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

Palaniyappan, Lena; Sabesan, Priyadharshini; Li, Xuan; Luo, Qiang

doi:10.3389/fpsyt.2021.796466

Cited by 19 publications

(12 citation statements)

References 50 publications

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“…This causes disinhibition of glutamatergic neurons along with higher subcortical dopamine manifested in the form of positive, negative, and cognitive symptoms. The figure was designed using the information taken from the existing literature. ,, …”

Section: Clinical Characteristicsmentioning

confidence: 99%

Schizophrenia, Bipolar and Major Depressive Disorders: Overview of Clinical Features, Neurotransmitter Alterations, Pharmacological Interventions, and Impact of Oxidative Stress in the Disease Process

Mandal

Gaur

Roy

et al. 2022

ACS Chem. Neurosci.

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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.

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Section: Clinical Characteristicsmentioning

confidence: 99%

Schizophrenia, Bipolar and Major Depressive Disorders: Overview of Clinical Features, Neurotransmitter Alterations, Pharmacological Interventions, and Impact of Oxidative Stress in the Disease Process

Mandal

Gaur

Roy

et al. 2022

ACS Chem. Neurosci.

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“…The hypothesis of greater glutamate variability in patients can be formally tested by conducting a meta-analysis of variability, as previously employed to examine the variability of glutathione [26], antipsychotic treatment response [27] and brain structure in schizophrenia [28]. One meta-analysis examined the variability of glutamate in schizophrenia compared to controls, but this was limited to glutamate in the dorsolateral prefrontal cortex (DLPFC) [29].…”

Section: Introductionmentioning

confidence: 99%

Variability and magnitude of brain glutamate levels in schizophrenia: a meta and mega-analysis

Merritt¹,

McCutcheon²,

Alemán³

et al. 2023

Mol Psychiatry

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Glutamatergic dysfunction is implicated in schizophrenia pathoaetiology, but this may vary in extent between patients. It is unclear whether inter-individual variability in glutamate is greater in schizophrenia than the general population. We conducted meta-analyses to assess (1) variability of glutamate measures in patients relative to controls (log coefficient of variation ratio: CVR); (2) standardised mean differences (SMD) using Hedges g; (3) modal distribution of individual-level glutamate data (Hartigan’s unimodality dip test). MEDLINE and EMBASE databases were searched from inception to September 2022 for proton magnetic resonance spectroscopy (1H-MRS) studies reporting glutamate, glutamine or Glx in schizophrenia. 123 studies reporting on 8256 patients and 7532 controls were included. Compared with controls, patients demonstrated greater variability in glutamatergic metabolites in the medial frontal cortex (MFC, glutamate: CVR = 0.15, p < 0.001; glutamine: CVR = 0.15, p = 0.003; Glx: CVR = 0.11, p = 0.002), dorsolateral prefrontal cortex (glutamine: CVR = 0.14, p = 0.05; Glx: CVR = 0.25, p < 0.001) and thalamus (glutamate: CVR = 0.16, p = 0.008; Glx: CVR = 0.19, p = 0.008). Studies in younger, more symptomatic patients were associated with greater variability in the basal ganglia (BG glutamate with age: z = −0.03, p = 0.003, symptoms: z = 0.007, p = 0.02) and temporal lobe (glutamate with age: z = −0.03, p = 0.02), while studies with older, more symptomatic patients associated with greater variability in MFC (glutamate with age: z = 0.01, p = 0.02, glutamine with symptoms: z = 0.01, p = 0.02). For individual patient data, most studies showed a unimodal distribution of glutamatergic metabolites. Meta-analysis of mean differences found lower MFC glutamate (g = −0.15, p = 0.03), higher thalamic glutamine (g = 0.53, p < 0.001) and higher BG Glx in patients relative to controls (g = 0.28, p < 0.001). Proportion of males was negatively associated with MFC glutamate (z = −0.02, p < 0.001) and frontal white matter Glx (z = −0.03, p = 0.02) in patients relative to controls. Patient PANSS total score was positively associated with glutamate SMD in BG (z = 0.01, p = 0.01) and temporal lobe (z = 0.05, p = 0.008). Further research into the mechanisms underlying greater glutamatergic metabolite variability in schizophrenia and their clinical consequences may inform the identification of patient subgroups for future treatment strategies.

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“…The point has also been made that TRS is associated with central oxidative stress and increased variability of glutathione 39 . Together with our ndings, such unfavorable factors may advance the disease stages and pathological changes in TRS.…”

Section: Discussionmentioning

confidence: 99%

Disease progression patterns of brain morphology in schizophrenia: More progressed stages in treatment-resistance

Nakajima

Sone

Young³

et al. 2023

Preprint

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Given the heterogeneity and possible disease progression in schizophrenia, identifying the neurobiological subtypes and progression patterns in each patient may lead to the development of clinically useful biomarkers. In this cross-sectional study, we adopted data-driven machine-learning techniques to classify and stage the progression patterns of brain morphological changes in schizophrenia and investigate the association with treatment resistance. We included 177 patients with schizophrenia, characterized by treatment response or resistance, with 3D T1-weighted magnetic resonance imaging from 3 institutions. Cortical thickness and subcortical volumes calculated by FreeSurfer were converted into Z-scores using 73 healthy controls data. The Subtype and Stage Inference (SuStaIn) algorithm was used for unsupervised machine-learning classification and staging. As a result, SuStaIn identified three different subtypes: 1) subcortical volume reduction (SC) type (73 patients, 47.4%), in which volume reduction of subcortical structures occurs first and moderate cortical thinning follows, 2) globus pallidus hypertrophy and cortical thinning (GP-CX) type (42 patients, 27.3%), in which globus pallidus hypertrophy initially occurs followed by progressive cortical thinning, 3) cortical thinning (pure CX) type (39 patients, 25.3%), in which thinning of the insular and lateral temporal lobe cortices primarily happens. The remaining 23 patients were assigned to baseline stage of progression (no change). SuStaIn also found 84 stages of progression, and treatment-resistant schizophrenia showed significantly more progressed stages of progression than treatment-responsive cases (p=0.001). The GP-CX type presented in earlier stages than the pure CX type (p=0.009). In conclusion, the brain morphological progressions in schizophrenia can be classified into three subtypes by SuStaIn algorithm. Treatment resistance was associated with more progressed stages of the disease, which may suggest a novel biomarker for schizophrenia.

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

Cited by 19 publications

References 50 publications

Schizophrenia, Bipolar and Major Depressive Disorders: Overview of Clinical Features, Neurotransmitter Alterations, Pharmacological Interventions, and Impact of Oxidative Stress in the Disease Process

Schizophrenia, Bipolar and Major Depressive Disorders: Overview of Clinical Features, Neurotransmitter Alterations, Pharmacological Interventions, and Impact of Oxidative Stress in the Disease Process

Variability and magnitude of brain glutamate levels in schizophrenia: a meta and mega-analysis

Disease progression patterns of brain morphology in schizophrenia: More progressed stages in treatment-resistance

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