Because of their widespread use, the acute and chronic effects of benzodiazepines on human performance are of considerable practical significance. The effects on the elderly (aged 60 to 78 years) are of particular concern since these individuals may be more sensitive to some of the adverse central effects of benzodiazepines. Moreover, normal age-related decline in cognitive functions may accentuate the significance of drug-induced deficits. Our current NIMH-sponsored study has found that diazepam, a benzodiazepine with a long elimination half-life (t 1/2), produced profound memory and psychomotor impairment after acute administration, and significant next-day memory impairment following chronic bedtime administration in elderly subjects. Moreover, only partial tolerance developed to the acute adverse effects after chronic administration. While it is often assumed that chronic treatment with benzodiazepines with shorter elimination half-lives (which results in less drug accumulation) will, in general, be associated with a smaller number of adverse effects on performance, there are few systematic studies of the effects of these drugs on performance in the elderly. Additionally, there are even fewer studies which include the very elderly, a group which may be partially vulnerable to the adverse effects of benzodiazepines.
The aim of the proposed study is to assess the acute and chronic effects on task performance of alprozolam and lorazepam, two commonly prescribed benzodiazepines with relatively short t 1/2s. More specifically, this study is designed to answer the following questions: 1. What are the acute and chronic effects of alprazolam and lorazepam on task performance in the elderly? Do the two drugs differ with respect to these effects? 2. Within the elderly group, is increasing age associated with increased adverse effects on task performance? 3. What is the relationship between the magnitude of drug-induced impairment and drug plasma concentration?

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National Institute of Mental Health (NIMH)
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Treatment Development and Assessment Research Review Committee (TDA)
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Nathan Kline Institute for Psychiatric Research
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Pomara, Nunzio; Willoughby, Lisa M; Ritchie, James C et al. (2005) Sex-related elevation in cortisol during chronic treatment with alprazolam associated with enhanced cognitive performance. Psychopharmacology (Berl) 182:414-9
Pomara, Nunzio; Willoughby, Lisa M; Ritchie, James C et al. (2004) Interdose elevation in plasma cortisol during chronic treatment with alprazolam but not lorazepam in the elderly. Neuropsychopharmacology 29:605-11
Pomara, N; Tun, H; DaSilva, D et al. (1998) The acute and chronic performance effects of alprazolam and lorazepam in the elderly: relationship to duration of treatment and self-rated sedation. Psychopharmacol Bull 34:139-53
Pomara, N; Tun, H; Deptula, D et al. (1998) ApoE-epsilon 4 allele and susceptibility to drug-induced memory impairment in the elderly. J Clin Psychopharmacol 18:179-81