Oxidative stress markers in bipolar disorder: A meta-analysis

Abstract

Background

Oxidative stress is thought to mediate neuropathological processes of a number of neuropsychiatric disorders and recent data suggest that oxidative stress may be involved in the pathophysiology of bipolar disorder (BD). In the present investigation, we conducted a meta-analysis of studies that evaluated markers of oxidative stress in individuals with BD, as compared to healthy controls.

Methods

A Medline search was conducted to identify studies that measured peripheral markers of oxidative stress in bipolar disorder. Data were subjected to meta-analysis using a random effects model to examine the effect sizes of the pooled results. Bias assessment (Egger's test) and assessment of heterogeneity (I²) were also carried out.

Results

Thiobarbituric acidic reactive substances (TBARS) (p = 0.001) as well as NO activity (p = 0.02) were significantly increased in BD with a large effect size for TBARS and a moderate effect size for increase in NO. No significant effect sizes were observed for the antioxidant enzymes superoxide dismutase, catalase and glutathione peroxidase (all p > 0.05).

Limitations

Some caution is warranted in interpreting these results: (1) Egger's test was positive for SOD, suggesting that SOD results may have been influenced by a publication bias. (2) We analyzed the absolute values of each antioxidant enzyme separately and the literature suggests that an imbalance between the antioxidant enzymes is a better indication of the presence of oxidative stress.

Conclusions

The present meta-analysis suggests that oxidative stress markers are increased in BD and that oxidative stress may play a role in the pathophysiology of BD.

Introduction

Bipolar disorder (BD) is a major mood disorder with an estimated prevalence of about 1–3% of the population worldwide (Belmaker, 2004, Kupfer, 2005, Merikangas et al., 2007). It has been increasingly recognized that individuals with BD are at higher risk of suffering from chronic general medical conditions, such as cardiovascular disease, obesity and diabetes mellitus (Kupfer, 2005, McIntyre et al., 2006), which is directly associated with increased morbidity and mortality observed in this disorder. Notably, recent studies have found impairment in a number of cognitive functions in BD patients that are present even after remission of symptoms (Martinez-Aran et al., 2004, Robinson et al., 2006, Torres et al., 2007), suggesting that BD may be associated with persistent cognitive dysfunction. The exact neurochemical mechanisms underlying the pathophysiology of BD are not completely understood. Several hypotheses have been postulated including a role for monoamines, gamma-amino butyric acid (GABA), glutamate, and second messenger singling pathways. More recently, oxidative stress has been implicated and there is evidence accumulating to support its' role (Andreazza et al., 2007a, Gergerlioglu et al., 2007, Machado-Vieira et al., 2007, Selek et al., 2008, Savas et al., 2006, Ozcan et al., 2004, Ranjekar et al., 2003, Kuloglu et al., 2002, Abdalla et al., 1986).

Oxidative stress is defined as a “disturbance in pro-oxidant–antioxidant balance in favour of the former, leading to potential damage” (Sies, 1991). Free radicals and other so-called ‘reactive species’ are constantly produced in vivo by all body tissues, mainly during oxidative phosphorylation in the mitochondrial matrix (Adam-Vizi and Chinopoulos, 2006). Under normal circumstances, reactive oxygen species (ROS) are eliminated by cellular enzymatic and non-enzymatic antioxidant defences. Within the enzymatic mechanisms, superoxide dismutase (SOD) converts the superoxide radical (O₂⁻) into hydrogen peroxide (H₂O₂), whereas catalase and glutathione peroxidase (Gpx) metabolize H₂O₂ into H₂O + O₂ (19). If ROS are not effectively eliminated, they can cause oxidative cell injury, such as peroxidation of lipids (membranes and organelles), proteins (receptors and enzymes) and DNA. The end products of lipid peroxidation (lipid damage), especially malondialdehyde, are usually assessed through the levels of thiobarbituric acid reactive substances (TBARS) (Garcia et al., 2005). Another important free radicals is the nitric oxide (NO), a reactive nitrogen species (RNS). NO reacts rapidly with O₂⁻ to form peroxynitrite (ONOO⁻) which is a very reactive species (Furchgott and Zawadzki, 1980). Oxidative damage to proteins can be assessed using the protein carbonyl test, which measures the amount of carbonyl groups that are generated by reactions between ROS/RNS and pro-oxidant cations in amino-acid sites (Reznick et al., 1992).

Several recent studies reported that patients with BD have significant alterations in antioxidant enzymes (Andreazza et al., 2007a, Gergerlioglu et al., 2007, Machado-Vieira et al., 2007, Selek et al., 2008, Savas et al., 2006, Ozcan et al., 2004, Ranjekar et al., 2003, Kuloglu et al., 2002, Abdalla et al., 1986), lipid peroxidation (Andreazza et al., 2007a, Gergerlioglu et al., 2007, Savas et al., 2006, Ozcan et al., 2004, Ranjekar et al., 2003, Kuloglu et al., 2002) and nitric oxide levels (Gergerlioglu et al., 2007, Selek et al., 2008, Savas et al., 2006, Savas et al., 2005, Yanik et al., 2004, Savas et al., 2002). However, the findings are not consistent with some reporting increases while others reporting no change or reductions in various markers. The objective of this work, therefore, is to review the studies of oxidative stress markers in BD and to quantify the magnitude of differences from the pooled data for various markers between patients and controls using a meta-analytical design.