Dissecting Heterogeneity of Treatment Response of First Episode Schizophrenia

描述（申请人提供）：目前有相当多的证据表明，精神分裂症首次发作时存在解剖病理学。很少有研究旨在了解这些解剖缺陷及其纵向过程是否可以用来预测治疗反应和神经心理学和功能结果的措施。在病程早期识别对标准抗精神病药物治疗无反应的患者可能对药物干预和改善后续预后的策略具有重要意义。然而，精神分裂症治疗反应的神经生物学预测因子尚未得到很好的定义，这种现象没有明确的神经生物学基础，尽管脑灰质的缺陷已经被牵连。此外，最近的经验和理论工作表明，大脑白色物质的缺陷可能是精神分裂症抗精神病药物无反应的一个因素。精神分裂症的神经生物学预测因子的研究在很大程度上受到限制，这是由于缺乏对照临床试验来招募患者和测试有关反应的假设。我们的初步数据表明，前额灰质缺陷，通过皮质表面映射方法评估，预测首发精神分裂症患者的治疗反应。额外的初步数据表明，较低的分数各向异性，通过扩散张量成像评估，在额颞区与治疗无反应，在这些患者。在本研究中，我们建议扫描一个独特的组75抗精神病药物初治，首发精神分裂症患者。患者将从NIMH申办的（2 R 01-MH 60004）利培酮与阿立哌唑的双盲随机12周试验中抽取，并在对照治疗下进行定期评估，作为CIDAR临床算法的一部分，为期一年。本研究的具体目的是：（1）确定首发精神分裂症患者大脑皮质灰质体积/密度和白色物质各向异性分数与12周随机临床试验和52周对照治疗后的治疗反应/结果之间的关系;（2）检查灰质体积的变化，12周随机临床试验期间和52周对照试验后首次发作患者的密度和白色部分各向异性治疗与治疗反应/结果的关系。这些异常的识别在第一次发病的疾病可能是有用的识别指标的脆弱性，这可能会导致改善早期识别个人的精神分裂症的风险。

Description (provided by applicant): There is now considerable evidence that anatomic pathology is present at the first episode of schizophrenia. Little research has been directed at understanding whether these anatomic deficits and their longitudinal course can be used to predict treatment response and neuropsychological and functional outcome measures. The identification of patients early in the course of illness who are nonresponsive to standard antipsychotic treatment could have significant implications for pharmacologic intervention and strategies for improving subsequent prognosis. Neurobiological predictors of treatment response in schizophrenia have not been well defined, however, and this phenomenon has no clear neurobiological basis, although a defect in the brain gray matter has been implicated. Moreover, recent empirical and theoretical work suggests that a defect in the brain white matter may be a contributing factor to antipsychotic nonresponse in schizophrenia. The investigation of neurobiological predictors in schizophrenia has been limited in large part due to the lack of controlled clinical trials from which to recruit patients and test hypotheses regarding response. Our preliminary data suggest that prefrontal gray matter deficits, as assessed via cortical surface mapping methods, predict treatment response in patients with first episode schizophrenia. Additional preliminary data suggest that lower fractional anisotropy, as assessed via diffusion tensor imaging, in frontotemporal regions is associated with treatment nonresponse in these patients. In the present study we propose scanning a unique group of 75 antipsychotic drug-naive, first episode schizophrenia patients. Patients will be drawn from an NIMH-sponsored (2R01-MH60004) double-blind randomized 12-week trial of risperidone vs. aripiprazole, and followed with regular assessments under controlled treatment as part of the CIDAR clinical algorithm for one year. The specific aims of this study are to: (1) determine the relationship between cortical gray matter volume/density and white matter fractional anisotropy in first episode patients with schizophrenia and treatment response/outcome following the 12 week randomized clinical trial and after 52 weeks of controlled treatment; and (2) examine changes in gray matter volume/density and white matter fractional anisotropy in first episode patients over the 12 week randomized clinical trial and after 52 weeks of controlled treatment in relationship to treatment response/outcome. The identification of these abnormalities at the first episode of illness may be useful for identifying indicators of vulnerability, which may lead to improved early identification of individuals at risk for schizophrenia.