Centers for Intervention Development and Applied Research (CIDAR)

干预发展和应用研究中心 (CIDAR)

• 批准号: 8327303
• 负责人: William T. Carpenter
• 金额: $ 179.77万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-22 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8327303
• 关键词: Address; Affect; Agonist; Animals; Applied Research; Biological; Clinical; Clinical Trials; Cognitive; Development; Drug Evaluation; Evaluation; Family; Human; Impaired cognition; Modeling; Molecular Target; Neurobehavioral Manifestations; Nicotinic Receptors; Oxytocin; Pathway interactions; Patients; Phenotype; Population; Psychopathology; Psychotic Disorders; Public Health; Rattus; Relative (related person); Schizophrenia; Stress; Symptoms; Techniques; Testing; Therapeutic; anabaseine; drug discovery; drug testing; functional outcomes; innovation; novel; novel strategies; pre-clinical; proband; research and development; therapy development

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.

精神分裂症是一个主要的公共卫生问题，几乎影响了1％的人口，精神病和功能不佳的成果。个人，家庭和社会影响是巨大的。两个精神病理学领域，负面症状和认知障碍，通常是预先精神病，并且与功能不良的结果牢固相关。没有治疗证明了这两个领域的功效。拟议的研究的目的是使用创新的评估平台和具有新型分子靶标的药物来促进这两个领域的药物发现。具体目的涉及建立创新的评估技术，并确定假设的化合物对负面症状具有疗效和假设具有认知障碍功效的化合物的作用。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单独的发育途径。这些目标将通过建立三个 评估平台：a]出生前应力大鼠模型，表现出两种心理病理领域的表型； b]从精神分裂症的生物学亲戚中选择的受试者，这些概率表现出了两种精神病理学的表型； c]一个具有精神分裂症受试者的临床试验平台，这些受试者选择了两种心理病理学的表型表现。选择用于测试的两种化合物是催产素的阴性症状和3 - （（2,4-二甲氧基）苄苯二苯甲酰酶（DXMB-A），一种α-7烟碱受体部分激动剂，用于认知障碍。我们将确定：a]每种化合物对每个评估平台中负面和认知表型的影响； b]在临床前和非静脉疾病的人类模型中的影响是否可以预测临床模型的影响； c]是否在临床试验中观察到功效； d]每种化合物的作用是否特定于假设的心理病理学领域。该项目通过测试新型化合物的负面症状和认知障碍来解决精神分裂症的未满足治疗需求。测试是对新型动物进行的 和人类评估平台，以开发新的早期药物评估方法。功效是在临床试验中确定的，该试验根据阴性症状和认知表型选择患者受试者。

项目成果

The effects of oxytocin and galantamine on objectively-defined vocal and facial expression: Data from the CIDAR study.

催产素和加兰他敏对客观定义的声音和面部表情的影响：来自 CIDAR 研究的数据。

• DOI: 10.1016/j.schres.2017.01.028
• 发表时间: 2017-10
• 期刊: Schizophrenia research
• 影响因子: 4.5
• 作者: Cohen AS;Mitchell KR;Strauss GP;Blanchard JJ;Buchanan RW;Kelly DL;Gold J;McMahon RP;Adams HA;Carpenter WT
• 通讯作者: Carpenter WT

Relationship of plasma oxytocin levels to baseline symptoms and symptom changes during three weeks of daily oxytocin administration in people with schizophrenia.

• DOI: 10.1016/j.schres.2016.02.014
• 发表时间: 2016-04
• 期刊: Schizophrenia research
• 影响因子: 4.5
• 作者: Lee MR;Wehring HJ;McMahon RP;Liu F;Linthicum J;Verbalis JG;Buchanan RW;Strauss GP;Rubin LH;Kelly DL
• 通讯作者: Kelly DL

The involvement of Type II Neuregulin-1 in rat visuospatial learning and memory.

• DOI: 10.1016/j.neulet.2012.10.018
• 发表时间: 2012-12-07
• 期刊: Neuroscience letters
• 影响因子: 2.5
• 作者: Taylor AR;Taylor SB;Koenig JI
• 通讯作者: Koenig JI

Corticotropin-releasing factor, serotonin, and sex: keys to the castle of depressive illness.

促肾上腺皮质激素释放因子、血清素和性：抑郁症城堡的钥匙。

• DOI: 10.1210/en.2009-0536
• 发表时间: 2009
• 期刊: Endocrinology
• 影响因子: 4.8
• 作者: Koenig,JamesI

A Randomized Clinical Trial of Oxytocin or Galantamine for the Treatment of Negative Symptoms and Cognitive Impairments in People With Schizophrenia.

• DOI: 10.1097/jcp.0000000000000720
• 发表时间: 2017-08
• 期刊: Journal of clinical psychopharmacology
• 影响因子: 2.9
• 作者: Buchanan RW;Kelly DL;Weiner E;Gold JM;Strauss GP;Koola MM;McMahon RP;Carpenter WT
• 通讯作者: Carpenter WT