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，特别是工作记忆和执行功能的损伤，是精神分裂症谱系疾病以及其他严重精神障碍（例如，双相情感障碍、注意力缺陷障碍）。此外，工作记忆和执行功能障碍预测功能结果，特别是在精神分裂症谱中;然而，常规疗法对认知障碍的益处有限，并且，最近临床前承诺的药物的临床试验结果令人失望。我们建议在这里检查DAR-0100 A-一种高度选择性的，完全的多巴胺-1受体（D1 R）激动剂-对典型人格障碍（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的中度和特异性损害，我们已经证明可以用多巴胺能药物如培高利特（一种混合的D1/D2受体激动剂）和安非他明可逆地改善。大量的基础和临床前神经科学数据表明，D1 R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障碍。然而，目前还没有发表的临床人体研究评估了选择性D1 R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年的随机、双盲、安慰剂对照研究，在该研究中，DAR-0100 A以15 mg的剂量在30分钟内静脉内给予60例SPD患者。将在基线（第1天）和药物/安慰剂给药第3天（第4天）进行认知测试。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施用的相反药剂（药物或安慰剂）上。仅认知测试（即，无药物/安慰剂给药）将在第1天和4至60名健康对照参与者进行。主要结局指标将包括以下认知测试：改良AX-CPT、N-back和起搏听觉序列加法任务。还将进行记忆、执行功能和语言学习的其他认知测试，作为次要结局指标;还将进行比较测试，假设不会随DAR-0100 A治疗而改变：Benton判断线方向测试（JLOT）和连线测试-A。我们假设：1.与对照组相比，SPD患者的基线主要结局指标将受损。2. DAR 100 A组的SPD受试者在基线和第4天之间的主要指标的改善将大于健康对照组和随机分配至安慰剂组的SPD患者。3.与安慰剂相比，SPD患者在药物的主要结局变量方面将显示出显著改善，但在感知（JLOT）和处理速度任务（试验A）的比较方面则无显著改善。