Elsevier

Psychiatry Research

Volume 218, Issues 1–2, 15 August 2014, Pages 61-68
Psychiatry Research

An updated meta-analysis of oxidative stress markers in bipolar disorder

https://doi.org/10.1016/j.psychres.2014.04.005Get rights and content

Abstract

Despite its debilitating symptoms, the pathophysiology of bipolar disorder (BD) remains unclear. One consistently compelling finding, however, has been the presence of oxidative stress. In the present investigation, we conducted a meta-analysis of studies that measured oxidative stress markers in BD patients compared to healthy controls. Search terms and selection criteria were determined a priori to identify and include all studies that measured a marker of oxidative stress in BD compared to healthy controls. Eight markers were included: superoxide dismutase, catalase, protein carbonyl, glutathione peroxidase, 3-nitrotyrosine, lipid peroxidation, nitric oxide, and DNA/RNA damage. A meta-analysis of standardized means was conducted using a random-effects model with generic inverse weighting. Between-study heterogeneity, publication bias, and sensitivity analyses were also examined for each marker. Twenty-seven papers were included in the meta-analysis, which comprised a total of 971 unique patients with BD and 886 healthy controls. Lipid peroxidation, DNA/RNA damage, and nitric oxide were significantly increased in BD patients compared to healthy controls. Additionally, the effect size for lipid peroxidation was very high. Publication bias was not detected for any of the markers. The main limitations in this meta-analysis are the high degree of heterogeneity between studies and the small number of studies used in the analysis of some markers. Additionally, the sensitivity analysis indicated that some results are not very robust. The results from this meta-analysis support the role of oxidative stress in bipolar disorder, especially to DNA, RNA, and lipids.

Introduction

Psychiatry, unlike most other fields of medicine, lacks specific and reliable biomarkers to diagnose and monitor illness. Although clinician observation is important in many branches of medicine, most also utilize diagnostic tests. Bipolar disorder can be difficult to diagnose because of symptom overlap with other mood and psychotic disorders such as major depressive disorder and schizophrenia. Genetic epidemiology findings have also provided evidence of shared genetic risk factors between bipolar disorder, schizophrenia, and major depressive disorder (Craddock and Owen, 2005). There may be a long delay (up to 10 years) between illness onset and a diagnosis of bipolar disorder in which time a misdiagnosis may lead to ineffective treatment and worse outcomes. For example, a misdiagnosis of BD as unipolar depression may lead to inappropriate prescriptions, such as the use of antidepressants without a mood-stabilizing drug, which may lead to mania and poor clinical and functional outcomes (Phillips and Kupfer, 2013). The development of a biomarker for bipolar disorder would improve diagnostic accuracy and potentially allow intervention at early stages of the illness, which may be critical to lowering the lifetime illness burden (Perry et al., 1999, Miklowitz et al., 2013).

The complexity of bipolar disorder makes the identification of its pathophysiology a challenge. One consistently compelling finding of biological alterations in BD is oxidative stress damage. A recent positional paper from the biomarkers network from the International Society for Bipolar Disorder (ISBD-BIONET) included oxidative stress markers, among others, as potential biomarkers for BD (Frey et al., 2013). Although many oxidative stress markers have been investigated in BD, the findings are not always consistent; some studies have identified oxidative damage to DNA, RNA, proteins, and lipids in BD subjects, while others report that altered levels of some antioxidant enzymes are altered. These results are supported by evidence such as mitochondrial DNA mutations and decreased levels of proteins from the mitochondrial electron transport chain. A meta-analysis from our group in 2008 showed a statistically significant increase in lipid peroxidation and nitric oxide in BD (Andreazza et al., 2008). Since then, there have been many additional studies and therefore it is the objective of this analysis to incorporate these new results and to identify any new oxidative stress markers in BD.

