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，影响了近1%的人口，他们年轻时发病，功能预后差。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，通常先于精神病，并与不良的功能预后密切相关。没有任何治疗方法对这两个领域有效。拟议研究的目的是利用创新的评估平台和具有新分子靶点的药物测试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了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目标来实现

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.