A D1 Agonist for Working Memory Enhancement in the Schizophrenia Spectrum

D1 激动剂可增强精神分裂症患者的工作记忆

• 批准号: 8506077
• 负责人: Larry J Siever
• 金额: $ 58.68万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8506077
• 关键词: Aging; Agonist; Amphetamines; Antipsychotic Agents; Attention Deficit Disorder; Attention deficit hyperactivity disorder; Auditory; Back; Bipolar Disorder; Chronic; Clinical; Clinical Data; Clinical Trials; Cognition; Cognitive; Cognitive deficits; Confounding Factors (Epidemiology); DRD2 gene; Data; Development; Disease; Dopamine; Dopamine D1 Receptor; Dopamine D2 Receptor; Dopaminergic Agents; Dose; Double-Blind Method; Functional disorder; Human; Impaired cognition; Impairment; Industry; Judgment; Marketing; Measures; Mediator of activation protein; Memory; Memory impairment; Mental disorders; Methods; Modeling; Neurosciences; Outcome Measure; Participant; Patients; Performance; Pergolide; Pharmaceutical Preparations; Phase; Pilot Projects; Placebos; Plasma; Population; Population Study; Protocols documentation; Psyche structure; Psychotic Disorders; Publishing; Randomized; Recording of previous events; Refractory; Research; Schizophrenia; Schizotypal Personality Disorder; Short-Term Memory; Testing; Therapeutic; Therapeutic Agents; Toxic effect; Trail Making Test; Verbal Learning; Work; aged; blind; cognitive change; cognitive enhancement; cognitive function; design; enantiomer; executive function; functional disability; functional outcomes; improved; placebo controlled study; pre-clinical; primary outcome; processing speed; public health relevance; receptor; secondary outcome; therapeutic target; young adult

DESCRIPTION (provided by applicant): Cognitive deficits, particularly impairments in working memory and executive function, are a core problem of schizophrenia-spectrum conditions, as well as other serious psychiatric disorders (e.g., bipolar disorder, attention-deficit disorder). Moreover, working memory and executive function impairments predict functional outcomes, particularly in the schizophrenia-spectrum; however, conventional therapeutics have limited benefit for cognitive impairments, and, recent clinical trials of agents with preclinical promise have had disappointing results. We propose here to examine the effects of DAR-0100A -- a highly selective, full, dopamine-1 receptor (D1R) agonist -- on working memory impairments in patients with schizotypal personality disorder (SPD). SPD is a schizophrenia- spectrum condition that manifests a moderate and specific impairment in working memory, and related cognitive functions, which we have demonstrated can be reversibly ameliorated with dopaminergic agents, such as pergolide (a mixed D1/D2 receptor agonist) and amphetamine. An abundance of basic and preclinical neuroscientific data indicate the D1R is a highly promising pharmacological target to enhance working memory impairments in models of schizophrenia and aging. Currently, however, no published clinical human studies have evaluated a selective D1R agonist as a therapeutic agent for cognitive impairments of psychiatric disorders. We propose here to perform a 5-year, randomized, double-blind, placebo-controlled study in which DAR-0100A is administered intravenously at a dose of 15 mg over 30 minutes to 60 patients with SPD. Cognitive tests will be administered at baseline (Day 1) and on the third day of drug/placebo administration (Day 4). On Day 15, participants will return to repeat this sequence, but placed in a double-blind manner on the opposite agent (drug or placebo) initially administered. Cognitive testing, only, (i.e., no drug/placebo administration) will be performed on Day 1 and 4 to 60 healthy control participants. Primary outcome measures will consist of the following cognitive tests: modified AX-CPT, N-back, and Paced Auditory Serial Addition Task. Other cognitive tests of memory, executive function, and verbal learning will also be administered, as secondary outcome measures; and, comparison tests, not hypothesized to change with DAR-0100A treatment will also be given: Benton Judgment of Line Orientation Test (JLOT) and the Trail Making Test-A. We hypothesize that: 1. Baseline primary outcome measures will be impaired in SPD patients compared to controls. 2. SPD subjects on DAR100A will show improvement on primary measures greater than healthy controls and SPD patients randomized to placebo between baseline and Day 4. 3. SPD patients will show significant improvements on primary outcome variables on drug compared to placebo but not on comparison on perceptual (JLOT) and processing speed tasks (Trails A).

描述（由申请人提供）：认知缺陷，尤其是工作记忆和执行功能的损害，是精神分裂症 - 谱系疾病的核心问题，以及其他严重的精神病（例如，双相情感障碍，注意缺陷障碍）。此外，工作记忆和执行功能障碍可以预测功能结果，尤其是在精神分裂症谱中；但是，常规的治疗剂对认知障碍的好处有限，并且最近对临床前承诺的药物的临床试验产生了令人失望的结果。我们在这里提议研究DAR-0100A（一种高度选择性，全面，多巴胺1受体（D1R）激动剂）对精神分裂型人格障碍（SPD）患者的工作记忆障碍的影响。 SPD是一种精神分裂症谱系，在工作记忆中表现出适度而特定的损害，以及相关的认知功能，我们已经证明，可以用多巴胺能剂（例如pergolide（混合的D1/D2受体激动剂））和十五胺将其逆转改善。大量的基本和临床前神经科学数据表明，D1R是一个高度有希望的药理学靶标，可增强精神分裂症和衰老模型的工作记忆障碍。但是，目前，尚无公开的临床人类研究评估选择性D1R激动剂作为精神疾病认知障碍的治疗剂。我们在这里提议进行5年，随机的双盲，安慰剂对照研究，其中DAR-0100A以15毫克的静脉内给予30分钟的静脉内给予SPD患者。认知测试将在基线（第1天）和药物/安慰剂给药的第三天（第4天）进行。在第15天，参与者将返回重复 该序列，但以双盲方式放置在最初给予的相反药物（药物或安慰剂）上。仅认知测试，（即，没有药物/安慰剂给药）将在第1天和第4至60位健康对照参与者进行。主要结果度量将包括以下认知测试：修改后的AX-CPT，N-BACK和节奏的听觉序列添加任务。记忆，执行功能和言语学习的其他认知测试也将作为次要结果指标进行管理；并且，还将给出比较测试，即未通过DAR-0100A处理进行更改的比较测试：Benton的线方向测试（JLOT）和TRAIL MADEN MADE MADING TEST-A。我们假设：1。与对照组相比，SPD患者的基线主要结局指标将受到损害。 2. DAR100A上的SPD受试者将显示出比健康对照组大的主要措施的改善，而SPD患者在基线和第4天之间随机分配了安慰剂。SPD患者将在药物上与安慰剂相比，对药物的主要结果变量的改善显着改善，但对感知性（JLOT）和处理速度任务的比较没有。