The research program for the application is designed to explore the concept that specific assessment of drug metabolism is relevant to the treatment of disruptive symptomatic behaviors in primary degenerative dementia. This research will provide an important model that will improve the treatment of older patients with psychotropic medications. The hypothesis to be tested is that identified adverse effects of the antipsychotic, perphenazine, used in the symptomatic management of patients suffering from dementia, are related to excessive concentrations of this medication. The applicant proposes to evaluate empirically the consequences of impairment of the P450 monooxygenase, debrisoquine hydroxylase (P450 1ID6). This enzyme is specifically and very directly responsible for perphenazine's metabolism. Approximately 10% of the population is born without a functioning enzyme. Moreover, P450 1ID6 may be significantly inhibited by many medications used by elderly patients. The adverse effects of interest include significant side effects, as quantified by objective clinical ratings and neurologic assessments. Inpatients on admission will be included. The long-term objective, of this research, is to introduce methods for prospectively identifying patients who are at risk for adverse consequences because of an inability to adequately metabolize conventional doses of medication. The applicant's long-term goal is to teach and conduct research in geriatric clinical psychopharmacology.
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