activation of threat assessment circuits in the brain involving the dorsal anterior cingulate cortex (dACC) and insula. 2 This latter effect of inflammation on threat and fear-related neurocircuitry may explain the emerging literature on the association of inflammatory markers with suicidal ideation and suicide attempts. 3 Indeed, threat sensitivity has been shown to independently predict suicide risk, and data suggest that increased inflammatory markers may be preferentially associated with depressed patients who have attempted suicide. 3,4 

Stress can trigger release of monocytes from the bone marrow which interact with danger or gut produced microbial products which can increase TNF which has been shown to activate microglia in the amygdala which is involved in regulating fear and anxiety.5 

Cortical brain regions associated with arousal, anxiety, and alarm 6-8  are influenced by inflammation.

 

The challenge. 

We need a simple biomarker that will tell us if our brain is inflamed. Using this we can then measure how much improvement is due to stem cells reducing inflammation in the brain, and how much improvement is due to pain reduction with improved sleep and less stress.

We have recently been successful at finding biomarkers of genetic activity that will predict whether patients will respond to their own stem cells or not. We believe that we can use this same technology to identify a group of biomarkers that will diagnose brain inflammation in the various subgroups that are currently being diagnosed with these psychiatric disorders. 

 

1. Setiawan E, Wilson AA, Mizrahi R, et al. Role of translocator protein density, a marker of neuroinflammation, in the brain during major depressive episodes. JAMA Psychiatry. 2015;72:268-275.

2. Slavich GM, Way BM, Eisenberger NI, et al. Neural sensitivity to social rejection is associated with inflammatory responses to social stress. Proc Natl Acad Sci USA. 2010;107:14817-14822.

3. Brundin L, Bryleva EY, Thirtamara Rajamani K. Role of inflammation in suicide: from mechanisms to treatment. Neuropsychopharmacol. 2017;42:271-283.

4. Venables NC, Sellbom M, Sourander A, et al. Separate and interactive contributions of weak inhibitory control and threat sensitivity to prediction of suicide risk. Psychiatry Res. 2015;226:461-466.

5. McKim DB, Weber MD, Niraula A, et al. Microglial recruitment of IL-1beta-producing monocytes to brain endothelium causes stress-induced anxiety. Mol Psychiatry. April 4, 2017; Epub ahead of print.

6. Capuron L, Pagnoni G, Drake DF, et al. Dopaminergic mechanisms of reduced basal ganglia responses to hedonic reward during interferon alfa administration. Arch Gen Psychiatry. 2012;69:1044-1053.

7. Eisenberger NI, Berkman ET, Inagaki TK, et al. Inflammation-induced anhedonia: endotoxin reduces ventral striatum responses to reward. Biol Psychiatry. 2010;68:748-754.

8. Harrison NA, Voon V, Cercignani M, et al. A neurocomputational account of how inflammation enhances sensitivity to punishments versus rewards. Biol Psychiatry. 2016;80:73-81.

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