Progress in Neuro-Psychopharmacology and Biological Psychiatry
Elevated serum superoxide dismutase and thiobarbituric acid reactive substances in different phases of bipolar disorder and in schizophrenia
Introduction
Bipolar disorder (BD) and schizophrenia (SZ) are illnesses that share many epidemiologic and clinical features (Berrettini, 2000). There is also increasing data suggesting an overlap in genetic susceptibility across the two traditional classification categories (Craddock et al., 2006). Although the pathophysiological mechanisms underlying these disorders remain unclear, many studies point towards an involvement of oxidative stress in both BD (Andreazza et al., 2007a, Kuloglu et al., 2002, Ranjekar et al., 2003) and SZ (Akyol et al., 2002, Gama et al., 2006, Gama et al., 2008, Grignon and Chianetta, 2007, Lohr and Browning, 1995, Mahadik and Mukherjee, 1996, Yao et al., 1998, Ng et al., 2008).
Zeviani and Di Donato (2004) have described that neurological syndromes are the most frequent presentations of mitochondrial disorders. This is concordant with the brain being the body's most metabolically active organ. Several postmortem studies have recently demonstrated the involvement of mitochondrial dysfunction in the brains of both BD and SZ patients (Iwamoto et al., 2005, Karry et al., 2004, Konradi et al., 2004, MacDonald et al., 2006, Sun et al., 2006), suggesting that mitochondrial dysfunction may be a pathophysiological mechanism in these disorders.
Mitochondria are the major sources of reactive oxygen species (ROS), which are quenched by the antioxidant defense system, most notably, the enzymes: superoxide dismutases (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px). Of these, SOD activity has been the most frequently examined. However, in situations of imbalance between ROS production and antioxidant activity, oxidative damage occurs, generating deleterious effects on signal transduction, structural plasticity and cellular resilience, mostly by inducing lipid peroxidation in membranes, and oxidation of proteins and genes (Takuma et al., 2004). Excessive formation of ROS can damage mitochondria, and at the same time, mitochondrial dysfunction increases the production of ROS (Serrano and Klann, 2004).
The end products of lipid peroxidation, especially malondialdehyde (MDA) assessment through thiobarbituric reactive substances levels (TBARS), have been by far the most widely used indices of oxidative stress in clinical studies (Grignon and Chianetta, 2007, Andreazza et al., 2008). Oxidative stress is associated with secondary DNA damage, and notably, it has been demonstrated that BD patients have a marked increase in DNA damage in white blood cells, the extent of which was positively correlated with the severity of symptoms (Andreazza et al., 2007b).
Despite the proliferation of information on oxidative stress mechanisms in the psychiatric literature on the last decade (Ng et al., 2008), the different biochemical pathways that might mediate oxidative stress in different psychiatric disorders are not yet fully explained.
Thus, in attempt to clarify different ways in which oxidative stress is involved in BD and SZ, we compared serum SOD and TBARS measured in depressive, manic and euthymic bipolar patients, in chronically medicated schizophrenic patients and in a group of healthy controls.
Section snippets
Methods
This study protocol was approved by the Ethical Committee of the Hospital de Clínicas de Porto Alegre, RS, Brazil (HCPA). In accordance with the Declaration of Helsinki, all subjects were advised about the procedure and signed the informed consent prior to participation in the study. Ninety-seven SZ outpatients from the HCPA Schizophrenia Program and 83 BD patients from the HCPA Bipolar Disorder Program were enrolled in this study protocol. The diagnosis of BD was carried out using the
Results
The subjects' characteristics are summarized in Table 1. A greater prevalence of male over female patients was found in both manic and schizophrenic groups, when compared to any of the other groups. There was no significant difference on the mean age of the different groups, except for the comparison between depressed and schizophrenic patients (p < 0.02).
Serum SOD (U/mg protein) activity was significantly increased (p < 0.001) in manic (7.44 ± 3.88) and depressed (6.12 ± 4.64) BD patients and
Discussion
The present findings provide additional evidence of increased oxidative stress in SZ and BD. There is increasing evidence that mitochondrial dysfunction is important in the pathophysiology of BD (Kato, 2007) and SZ (Karry et al., 2004). During periods of high neuronal activity, a significant volume of oxygen is used to maintain neuronal membrane potentials, which subsequently may produce excessive ROS (Chance et al., 1979, Coyle and Puttfarcken, 1993). Mitochondrial dysregulation associated
Acknowledgements
Clarissa Severino Gama is funded by CNPq (PDE #200310/2007-0), Brazil; and Endeavour Awards Programme (#539/2008), Australia.
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