OXIDATIVE CELL INJURY: FIRST-EPISODE PSYCHOTIC PATIENTS

这一建议的目的是确定在精神病发作时存在氧化细胞损伤的增加，并且在一些患者中持续的损伤可能导致疾病的不良结局。这一建议的基础是我们之前研究的初步结果，即抗氧化剂防御受损和脂质过氧化增加，这与精神病开始时的大脑形态计量学变化有关。这些研究旨在系统地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名正常对照，这些患者在年龄、性别、教育程度、种族背景和职业状况方面都与患者匹配。氧化细胞损伤的影响将在淋巴细胞质膜脂类、线粒体膜、细胞蛋白和DNA(线粒体和核)中进行检测。具体措施包括膜脂过氧化产物(丙二醛、丙二醛)、磷脂酶A2(PLA2)、共轭二烯和脂肪酸含量、碳化蛋白质水平和DNA链断裂。将测定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。还将测定与抗氧化酶活性有关的血浆丙二醛、磷脂酶A2、非酶抗氧化剂(维生素C和E、尿酸盐)和微量营养素(铜、锌、硒)的水平。在抗精神病药物治疗6周和12周后，将重复测定抗氧化剂和氧化损伤指数。将进行相关研究，以检验氧化损伤的特定指标与临床参数(病前功能病史、首次出现的精神病严重程度和阴性症状、神经体征、立即治疗反应的质量、首次康复后精神病的早期复发、治疗3个月后的残留症状等)、磁共振成像的脑形态以及神经递质受体介导的第二信使(如花生四烯酸和肌醇多磷酸)的磷脂释放水平的关系。这些研究将确定氧化细胞损伤的程度和性质，尽管是在外周细胞中，这将反映与精神病发病时的精神病理学相关的脑神经病理学。如果在这项全面的研究中证明，精神病发作时的氧化损伤有助于不利的早期病程，这将表明从精神病发作起就需要辅助抗氧化剂治疗。对氧化损伤性质的研究可能会为制定合理有效的治疗策略提供方向。可想而知，这些措施可以通过降低复发风险来降低临床护理成本，甚至有望防止某些患者病情恶化。

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.