An updated meta-analysis of oxidative stress markers in bipolar disorder
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)
- et al.
Serum S100B and antioxidant enzymes in bipolar patients
Journal of Psychiatric Research
(2007) - et al.
DNA damage in bipolar disorder
Psychiatry Research
(2007) - et al.
Oxidative stress markers in bipolar disorder: a meta-analysis
Journal of Affective Disorders
(2008) - et al.
Effects of lithium therapy on Na+–K+-ATPase activity and lipid peroxidation in bipolar disorder
Progress in Neuro-Psychopharmacology and Biological Psychiatry
(2012) - et al.
DNA fragmentation is increased in non-GABAergic neurons in bipolar disorder but not in schizophrenia
Schizophrenia Research
(2007) - et al.
Mitochondrial dysfunction and pathology in bipolar disorder and schizophrenia
International Journal of Developmental Neuroscience
(2011) - et al.
Increased oxidative stress and DNA damage in bipolar disorder: a twin-case report
Progress in Neuro-Psychopharmacology and Biological Psychiatry
(2007) - et al.
Changes in nitric oxide level and superoxide dismutase activity during antimanic treatment
Progress in Neuro-Psychopharmacology and Biological Psychiatry
(2007) - et al.
Decreased mRNA expression of uncoupling protein 2, a mitochondrial proton transporter, in post-mortem prefrontal cortex from patients with bipolar disorder and schizophrenia
Neuroscience Letters
(2011) - et al.
Oxidative stress induces DNA demethylation and histone acetylation in SH-SY5Y cells: potential epigenetic mechanisms in gene transcription in Abeta production
Neurobiology of Aging
(2013)
Peripheral biomarkers and illness activity in bipolar disorder
Journal of Psychiatric Research
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
Oxidative stress parameters in unmedicated and treated bipolar subjects during initial manic episode: a possible role for lithium antioxidant effects
Neuroscience Letters
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
Bipolar disorder diagnosis: challenges and future directions
Lancet
Reduced antioxidant defense systems in schizophrenia and bipolar I disorder
Progress in Neuro-Psychopharmacology and Biological Psychiatry
Decreased antioxidant enzymes and membrane essential polyunsaturated fatty acids in schizophrenic and bipolar mood disorder patients
Psychiatry Research
The course of nitric oxide and superoxide dismutase during treatment of bipolar depressive episode
Journal of Affective Disorders
Activities of superoxide-dismutase and glutathione-peroxidase in schizophrenic and manic-depressive patients
Clinical Chemistry
Treatment with lithium, alone or in combination with olanzapine, relieves oxidative stress but increases atherogenic lipids in bipolar disorder
Tohoku Journal Experimental Medicine
3-Nitrotyrosine and glutathione antioxidant system in patients in the early and late stages of bipolar disorder
Journal of Psychiatry and Neuroscience
Mitochondrial complex I activity and oxidative damage to mitochondrial proteins in the prefrontal cortex of patients with bipolar disorder
Archives of General Psychiatry
Specific subcellular changes in oxidative stress in prefrontal cortex from patients with bipolar disorder
Journal of Neurochemistry
DNA fragmentation decreased in schizophrenia but not bipolar disorder
Archives of General Psychiatry
Cited by (265)
Peripheral markers of nitrosative stress in children with autism spectrum disorder and bipolar disorder comorbidity during euthymic phase
2023, Research in Autism Spectrum DisordersZingerone neuroprotective effects in a rat model of manic-like behavior induced by ketamine
2023, Learning and MotivationEndocan: A novel biomarker of endothelial dysfunction in depression?
2023, Journal of Psychiatric Research