ReviewOxidative stress in schizophrenia: An integrated approach
Research highlights
▶ Evidence of oxidative stress in schizophrenia. ▶ Redox dysregulation during neurodevelopment may play a role in schizophrenia. ▶ Antioxidants may prove to be a useful adjunctive treatment for schizophrenia.
Introduction
Schizophrenia is a chronic, severe and disabling psychiatric illness that affects about 1% of the population worldwide (Jablensky et al., 1992, Perälä et al., 2007, McGrath et al., 2008). The symptoms of the disorder can be divided into three main categories: positive symptoms (e.g. delusions and hallucinations), negative symptoms (e.g. flat affect, lack of motivation and deficits in social function) and cognitive deficits (Carpenter, 1994, Tamminga and Holcomb, 2005). Although the symptoms that establish the diagnosis are usually not present until young adulthood, prodromal symptoms and endophenotypic features of cognitive and social deficits can precede psychotic illness and manifest in unaffected relatives.
The prevailing hypothesis for the etiology of schizophrenia is that variations in multiple risk genes, each contributing a subtle effect, interact with each other and with environmental stimuli to impact both early and late brain development (Weinberger, 1987, Lewis and Lieberman, 2000, McDonald and Murray, 2000, Lewis and Levitt, 2002, Sawa and Snyder, 2002, Mueser and McGurk, 2004, Harrison and Weinberger, 2005, Jaaro-Peled et al., 2009). Although a clear mechanism underlying the pathogenesis of schizophrenia remains unknown, oxidative stress as a consequence of aberrant reduction–oxidation (redox) control has become an attractive hypothesis for explaining, at least in part, the pathophysiology of schizophrenia (Cadet and Kahler, 1994, Reddy and Yao, 1996, Fendri et al., 2006, Li et al., 2006, Ng et al., 2008, Behrens and Sejnowski, 2009, Dean et al., 2009a, Do et al., 2009, Do et al., 2010, Wood et al., 2009a, Yao et al., 2001, Yao et al., 2004, Yao et al., 2006, Yao et al., 2009, Matsuzawa and Hashimoto, 2010, Zhang et al., 2010).
The last four decades have witnessed a great increase in our knowledge of the basic molecular mechanisms underlying oxidative stress. Most remarkably, functional genetic analysis has identified molecular mechanisms that are conserved in yeast, nematodes, flies and mammals. Analysis of these model systems suggests that redox mechanisms are not fixed but are reversible. Similarly, cognitive dysfunction associated with an imbalance in the generation and clearance of reactive oxygen species (ROS) and reactive nitrogen species (RNS) also seems to be variable and possibly open to modification (Kamsler and Segal, 2003, Calabrese et al., 2006, Massaad and Klann, 2010). Recent studies have implicated these mechanisms in the control of brain pathology, raising the possibility that altered regulation of fundamental mechanisms of oxidative stress may contribute to the pathogenesis of schizophrenia and related disorders (Floyd, 1999, Chauhan and Chauhan, 2006, Ng et al., 2008, Do et al., 2009, Wood et al., 2009a, Berk et al., 2010).
In this review, we explore the basic molecular mechanisms of redox regulation in the brain. We begin with a brief description of oxidative stress and its regulation. Then we turn to a discussion of clinical and preclinical findings of redox impairment that induce brain pathology in schizophrenia, through mechanisms that likely involve aberrant inflammatory responses, mitochondrial dysfunction, oligodendrocyte abnormalities, epigenetic changes, hypoactive N-methyl-d-aspartate (NMDA) glutamate receptors and the impairment of fast-spiking gamma-aminobutyric acid (GABA) interneurons (see Fig. 1). There is hope that our growing understanding of the molecular basis of oxidative stress mechanisms within the brain will allow us to rise to the challenge of treating and preventing the clinical symptoms and cognitive deficits associated with schizophrenia.
Section snippets
What is oxidative stress?
