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: 8641420
• 负责人: ANTONIA S NEW
• 金额: $ 48.77万
• 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/8641420
• 关键词: Aging; Agonist; Amphetamines; Analysis of Variance; 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，特别是工作记忆和执行功能的损害，是精神分裂症谱系疾病以及其他严重精神疾病（例如双相情感障碍、注意力缺陷障碍）的核心问题。此外，工作记忆和执行功能损伤可预测功能结果，特别是在精神分裂症谱系中；然而，传统疗法对认知障碍的益处有限，而且最近具有临床前前景的药物的临床试验结果令人失望。我们在此建议检查 DAR-0100A（一种高度选择性、完全的多巴胺 1 受体 (D1R) 激动剂）对精神分裂型人格障碍 (SPD) 患者工作记忆障碍的影响。 SPD 是一种精神分裂症谱系疾病，表现为工作记忆和相关认知功能中度和特定的损害，我们已经证明可以通过多巴胺能药物（例如培高利特（一种混合 D1/D2 受体激动剂）和安非他明）可逆地改善这种情况。大量的基础和临床前神经科学数据表明，D1R 是一个非常有前途的药理学靶点，可以增强精神分裂症和衰老模型中的工作记忆损伤。然而，目前尚无已发表的临床人体研究评估选择性 D1R 激动剂作为精神疾病认知障碍的治疗剂。我们在此建议进行一项为期 5 年、随机、双盲、安慰剂对照的研究，其中 DAR-0100A 以 15 mg 的剂量在 30 分钟内静脉注射给 60 名 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。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施用的相反药物（药物或安慰剂）上。仅在第 1 天和第 4 天对 60 名健康对照参与者进行认知测试（即不给予药物/安慰剂）。主要结果测量将包括以下认知测试：改良的 AX-CPT、N-back 和节奏听觉串行添加任务。作为次要结果指标，还将进行记忆、执行功能和言语学习等其他认知测试；并且，还将进行假设不会因 DAR-0100A 处理而改变的比较测试：本顿线方向判断测试 (JLOT) 和轨迹制作测试-A。我们假设： 1. 与对照组相比，SPD 患者的基线主要结局指标会受到损害。 2. 在基线和第 4 天之间，使用 DAR100A 的 SPD 受试者在主要指标上的改善将大于健康对照组和随机接受安慰剂的 SPD 患者。 3. 与安慰剂相比，SPD 患者在药物的主要结果变量上将显示出显着改善，但在知觉 (JLOT) 和处理速度任务 (轨迹 A) 的比较上没有显着改善。