ALZHEIMER'S IN LONG TERM PROPRANOLOL FOR AGITATION

破坏性激动行为经常发生在阿尔茨海默病（AD）中，特别是在养老院的居民中。这些问题行为经常促成养老院的安置，并继续造成病人的痛苦和干扰必要的护理在养老院设置。有限的临床试验数据表明，抗精神病药物和其他精神药物对这些问题只有适度的疗效和显著的不良反应。药物治疗这些问题行为的新方法将是有益的。最近的研究表明，阿尔茨海默病患者对中枢神经系统（CNS）去甲肾上腺素能刺激的行为敏感性增加，阿尔茨海默病晚期中枢神经系统去甲肾上腺素能流出量增加。这些中枢神经系统去肾上腺素能特征可能有助于AD中破坏性激动行为的表达。心得安是一种β -肾上腺素能拮抗剂，可降低中枢神经系统对去肾上腺素能刺激的反应性。轶事报道和我们的初步研究结果表明，心得安可以减少AD患者的破坏性激动行为。本提案的主要目的是评估心得安在养老院AD患者破坏性激动行为管理中的有效性和安全性。在为期8周的平行双盲试验中，受试者将随机接受心得安（最大剂量每天120毫克）或安慰剂治疗。主要结果测量将是临床总体变化印象评分和从基线到最后一次观察的简短精神病学评定量表和神经精神病学量表的变化评分。认知、功能状态和不良事件也将被评估。第二个目的是评估去甲肾上腺素能流出量和对去甲肾上腺素能刺激的敏感性，作为对心得安治疗反应的预测因子。虽然在拟议的治疗试验中测量中枢神经系统去甲肾上腺素能流出量或中枢神经系统肾上腺素能受体是不可行的，但测量血浆去甲肾上腺素（NE）和淋巴细胞β -肾上腺素能受体密度、亲和力和敏感性分别提供了可实现的去甲肾上腺素能流出量和β -肾上腺素能受体状态的估计。我们将确定高血浆NE和/或高淋巴细胞β -肾上腺素能受体密度、亲和力和/或敏感性是否定义AD患者对心得安最敏感的破坏性躁动。

Disruptive agitated behaviors frequently occur in Alzheimer's disease (AD), particularly among nursing home residents. These problem behaviors frequently precipitate nursing home placement and continue to cause patient distress and interfere with necessary care in the nursing home setting. Limited clinical trial data available suggest only modest efficacy and substantial adverse effects for antipsychotic and other psychotropic drugs prescribed for these problems. New approaches to pharmacologic treatment of these problem behaviors would be beneficial. Recent studies suggest increased behavioral sensitivity to central nervous system (CNS) noradrenergic stimulation in AD, and increased CNS noradrenergic outflow in the advanced stages of AD. These CNS noradrenergic characteristics may contribute to the expression of disruptive agitated behaviors in AD. Propranolol is a beta-adrenergic antagonist drug that decreases responsiveness to CNS noradrenergic stimulation. Anecdotal reports and our preliminary findings suggest propranolol decreases disruptive agitated behaviors in AD. The primary goal of this proposal is to evaluate the efficacy and safety of propranolol in the management of disruptive agitated behaviors in nursing home patients with AD. Subjects will be randomized to propranolol (maximum dose 120 mg per day) or placebo in an 8-week parallel design, double-blind trial. Primary outcome measures will be Clinical Global Impression of Change score and change scores from baseline to last observation on the Brief Psychiatric Rating Scale and Neuropsychiatric Inventory. Cognition, functional status, and adverse events will also be assessed. A secondary goal is to evaluate noradrenergic outflow and sensitivity to noradrenergic stimulation as predictors of therapeutic response to propranolol. Although measuring CNS noradrenergic outflow or CNS adrenergic receptors is not feasible in the proposed treatment trial, measurements of plasma norepinephrine (NE) and lymphocyte beta-adrenergic receptor density, affinity, and sensitivity provide achievable estimates of noradrenergic outflow and beta-adrenergic receptor status respectively. We will determine if high plasma NE and/or high lymphocyte beta-adrenergic receptor density, affinity, and/or sensitivity define AD patients with disruptive agitation most responsive to propranolol.