LONGTERM LORAZEPAM USE AND ACUTE TOXICITY IN THE ELDERLY

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。苯二氮(BZP)，劳拉西潘，被广泛用于治疗患有广泛性焦虑症(GAD)的老年人，GAD可能是该人群中最常见的焦虑症。劳拉西潘通常被推荐用于老年人的治疗，因为与年龄相关的肝脏代谢和清除缺乏明显的减少。然而，研究表明，急性剂量的劳拉西泮会对言语记忆产生有害影响，并增加姿势摆动，这与摔倒的风险更大有关。我们小组已经证明，劳拉西潘治疗21天后，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通常早上服用的剂量的挑战。此外，在长期服用BZP多年的以年轻人为主的人群中，BZP的急性挑战被发现会导致显著的神经认知障碍。这些研究表明，即使在长期治疗后，急性剂量的BZP的不良反应也可能持续存在。流行病学研究还发现，老年人长期服用BZP会增加摔倒和机动车事故的风险。然而，目前还没有研究研究长期服用BZP对老年患者的急性绩效影响，以及可能影响这些不良急性反应易感性的各种主观因素。我们的研究有证据表明，劳拉西潘的剂量，而不是血浆药物浓度，会影响慢性三周治疗后劳拉西潘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会影响未经治疗的健康老年人劳拉西潘引起的急性损害的程度。然而，这些因素在多大程度上影响长期治疗的老年人的急性表现效果尚不清楚。确定劳拉西潘对记忆和姿势平衡的有害急性影响的最主要因素具有理论和临床意义，并可能有助于指导临床实践更安全地使用劳拉西潘长期治疗老年广泛性AD患者。这项研究的目的是回答以下问题：1.在长期服用劳拉西潘治疗广泛性焦虑症的老年人中，在给予他们每天最高单位剂量后，在认知和精神运动表现或姿势摆动方面存在哪些显著的有害影响？2.哪些主题因素(即最高日单位剂量的强度、给药频率、治疗持续时间和脑白质组织指数)对长期服用劳拉西潘的老年人的认知/运动表现或姿势摆动的急性影响最大

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