Adverse effects of medications prescribed for elderly patients are common causes of the mental disorders of aging. Therefore, studies of the cognitive, affective, and behavioral symptoms that result from the administration of centrally-acting medications can provide information about the symptoms that characterize the toxic encephalopathies. From a practical perspective, they can provide clinicians and patients with information on the risks associated with use of the tested medications that could facilitate the prevention of disability. Accordingly, we are proposing to conduct randomized, double-blind, placebo-controlled challenge studies in which we will administer commonly prescribed medications for a period of several weeks to healthy, medically stable elderly volunteers. We will test for effects of active medications versus placebo with weekly tests of cognition, depression, other mood states, and sleepiness/alertness, and with daily self-reports of events and of both positive and negative affects. The medications to be studied were selected because they are commonly used, sufficiently safe to allow administration to elderly volunteers, and are suspected as causes of cognitive or affective toxicity. We propose two studies: Study I will compare the effects of 5 weeks of metoclopramide (up to 40 mg/day), sertraline (up to 200 mg/day), naproxen (up to 1000 mg/day), and placebo. Study II will compare 14 weeks of simvastatin (up to 20 mg/day) with placebo. Analyses will include modeling using random regression models. The hypotheses to be tested are that the medications under investigation can cause behavioral toxicity manifest by changes in cognitive performance assessed through weekly assessments; depressive or related symptoms manifest through weekly clinical interviews or self- reports on depression and behavioral rating scales; and increased negative affect and/or decreased positive affect as assessed through daily self-reports. We will also explore the impact of medications on daily reports of positive or negative events and on the relationship between daily events and daily affect.
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