Negative correlation between brain glutathione level and negative symptoms in schizophrenia: a 3T 1H-MRS study

Abstract

Background: Glutathione (GSH), a major intracellular antioxidant, plays a role in NMDA receptor-mediated neurotransmission, which is involved in the pathophysiology of schizophrenia. In the present study, we aimed to investigate whether GSH levels are altered in the posterior medial frontal cortex of schizophrenic patients. Furthermore, we examined correlations between GSH levels and clinical variables in patients.

Methods and findings: Twenty schizophrenia patients and 16 age- and gender-matched normal controls were enrolled to examine the levels of GSH in the posterior medial frontal cortex by using 3T SIGNA EXCITE (1)H-MRS with the spectral editing technique, MEGA-PRESS. Clinical variables of patients were assessed by the Global Assessment of Functioning (GAF), Scale for the Assessment of Negative Symptoms (SANS), Brief Psychiatric Rating Scale (BPRS), Drug-Induced Extra-Pyramidal Symptoms Scale (DIEPSS), and five cognitive performance tests (Word Fluency Test, Stroop Test, Trail Making Test, Wisconsin Card Sorting Test and Digit Span Distractibility Test). Levels of GSH in the posterior medial frontal cortex of schizophrenic patients were not different from those of normal controls. However, we found a significant negative correlation between GSH levels and the severity of negative symptoms (SANS total score and negative symptom subscore on BPRS) in patients. There were no correlations between brain GSH levels and scores on any cognitive performance test except Trail Making Test part A.

Conclusion: These results suggest that GSH levels in the posterior medial frontal cortex may be related to negative symptoms in schizophrenic patients. Therefore, agents that increase GSH levels in the brain could be potential therapeutic drugs for negative symptoms in schizophrenia.

Figure 1

Proton MRS of GSH. (A): T2-weighed magnetic resonance imaging of the targeted region. The blue boxes show the voxel size (28 x 22 x 30 mm) in the posterior medial frontal cortex of a human brain. (B): representative data of reference phantom spectra of GSH (0.5, 1.0, 3.0 mM). Note that the GSH signal increases according to the phantom concentration. (C): Quantification of GSH. Plots showing a linear correlation (r2 = 0.994) between the GSH signal area at 2.95 ppm and the concentration of GSH. (D): Representative data of GSH signals of the posterior medial frontal cortex of a human subject. The GSH level was calculated as 0.735 mM by applying the linear concentration curve on (C).

Figure 2

Correlation between GSH levels and the severity of negative symptoms in schizophrenia. There was a significant negative correlation (r = −068, p<0.001) between GSH levels and SANS total scores of schizophrenic patients (n = 20).