GEROPSYCHOPHARMACOLOGY--ENHANCING BENEFIT, REDUCING RISK

本申请的首要目标是独立科学家 该奖项旨在改善老年精神障碍的药物治疗。 药物氧化的个体间差异是最重要的 由于药物浓度范围广泛，影响临床 老年患者的反应。候选人建议将最近的 分子药物遗传学和体外药物代谢的进展， 他正在进行的老年药物代谢研究项目这个程序 目前利用细胞色素P450同工酶特异性代谢探针 GYP 2D6、2C19、1A2和3A4，结合药物分析 浓度、活性代谢物和对映体。的新倡议 正电子发射断层扫描将与正在进行的评估相结合， 外周肾上腺素能和胆碱能受体指数和敏感 认知、行为障碍、 平衡和运动功能。这项研究计划是在 常规和实验性比较试验框架 治疗老年人两大精神问题的药物， 和痴呆相关的行为障碍研究一（MH55106）是一项 正在进行的西酞普兰、奋乃静和安慰剂治疗试验 与痴呆症相关的行为障碍。研究 两个（MH52247）是一个正在进行的，比较研究的认知和 帕罗西汀与去甲替林抗抑郁疗效比较 60岁及以上患有严重抑郁症。研究三 （妇女健康补充MH52247）是P450的试点检查 雌激素替代疗法对40例绝经后妇女同工酶特异性影响 轻度至中度抑郁的绝经期妇女。的长期目标 候选人的研究是推导和验证方法， 为老年患者选择特定的精神药物及其剂量， 在存在强烈异质性药效学和药物的情况下， 遗传多态性的综合作用引起的代谢变化， 与年龄或疾病相关，以及药物诱导的抑制或诱导。

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.