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，造成重大损害，与长期残疾高度相关（Green 1996a）。包括临床和临床前数据在内的多种证据都强调了D1受体在这种认知缺陷中的主要作用。最近，由美国国家精神卫生研究所（NIMH）赞助的matrix（改善精神分裂症认知的测量和治疗研究）会议召集的一个专家小组得出结论，D1激动剂是治疗精神分裂症认知障碍的一种有希望的方法。

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.