LONGTERM LORAZEPAM USE AND ACUTE TOXICITY IN THE ELDERLY

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。苯二氮卓类药物（BZP），劳拉西泮，被广泛用于治疗老年人广泛性焦虑症（GAD），这可能是这一人群中最常见的焦虑症。劳拉西泮通常被推荐用于老年人的治疗，因为它在肝脏代谢和清除方面没有明显的年龄相关性降低。然而，急性剂量的劳拉西泮已被证明会对言语记忆产生有害影响，并增加姿势摇摆，这与更大的跌倒风险有关。我们的研究小组已经证明，在劳拉西泮治疗21天后，劳拉西泮对记忆和精神运动功能的不良影响仍然存在。在这项研究中，每个受试者都接受了他或她平常早晨的剂量。此外，在长期BZP治疗多年的主要是年轻人的人群中，他或她通常早晨剂量的急性BZP挑战已被发现导致显着的神经认知障碍。这些研究表明，急性BZP剂量的不良表现影响甚至可能在长期治疗后持续存在。流行病学研究还发现，老年人长期服用BZP与跌倒和机动车事故风险增加有关。然而，目前还没有研究检验BZP对老年患者长期BZP治疗的急性表现影响，以及可能影响这些不良急性反应易感性的各种受试者因素。我们的研究有证据表明，慢性三周治疗后，劳拉西泮的剂量而不是血浆药物水平会影响劳拉西泮引起的急性认知毒性。我们也有初步数据表明，扩散张量成像（DTI）测量的白质纤维组织可能影响未经治疗的健康老年人劳拉西泮引起的急性损伤的程度。然而，这些因素在多大程度上影响老年人长期治疗的急性表现效果尚不清楚。确定导致劳拉西泮对记忆和体位平衡产生有害急性影响的最重要因素具有理论和临床意义，并可能有助于指导临床实践中更安全地使用劳拉西泮长期治疗老年GAD患者。拟议研究的目的是为了回答以下问题：1。在长期使用劳拉西泮治疗广泛性焦虑症的老年人中，在给予最高日单位剂量后，在认知和精神运动表现或姿势摇摆方面存在哪些显著的有害影响？2. 哪些受试者因素（即最高每日单位剂量的强度、给药频率、治疗持续时间和脑白质组织指数）对劳拉西泮长期治疗GA对老年人认知/运动表现或姿势摇摆的急性影响贡献最大

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 GA