Is There a Glutathione Centered Redox Dysregulation Subtype of Schizophrenia?

Abstract

Schizophrenia continues to be an illness with poor outcome. Most mechanistic changes occur many years before the first episode of schizophrenia; these are not reversible after the illness onset. A developmental mechanism that is still modifiable in adult life may center on intracortical glutathione (GSH). A large body of pre-clinical data has suggested the possibility of notable GSH-deficit in a subgroup of patients with schizophrenia. Nevertheless, studies of intracortical GSH are not conclusive in this regard. In this review, we highlight the recent ultra-high field magnetic resonance spectroscopic studies linking GSH to critical outcome measures across various stages of schizophrenia. We discuss the methodological steps required to conclusively establish or refute the persistence of GSH-deficit subtype and clarify the role of the central antioxidant system in disrupting the brain structure and connectivity in the early stages of schizophrenia. We propose in-vivo GSH quantification for patient selection in forthcoming antioxidant trials in psychosis. This review offers directions for a promising non-dopaminergic early intervention approach in schizophrenia.

Schizophrenia Increases Variability of the Central Antioxidant System: A Meta-Analysis of Variance From MRS Studies of Glutathione

“…In the context of our current observation of increased variation in GSH levels in schizophrenia, the extant literature supports the model of ‘Primary GSH Deficit' ( Figure 2 ) in some individuals with schizophrenia; this deficit may be pathoplastic and influence the treatment outcomes [e.g., treatment resistance ( 47 )] among patients. Demonstrating bimodal distribution of GSH levels in large samples of patients in early illness stages, in conjunction with clinical and functional validation of the distributed values, will add substantial evidence to our claim regarding the existence of subgroups ( 16 ).…”

“…See Koga et al (36), and Sedlak et al (37), for how GSH levels may relate to glutamate and Limongi et al (38) for observations relating to opposing effects of anterior cingulate GSH and glutamate on effective connectivity. The relationship between GSH and glutamate is discussed in detail elsewhere (16) GSH-deficit (or redox-deficient) subgroup. (2) some individuals from the putative GSH-excess subgroup (or redox sufficient) may still progress to chronic or resistant stages of schizophrenia.…”

“…In addition to the above considerations, it is also likely that the use of antipsychotics and other medications as well as a high degree of variability in lifestyle factors and daily functioning (including diet) may make the patient group more heterogenous. A detailed exposition of methodological approaches required to conclusively establish the presence of the deficient/sufficient subtype can be found elsewhere ( 16 ).…”

“…Each study was independently extracted by at least 2 raters and recorded in an Excel sheet. A table with the demographic details of the studies before 2018 can be found in Das et al ( 7 ); for studies after 2018, see Table 1 in a recent review discussing challenges and opportunities related to glutathione in schizophrenia ( 16 ).…”

“…See Koga et al(36), and Sedlak et al(37), for how GSH levels may relate to glutamate and Limongi et al(38) for observations relating to opposing effects of anterior cingulate GSH and glutamate on effective connectivity. The relationship between GSH and glutamate is discussed in detail elsewhere(16).Credits for images used in this figure: Scidraw.io doi: 10.5281/zenodo.4421165; 10.5281/zenodo.3926048; 10.5281/zenodo.3926143; 10.5281/zenodo.3926604. Ball-and-stick model of the glutathione molecule from Ben Mills via Wikimedia commons.…”