Centers for Intervention Development and Applied Research (CIDAR)

精神分裂症是一个主要的公共卫生问题，影响着近1%的人口，他们年轻时就会出现精神病，功能结果很差。对个人、家庭和社会的影响是巨大的。两个精神病理领域，阴性症状和认知障碍，通常是精神病的先兆，与不良的功能结果密切相关。目前还没有记录的治疗方法对这两个领域的疗效。拟议研究的目的是利用创新的评估平台和测试具有新分子靶点的药物来推进这两个领域的药物发现。具体目标包括建立创新的评估技术，并确定一种被认为对阴性症状有效的复合假设和一种对认知障碍有效的复合假设的效果。第二个目标是确定这两个领域是代表药物发现的相似还是不同的发展路径。这些目标将通过建立三个目标来实现 评估平台：a)显示两种精神病理领域表型的产前应激大鼠模型；b)从精神分裂症先证者的生物学亲属中挑选的具有两种精神病理表型的受试者；以及c)临床试验平台，选择具有两种精神病理学表型的精神分裂症受试者。选择进行测试的两种化合物是用于治疗阴性症状的催产素和用于认知障碍的3-[(2，4-二甲氧基)亚甲基]阿纳巴辛(DXMB-A)，这是一种α-7尼古丁受体部分激动剂。我们将确定：a)在每个评估平台中，每种化合物对阴性和认知表型的影响；b)在临床前和非精神分裂症人体模型中的效果是否预示着临床模型中的效果；c)是否在临床试验中观察到疗效；以及d)每种化合物的效果是否针对假设的精神病理领域。该项目通过测试新化合物的阴性症状和认知障碍来解决精神分裂症未得到满足的治疗需求。在新的动物身上进行测试 以及人类评估平台，以开发早期药物评估的新方法。疗效是在临床试验中确定的，根据阴性症状和认知表型选择患者对象。

Schizophrenia is a major public health problem affecting almost 1% of the population with youthful onset of psychosis and poor functional outcomes. Personal, family, and societal impact is substantial. Two psychopathological domains, negative symptoms and cognitive impairments, typically preceed psychosis, and are robustly associated with poor functional outcome. No treatment has documented efficacy for these two domains. The purpose of the proposed studies is to advance drug discovery for these two domains using innovative evaluation platforms and testing drugs with novel molecular targets. Specific aims involve establishing innovative evaluation techniques and to determine the effect of a compound hypothesized to have efficacy for negative symptoms and a compound hypothesized to have efficacy for cognitive impairments. A second aim is to determine whether these two domains represent similar or separate developmental pathways for drug discovery. These aims will be accomplished by establishing three evaluation platforms: a] a pre-natal stress rat model which manifests phenotypes of both psychopathological domains; b] subjects selected from the biological relatives of schizophrenia probands who manifest phenotypes for both psychopathologies; and c] a clinical trials platform with schizophrenia subjects selected with phenotypic manifestations of the two psychopathologies. The two compounds chosen for testing are oxytocin for negative symptoms and 3-[(2,4-dimethoxy) benzylidene]anabaseine (DXMB-A), an alpha-7 nicotinic receptor partial agonist, for cognitive impairments. We will determine: a] the effect of each compound on both negative and cognitive phenotypes in each evaluation platform; b] whether effects in the pre-clinical and non-schizophrenia human models predicts effects in the clinical model; c] whether efficacy is observed in the clinical trial; and d] whether effects of each compound are specific for the hypothesized psychopathological domain. This project addresses the unmet therapeutic needs for schizophrenia by testing novel compounds for negative symptoms and cognitive impairments. Testing is performed on novel animal and human evaluation platforms in order to develop new approaches to early drug evaluation. Efficacy is determined in a clinical trial where patient subjects are selected according negative symptom and cognitive phenotypes.