Oxidative stress occurs when cellular antioxidant defense mechanisms fail to counterbalance and control endogenous ROS and RNS generated from normal oxidative metabolism or from pro-oxidant environmental exposures (Kohen and Nyska, 2002, Berg et al., 2004). The link between oxidative stress and the pathophysiology of disease can be explained by the physiological phenomenon commonly referred to as the ‘oxygen paradox’ (Davies, 1995). This concept states that oxygen plays contradictory roles, one
Antioxidant systems
The potential toxicity of ROS/RNS in the brain is counteracted by a number of antioxidants that can protect the brain against oxidative damage in several ways, including: (1) removal of ROS/RNS, (2) inhibition of ROS/RNS formation, and (3) binding metal ions needed for catalysis of ROS/RNS generation. Glutathione peroxidase and glutathione reductase are well-known intracellular antioxidant enzymes. Glutathione peroxidase converts peroxides and hydroxyl radicals into nontoxic forms, often with
Alterations in antioxidant defense systems in schizophrenia
Clinical and preclinical investigations of the actions of antioxidative defense systems in the brain suggest several ways in which ongoing oxidative stress might impact the occurrence and course of schizophrenia. In this section, we describe clinical and preclinical studies that may shed light on the role that oxidative stress plays in schizophrenia.
Nitric oxide in schizophrenia
Evidence is accumulating that NO may be involved in the pathophysiology of schizophrenia given the various roles that NO plays in the brain, such as regulating synaptic plasticity (Hölscher and Rose, 1992), neurotransmitter release (Lonart et al., 1992), and neurodevelopment (Truman et al., 1996, Hindley et al., 1997, Downen et al., 1999, Contestabile, 2000, Gibbs, 2003). Nitric oxide is especially important as the second messenger of NMDA receptor activation, which interacts with both
Imbalance in homocysteine metabolism and epigenetic changes in schizophrenia
Hyperhomocysteinaemia (a medical condition characterized by an abnormally elevated level of homocysteine in the blood) can cause oxidative stress via a number of mechanisms such as auto-oxidation of homocysteine to form ROS (Heinecke et al., 1987), increased lipid peroxidation (Jones et al., 1994) and reduced production of glutathione peroxidase (Upchurch et al., 1997). A recent study by Brown et al. (2007) reported that higher maternal homocysteine levels may be a risk factor for
Genetic susceptibility to schizophrenia
Genetic factors may also contribute in modulating the threshold for vulnerability to oxidative stress in schizophrenia (for a review see Kodavali et al., 2010). Recent evidence has shown manganese superoxide dismutase (Akyol et al., 2005) and glutathione S-transferase T1 (Saadat et al., 2007) to be associated with schizophrenia. A functional polymorphism in the glutathione S-transferase p1 gene has been reported to be associated with vulnerability to develop psychosis in the setting of
Neurotransmitter metabolism and oxidative stress in schizophrenia
The biological effects of neurotransmitters are linked to their chemical properties. It has been shown that metabolism of serotonin (Yao et al., 2009), glutamate (Smythies, 1999) and dopamine (Smythies, 1999) play important roles in mediating redox balance within biological systems. These neurotransmitters have generated a great deal of research in a variety of mental disorders, including schizophrenia (Grima et al., 2003, Smythies, 1999, Yao et al., 2009). In this section, we specifically
Abnormal iron metabolism as a mechanism for oxidative stress
Several studies have implicated imbalances of trace elements, including manganese, zinc, copper, and iron in schizophrenia (Yanik et al., 2004, Rahman et al., 2009). A disruption in the homeostasis of the latter two redox-active metals is particularly significant in light of the increases in oxidative stress parameters such as lipid peroxidation, and the oxidative damage to proteins and nucleic acids. Because free iron has been implicated in undergoing redox transitions in vivo (via
Mitochondrial dysfunction and abnormal energy metabolism in schizophrenia
Oxidative phosphorylation in the mitochondria generates superoxide anion. Furthermore, enzymatic oxidation of biogenic amines by monoamine oxidase in the mitochondrial outer membrane produces hydrogen peroxide. Damaged mitochondria not only produce more oxidants, but mitochondria are also vulnerable to oxidative stress (Kowaltowski and Vercesi, 1999). Notably, peroxidation of membrane lipids yields toxic aldehydes (Keller et al., 1997), which impair critical mitochondrial enzymes (Humphries and
