REVIEW ARTICLE Oxidative stress, antioxidant defenses, and schizophrenia Wei-Yi Ong 1,2 BDS PhD, Kang Sim 3 MBBS MMed (Psychiatry) FAMS & Akhlaq A. Farooqui 4 PhD 1 Department of Anatomy, National University of Singapore, Singapore 2 Aging/Neurobiology Research Programme, National University of Singapore, Singapore 3 Institute of Mental Health, Singapore 4 Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, Ohio, USA Keywords antioxidant defenses, free radicals, mitochondria, oxidative stress, schizophrenia Correspondence Wei-Yi Ong, Department of Anatomy, National University of Singapore, Singapore 119260. Tel: 165 65 163 662 Email: wei_yi_ong@nuhs.edu.sg Received 25 September 2010 Accepted 26 October 2010 DOI:10.1111/j.1758-5872.2010.00090.x Abstract Schizophrenia is a complex neuropsychiatric disorder with a prevalence of nearly 1% of the world population. Accumulating evidence suggests that increase in production of reactive oxygen species (ROS) along with de- crease in antioxidants and antioxidant enzymes (superoxide dismutase, glutathione peroxidase and catalase) may be closely associated with the pathogenesis of schizophrenia. Genes associated with glutamate transmis- sion, dopamine transmission, synaptic plasticity, mitochondrial function, oxidative stress, lipid metabolism, and neuroinflammation have been closely linked to schizophrenia. Proteins encoded by many of the above genes affect the level of ROS, and lipid mediators that regulate signaling in the brain through cross-talk among glutamate, dopamine, and eicosanoid receptors. Under physiological conditions, this refines the communication between neurons, glial cells and vascular cells, but in schizophrenia, the cross-talk might initiate and promote oxidative stress-mediated abnormal neuronal signaling responsible for symptoms of the disease. Introduction Schizophrenia is a devastating brain disorder with abnormalities in perception of reality (e.g. hallucina- tions and delusions). In addition, patients suffer from cognitive deficits in several domains, including mem- ory, attention and executive functioning. Together, these result in significant morbidity for the individual and substantial burden of care to the family (Castle & Gill, 1992). The disease has its onset typically in early adulthood, and approximately 1% of the population can be affected throughout the lifetime (Goldner et al., 2002; Bhugra, 2005). Twin and family studies have implicated genetic factors as being important in the etiology of schizophrenia (McGue & Gottesman, 1991). Several candidate genes have been suggested, with strong evidence for those encoding D-amino acid oxidase, D-amino acid oxidase activator, dysbindin 1, dystrobrevin-binding protein 1, neuregulin 1, v-erb-a erythroblastic leukemia viral oncogene homolog 4 (avian), nitric oxide synthase 1 (neuronal), neurogra- nin and disrupted in schizophrenia 1 (DISC1), as well as several neurotrophic factors. The proteins encoded by the above genes are involved in intracellular cal- cium ion homeostasis, neurotransmitter release, and synaptic plasticity (Giegling et al., 2010). Although the etiology of schizophrenia remains to be fully eluci- dated, specific genetic factors are thought to interact with environmental factors or stressors in the onset and course of schizophrenia (Fulker, 1973; Mittal et al., 2008; Haukvik et al., 2010). This is propounded in the stress–diathesis model, whereby an inherent vulner- ability (or diathesis) in some individuals, may be unmasked by biological, psychological or environmen- tal stressors. A major challenge involves understanding the precise function of the specific genes implicated and their potential interactions with other genes and/ or the environment (van Os et al., 2008). The brain is vulnerable to oxidative injury, because its membranes are preferentially enriched in oxyradical-sensitive polyunsaturated fatty acids (PUFAs). Oxygen free radicals affect critical physiolo- gical functions in neuronal development, differentia- tion, and signal transduction. The major sources of oxyradicals and reactive oxygen species (ROS) are the mitochondrial respiratory chain, phospholipase 180 Asia-Pacific Psychiatry 2 (2010) 180–190 Copyright c  2010 Blackwell Publishing Asia Pty Ltd Asia-Pacific Psychiatry ISSN 1758-5864 Official journal of the Pacific Rim College of Psychiatrists