A D1 Agonist for Working Memory Enhancement in the Schizophrenia Spectrum

描述(由申请人提供)：认知缺陷，特别是工作记忆和执行功能障碍，是精神分裂症谱系疾病以及其他严重精神障碍(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障碍可以预测功能结果，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，而且最近对具有临床前前景的药物的临床试验结果令人失望。在这里，我们建议研究DAR-0100A--一种高选择性、完全的多巴胺-1受体(D1R)激动剂--对分裂型人格障碍(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，在工作记忆和相关认知功能方面表现出中度和特定的损害，我们已经证明，多巴胺能药物可以可逆地改善这种情况，如培高利特(一种混合的D1/D2受体激动剂)和苯丙胺。大量的基础和临床前神经科学数据表明，D1R是一个非常有希望的药物靶点，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类研究评估选择性D1R激动剂作为精神障碍认知障碍的治疗剂。我们建议在这里进行一项为期5年的随机、双盲、安慰剂对照研究，在该研究中，60名SPD患者在30分钟内静脉注射DAR-0100A 15 mg。认知测试将在基线(第1天)和服用药物/安慰剂的第三天(第4天)进行。在第15天，参与者将返回重复 这一序列，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。认知测试将仅在第一天和第四至60名健康对照组参与者进行(即不服用药物/安慰剂)。主要结果测量将由以下认知测试组成：改良的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，作为次要结果衡量标准；还将进行不假定随着DAR-0100A治疗而改变的比较测试：线定向测试(JLOT)的本顿判断和连线测试-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.在基线至第4天期间，服用DAR100A的SPD患者在主要指标上的改善幅度将大于健康对照组和随机服用安慰剂的SPD患者。3.与安慰剂相比，SPD患者在用药后的主要结果变量上将有显著改善，但在知觉(JLOT)和处理速度任务(Trails A)的比较上没有显著改善。

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).