OXIDATIVE CELL INJURY: FIRST-EPISODE PSYCHOTIC PATIENTS

本建议的目的是确定在精神病发病时存在氧化细胞损伤的增加，并且可能持续的损伤导致一些患者的疾病预后不良。这一建议的基础是我们先前研究的初步发现，即抗氧化防御受损和脂质过氧化增加与精神病发病时大脑形态变化有关。本研究旨在以系统的方式研究外周氧化细胞损伤的存在和程度及其与相关神经病理学和神经递质受体介导的信号转导的关系，并阐明首发精神病患者的临床意义。这项为期4年的研究将包括D. D.艾森豪威尔陆军医疗中心的40名首发精神病患者和40名与患者年龄、性别、教育程度、种族背景和职业状况相匹配的正常对照。氧化细胞损伤的影响将在淋巴细胞质膜脂、线粒体膜、细胞蛋白和DNA（线粒体和细胞核）中进行检查。具体措施将包括膜脂过氧化产物（丙二醛，MDA）、磷脂酶A2 （PLA2）、共轭二烯和脂肪酸含量、羰基化蛋白质水平和DNA链断裂。红细胞和淋巴细胞线粒体中抗氧化酶（超氧化物歧化酶、谷胱甘肽过氧化物酶和过氧化氢酶）的活性将被测定。血浆中MDA、PLA2、非酶抗氧化剂（维生素C和E、尿酸盐）和参与抗氧化酶活动的微量营养素（铜、锌、硒）的水平也将被测定。治疗6周和12周后重复测定抗氧化剂和氧化损伤指标。将进行相关研究，以检查氧化损伤的特定指标与临床参数（病前功能史、精神病的严重程度和最初出现的阴性症状、神经学体征、即时治疗反应的质量、初步恢复后精神病的早期复发、治疗三个月后的残余症状等）、脑形态学（磁共振成像）的关系。神经递质受体介导的磷脂衍生的第二信使释放水平（如花生四烯酸和肌醇多磷酸）。这些研究将界定氧化细胞损伤的程度和性质，这将反映精神病发病时与精神病理相关的脑神经病理学。如果在这项综合研究中证明，精神病发病时的氧化损伤有助于不利的早期病程，则表明需要从精神病发病时开始辅助抗氧化治疗。研究氧化损伤的性质，为制定合理有效的治疗策略提供指导。可以想象，这些可以通过降低复发的风险来降低临床护理的成本，甚至有希望防止一些患者的病情恶化。

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.