OXIDATIVE CELL INJURY: FIRST EPISODE PSYCHOTIC PATIENTS

该提案的目的是确定精神病发作时存在增加的氧化细胞损伤，并且持续的损伤可能会导致某些患者的疾病结果不佳。 这一提议的基础是我们之前的研究的初步发现，即抗氧化防御受损和脂质过氧化增加与精神病发作时大脑形态变化有关。拟议的研究是系统性地检查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的延伸，并阐明首次精神病发作患者的临床意义。 这项为期 4 年的研究将涉及 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。将在淋巴细胞质膜脂质、线粒体膜、细胞蛋白和 DNA（线粒体和细胞核）中检查氧化细胞损伤的影响。 具体测量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。 将测定红细胞和淋巴细胞线粒体中的抗氧化酶（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。还将测定参与抗氧化酶活性的 MDA、PLA2、非酶抗氧化剂（维生素 C 和 E、尿酸盐）以及微量营养素（铜、锌、硒）的血浆水平。 抗氧化剂和氧化损伤指数的测量将在抗精神病药治疗 6 周和 12 周后重复进行。 将进行相关性研究，以检查氧化损伤的具体指标与临床参数（病前功能史、精神病严重程度和初次出现的阴性症状、神经系统体征、立即治疗反应的质量、初次恢复后精神病的早期复发、治疗三个月后残留症状等）、使用磁共振成像的脑形态以及神经递质受体介导的磷脂衍生的第二信使释放水平（例如花生四烯酸和肌醇）的关系。聚磷酸盐）。尽管是在外周细胞中，这些研究将定义氧化细胞损伤的程度和性质，这将反映与精神病发作时的精神病理学相关的脑神经病理学。如果这项综合研究证明精神病发作时的氧化损伤会导致不利的早期病程，则表明需要从精神病发作时开始进行辅助抗氧化治疗。 对氧化损伤本质的研究可能为制定合理有效的治疗策略提供方向。可以想象，这些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.