Treatment of psychosis and agitation in Alzheimers disease

阿尔茨海默病精神病和躁动的治疗

• 批准号: 9217541
• 负责人: DAVANGERE P DEVANAND
• 金额: $ 57.93万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-15 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9217541
• 关键词: Address; Adverse effects; Aggressive behavior; Agitation; Alzheimer' s Disease; Antipsychotic Agents; Behavior; Behavioral Symptoms; Biological Markers; Bipolar Disorder; Blood; Brain-Derived Neurotrophic Factor; Caregivers; Case Series; Case Study; Clinical; Clinical Trials; Cognition; Data; Death Rate; Delusions; Dementia; Distress; Dose; Double-Blind Method; Equipment and supply inventories; FDA approved; Genes; Goals; Hallucinations; Haloperidol; Healthcare; Healthcare Systems; Institutionalization; Introns; Lead; Literature; Lithium; Maintenance; Measures; Meta-Analysis; Patient Selection; Patients; Pharmaceutical Preparations; Phase; Placebo Control; Placebos; Plasma; Prevalence; Psychotic Disorders; Publishing; Randomized; Reporting; Risk; Risperidone; Role; Serum; Sum; Symptoms; Therapeutic; Time; United States; Variant; aging population; alternative treatment; base; control trial; discontinuation trial; double-blind placebo controlled trial; improved; indexing; innovation; mortality; neuropsychiatry; older patient; partial response; personalized medicine; phase II trial; psychiatric symptom; public health relevance; relapse risk; response; treatment response; treatment strategy; week trial

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.

描述（由申请人提供）：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，给患者和护理人员带来痛苦，通常导致住院，与死亡率增加和医疗保健系统的财务负担增加有关，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的效果，尽管其效应大小为中小。抗精神病药物的副作用，包括导致 FDA 黑框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表明，对抗精神病药物没有反应或部分反应的 AD 患者服用锂后病情有所改善，这支持了锂盐治疗 AD 患者伴或不伴精神病激越/攻击行为的系统研究。老年痴呆症患者对低剂量锂（每天 150-600 毫克）和低血液水平（0.2-0.6 毫摩尔/升）的耐受性良好。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 患者使用低剂量锂盐治疗伴或不伴精神病的躁动/攻击行为的疗效和副作用进行研究。结果将确定大规模临床试验的可能性，以确定锂在这些患者中的效用。主要假设是，与安慰剂相比，服用锂剂后神经精神量表（NPI）中的激越/攻击领域评分下降幅度显着更多。第二个假设是，对锂剂有反应的人的比例将显着大于对安慰剂有反应的人的比例。探索性假设是，通过妄想和幻觉的 NPI 域总和来衡量的精神病评分在服用锂剂时比服用安慰剂时下降得更多。我们还将通过评估锂试验过程中与安慰剂相比出现的突发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)、ACCN1 基因内含子 1 上的 SNP 以及 7q11.2 基因位点，并检查这些指标是否可以预测锂盐反应，以改善临床试验的患者选择并最终实现个性化治疗。 BDNF 水平随时间的变化将作为锂治疗的生物标志物相关性进行检查。如果发现低剂量锂治疗在临床实践中有效且安全（这些作用并不相互排斥），我们的研究将提供有关低剂量锂治疗的三种潜在作用的初步数据：（1）一线治疗； (2) 对部分缓解者进行抗精神病药物的辅助治疗； 3) 抗精神病药物无反应或不耐受后的二线药物。如果大规模试验证实了初步试验的积极效果，那么就有很大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。