Dissecting Heterogeneity of Treatment Response of First Episode Schizophrenia

描述（由申请人提供）：现在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用于预测治疗反应和神经心理和功能结果测量。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素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，尽管涉及到脑灰质缺陷。此外，最近的经验和理论工作表明，脑白质的缺陷可能是精神分裂症抗精神病药无反应的一个因素。精神分裂症神经生物学预测因子的研究在很大程度上受到限制，因为缺乏对照临床试验来招募患者并检验有关反应的假设。我们的初步数据表明，通过皮质表面作图方法评估的前额叶灰质缺陷可以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，通过扩散张量成像评估，额颞叶区域较低的分数各向异性与这些患者的治疗无反应有关。在目前的研究中，我们建议扫描一组独特的75抗精神病药物，首次发作精神分裂症患者。患者将从nimh赞助的（2R01-MH60004）利培酮与阿立哌唑的12周随机双盲试验中抽取，并在对照治疗下进行为期一年的定期评估，作为CIDAR临床算法的一部分。本研究的具体目的是：(1)通过12周的随机临床试验和52周的对照治疗，确定首发精神分裂症患者皮质灰质体积/密度和白质分数各向异性与治疗反应/结局之间的关系；(2)在12周的随机临床试验和52周的对照治疗后，检查首发患者灰质体积/密度和白质分数各向异性的变化与治疗反应/结果的关系。在疾病首次发作时识别这些异常可能有助于识别易受伤害的指标，这可能有助于改善对精神分裂症风险个体的早期识别。

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.