Treatment of psychosis and agitation in Alzheimers disease

描述(申请人提供)：躁动/攻击性和精神病症状通常出现在阿尔茨海默病(AD)患者中，令患者和照顾者痛苦，通常导致住院，与增加死亡率和医疗系统的经济负担有关，并且非常难以治疗。在精神药物中，抗精神病药物在治疗痴呆症的随机、双盲、安慰剂对照试验中显示出优于安慰剂，尽管效果规模为小到中等。抗精神病药物的副作用，包括导致FDA黑匣子警告的死亡风险增加，表明需要评估其他治疗方法。我们最初的开放治疗试点数据显示，对抗精神病药物没有反应或部分有反应的AD患者的锂盐治疗效果有所改善，支持了锂盐治疗AD患者伴有或不伴有精神病的激越/攻击行为的系统研究。老年痴呆患者对低剂量锂(150-600 mg/d)和低血药浓度(0.2-0.6 mmol/L)耐受性良好。我们的创新项目将首次在一项为期12周的随机、双盲、安慰剂对照试验中，对80名AD患者进行小剂量锂治疗激越/攻击性精神障碍的疗效和副作用。这一结果将决定大规模临床试验的潜力，以确定锂在这些患者中的效用。主要的假设是，服用锂盐的患者在神经精神病学问卷(NPI)上的激动/攻击性领域得分将比服用安慰剂的患者下降得更多。第二个假设是，服用锂的应答者的比例将显著高于服用安慰剂的应答者的比例。探索性的假设是，通过妄想和幻觉的NPI领域的总和来衡量精神病评分，服用锂盐的人比服用安慰剂的人下降得更多。我们还将通过与安慰剂相比，在试验过程中评估锂的紧急躯体副作用来评估耐受性。我们将评估基线和12周时血浆脑源性神经营养因子(BDNF)、ACCN1基因内含子1上的SNP和7q11.2基因位点，并检查这些指标是否可以预测锂盐反应，目的是改善临床试验和最终个性化治疗的患者选择。随着时间的推移，脑源性神经营养因子水平的变化将被视为与锂治疗相关的生物标记物。我们的研究将为临床实践中发现有效和安全(这些作用不是相互排斥的)的小剂量锂盐治疗的三个潜在作用提供初步数据：(1)一线治疗；(2)部分应答者的抗精神病药物的辅助治疗；3)抗精神病药物无反应或耐受后的二线治疗。如果PIOT试验的积极作用在大规模试验中得到证实，那么很有可能显着改变临床实践，使美国和世界各地的这些患者受益。

DESCRIPTION (provided by applicant): Symptoms of agitation/aggression and psychosis commonly occur in patients with Alzheimer's disease (AD), are distressing to patients and caregivers, often lead to institutionalization, are associated with increased mortality and financil burden to the healthcare system, and are very difficult to treat. Among the psychotropic medications, antipsychotics show superiority to placebo in randomized, double-blind, placebo-controlled trials in dementia, albeit with small to medium effect sizes. Antipsychotic side effects including the increased risk of mortality that led to an FDA black box warning, suggest that other treatments need to be evaluated. Our initial open treatment pilot data demonstrated that patients with AD who showed no response or partial response to antipsychotics improved on lithium, supporting the systematic study of lithium treatment for agitation/aggression with or without psychosis in AD. Low doses of lithium (150-600 mg daily) with low blood levels (0.2-0.6 mmol/l) are tolerated well in elderly patients with dementia. Our innovative project will examine, for the first time, the efficacy and side effects of low dose lithium treatment of agitation/aggression with or without psychosis in 80 patients with AD in a randomized, double-blind, placebo-controlled, 12-week trial. The results will determine the potential for a large-scal clinical trial to establish the utility of lithium in these patients. The primary hypothesis is tha the agitation/aggression domain score on the Neuropsychiatric Inventory (NPI) will decrease significantly more on lithium than placebo. The secondary hypothesis is that the proportion of responders on lithium will be significantly greater than the proportion of responders on placebo. The exploratory hypothesis is that the psychosis score, measured by the sum of the NPI domains for delusions and hallucinations, will decrease significantly more on lithium than placebo. We will also evaluate tolerability by assessing emergent somatic side effects over the course of the trial on lithium compared to placebo. We will evaluate plasma brain-derived neurotrophic factor (BDNF) at baseline and 12 weeks, a SNP on intron 1 of the ACCN1 gene, and the 7q11.2 gene locus, and examine whether these indices can predict lithium response with the goal of improving patient selection for clinical trials and eventually personalized treatment. Change over time in BDNF levels will be examined as a biomarker correlate of lithium treatment. Our study will provide initial data on three potential roles for low-dose lithiu treatment if it is found to be effective and safe (these roles are not mutually exclusive) in clinial practice: (1) first-line treatment; (2) adjunct treatment to antipsychotics in partial responders; 3) second-line agent after antipsychotic non-response or intolerability. If positive effects in the piot trial are confirmed in a large-scale trial there is considerable potential to markedly alter clinicl practice to benefit these patients in the United States and around the world.