Review
Oxidative stress in schizophrenia: An integrated approach

https://doi.org/10.1016/j.neubiorev.2010.10.008Get rights and content

Abstract

Oxidative stress has been suggested to contribute to the pathophysiology of schizophrenia. In particular, oxidative damage to lipids, proteins, and DNA as observed in schizophrenia is known to impair cell viability and function, which may subsequently account for the deteriorating course of the illness. Currently available evidence points towards an alteration in the activities of enzymatic and nonenzymatic antioxidant systems in schizophrenia. In fact, experimental models have demonstrated that oxidative stress induces behavioral and molecular anomalies strikingly similar to those observed in schizophrenia. These findings suggest that oxidative stress is intimately linked to a variety of pathophysiological processes, such as inflammation, oligodendrocyte abnormalities, mitochondrial dysfunction, hypoactive N-methyl-d-aspartate receptors and the impairment of fast-spiking gamma-aminobutyric acid interneurons. Such self-sustaining mechanisms may progressively worsen producing the functional and structural consequences associated with schizophrenia. Recent clinical studies have shown antioxidant treatment to be effective in ameliorating schizophrenic symptoms. Hence, identifying viable therapeutic strategies to tackle oxidative stress and the resulting physiological disturbances provide an exciting opportunity for the treatment and ultimately prevention of schizophrenia.

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)

  • H.G. Bernstein et al.

    Nitric oxide synthase-containing neurons in the human hypothalamus: reduced number of immunoreactive cells in the paraventricular nucleus of depressive patients and schizophrenics

    Neuroscience

    (1998)
  • J.E. Brenman et al.

    Synaptic signaling by nitric oxide

    Curr. Opin. Neurobiol.

    (1997)
  • L.M. Brzustowicz et al.

    Linkage disequilibrium mapping of schizophrenia susceptibility to the CAPON region of chromosome 1q22

    Am. J. Hum. Genet.

    (2004)
  • S.L. Buka et al.

    Maternal cytokine levels during pregnancy and adult psychosis

    Brain Behav. Immun.

    (2001)
  • J.H. Cabungcal et al.

    Transitory glutathione deficit during brain development induces cognitive impairment in juvenile and adult rats: relevance to schizophrenia

    Neurobiol. Dis.

    (2007)
  • J.L. Cadet et al.

    Free radical mechanisms in schizophrenia and tardive dyskinesia

    Neurosci. Biobehav. Rev.

    (1994)
  • J. Cai et al.

    Superoxide in apoptosis, mitochondrial generation triggered by cytochrome c loss

    J. Biol. Chem.

    (1998)
  • W. Cammer

    Apoptosis of oligodendrocytes in secondary cultures from neonatal rat brains

    Neurosci. Lett.

    (2002)
  • W. Cammer

    Protection of cultured oligodendrocytes against tumor necrosis factor-alpha by the antioxidants coenzyme Q(10) and N-acetyl cysteine

    Brain Res. Bull.

    (2002)
  • W. Cammer et al.

    Maturation of oligodendrocytes is more sensitive to TNF alpha than is survival of precursors and immature oligodendrocytes

    J. Neuroimmunol.

    (1999)
  • M.F. Casanova et al.

    A postmortem quantitative study of iron in the globus pallidus of schizophrenic patients

    Biol. Psychiatry

    (1990)
  • E. Casanueva et al.

    Iron and oxidative stress in pregnancy

    J. Nutr.

    (2003)
  • A. Chauhan et al.

    Oxidative stress in autism

    Pathophysiology

    (2006)
  • A. Contestabile

    Roles of NMDA receptor activity and nitric oxide production in brain development

    Brain Res. Brain Res. Rev.

    (2000)
  • J.K. Coward et al.

    Inhibition of catechol-O-methyltransferase by S-adenosylhomocysteine and S-adenosylhomocysteine sulfoxide, a potential transition-state analog

    Biochem. Pharmacol.

    (1972)
  • O. Dean et al.

    Glutathione depletion in the brain disrupts short-term spatial memory in the Y-mazein rats and mice

    Behav. Brain Res.

