Oxidative/Nitrosative stress in psychiatric disorders: are we there yet?

While oxidative stress has a clear role in neurodegenerative diseases, its involvement in psychiatric disorders is only beginning to be understood. Evidence for oxidative stress and redox dysregulation in psychiatric disorders is rapidly mounting, and preclinical data are increasingly suggesting oxidative stress can affect brain circuits involved in schizophrenia, yielding altered behaviors. This issue of Schizophrenia Bulletin covers some recent developments in human and animal studies highlighting the possibility of oxidative and nitrosative stress contributing to abnormal behaviors. Hayes et al 1 present data of inflammation-related measures in patients, at-risk subjects, and healthy controls revealing altered cytokines in the cerebrospinal fluid (CSF) of patients and at-risk mental state subjects. Fournier et al 2 provide an interesting metabolomics approach in cells derived from patients and controls that highlight the possibility of using metabolic signatures of oxidative stress reactivity as biomarkers for prodrome or early psychosis. Overall, the articles point to the use of oxidative/nitrosative stress and inflammation measures as biomarkers for early psychosis and may pave the way to novel therapeutic approaches.

[1]  P Boesiger,et al.  Schizophrenia: glutathione deficit in cerebrospinal fluid and prefrontal cortex in vivo , 2000, The European journal of neuroscience.

[2]  Thomas Werge,et al.  Redox dysregulation in the pathophysiology of schizophrenia and bipolar disorder: insights from animal models. , 2013, Antioxidants & redox signaling.

[3]  R. Pinkas-Kramarski,et al.  Neuregulin rescues PC12-ErbB4 cells from cell death induced by H(2)O(2). Regulation of reactive oxygen species levels by phosphatidylinositol 3-kinase. , 2001, The Journal of biological chemistry.

[4]  M. Knyazeva,et al.  Glutathione Precursor N-Acetyl-Cysteine Modulates EEG Synchronization in Schizophrenia Patients: A Double-Blind, Randomized, Placebo-Controlled Trial , 2012, PloS one.

[5]  P. Kochunov,et al.  Electrophysiological intermediate biomarkers for oxidative stress in schizophrenia , 2013, Clinical Neurophysiology.

[6]  R. Kraftsik,et al.  Early-Life Insults Impair Parvalbumin Interneurons via Oxidative Stress: Reversal by N-Acetylcysteine , 2013, Biological Psychiatry.

[7]  Ravinder Reddy,et al.  Altered Glutathione Redox State in Schizophrenia , 2005, Disease markers.

[8]  M. Keshavan,et al.  Antioxidants, redox signaling, and pathophysiology in schizophrenia: an integrative view. , 2011, Antioxidants & redox signaling.

[9]  M. Cuénod,et al.  Redox dysregulation, neurodevelopment, and schizophrenia , 2009, Current Opinion in Neurobiology.

[10]  Jennifer M. Coughlin,et al.  Marked reduction of soluble superoxide dismutase-1 (SOD1) in cerebrospinal fluid of patients with recent-onset schizophrenia , 2013, Molecular Psychiatry.

[11]  Reto Meuli,et al.  Glutathione Precursor, N-Acetyl-Cysteine, Improves Mismatch Negativity in Schizophrenia Patients , 2008, Neuropsychopharmacology.

[12]  T. Sejnowski,et al.  Behavioral and neurochemical consequences of cortical oxidative stress on parvalbumin-interneuron maturation in rodent models of schizophrenia , 2012, Neuropharmacology.

[13]  F. Schneider,et al.  Rationale and baseline characteristics of PREVENT: a second-generation intervention trial in subjects at-risk (prodromal) of developing first-episode psychosis evaluating cognitive behavior therapy, aripiprazole, and placebo for the prevention of psychosis. , 2011, Schizophrenia bulletin.

[14]  P. O’Donnell Adolescent onset of cortical disinhibition in schizophrenia: insights from animal models. , 2011, Schizophrenia bulletin.

[15]  T. Werge,et al.  Impaired glutathione synthesis in schizophrenia: Convergent genetic and functional evidence , 2007, Proceedings of the National Academy of Sciences.

