GEROPSYCHOPHARMACOLOGY--ENHANCING BENEFIT, REDUCING RISK

这份申请独立科学家的首要目标是 该奖项旨在改善老年精神障碍的药物治疗。 药物氧化的个体差异是最重要的 影响临床的药物浓度变化范围较大的原因 老年患者的反应。候选人提议将最近的 分子药物遗传学及其体外药物代谢研究进展 他正在进行的老年药物新陈代谢研究计划。本节目 目前利用细胞色素P450同工酶特异的代谢探针 GYP 2D6、2C19、1A2和3A4，结合药物分析 浓度、活性代谢物和对映体。新计划在 正电子发射断层扫描将与正在进行的 外周5-羟色胺能和胆碱能受体指数及其敏感性 认知、行为障碍、 平衡和运动功能。这项研究计划是在 常规试验与试验性试验的比较框架 治疗老年两大精神问题的药物--抑郁症 和痴呆症相关的行为障碍。研究一(MH55106)是一项 西酞普兰、奋乃静和安慰剂正在进行治疗试验 112例痴呆症患者的行为障碍。学习 二(MH52247)是一项正在进行的认知和比较研究 帕罗西汀与去甲替林联合治疗120例抗抑郁疗效观察 60岁及以上患有严重抑郁症。研究三 (MH52247的妇女健康补充)是对P450的试点检查 40后雌激素替代治疗对同工酶的影响 患有轻度到中度抑郁症的绝经期女性。的长期目标是 应聘者的研究是为了推导和验证预期的方法 老年患者特定精神药物及其剂量的选择， 在存在高度异质的药效和药物的情况下 基因多态引起的新陈代谢、变化的综合作用 与年龄或疾病有关，与药物引起的抑制或诱导有关。

The overarching goal of this application for an Independent Scientist Award is to improve the pharmacotherapy of late-life mental disorders. Inter-individual differences in drug oxidation are the most important cause of the wide range in drug concentrations which affect clinical response in older patients. The candidate proposes to incorporate recent advances in molecular pharmacogenetics and in vitro drug metabolism into his ongoing program of research on geriatric drug metabolism. This program currently utilizes cytochrome P450 isoenzyme-specific metabolic probes for GYPs 2D6, 2C19, 1A2 and 3A4, in conjunction with analyses for drug concentrations, active metabolites, and enantiomers. New initiatives in positron emission tomography will be integrated with ongoing appraisal of peripheral serotonergic and cholinergic receptor indices and sensitive quantitative outcome measures of cognition, behavioral disturbance, balance and motor function. This research plan is conducted within the framework of comparative trials of conventional and experimental medications for the two major psychiatric problems of old age, depression and dementia-associated behavioral disturbance. Study One (MH55106) is an ongoing, trial of citalopram, perphenazine and placebo for the treatment of behavioral disturbances associated with dementia in 112 patients. Study Two (MH52247) is an ongoing, comparative study of the cognitive and antidepressant effects of paroxetine and nortriptyline in 120 patients aged 60 years and older suffering from major depression. Study Three (Women's Health Supplement to MH52247) is a pilot examination of the P450 isozyme-specific effects of estrogen replacement therapy in 40 post menopausal women with mild to moderate depression. The long-term goal of the candidate's research is to derive and validate methods for prospective selection of specific psychotropics and their dosages for older patients, in the presence of intensely heterogeneous pharmacodynamics and drug metabolism caused by the combined effects of genetic polymorphism, changes associated with age or illness, and drug-induced inhibition or induction.