# Inflammation-Induced CNS Glutamate Changes in Depression

> **NIH NIH R01** · EMORY UNIVERSITY · 2020 · $408,239

## Abstract

Project Summary
The proposed research will test the hypothesis that increased inflammation causes increased basal ganglia
glutamate and consequently anhedonia and psychomotor retardation in patients with major depressive
disorder (MDD). Excessive inflammation and glutamate excitotoxicity are two pathways that have received
increasing attention regarding the pathophysiology of neuropsychiatric disease including mood disorders.
Patients with depression exhibit increased peripheral and central nervous system (CNS) markers of
inflammation as well as altered CNS glutamate as measured by magnetic resonance spectroscopy (MRS). In
addition, drugs that block either inflammation or glutamate signaling can reverse depressive symptoms,
especially in depressed patients with treatment resistance. Interestingly, recent data suggest there may be
convergence of these two pathways to pathology. Inflammatory cytokines are known to inhibit glutamate
reuptake and increase glutamate release from astrocytes, and glutamate antagonists have been shown to
block inflammation-induced depressive-like behavior in mice. Moreover, using MRS, our data has shown that
administration of the inflammatory cytokine interferon (IFN)-alpha significantly increases glutamate in the basal
ganglia in association with IFN-alpha-induced anhedonia and psychomotor slowing. In addition, our group has
demonstrated that increased inflammation as reflected by peripheral blood C-reactive protein (CRP) is
correlated with increased basal ganglia glutamate in association with decreased motivation and psychomotor
speed in patients with MDD. Nevertheless, the data to date has been correlational, and whether increased
inflammation causes increased glutamate in the basal ganglia, which in turn contributes to behavioral changes
in patients with depression has not been established. To test this hypothesis, we plan to determine the cause
and effect relationship between increased inflammation and increased CNS glutamate by blocking
inflammation in depressed patients with high inflammation (CRP>3mg/L) using the highly specific TNF
antagonist infliximab (n=30) versus placebo (n=30). In addition, we will examine whether changes in basal
ganglia glutamate are linked to changes in behaviors related to the basal ganglia including anhedonia and
psychomotor retardation (as measured by performance-based, clinical administered and self-report
assessments targeting research domain criteria that examine positive and negative valence systems). Finally,
we will explore the specific immunologic pathways that affect basal ganglia glutamate. These data will be the
first to establish a link between pathophysiologic mechanisms involving inflammation and glutamate, while also
helping personalize care through the identification of peripheral biomarkers of inflammation to guide future
studies using anti-inflammatory agents and/or glutamate antagonists to treat patients with depression and
other psychiatric disorders with increased ...

## Key facts

- **NIH application ID:** 9981047
- **Project number:** 5R01MH112076-05
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Ebrahim Haroon
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $408,239
- **Award type:** 5
- **Project period:** 2016-09-23 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9981047

## Citation

> US National Institutes of Health, RePORTER application 9981047, Inflammation-Induced CNS Glutamate Changes in Depression (5R01MH112076-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9981047. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*