Treatment of psychosis and agitation in Alzheimers disease

描述（申请人提供）：在阿尔茨海默病（AD）患者中，激动/攻击和精神病的症状通常发生，使患者和护理者感到痛苦，通常导致机构化，与死亡率增加和医疗保健系统的财政负担相关，并且非常难以治疗。在精神药物中，抗精神病药物在随机、双盲、痴呆症的安慰剂对照试验，尽管具有小到中等的效应量。抗精神病药物的副作用，包括导致FDA黑盒警告的死亡风险增加，表明需要评估其他治疗方法。 我们最初的开放式治疗试验数据表明，对抗精神病药物无反应或部分反应的AD患者在锂治疗后有所改善，支持锂治疗AD伴或不伴精神病的激越/攻击的系统研究。低剂量锂（每日150-600 mg）和低血药浓度（0.2-0.6 mmol/l）在老年痴呆患者中耐受良好。我们的创新项目将在一项随机、双盲、安慰剂对照、为期12周的试验中，首次检查低剂量锂治疗80名AD患者伴或不伴精神病的激越/攻击的疗效和副作用。这些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。主要假设是神经精神量表（NPI）上的激越/攻击领域评分在锂剂组比安慰剂组下降得更明显。次要假设是锂治疗的应答者比例将显著高于安慰剂治疗的应答者比例。探索性假设是，精神病评分（通过妄想和幻觉的NPI域总和测量）在锂剂组比安慰剂组显著降低。我们还将通过评估试验过程中锂与安慰剂相比出现的躯体副作用来评估耐受性。我们将评估基线和12周时的血浆脑源性神经营养因子（BDNF），ACCN 1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反应，以改善临床试验和最终个性化治疗的患者选择。BDNF水平随时间的变化将作为锂处理的生物标志物相关性进行检查。我们的研究将提供关于低剂量锂治疗的三个潜在作用的初始数据，如果发现它在临床实践中是有效和安全的（这些作用不是相互排斥的）：（1）一线治疗;（2）部分应答者中抗精神病药物的辅助治疗;（3）抗精神病药物无应答或不耐受后的二线药物。如果在大规模的试验中证实了在试点试验中的积极作用，那么在美国和世界各地，有相当大的潜力显著改变临床实践，使这些患者受益。

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.