Inflammation’s role in depression

Emory researchers are now making it possible for us to know what inflammation, in the context of depression, looks like inside the brain and how it might be combated.

About one-third of people with depression have high levels of inflammation markers in their blood. Persistent inflammation affects the brain in ways that are connected to stubborn symptoms of depression such as anhedonia, the inability to experience pleasure. The findings bolster the case that the high-inflammation form of depression is distinct — hence, requiring a tailored treatment.

The results were published online on November 10, 2015, in Molecular Psychiatry. The colead author, research associate Zhihao Li, is at Shenzhen University. Emory coauthors include Andrew H. Miller, professor of psychiatry and behavioral sciences at the School of Medicine and Winship Cancer Institute; Ebrahim Haroon, assistant professor of psychiatry and behavioral sciences at the School of Medicine; and Xiaoping Hu, professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory. Anhedonia is a core symptom of depression that is particularly difficult to treat, says lead author Jennifer Felger, assistant professor of psychiatry and behavioral sciences at Emory University School of Medicine and Winship Cancer Institute.

“Some patients taking antidepressants continue to suffer from anhedonia,” Felger says. “Our data suggest that by blocking inflammation or its effects on the brain, we may be able to reverse anhedonia and help depressed individuals who fail to respond to antidepressants.”

In a study of 48 patients with depression, high levels of the inflammatory marker C-reactive protein (CRP) were linked to a “failure to communicate,” seen through brain imaging, between brain regions important for motivation and reward — namely, the ventromedial prefrontal cortex and the ventral striatum. In contrast, patients with low CRP had robust connectivity.

“We were interested in these regions of the brain because of their known importance for response to reward,” Felger says. "In addition, we had seen reduced activation of these areas in people receiving immunostimulatory treatments for hepatitis C virus or cancer, which suggested that they may be sensitive to inflammation.”

doctor and studying brain scans

Steps toward tailored treatment

Another key factor for depressed patients with signs of systemic inflammation is that they show elevated levels of glutamate in regions of the brain important for motivation. Emory researchers published these findings online on January 12, 2016, in Molecular Psychiatry. Emory coauthors include Miller, professor of psychiatry and behavioral sciences; Felger, assistant professor of psychiatry and behavioral sciences at the School of Medicine and Winship Cancer Institute; and Hu, professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory.

“Our results suggest that inflammation markers can guide us to which depressed patients respond best to glutamate blockers,” says lead author Ebrahim Haroon, assistant professor of psychiatry and behavioral sciences at the School of Medicine and Winship Cancer Institute. “This could be an important step toward personalizing treatment for depression.”

Glutamate is a chemical messenger used by neurons to communicate. However, at high levels it can become toxic to both neurons and glia, cells that support brain health. It is unlikely that the elevated levels seen in some depressed patients are acutely toxic, Haroon says.

“Still, we think that one of the ways that inflammation may harm the brain and cause depression is by increasing levels of glutamate in sensitive regions of the brain, possibly through effects on glia,” he says.

Researchers examined 50 patients with depression who were not receiving antidepressant medication at that time. Inflammation was determined by a blood test for CRP, which was measured on repeat visits to make sure its levels were stable.

The team used an imaging technique called magnetic resonance spectroscopy to measure glutamate levels in the basal ganglia, a brain region important for motor control, motivation, and decision making. The researchers also measured levels of myo-inositol, a marker of glial health.

High glutamate and myo-inositol levels in the basal ganglia were associated with patients' reports of anhedonia and slow motor function, as measured by finger-tapping speed.

Haroon adds that the paper's findings do not directly address how ketamine and other glutamate-targeting drugs may work against depression, but may indicate which patients would be likely candidates.

A previous study of people with difficult-to-treat depression found that only those with high-inflammation markers tended to improve in response to the anti-inflammatory antibody infliximab.