The objective of this proposal is to establish that the increased oxidative cell injury exists at the onset of psychosis and probably continued injury contributes to poor outcome of illness in some patients. The basis of this proposal is the initial findings from our previous studies of an impaired antioxidant defense and increased lipid peroxidation that were associated with the brain morphometric changes at the onset of psychosis. The proposed studies are an extension to examine in a systematic way the presence and extent of oxidative cell injury in periphery and its relationship to relevant neuropathology and neurotransmitter receptor-mediated signal transduction, and to elucidate the clinical implications in patients with a first episode of psychosis. The 4 year study will involve 40 first-episode psychosis patients at the D. D. Eisenhower Army Medical Center and 40 normal controls matched with patients for age, gender, education, ethnic background, and occupational status. Effects of oxidative cell injury will be examined in lymphocyte plasma membrane lipids, mitochondrial membranes, cellular proteins, and DNA (both Mitochondrial and nuclear). Specific measures will include membrane lipid peroxidation products (malondialdehyde, MDA), phospholipase A2 (PLA2), conjugated dienes and fatty acid contents, levels of carbonylated proteins, and DNA strand breaks. Activities of antioxidant enzymes (superoxide dismutase, glutathione peroxidase, and catalase) will be determined in red blood cells and in lymphocyte mitochondria. Plasma levels of MDA, PLA2, nonenzymatic antioxidants (vitamins C and E, urate), and micronutrients (copper, zinc, selenium) that are involved in activities of antioxidant enzymes will also be determined. Measures of antioxidants and indices of oxidative injury will be repeated after 6 and 12 weeks of neuroleptic treatment. Correlational studies will be conducted to examine the relationships of specific indices o oxidative injury with clinical parameters (history of premorbid functioning, severity of psychosis and negative symptoms at initial presentation, neurological signs, quality of immediate treatment response, early recurrence of psychosis after initial recovery, residual symptoms after three months of treatment, etc.), brain morphology using magnetic resonance imaging, and levels of neurotransmitter receptor-mediated phospholipid-derived release of second messengers (e.g., arachidonic acid and inositol polyphosphates). These studies will, albeit in peripheral cells, define the extent and nature of oxidative cell injury that will reflect the brain neuropathology associated with psychopathology at the onset of psychosis. If it is demonstrated in this comprehensive study that oxidative injury at the onset of psychosis contributes to a unfavorable early course of illness, it would suggest the need for adjunctive antioxidant treatment from the onset of psychosis. Studies on the nature of oxidative injury might then provide directions for developing rational and effective treatment strategies. Conceivably these could reduce the costs of clinical care by lowering risk of relapse and, hopefully, even prevent a deteriorating course of illness in some patients.

National Institute of Health (NIH)
National Center for Complementary & Alternative Medicine (NCCAM)
Research Project (R01)
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Clinical Neuroscience and Biological Psychopathology Review Committee (CNBP)
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Hopp, Craig
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Medical College of Georgia (MCG)
Schools of Medicine
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Buckley, Peter F; Pillai, Anilkumar; Evans, Denise et al. (2007) Brain derived neurotropic factor in first-episode psychosis. Schizophr Res 91:1-5
Mahadik, Sahebarao P; Evans, Denise R (2003) Is schizophrenia a metabolic brain disorder? Membrane phospholipid dysregulation and its therapeutic implications. Psychiatr Clin North Am 26:85-102
Evans, D R; Parikh, V V; Khan, M M et al. (2003) Red blood cell membrane essential fatty acid metabolism in early psychotic patients following antipsychotic drug treatment. Prostaglandins Leukot Essent Fatty Acids 69:393-9
Parikh, Vinay; Khan, Mohammad M; Mahadik, Sahebarao P (2003) Differential effects of antipsychotics on expression of antioxidant enzymes and membrane lipid peroxidation in rat brain. J Psychiatr Res 37:43-51
Parikh, Vinay; Evans, Denise R; Khan, Mohammad M et al. (2003) Nerve growth factor in never-medicated first-episode psychotic and medicated chronic schizophrenic patients: possible implications for treatment outcome. Schizophr Res 60:117-23
Khan, Mohammad M; Evans, Denise R; Gunna, Vijayasudha et al. (2002) Reduced erythrocyte membrane essential fatty acids and increased lipid peroxides in schizophrenia at the never-medicated first-episode of psychosis and after years of treatment with antipsychotics. Schizophr Res 58:1-10
Mahadik, Sahebarao P; Khan, Mohammad M; Evans, Denise R et al. (2002) Elevated plasma level of apolipoprotein D in schizophrenia and its treatment and outcome. Schizophr Res 58:55-62