Section snippets

Search strategy

A prospective protocol for this study was developed a priori with search terms and inclusion criteria chosen in an attempt to include all relevant publications. Web of Science, BIOSIS, and MEDLINE databases were searched for the term bipolar disorder with the following: oxidative stress, reactive oxygen species, free radicals, antioxidant, nitric oxide, lipid peroxidation, TBARS, protein carbonyl, 3-nitrotyrosine, catalase, glutathione, DNA oxidation, DNA damage, or DNA fragmentation.

Results

In total, 226 studies were screened and 29 fit the selection criteria. Of the 226 screened papers, 68 were review articles, 48 were animal or cell studies, 51 did not measure an included marker of oxidative stress, 28 were genetic studies, and two did not include a healthy control group. Twenty-seven studies were included in the meta-analysis out of the 29 that fit the selection criteria; two studies were excluded due to missing means and standard deviations (Benes et al., 2003, Buttner et al.,

Discussion

This meta-analysis further supports the presence of oxidative damage in BD; specifically, our results showed increased lipid peroxidation, increased DNA/RNA damage, and increased levels of nitric oxide in BD patients compared to healthy controls. Many lines of examination in the pathophysiology of BD converge on oxidative stress and an underlying abnormality in oxidative energy generation. Mitochondria are intracellular organelles that are responsible for ATP production through oxidative

References (49)

  • F. Kapczinski et al.

    Peripheral biomarkers and illness activity in bipolar disorder

    Journal of Psychiatric Research

    (2011)
  • M. Kunz et al.

    Elevated serum superoxide dismutase and thiobarbituric acid reactive substances in different phases of bipolar disorder and in schizophrenia

    Progress in Neuro-Psychopharmacology and Biological Psychiatry

    (2008)
  • R. Machado-Vieira et al.

    Oxidative stress parameters in unmedicated and treated bipolar subjects during initial manic episode: a possible role for lithium antioxidant effects

    Neuroscience Letters

    (2007)
  • D.J. Miklowitz et al.

    Early Intervention for Symptomatic Youth at Risk for Bipolar Disorder: a randomized trial of family-focused therapy

    Journal of the American Academy of Child and Adolescent Psychiatry

    (2013)
  • M.L. Phillips et al.

    Bipolar disorder diagnosis: challenges and future directions

    Lancet

    (2013)
  • M. Raffa et al.

    Reduced antioxidant defense systems in schizophrenia and bipolar I disorder

    Progress in Neuro-Psychopharmacology and Biological Psychiatry

    (2012)
  • P.K. Ranjekar et al.

    Decreased antioxidant enzymes and membrane essential polyunsaturated fatty acids in schizophrenic and bipolar mood disorder patients

    Psychiatry Research

    (2003)
  • S. Selek et al.

    The course of nitric oxide and superoxide dismutase during treatment of bipolar depressive episode

    Journal of Affective Disorders

    (2008)
  • D.S.P. Abdalla et al.

    Activities of superoxide-dismutase and glutathione-peroxidase in schizophrenic and manic-depressive patients

    Clinical Chemistry

    (1986)
  • R. Aliyazicioglu et al.

    Treatment with lithium, alone or in combination with olanzapine, relieves oxidative stress but increases atherogenic lipids in bipolar disorder

    Tohoku Journal Experimental Medicine

    (2007)
  • A.C. Andreazza et al.

    3-Nitrotyrosine and glutathione antioxidant system in patients in the early and late stages of bipolar disorder

    Journal of Psychiatry and Neuroscience

    (2009)
  • A.C. Andreazza et al.

    Mitochondrial complex I activity and oxidative damage to mitochondrial proteins in the prefrontal cortex of patients with bipolar disorder

    Archives of General Psychiatry

    (2010)
  • A.C. Andreazza et al.

    Specific subcellular changes in oxidative stress in prefrontal cortex from patients with bipolar disorder

    Journal of Neurochemistry

    (2013)
  • F.M. Benes et al.

    DNA fragmentation decreased in schizophrenia but not bipolar disorder

    Archives of General Psychiatry

    (2003)
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