Inflammatory response induces oxidative stress in schizophrenia
Maternal exposure to infection during pregnancy has been associated with an increased risk of offspring developing schizophrenia (Brown and Susser, 2002, Brown and Derkits, 2010). Although the epidemiological relationship between in utero infections and schizophrenia remain unclear, the maternal cytokine-associated inflammatory response to infection may be a crucial link, as the identity of the pathogen seems irrelevant (Gilmore and Jarskog, 1997, Buka et al., 2001, Pearce, 2001, Brown, 2006,
Oligodendrocyte dysfunction in schizophrenia
Schizophrenia has long been considered a disorder consisting of a disconnection between different cortical areas (Friston and Frith, 1995, Stephan et al., 2006). Given that white matter constitutes the anatomical infrastructure for neural connectivity, it has been hypothesized that aberrant connectivity of brain regions may explain altered processing patterns documented by functional neuroimaging and electrophysiology studies in patients with schizophrenia (Bartzokis, 2002, Hulshoff Pol et al.,
Redox dysregulation of NMDA-receptor mediated transmission in parvalbumin-containing interneurons
Although the evidence from experimental studies and from postmortem investigation shows that NMDA receptor dysfunction has relevance to schizophrenia, it is still debatable as to which specific NMDA receptor subunits are involved in the cascade of molecular events leading to the neuronal deficits and dysfunction associated with schizophrenia.
Postmortem evidence from human brain has shown that the expression of the NR2A subunit is reduced in subjects with schizophrenia (Beneyto and
Current therapeutic modalities
Therapy using antioxidants has the potential to prevent, delay, or ameliorate many neurologic disorders including schizophrenia (Delanty and Dichter, 2000, Moosmann and Behl, 2002, Ng et al., 2008, Dodd et al., 2008, Reddy and Reddy, 2010, Seybolt, 2010). For example, supplementation of omega-3 poly unsaturated fatty acids in combination with ascorbic acid and α-tocopherol is effective in improving psychopathology (viz. increased scores on the Brief Psychiatric Rating and the PANNS) in
Conclusion
There is growing evidence supporting increased oxidative stress in schizophrenia with likely contributions from environment, genetic and immunological factors. However, the exact molecular mechanisms are yet to be determined. Indeed, the maintenance of redox balance within cells is a primary component of homeostasis underlying neuronal survival. It may not be too surprising therefore that any process that leads to a disruption of the redox balance can drastically interfere with a range of other
Conflict of interest
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
Acknowledgements
This work was supported by NIH grants MH080272, MH076060, MH082235 (to T-U. W.W.). We thank Dr. Jean-Charles Paterna and Dr. Helen Pothuizen for carefully reading through the manuscript and providing helpful comments. We are also grateful to two anonymous reviewers, whose comments have greatly improved the manuscript.
References (320)
- et al.
Normalization by nicotine of deficient auditory sensory gating in the relatives of schizophrenics
Biol. Psychiatry
(1992) - et al.
Association between Ala-9Val polymorphism of Mn-SOD gene and schizophrenia
Prog. Neuropsychopharmacol. Biol. Psychiatry
(2005) Schizophrenia: the fundamental questions
Brain Res. Brain Res. Rev.
(2000)- et al.
Homocysteine levels in newly admitted schizophrenic patients
J. Psychiatr. Res.
(2004) - et al.
Supplementation with a combination of omega-3 fatty acids and antioxidants (vitamins E and C) improves the outcome of schizophrenia
Schizophr. Res.
(2003) - et al.
Neurodegenerative disorders in humans: the role of glutathione in oxidative stress-mediated neuronal death
Brain Res. Brain Res. Rev.
(1997) Schizophrenia: breakdown in the well-regulated lifelong process of brain development and maturation
Neuropsychopharmacology
(2002)- et al.
Does schizophrenia arise from oxidative dysregulation of parvalbumin-interneurons in the developing cortex?
Neuropharmacology
(2009) - et al.
Mitochondria, synaptic plasticity, and schizophrenia
Int. Rev. Neurobiol.
(2004) - et al.
N-acetyl cysteine as a glutathione precursor for schizophrenia – a double-blind, randomized, placebo-controlled trial
Biol. Psychiatry
(2008)