LONGTERM LORAZEPAM USE AND ACUTE TOXICITY IN THE ELDERLY

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The benzodiazepine (BZP), lorazepam, is widely utilized in the treatment of elderly individuals with Generalized Anxiety Disorder (GAD), probably the most common anxiety disorder in this population. Lorazepam is usually recommended for the treatment of the elderly due to the lack of significant age-related reduction in hepatic metabolism and clearance. However, acute lorazepam doses have been shown to produce deleterious effects on verbal memory and increases in postural sway, which has been associated with greater risk for falls. Our group has demonstrated that the adverse effects of lorazepam on memory and psychomotor functioning are still present after 21 days of lorazepam treatment. In this study, each subject was challenged with his or her usual morning dose. Additionally, among predominantly younger population on long-term BZP treatment for years, acute BZP challenges of his or her usual morning dose have been found to result in significant neurocognitive impairment. These studies suggest that the adverse performance effects of acute BZP doses may persist even following long-term treatment. Epidemiological studies have also linked long-term BZP use in the elderly with increased risk for falls and motor vehicle accidents. However, there are no studies that have examined the acute performance effects of BZP in elderly patients on long-term BZP treatment and the various subject factors that may influence the susceptibility to these adverse acute effects. There is evidence from our study that the dose of lorazepam but not the plasma durg levels influence acute lorazepam-induced cognitive toxicity following chronic three-week treatment. We also have preliminary data suggesting that white matter fiber organization, as measured by diffusion tensor imaging (DTI), may influence the magnitude of lorazepam-induced acute impairment in untreated healthy elderly. However, the extent to which these factors influence acute performance effects among elderly individuals on long-term treatment is not known. Identifying the factors that may contribute most strongly to the deleterious acute effects of lorazepam on memory and postural balance is of theoretical and clinical interest, and may serve to guide clinical practice in the safer use of lorazepam for the long-term treatment of elderly patients with GAD. The objectives of the proposed study are designed to answer the following questions: 1. Among elderly individuals on long-term treatment with lorazepam for GAD, what significant deleterious effects are present in terms of cognitive and psychomotor performance or postural sway following administration of their highest daily unit dose? 2. Which subject factors (i.e., strength of highest daily unit dose, frequency of dosing, duration of treatment, and an index of brain white matter organization) contribute most strongly to the acute effects of lorazepam on cognitive/motor performance or postural sway in elderly individuals on long-term lorazepam treatment for GAD?