Inflammation of Reward Circuits of the Brain and High Inflammatory Marker Levels Linked to Depression

Depression is one of the most common psychiatric disorders and has a prevalence of 5%. There are various causes of depression ranging from devastating or stressful life events to having a genetic predisposition. Researchers from Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta – Dr. J.C. Felger et al. tried to correlate the elevated biomarkers of inflammation with the disease process of depression and came to a conclusion that could alter the entire modality of treatment for depression.

They conducted resting state functional MRI scans in 48 patients with major depression who were not on medication. Whole brain scans revealed that the areas (vmPFC) that were identified corresponded with a region of the brain recently found to be associated with anhedonia in patients with major unipolar depression. The area (vmPFC) is also known to have been activated by rewarding stimuli.

An earlier study was done in persons suffering from persistent anhedonia (even after treatment) and also with high levels of inflammatory markers. There was evidence of an improved response to treatment with anti-inflammatory antibody infliximab.

Studies have shown that hypofunction of monoamine neurotransmitter systems (5-HT & norepinephrine), and abnormal hypothalamo-pituitary-adrenal axis regulation might be a few organic causes for this disease.

Depression may be:

• Reactive/Neurotic/Psychological – It involves an exaggerated response in grief or particular adverse situations.
• Melancholic/Endogenous – It usually occurs in middle or later years of life and people have a greater tendency to commit suicide in this group.

The scans were examined as a function of C-reactive protein (CRP), which is an inflammatory marker, using ventral and dorsal striatum seeds, which are associated with motivation and motor control. There was an increased CRP, which showed a possible association with decreased connectivity between the ventral striatum and the ventromedial prefrontal cortex (vmPFC). These were in turn linked to increased anhedonia, or inability to enjoy pleasurable activities, which is an important symptom of melancholic type of depression according to DSM-IV criteria.

“Anhedonia is a core symptom of depression that is particularly difficult to treat. Some patients taking antidepressants continue to suffer from anhedonia,” says Dr.Felger.

Increased CRP was also shown to have a relation with decreased connectivity between dorsal striatum and vmPFC and dorsal striatum with presupplementary motor area (area in the brain related to motor response – i.e. bodily movements etc). This caused decreased motor speed and psychomotor slowing. It was also associated with increased interleukin – IL-6, which is an inflammatory mediator.

“High levels of the inflammatory marker CRP (C-reactive protein) in patients with depression were linked to a failure in communication between regions of the brain important for motivation and reward, as seen through brain imaging.”

The researchers have come up with potential mechanisms to explain how inflammation causes depression. Their previous primate based study has demonstrated that chronic administration of inflammatory cytokines decreases striatal dopamine release. This in turn causes reduced effort based sucrose consumption, which measures reward sensitivity in monkeys. Similar responses can be mirrored in rats by administering IL-1β. On the other hand decreased motivation has been reported in mice following the administration of lipopolysaccharides. L-DOPA or levodopa (Dopamine precursor) was then given to the monkeys and it showed marked improvement.

The major limitation of the study was the presence of a healthy control group. Yet, Dr. Felger hopes that their data will help reverse anhedonia in depressed patients who do not respond to antidepressants. She is now planning on testing the efficacy of L-DOPA in the treatment of resistant major depression.

“We hope our investigations may lead to new therapies to treat anhedonia in patients with depression and high inflammation,” she says.

In conclusion, the study has provided a new perspective on depression and its treatment. An effort to remove the stigma revolving around mental health issues, and such research to improve existing methods of their management will help the wide majority of depressed people emerge out of their cocoons and seek timely medical assistance.

References:

1. http://news.emory.edu/stories/2015/11/brain_imaging_depression_felger/

2. Davidson’s Principles & Practice of Medicine – 21^st Edition

3. Pharmacology and Pharmacotherapeutics by R.S. Satoskar – 21^st Edition

Source-Medindia