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 inflammation.

Public Health Relevance

Increased inflammation has been implicated in the pathophysiology of a number of neuropsychiatric illnesses including mood disorders, which affect almost 30 million adults in the US alone. One mechanism by which inflammation may alter behavior is through increasing brain glutamate, a neurotransmitter that in excess has been implicated in neuronal toxicity and resistance to conventional antidepressant therapy. The goal of the proposed research is to test the hypothesis that inflammation alters behavior through increasing glutamate in specific brain regions, ultimately leading to behavioral changes.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
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Hillefors, MI
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Emory University
Schools of Medicine
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Mehta, Neeti D; Haroon, Ebrahim; Xu, Xiaodan et al. (2018) Inflammation negatively correlates with amygdala-ventromedial prefrontal functional connectivity in association with anxiety in patients with depression: Preliminary results. Brain Behav Immun 73:725-730
Bekhbat, Mandakh; Chu, Karen; Le, Ngoc-Anh et al. (2018) Glucose and lipid-related biomarkers and the antidepressant response to infliximab in patients with treatment-resistant depression. Psychoneuroendocrinology 98:222-229
Haroon, Ebrahim; Daguanno, Alexander W; Woolwine, Bobbi J et al. (2018) Antidepressant treatment resistance is associated with increased inflammatory markers in patients with major depressive disorder. Psychoneuroendocrinology 95:43-49
Haroon, Ebrahim; Chen, Xiangchuan; Li, Zhihao et al. (2018) Increased inflammation and brain glutamate define a subtype of depression with decreased regional homogeneity, impaired network integrity, and anhedonia. Transl Psychiatry 8:189
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