Glutathione as a Molecular Marker of Functional Impairment in Patients with At-Risk Mental State: 7-Tesla 1H-MRS Study

Abstract

A substantial number of individuals with clinical high-risk (CHR) mental state do not transition to psychosis. However, regardless of future diagnostic trajectories, many of these individuals develop poor social and occupational functional outcomes. The levels of glutathione, a crucial cortical antioxidant, may track variations in functional outcomes in early psychosis and prodromal states. Thirteen clinical high-risk and 30 healthy control volunteers were recruited for a 7-Tesla magnetic resonance spectroscopy scan with a voxel positioned within the dorsal anterior cingulate cortex (ACC). Clinical assessment scores were collected to determine if any association was observable with glutathione levels. The Bayesian Spearman’s test revealed a positive association between the Social and Occupational Functioning Assessment Scale (SOFAS) and the glutathione concentration in the clinical high-risk group but not in the healthy control group. After accounting for variations in the SOFAS scores, the CHR group had higher GSH levels than the healthy subjects. This study is the first to use 7-Tesla magnetic resonance spectroscopy to test whether ACC glutathione levels relate to social and occupational functioning in a clinically high-risk group and offers preliminary support for glutathione levels as a clinically actionable marker of prognosis in emerging adults presenting with risk features for various severe mental illnesses.

Is There a Glutathione Centered Redox Dysregulation Subtype of Schizophrenia?

“…We observed that in untreated first episode patients, an elevated ACC GSH at the time of presentation occurred in those with more florid disorganization [73] but most of these subjects responded briskly to the regular antipsychotic treatments over the next 6 months [69]. Help seeking subjects with subthreshold psychotic symptoms display better social and occupational functioning when ACC GSH levels are higher [77]. In the metaanalysis of Das and colleagues we noted a small but significant increase in ACC GSH in bipolar disorder, a phenotype that is often associated with better functional outcomes than schizophrenia [64].…”

“…Higher intracortical glutamate levels relate to reduced social function [69,125] and poorer treatment response [81] in early stages and reduced cortical grey matter [83,126,127]. On the other hand, higher GSH levels relate to faster treatment response [69], better functioning [77] and preserved cortical grey matter [102] [See [128,129] for association with peripheral GSH]. We recently observed opposing influence of glutamate and GSH on the intrinsic connectivity within the dACC node of the Salience Network in first episode psychosis [72].…”

The trajectory of putative astroglial dysfunction in first episode schizophrenia: a longitudinal 7-Tesla MRS study

“…MRS measurements were acquired using a Siemens MAGNETOM 7 T head-only MRI scanner (Siemens, Erlangen, Germany) and a site-built head coil (8-channel transmit, 32-channel receive) at the Centre for Functional and Metabolic Mapping of Western University (London, Ontario). This acquisition has been employed in our prior MRS studies 48 , 52 , 53 . Further details of the acquisition and spectral fitting are described in the Supplementary Materials .…”

Is There a Glutathione Centered Redox Dysregulation Subtype of Schizophrenia?

“…We observed that in untreated first episode patients, an elevated ACC GSH at the time of presentation occurred in those with more florid disorganization [ 73 ] but most of these subjects responded briskly to the regular antipsychotic treatments over the next 6 months [ 69 ]. Help seeking subjects with subthreshold psychotic symptoms display better social and occupational functioning when ACC GSH levels are higher [ 77 ]. In the meta-analysis of Das and colleagues we noted a small but significant increase in ACC GSH in bipolar disorder, a phenotype that is often associated with better functional outcomes than schizophrenia [ 64 ].…”

“…Higher intracortical glutamate levels relate to reduced social function [ 69 , 123 ] and poorer treatment response [ 81 ] in the early stages and reduced cortical grey matter [ 83 , 124 , 125 ]. On the other hand, higher GSH levels relate to faster treatment response [ 69 ], better functioning [ 77 ], and preserved cortical grey matter [ 101 ] (See also [ 126 , 127 ] for association with peripheral GSH). We recently observed an opposing influence of glutamate and GSH on the intrinsic connectivity within the dACC node of the Salience Network in first episode psychosis [ 72 ].…”