    (2009)
  • B.E. Deverman et al.

    Cytokines and CNS development

    Neuron

    (2009)
  • K.Q. Do et al.

    Redox dysregulation, neurodevelopment, and schizophrenia

    Curr. Opin. Neurobiol.

    (2009)
  • R. Dringen

    Metabolism and functions of glutathione in brain

    Prog. Neurobiol.

    (2000)
  • M.D. Fallin et al.

    Bipolar I disorder and schizophrenia: a 440-single-nucleotide polymorphism screen of 64 candidate genes among Ashkenazi Jewish case-parent trios

    Am. J. Hum. Genet.

    (2005)
  • C. Fendri et al.

    Oxidative stress involvement in schizophrenia pathophysiology: a review

    Encephale

    (2006)
  • T.F. Freund et al.

    Perisomatic inhibition

    Neuron

    (2007)
  • T.F. Freund

    Interneuron diversity series: rhythm and mood in perisomatic inhibition

    Trends Neurosci.

    (2003)
  • J.H. Gilmore et al.

    Exposure to infection and brain development: cytokines in the pathogenesis of schizophrenia

    Schizophr. Res.

    (1997)
  • A. Aguilar-Valles et al.

    Prenatal inflammation-induced hypoferremia alters dopamine function in the adult offspring in rat: relevance for schizophrenia

    PLoS One

    (2010)
  • S. Akbarian et al.

    Altered distribution of nicotinamide-adenine dinucleotide phosphate-diaphorase cells in frontal lobe of schizophrenics implies disturbances of cortical development

    Arch. Gen. Psychiatry

    (1993)
  • S. Akbarian et al.

    Distorted distribution of nicotinamide-adenine dinucleotide phosphate-diaphorase neurons in temporal lobe of schizophrenics implies anomalous cortical development

    Arch. Gen. Psychiatry

    (1993)
  • A. Aleman et al.

    Sex differences in the risk of schizophrenia: evidence from meta-analysis

    Arch. Gen. Psychiatry

    (2003)
  • A.C. Andreazza et al.

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

    Arch. Gen. Psychiatry

    (2010)
  • H. Baba et al.

    Expression of nNOS and soluble guanylate cyclase in schizophrenic brain

    Neuroreport

    (2004)
  • S.A. Back et al.

    Maturation-dependent vulnerability of oligodendrocytes to oxidative stress-induced death caused by glutathione depletion

    J. Neurosci.

    (1998)
  • M.M. Behrens et al.

    Interleukin-6 mediates the increase in NADPH-oxidase in the ketamine model of schizophrenia

    J. Neurosci.

    (2008)
  • M.M. Behrens et al.

    Ketamine-induced loss of phenotype of fast-spiking interneurons is mediated by NADPH-oxidase

    Science

    (2007)
  • M. Beneyto et al.

    Lamina-specific abnormalities of NMDA receptor-associated postsynaptic protein transcripts in the prefrontal cortex in schizophrenia and bipolar disorder

    Neuropsychopharmacology

    (2008)
  • D. Ben-Shachar

    Mitochondrial dysfunction in schizophrenia: a possible linkage to dopamine

    J. Neurochem.

    (2002)
  • D. Ben-Shachar et al.

    Increased mitochondrial complex I activity in platelets of schizophrenic patients

    Int. J. Neuropsychopharmacol.

    (1999)
  • D. Berg et al.

    Redox imbalance

    Cell Tissue Res.

    (2004)
  • Berk, M., Kapczinski, F., Andreazza, A.C., Dean, O.M., Giorlando, F., Maes, M., Yucel, M., Gama, C.S., Dodd, S., Dean,...
  • H.G. Bernstein et al.

    Increased number of nitric oxide synthase immunoreactive Purkinje cells and dentate nucleus neurons in schizophrenia

    J. Neurocytol.

    (2001)
  • B.K. Bitanihirwe et al.

    Glutamatergic deficits and parvalbumin-containing inhibitory neurons in the prefrontal cortex in schizophrenia

    BMC Psychiatry

    (2009)
  • Cited by (0)

    View full text