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.
Highlights
Schizophrenia is one of the most devastating of adolescent onset illnesses
In the meta-analysis of Das and colleagues we noted a small but significant increase in anterior cingulate cortex (ACC) GSH in bipolar disorder, a phenotype that is often associated with better functional outcomes than schizophrenia [64]
In First Episode Psychosis (n = 30), glutamate relates to reduced relates to reduced prefrontal, orbitofrontal, and superior temporal intracortical myelin (1/qT1) only when GSH levels are prefrontal, orbitofrontal, and superior temporal intracortical myelin (1/qT1) only when GSH levels are lower
Summary
Schizophrenia is one of the most devastating of adolescent onset illnesses. Despite the advances in pharmacological, psychological, and social aspects of care in the last 50 years, only a small sub-group achieves combined clinical and functional recovery (~13%) [1,2]. (2) dysconnectivity of large-scale brain networks (especially involving the dorsal anterior cingulate cortex [ACC] and insula) in prodromal stages before the first-episode [13,14,15,16], related to persistent symptom burden [17,18,19] and cognitive deficits [20,21,22], and (3) microstructural changes in the grey [23,24] and white matter [25,26,27], predating the illness but becoming more prominent during the first-episode [24], possibly reflecting the loss of dendritic spines [28,29] and myelination deficits [30,31] Despite these mechanistic insights no accessible therapeutic targets have emerged yet. There is an urgent need to identify pathways of poor outcome in schizophrenia that remain ‘modifiable’ after the symptom onset
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