Meta-analysis of oxidative stress in schizophrenia

Abstract

Background: Schizophrenia is associated with impaired antioxidant defense, including abnormal serum, plasma, and red blood cell (RBC) oxidative stress parameters. We performed a meta-analysis of these associations, considering the effect of clinical status and antipsychotic treatment after an acute exacerbation of psychosis.

Methods: We identified articles by searching PubMed, PsychInfo, and Institute for Scientific Information, and the reference lists of identified studies.

Results: Forty-four studies met the inclusion criteria. Total antioxidant status seemed to be a state marker, because levels were significantly decreased in cross-sectional studies of serum and plasma in first-episode psychosis (FEP) and significantly increased in longitudinal studies of antipsychotic treatment for acute exacerbations of psychosis (p < .01 for each). The RBC catalase and plasma nitrite seemed to be state-related markers, because levels in cross-sectional studies were significantly decreased in FEP (p < .01) and significantly increased in stable outpatients (p = .01). In contrast, RBC superoxide dismutase seemed to be a trait marker for schizophrenia, because levels in cross-sectional studies were significantly decreased in acutely relapsed inpatients, FEP, and stable outpatients (p < .01 for each).

Conclusions: Oxidative stress abnormalities in FEP suggest an effect that might be independent of antipsychotic medications. Although some parameters (total antioxidant status, RBC catalase, and plasma nitrite) might be state markers for acute exacerbations of psychosis, others (RBC superoxide dismutase) might be trait markers; however, more longitudinal studies are needed. Our findings suggest that oxidative stress might serve as a potential biomarker in the etiopathophysiology and clinical course of schizophrenia.

Keywords: Antioxidants; first-episode psychosis; meta-analysis; oxidative stress; relapse; schizophrenia.

Conflict of interest statement

Mr. Flatow reports no biomedical financial interests or potential conflicts of interest.

Copyright © 2013 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1

Potential relationships between free radicals and antioxidant defenses. Superoxide dismutase (SOD) catalyzes the conversion of superoxide radicals (O2−) to hydrogen peroxide (H2O2). Both catalase (CAT) and glutathione peroxidase (GSH-Px) convert H2O2 to water (H2O) and oxygen (O2). Reduced glutathione (GSH) is oxidized by GSH-Px to oxidized glutathione (GSSG). The GSH-Px also converts nitrate (NO3−, a byproduct of nitric oxide radicals) to nitrite. Nitrite is often used as a marker for nitric oxide (NO) activity. Hydroxyl radicals (OH.), which are produced from both H2O2 and NO, promote apoptosis, DNA damage, protein carbonylation, and lipid peroxidation. Thiobarbituric acid reactive substances (TBARS) and malondialdehyde (MDA) are important end products of lipid peroxidation. The TBARS measures endogenous MDA, although additional MDA might be generated in the assay.

Figure 2

Oxidative stress parameters in schizophrenia by sample source and clinical status. Effect size estimates and 95% confidence intervals (CIs) for oxidative stress parameters in cross-sectional studies of acute relapse of psychosis (A) and drug-naïve first-episode psychosis (C), stable medicated outpatients (D), and chronic inpatients (F) versus control subjects are represented by gray bars and black error bars in each panel, respectively. Effect size estimates and 95% CIs for oxidative stress parameters in cross-sectional studies of patients with schizophrenia versus control subjects stratified by smoking status (E) are represented by gray bars and black error bars, respectively. Effect size estimates and 95% CIs for changes in oxidative stress parameters in longitudinal studies after antipsychotic treatment for an acute exacerbation of psychosis (B) are represented by gray bars and black error bars, respectively. Positive effect sizes (bars going to the right) indicate that the parameter was higher in schizophrenia than control subjects (A, C–F) or that the parameter increased after antipsychotic treatment for acute psychosis (B); negative effect sizes (bars going to the left) indicate that levels were higher in control subjects than in patients with schizophrenia (A, C–F) or that the parameter decreased after antipsychotic treatment for acute psychosis (B). Error bars that exclude an effect size of 0 are significant at the p < .05 level. *Effect size is for studies that did not match/control for smoking. All other effect sizes in this figure are for studies that matched/controlled for smoking. Abbreviations as in Figure 1.

Figure 3

Potential interrelationships between immune function, oxidative stress, and membrane polyunsaturated fatty acids in the pathophysiology of schizophrenia. This figure describes potential inter-relationships between immune function, oxidative stress, and membrane phospholipids in response to environmental, dietary, and genetic factors. Membrane phospholipids are enriched in both arachidonic acid (AA) and docosahexaenoic acid (DHA), which are released by receptor-mediated phospholipases (PL). The AA and DHA, their downstream metabolites—including diacylglycerol (DAG), inositol phosphates (IP), and prostaglandins (PG)—and other secondary messengers such as cytokines impact on the regulation of gene expression, resulting in changes at the cellular level. Reprinted with permission from the American Psychiatric Publishing Textbook of Schizophrenia, (Copyright 2006) (158). American Psychiatric Association.