Glutathione and glutamate in schizophrenia: a 7T MRS study

Abstract

In schizophrenia, abnormal neural metabolite concentrations may arise from cortical damage following neuroinflammatory processes implicated in acute episodes. Inflammation is associated with increased glutamate, whereas the antioxidant glutathione may protect against inflammation-induced oxidative stress. We hypothesized that patients with stable schizophrenia would exhibit a reduction in glutathione, glutamate, and/or glutamine in the cerebral cortex, consistent with a post-inflammatory response, and that this reduction would be most marked in patients with "residual schizophrenia", in whom an early stage with positive psychotic symptoms has progressed to a late stage characterized by long-term negative symptoms and impairments. We recruited 28 patients with stable schizophrenia and 45 healthy participants matched for age, gender, and parental socio-economic status. We measured glutathione, glutamate and glutamine concentrations in the anterior cingulate cortex (ACC), left insula, and visual cortex using 7T proton magnetic resonance spectroscopy (MRS). Glutathione and glutamate were significantly correlated in all three voxels. Glutamine concentrations across the three voxels were significantly correlated with each other. Principal components analysis (PCA) produced three clear components: an ACC glutathione-glutamate component; an insula-visual glutathione-glutamate component; and a glutamine component. Patients with stable schizophrenia had significantly lower scores on the ACC glutathione-glutamate component, an effect almost entirely leveraged by the sub-group of patients with residual schizophrenia. All three metabolite concentration values in the ACC were significantly reduced in this group. These findings are consistent with the hypothesis that excitotoxicity during the acute phase of illness leads to reduced glutathione and glutamate in the residual phase of the illness.

Fig. 1

Average voxel placements (ACC anterior cingulate cortex, Ins left insula, Vis visual cortex) across all subjects overlaid on an MNI brain; illustrative ¹H spectra with baseline and residuals from a voxel located in the ACC of subjects from all three groups (healthy controls, residual schizophrenia, and non-residual schizophrenia) and corresponding fits from LCModel for glutamine (Gln), glutamate (Glu), and glutathione (GSH)

Fig. 2

Correlation between glutathione (GSH) and glutamate (Glu) concentrations in the three regions (anterior cingulate cortex (ACC), visual cortex, and insula) in the three groups (healthy controls, patients with residual schizophrenia, and patients with non-residual schizophrenia). Values represent standardized residuals after covarying for gender in the ACC and insula; and gender and spectral line-width in the visual cortex. Note: For the correlation between GSH and Glu in the ACC in healthy controls and in the insula in patients with residual schizophrenia, data did not satisfy the assumption of multivariate normality. Therefore, bootstrapped bias-corrected accelerated 95% confidence intervals were computed (10,000 samples), and the correlations remained significant

Fig. 3

Panel a shows mean component scores for the second PCA component loading on glutathione and glutamate concentrations in the ACC. Error bars represent 95% confidence intervals. There were no significant differences in variances between any groups or sub-groups. Panel b shows the effect sizes for differences in mean metabolite concentrations in the ACC between healthy controls and all patients (green bars) and the sub-group of patients with residual schizophrenia (blue bars). Error bars represent 95% confidence limits of the effect size.