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，影响到近1%的人口，具有年轻的精神病发作和不良的功能结果。对个人、家庭和社会的影响是巨大的。两个精神病理学领域，阴性症状和认知障碍，通常先于精神病，并与不良的功能结果密切相关。没有治疗记录了这两个领域的疗效。拟议研究的目的是使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。具体目标涉及建立创新的评价技术，并确定假设对阴性症状有效的化合物和假设对认知障碍有效的化合物的效果。第二个目的是确定这两个领域是否代表药物发现的相似或独立的发展途径。这些目标将通过建立三个 评价平台：a]产前应激大鼠模型，其表现出两种精神病理学领域的表型; B]受试者，其选自表现出两种精神病理学的表型的精神分裂症先证者的生物学亲属;和c]临床试验平台，其具有所述两种精神病理学的表型表现。选择用于测试的两种化合物是用于阴性症状的催产素和用于认知障碍的3-[（2，4-二甲氧基）亚苄基]anabaseine（DXMB-A），一种α-7烟碱受体部分激动剂。我们将确定：a]每种化合物在每种评估平台中对阴性和认知表型的作用; B]在临床前和非精神分裂症人类模型中的作用是否预测在临床模型中的作用; c]在临床试验中是否观察到功效;和d]每种化合物的作用是否对假设的精神病理学领域具有特异性。该项目通过测试用于阴性症状和认知障碍的新型化合物来解决精神分裂症未满足的治疗需求。对新动物进行试验 和人类评估平台，以开发早期药物评估的新方法。在临床试验中确定疗效，其中根据阴性症状和认知表型选择患者受试者。

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.