[16]  U. Meyer Developmental neuroinflammation and schizophrenia , 2013, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[17]  T. Hensch,et al.  Perineuronal nets protect fast-spiking interneurons against oxidative stress , 2013, Proceedings of the National Academy of Sciences.

[18]  S. Snyder,et al.  S-nitrosylated GAPDH initiates apoptotic cell death by nuclear translocation following Siah1 binding , 2005, Nature Cell Biology.

[19]  M. Dickman,et al.  Proline modulates the intracellular redox environment and protects mammalian cells against oxidative stress. , 2008, Free radical biology & medicine.

[20]  P. O’Donnell Cortical interneurons, immune factors and oxidative stress as early targets for schizophrenia , 2012, The European journal of neuroscience.

[21]  H. Beck,et al.  N-acetyl Cysteine Treatment Rescues Cognitive Deficits Induced by Mitochondrial Dysfunction in G72/G30 Transgenic Mice , 2011, Neuropsychopharmacology.

[22]  August G. Wang,et al.  Schizophrenia and oxidative stress: glutamate cysteine ligase modifier as a susceptibility gene. , 2006, American journal of human genetics.

[23]  Peter Buckley,et al.  Meta-Analysis of Oxidative Stress in Schizophrenia , 2013, Biological Psychiatry.

[24]  R. Kraftsik,et al.  Redox Dysregulation Affects the Ventral But Not Dorsal Hippocampus: Impairment of Parvalbumin Neurons, Gamma Oscillations, and Related Behaviors , 2010, The Journal of Neuroscience.

[25]  Mahmut Bulut,et al.  Beneficial effects of N-acetylcysteine in treatment resistant schizophrenia , 2009, The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry.

[26]  S. Akhondzadeh,et al.  N-Acetylcysteine as an Adjunct to Risperidone for Treatment of Negative Symptoms in Patients With Chronic Schizophrenia: A Randomized, Double-Blind, Placebo-Controlled Study , 2013, Clinical neuropharmacology.

[27]  M. Cuénod,et al.  N-Acetyl Cysteine as a Glutathione Precursor for Schizophrenia—A Double-Blind, Randomized, Placebo-Controlled Trial , 2008, Biological Psychiatry.

[28]  K. Nakazawa,et al.  Social Isolation Exacerbates Schizophrenia-Like Phenotypes via Oxidative Stress in Cortical Interneurons , 2013, Biological Psychiatry.

[29]  Alexander W. Johnson,et al.  Cognitive and motivational deficits together with prefrontal oxidative stress in a mouse model for neuropsychiatric illness , 2013, Proceedings of the National Academy of Sciences.

[30]  M. Cuénod,et al.  Impaired metabolic reactivity to oxidative stress in early psychosis patients. , 2014, Schizophrenia bulletin.

[31]  Jun-Feng Wang,et al.  Decreased levels of glutathione, the major brain antioxidant, in post-mortem prefrontal cortex from patients with psychiatric disorders. , 2011, The international journal of neuropsychopharmacology.

[32]  P. Kochunov,et al.  No evidence of exogenous origin for the abnormal glutathione redox state in schizophrenia , 2013, Schizophrenia Research.

[33]  L. Armengol,et al.  Association of common copy number variants at the glutathione S-transferase genes and rare novel genomic changes with schizophrenia , 2010, Molecular Psychiatry.

[34]  David A. Lewis,et al.  Cortical parvalbumin interneurons and cognitive dysfunction in schizophrenia , 2012, Trends in Neurosciences.

[35]  Jennifer M. Coughlin,et al.  Inflammatory molecular signature associated with infectious agents in psychosis. , 2014, Schizophrenia bulletin.

[36]  R. Reddy,et al.  Free radical pathology in schizophrenia: a review. , 1996, Prostaglandins, leukotrienes, and essential fatty acids.

[37]  R. Emsley,et al.  Social isolation rearing induces mitochondrial, immunological, neurochemical and behavioural deficits in rats, and is reversed by clozapine or N-acetyl cysteine , 2013, Brain, Behavior, and Immunity.