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: 8670190
• 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/8670190
• 关键词: 7q11.2; Address; Adverse effects; Aggressive behavior; Agitation; Alzheimer' s Disease; Antipsychotic Agents; Behavior; Behavioral Symptoms; Biological Markers; Bipolar Disorder; Blood; Boxing; Brain-Derived Neurotrophic Factor; Caregivers; Case Series; Case Study; Clinical; Clinical Trials; Clinical assessments; 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 II Clinical Trials; Phase III Clinical Trials; Placebo Control; Placebos; Plasma; Prevalence; Psychotic Disorders; Publishing; Randomized; Relapse; Reporting; Risk; Risperidone; Role; Serum; Sum; Symptoms; Therapeutic; Time; United States; Variant; aging population; alternative treatment; base; discontinuation trial; double-blind placebo controlled trial; improved; indexing; innovation; mortality; neuropsychiatry; older patient; partial response; public health relevance; 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）：阿尔茨海默氏病（AD）患者通常发生躁动/侵略和精神病的症状，对患者和看护者感到沮丧，通常导致制度化，与医疗保健系统的死亡率增加和融资负担有关，并且很难治疗。在精神药物中，抗精神病药在痴呆症中的随机，双盲，安慰剂对照试验中表现出优于安慰剂，尽管具有中小型效应大小。抗精神病药副作用，包括导致FDA黑匣子警告的死亡风险增加，这表明需要评估其他治疗方法。 我们最初的开放治疗试验数据表明，AD患者对锂的反应或部分反应没有反应或部分反应，这支持了锂治疗的系统研究，用于搅动/侵略性或没有精神病。低剂量的锂（每天150-600毫克）的血液水平低（0.2-0.6 mmol/L）在老年痴呆症患者中耐受性良好。我们的创新项目将首次研究在一项随机，双盲，安慰剂对照，为期12周的试验中，在80例AD患者中，低剂量锂治疗搅拌/侵略性的疗效和副作用。结果将确定大规模临床试验在这些患者中建立锂效用的潜力。主要的假设是神经精神库存（NPI）上的搅动/侵略域评分将比安慰剂上的降低明显降低。次要假设是，锂的响应者比例将明显大于安慰剂上的响应者的比例。探索性假设是，通过妄想和幻觉的NPI结构域的总和来衡量的精神病评分将在锂上降低而不是安慰剂。与安慰剂相比，我们还将通过评估锂试验过程中新兴的体细胞副作用来评估耐受性。我们将在基线时评估血浆脑衍生的神经营养因子（BDNF）和12周，ACCN1基因内含子1的SNP和7q11.2基因座，并检查这些指数是否可以通过改善临床试验和最终个性化治疗的患者选择的目标来预测锂反应。随着时间的流逝，BDNF水平的变化将被检查为锂处理的生物标志物相关。如果发现有效且安全（这些角色不是相互排斥的），我们的研究将提供有关低剂量LITHIU治疗的三个潜在作用的初始数据：（1）一线治疗； （2）部分响应者对抗精神病药的辅助治疗； 3）抗精神病药无响应或无法忍者后的二线试剂。如果在一项大规模试验中证实了PIOT试验中的积极影响，则有很大的潜力可以显着改变诊所实践，以使美国和世界各地这些患者受益。