Pharmacologic and Clinical Testing of a D1 Agonist for Neuropsychiatric Disorders

D1 激动剂治疗神经精神疾病的药理学和临床测试

• 批准号: 7126751
• 负责人: JEFFREY A. LIEBERMAN
• 金额: $ 83.84万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7126751
• 关键词: Address; Affect; Agonist; Antipsychotic Agents; Area; Arts; Back; Biological Markers; Biological Markers; Blood flow; Brain imaging; Chronic; Clinical; Clinical Trials; Cognition; Cognitive; Cognitive deficits; Collaborations; Communities; Data; Data Set; Development; Discipline; Disease; Dopamine; Dopamine D1 Receptor; Dose; Down-Regulation; Floor; Functional Magnetic Resonance Imaging; Functional disorder; Gadolinium; Hand; Human; Image; Impaired cognition; Impairment; Individual; Injection of therapeutic agent; Inpatients; Institution; Investigation; Joints; Ketamine; Lead; Magnetic Resonance Imaging; Measurement; Measures; Memory impairment; Modeling; National Institute of Mental Health; Outcome Measure; Patients; Performance; Performance at work; Perfusion; Pharmaceutical Preparations; Pharmacologic Substance; Placebos; Plasma; Positron-Emission Tomography; Pre-Clinical Model; Prefrontal Cortex; Primates; Principal Investigator; Relative (related person); Research; Research Personnel; Rest; Risperidone; Role; Scanning; Schizophrenia; Scientist; Short-Term Memory; Signal Transduction; Societies; Symptoms; System; Taxes; Testing; Therapeutic; Universities; Up-Regulation; Visual; Withholding Treatment; Work; Workload; base; blood oxygen level dependent; design; disability; improved; in vivo; interest; meetings; memory process; neuropsychiatry; neuropsychological; novel therapeutic intervention; pre-clinical; radioligand; receptor; receptor binding; receptor expression; receptor upregulation; relating to nervous system; research clinical testing; severe mental illness; subcutaneous; success; tool; transmission process; treatment duration; treatment strategy

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.

描述（由申请人提供）：认知障碍，包括工作记忆（WM）赤字，是精神分裂症的核心特征，在整个疾病的过程中保持稳定，会引起重大障碍，并且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，强调了D1受体在这种认知缺陷中的主要作用。最近，由美国国家心理健康研究所（NIMH）赞助的基质（测量和治疗研究以改善精神分裂症认知）聚集的专家小组结论，D1激动剂代表了一种有希望的治疗精神分裂症认知障碍的方法。 该提案是学术机构哥伦比亚大学与制药公司Darpharma Inc.之间的共同合作，以及整个社区的许多杰出科学家，以评估评估选择性D1激动剂，DAR-0100的概念证明，在Schizizophrenia的认知性赤字治疗中使用。 在拟议的研究中，将将两种剂量的DAR-0100或安慰剂（10和30 mg，s.c.）提供给三个不同的组（n = 20）（n = 20），临床上稳定的住院患者接受了利培酮治疗的精神分裂症。 参与工作记忆功能的区域中的静止血流和神经活动将被用作生物学标记物，以评估DAR-0100急性（2天）和亚基疗法治疗（7天）在改善精神分裂症的认知缺陷方面的潜在疗效，（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).此外，将在7天和3个月后评估对一般认知的影响（SA3）。 为了符合该标准杆的精神，我们认为我们的建议将导致一项结论性的工作，重点是治疗最严重的精神疾病之一的最具挑战性的临床方面，这些方面对其所影响的个人和整个社会所影响的人一样多。