Pharmacologic and Clinical Testing of a D1 Agonist for Neuropsychiatric Disorders

描述（由申请人提供）：认知障碍，包括工作记忆（WM）缺陷，是精神分裂症的核心特征，在整个病程中保持稳定，导致显著障碍，并与长期残疾高度相关（绿色1996 a）。包括临床和临床前数据在内的多条证据线强调了D1受体在这种认知缺陷中的主要作用。最近，由国家精神卫生研究所（NIMH）主办的MATRICS（改善精神分裂症认知的测量和治疗研究）会议聚集的专家小组得出结论，D1激动剂是治疗精神分裂症认知障碍的一种有前途的方法。 该提案是学术机构哥伦比亚大学和制药公司DarPharma Inc.之间的联合合作，以及许多来自社区的杰出科学家，进行一项概念验证研究，评估选择性D1激动剂DAR-0100在治疗精神分裂症认知缺陷中的应用。 在拟定的研究中，两个剂量（10和30 mg，s.c.）将DAR-0100或安慰剂给予三个不同组（每组N=20）的用利培酮治疗的临床稳定的精神分裂症住院患者。 涉及工作记忆功能的区域中的静息血流和神经活动将用作生物标志物，以评价DAR-0100在急性（2天）和亚慢性治疗后（7天）改善精神分裂症认知缺陷的潜在功效（SA 1）。 PET和[11 C]NNC 112将用于确定急性（第1天）达到的D1受体占用水平，评估与精神分裂症患者最大WM改善相关的占用水平（SA 2），并检验亚急性D1激动剂给药可诱导DLPFC D1受体下调预测WM表现改善的假设（SA 2）。此外，将在7天和3个月后评估对一般认知的影响（SA 3）。 本着这一PAR的精神，我们相信我们的建议将导致一个结论性的工作机构，专注于治疗最严重的精神疾病之一的最具挑战性的临床方面，这种疾病对个人的影响与整个社会一样大。

DESCRIPTION (provided by applicant): Cognitive impairment, including working memory (WM) deficit, is a core feature of schizophrenia which remains stable throughout the course of the illness, causes significant impairment and is highly correlated to long term disability (Green 1996a). Multiple lines of evidence including clinical and preclinical data, have emphasized a major role for the D1 receptor in this cognitive deficit. Recently a panel of experts gathered by the National Institute of Mental Health (NIMH)-sponsored MATRICS (Measurement and Treatment Research to Improve Cognition in Schizophrenia) meeting concluded that D1 agonists represent a promising approach to the treatment of cognitive impairment in schizophrenia. This proposal is a joint collaboration between an academic institution, Columbia University, and a pharmaceutical company, DarPharma Inc., as well as many outstanding scientists from the community at large, to conduct a proof of concept study assessing the use of a selective D1 agonist, DAR-0100, in the treatment of cognitive deficit in schizophrenia. In the proposed study, two doses (10 and 30 mg, s.c.) of a DAR-0100 or placebo will be given to three different groups (N=20 each) of clinically stable inpatients with schizophrenia treated with risperidone. Resting blood flow and neural activity in regions involved in working memory function will be used as biological markers to evaluate the potential efficacy of DAR-0100 acutely (2 days) and after subchronic treatment (7 days) in improving cognitive deficits in schizophrenia, (SA1). PET and [11C]NNC 112 will be used to establish the level of D1 receptor occupancy achieved acutely (day 1), to assess the level of occupancy associated with maximal WM improvement in patients with schizophrenia (SA2), and to test the hypothesis that, subacute D1 agonists administration can induce downregulation of DLPFC D1 receptors predictive of improvement in WM performance (SA2). In addition the impact on general cognition will be assessed after 7 days and 3 months (SA3). In keeping with the spirit of this PAR, we believe our proposal will lead to a conclusive body of work focused on the treatment of the most challenging clinical aspect of one of the most severe mental illnesses, which taxes as much the individual it affects as the society as a whole.