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Inflammation Connected to Elevated Glutamate Could Guide Depression Treatments

Psychiatrists investigating depression have been energized in recent years by reports of rapid, successful treatment with drugs that interfere with the brain chemical glutamate, such as the anesthetic ketamine.

New research from Emory University School of Medicine is providing hints as to which forms of depression may respond best to drugs that target glutamate.

The findings are scheduled for publication online on January 12 in Molecular Psychiatry.

Depressed patients with signs of systemic inflammation have elevated levels of glutamate in regions of the brain that are important for motivation, the researchers have found.

“Our results suggest that inflammation markers can guide us to which depressed patients respond best to glutamate blockers,” says lead author Ebrahim Haroon, MD, assistant professor of psychiatry and behavioral sciences at Emory University 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 C-reactive protein (CRP), which was measured on repeat visits to make sure its levels were stable.

The team used an imaging technique called magnetic resonance spectroscopy (MRS) 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, an inability to experience pleasure, and slow motor function, as measured by finger tapping speed.

Image shows a girl in gray.

Researchers examined 50 patients with depression who were not receiving antidepressant medication at that time. Inflammation was determined by a blood test for C-reactive protein (CRP), which was measured on repeat visits to make sure its levels were stable. Image is for illustrative purposes only.

“We focused on the basal ganglia because we had previously seen that a treatment for hepatitis C virus that arouses inflammation and can trigger depressive symptoms could also increase glutamate levels there,” Haroon says.

He 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.

About this Psychology research

Emory co-authors include Andrew H. Miller, MD, professor of psychiatry and behavioral sciences, Jennifer Felger, PhD, assistant professor of psychiatry and behavioral sciences, and Xiaoping Hu, PhD, professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory.

Funding: Funding was provided by NIH/National Institute of Mental Health, Brain and Behavioral Research Foundation.

Source: Quinn Eastman – Emory University
Image Source: The image is in the public domain
Original Research: Full open access research for for “Conceptual convergence: increased inflammation is associated with increased basal ganglia glutamate in patients with major depression” by E Haroon, C C Fleischer, J C Felger, X Chen, B J Woolwine, T Patel, X P Hu and A H Miller in Molecular Psychiatry. Published online January 12 2016 doi:10.1038/mp.2015.20


Abstract

Conceptual convergence: increased inflammation is associated with increased basal ganglia glutamate in patients with major depression

Inflammation and altered glutamate metabolism are two pathways implicated in the pathophysiology of depression. Interestingly, these pathways may be linked given that administration of inflammatory cytokines such as interferon-α to otherwise non-depressed controls increased glutamate in the basal ganglia and dorsal anterior cingulate cortex (dACC) as measured by magnetic resonance spectroscopy (MRS). Whether increased inflammation is associated with increased glutamate among patients with major depression is unknown. Accordingly, we conducted a cross-sectional study of 50 medication-free, depressed outpatients using single-voxel MRS, to measure absolute glutamate concentrations in basal ganglia and dACC. Multivoxel chemical shift imaging (CSI) was used to explore creatine-normalized measures of other metabolites in basal ganglia. Plasma and cerebrospinal fluid (CSF) inflammatory markers were assessed along with anhedonia and psychomotor speed. Increased log plasma C-reactive protein (CRP) was significantly associated with increased log left basal ganglia glutamate controlling for age, sex, race, body mass index, smoking status and depression severity. In turn, log left basal ganglia glutamate was associated with anhedonia and psychomotor slowing measured by the finger-tapping test, simple reaction time task and the Digit Symbol Substitution Task. Plasma CRP was not associated with dACC glutamate. Plasma and CSF CRP were also associated with CSI measures of basal ganglia glutamate and the glial marker myoinositol. These data indicate that increased inflammation in major depression may lead to increased glutamate in the basal ganglia in association with glial dysfunction and suggest that therapeutic strategies targeting glutamate may be preferentially effective in depressed patients with increased inflammation as measured by CRP.

“Conceptual convergence: increased inflammation is associated with increased basal ganglia glutamate in patients with major depression” by E Haroon, C C Fleischer, J C Felger, X Chen, B J Woolwine, T Patel, X P Hu and A H Miller in Molecular Psychiatry. Published online January 12 2016 doi:10.1038/mp.2015.20

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