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

Abstract

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.

Glutamate and Gamma-Aminobutyric Acid Systems in the Pathophysiology of Major Depression and Antidepressant Response to Ketamine

“…A recent study showed that elevated Glu in the ACC associated with BD patients in euthymic states was related to number of depressive/manic episodes (21); notably, this finding may allow for differentiation of depression between BD and MDD. Impaired oxidative metabolism in glutamatergic neurons has been hypothesized to explain elevated Glx and lactate levels associated with mixed or depressed states in BD (33), and further supports a contributory role of inflammation in the pathophysiology of depression (34). Wide and overlapping ranges of mood and neurocognitive states in BD (35) increase variation within and between study samples, contributing to challenges in interpreting neurochemical and functional imaging studies of BD.…”

Inflammation Effects on Motivation and Motor Activity: Role of Dopamine

“…Although mood disorders may have complex pathophysiology with heterogeneous etiologies, it is thought that increased inflammation may be involved in the disease process and contribute to discreet symptomologies in a subset of patients. Indeed, recent studies have indicated that high inflammation (plasma CRP concentrations 43 mg/l, as defined by the American Heart Association; Ridker, 2003) is consistently found in 20-40% of patients with MDD, with higher concentrations observed in patients who are resistant to standard antidepressant therapies Haroon et al, 2016;Raison et al, 2013a;Raison et al, 2013b;Rapaport et al, 2016). Similar increases in inflammatory cytokines and acute-phase reactants have also been reported in patients with bipolar disorder and schizophrenia, including meta-analyses (Goldsmith et al, 2016b;Miller et al, 2011;Potvin et al, 2008).…”

“…For example, in patients from a high-risk urban setting with a history of trauma, those who carried a CRP genotype (rs1130864) that is associated with elevated CRP concentrations had higher rates of posttraumatic stress disorder and reported higher scores for the loss of interest in activities (Michopoulos et al, 2015). Furthermore, recent data indicate that increased plasma concentrations of CRP and inflammatory cytokines and their soluble receptors correlate with symptoms of both anhedonia and psychomotor slowing in medically stable patients with MDD Goldsmith et al, 2016a;Haroon et al, 2016). These findings provide encouraging data that increased inflammation may be associated with symptoms of motivation and motor behavior across disorders, and may be useful for identifying subtypes of patients with psychiatric illness.…”

Brain Structures Implicated in Inflammation-Associated Depression

“…In their study using 18F-DOPA PET Martinot et al [86] demonstrated a reduction in left caudate tracer uptake in MDD patients with psychomotor retardation but not MDD patients with high impulsivity or comparison control participants, providing direct evidence of a link between striatal dopamine hypofunction and psychomotor retardation. The importance of the left dorsal striatum to psychomotor retardation associated with MDD and inflammation has been further strengthened by a recent paper demonstrating a link between plasma and CSF levels of C-reactive protein (CRP), left basal ganglia glutamate, and psychomotor slowing in untreated depressed patients [89].…”