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.

Figure 1

Association between plasma C-reactive protein (CRP) and the left basal ganglia glutamate in depressed patients. Plasma CRP was positively associated with the left basal ganglia absolute glutamate in both a linear (a) and step-wise manner (b), in medication-free patients with major depressive disorder. (a) Increased log plasma CRP correlated and log left basal ganglia absolute glutamate concentrations in depressed subjects after controlling for age, sex, race, smoking status, body mass index and 17-item Hamilton Depression Rating Scale scores (β=0.36, t=2.57, P=0.014). (b) Group-wise comparison of log left basal ganglia absolute glutamate concentrations among patients grouped by CRP revealed a significant main effect of group (F[2,43]=4.42, P=0.018). *P<0.025.

Figure 2

Correlations between the left basal ganglia glutamate and anhedonia and psychomotor speed in depressed patients. (a) Logged values of absolute glutamate concentrations in the left basal ganglia were correlated with the IDS-SR–Anhedonia subscale (β=0.42, t=3.03, P=0.004). (b) Log absolute basal ganglia glutamate concentrations were correlated with finger-tapping frequency on the FTT (β=−0.40, t=−2.96, P=0.005). (c) Log absolute basal ganglia glutamate concentrations were correlated with log simple reaction time assessed using the CANTAB (β=0.35, t=2.44, P=0.019). (d) Log absolute basal ganglia glutamate concentrations were correlated with performance on the DSST (β=−0.36, t=−2.57, P=0.01). Statistical values controlling for covariates including age, sex, race, body mass index, smoking status, Hamilton Scale of Depression scores and plasma CRP are indicated in parentheses. CANTAB, Cambridge automated neuropsychological test battery; DSST, digit symbol substitution test; FTT, finger-tapping test; IDS-SR, inventory for depressive symptoms-self rated.