Psychiatric disorders are one of the leading causes of disability worldwide and affect the quality of life of both individuals and the society. The current understanding of these disorders points toward receptor dysfunction and neurotransmitter imbalances in the brain. Treatment protocols are hence oriented toward normalizing these imbalances and ameliorating the symptoms. However, recent literature has indicated the possible role of depleted levels of antioxidants like glutathione (GSH) as well as an alteration in the levels of the pro-oxidant, iron in the pathogenesis of major psychiatric diseases, viz., schizophrenia (Sz), bipolar disorder (BD), and major depressive disorder (MDD). This review aims to highlight the involvement of oxidative stress (OS) in these psychiatric disorders. An overview of the clinical features, neurotransmitter abnormalities, and pharmacological treatments concerning these psychiatric disorders has also been presented. Furthermore, it attempts to synthesize literature from existing magnetic resonance spectroscopy (MRS) and quantitative susceptibility mapping (QSM) studies for these disorders, assessing GSH and iron, respectively. This manuscript is a sincere attempt to stimulate research discussion to advance the knowledge base for further understanding of the pathoetiology of Sz, BD, and MDD.

Alzheimer’s disease (AD) is the most common neurodegenerative disorder with heterogeneous etiology. Intracellular neurofibrillary tangles caused by tau (τ) protein phosphorylation and extracellular senile plaques caused by aggregation of amyloid-beta (Aβ) peptide are characteristic histopathological hallmarks of AD. Oxidative stress (OS) is also suggested to play a role in the pathophysiology of AD. The antioxidant glutathione (GSH) is able to mitigate OS through the detoxification of free radicals. The clearance of these free radicals is reported to be affected when there is a decline in GSH levels in AD. These radicals further react with the methionine-35 (M-35) residue of Aβ and facilitate its subsequent oligomerization. This review presents a plausible model indicating the role of master antioxidant GSH to protect M35 of Aβ 1–40 /Aβ 1–42 from oxidation in pathological conditions as compared to healthy controls.

Alzheimer's disease (AD) is an insidious and progressive neurodegenerative disorder that affects millions of people worldwide. Although the pathogenesis remains obscure, there are two dominant causal hypotheses. Since last three decades, amyloid beta (Aβ) deposition was the most prominent hypothesis, and the other is the tau hyperphosphorylation hypothesis. The confirmed diagnostic criterion for AD is the presence of neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau and the deposition of toxic oligomeric Aβ in the autopsied brain. Consistent with these hypotheses, oxidative stress (OS) is garnering major attention in AD research. OS results from an imbalance of pro-oxidants and antioxidants. There is a considerable debate in the scientific community on which process occurs first, OS or plaque deposition/tau hyperphosphorylation. Based on recent scientific observations of various laboratories including ours along with critical analysis of those information, we believe that OS is the early event that leads to oligomeric Aβ deposition as well as dimerization of tau protein and its subsequent hyperphosphorylation. This OS hypothesis immediately suggests the consideration of novel therapeutic approaches to include antioxidants involving glutathione enrichment in the brain by supplementation with or without an iron chelator.

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Glutathione (GSH) is a potent antioxidant synthesized de novo in cells and helps to detoxify free radicals in the brain and other organs. In vitro NMR studies from various research groups have reported primarily two sets of chemical shifts (2.80 or 2.96 ppm) of Cys-βCH 2 depending on GSH sample preparation in either inert or oxygenated environments. A multi-center in vivo MRS human study has also validated the presence of two types of GSH conformer in the human brain. Our study is aimed at investigating the distribution patterns of the two GSH conformers from five brain regions, namely, ACC (anterior cingulate cortex), PCC (posterior cingulate cortex), LPC (left parietal cortex), LH (left hippocampus), and CER (cerebellum). GSH was measured using a 3T MRI scanner using MEGA-PRESS pulse sequence in healthy young male and female populations (M/F = 5/9; age 32.8 ± 5.27 years). We conclude that the closed GSH conformer (characteristic NMR shift signature: Cys H α 4.40-H β 2.80 ppm) is more abundant than the extended GSH form (characteristic NMR shift signature Cys H α 4.56-H β 2.95 ppm). Closed conformer has a non-uniform distribution (ACC < CER < LH < PCC < LPC) in the healthy brain. On the contrary, the extended form of GSH has a uniform distribution in various anatomical regions.