A Potential State and Relapse Predictive Marker in Schizophrenia

描述(由申请者提供)：我在这个以患者为导向的研究职业发展奖(K23)中的职业发展目标是获得所需的技能和培训，以成为精神分裂症免疫学以患者为导向的研究中的独立内科科学家。职业发展计划将侧重于：1)增加我对单核细胞和T辅助淋巴细胞亚群的知识，2)发展对免疫学研究中现代技术的理解和经验，3)增加我在纵向研究设计、实施和分析方面的知识和技能，4)在精神分裂症研究中对复发有更多的理解和经验，以及5)磨练我的批判性思维、科学写作和陈述技能。我将把这些知识应用到以患者为导向的研究中，以促进我们对精神分裂症复发的病理生理学和潜在治疗的理解。我的研究目标是使用新的、互补的横断面和纵向方法来评估血清白介素6(IL-6)水平作为精神分裂症潜在的临床状态和复发预测标志物的价值。项目1是对NIMH资助的前瞻性研究(预防复发口服抗精神病药物与注射剂评估疗效的比较)参与者的血清IL-6水平的纵向研究，这是一项为期30个月的复发预防试验，定期采集血样，复发是主要的结果衡量标准。主要目标是确定血清IL-6水平的变化是否可以预测复发。项目2是对复发和稳定的精神分裂症患者和对照组的血清IL-6水平、色氨酸分解代谢和白细胞亚群的横断面研究。主要目的是评估血清IL-6水平作为急性精神病的潜在状态标记物。包括炎症在内的免疫异常在精神分裂症中的病理生理学作用最早是在1967年提出的，这是该领域最持久的发现之一。最近，对其他慢性病中炎症和大脑之间复杂相互作用的了解增加，更好地了解了精神分裂症中的这种关系。此外，几项随机、双盲试验发现，非类固醇抗炎药(NSAIDs)的辅助治疗显著改善了复发患者的精神病理学，血清细胞因子水平预测了对NSAIDs的反应。这些发现的融合为炎症在某些精神分裂症患者复发中的病理生理学作用提供了重要的经验支持。这项应用通过探索精神分裂症复发的新的潜在标记物来促进NIMH战略计划，该标记物可用于评估治疗效果、告知和推进复发预防努力，甚至有助于为未来基于免疫的治疗干预铺平道路。

DESCRIPTION (provided by applicant): My career development goal during this Mentored Patient-Oriented Research Career Development Award (K23) is to obtain the skills and training needed to become an independent physician-scientist in patient-oriented research in the immunology of schizophrenia. The Career Development Plan will focus on: 1) increasing my knowledge of monocyte and T-helper lymphocyte subsets, 2) developing an understanding of and experience with modern techniques in immunological research, 3) increasing my knowledge and skills in the design, conduct, and analysis of longitudinal studies, 4) developing a greater understanding and experience with relapse in schizophrenia research, and 5) honing my skills in critical thinking, scientific writing, and presentation. I will apply this knowledge to patient-orinted research to advance our understanding of the pathophysiology and potentially the treatment of relapse in schizophrenia. My research goal is to evaluate serum interleukin-6 (IL-6) levels as a potential clinical state and relapse predictive marker in schizophrenia using novel, complementary cross-sectional and longitudinal approaches. Project # 1 is a longitudinal study of serum IL-6 levels in participants in the NIMH-funded PROACTIVE (Preventing Relapse Oral Antipsychotics Compared to Injectables Evaluating Efficacy) study, a 30-month relapse prevention trial for which blood samples were drawn regularly, and relapse was the primary outcome measure. The primary goal is to determine if changes in serum IL-6 levels predict relapse. Project #2 is a cross-sectional study of serum IL-6 levels, tryptophan catabolites, and leukocyte subsets in relapsed and stable outpatients with schizophrenia, and controls. The primary goal is to evaluate serum IL-6 levels as a potential state marker for acute psychosis. A pathophysiological role for immune abnormalities in schizophrenia, including inflammation, was first hypothesized in 1967, and has been one of the more enduring findings in the field. Recently, increased understanding of the complex interactions between inflammation and the brain in other chronic diseases has better informed this relationship in schizophrenia. Moreover, several randomized, double-blinded trials found that adjunctive treatment with non-steroidal anti-inflammatory drugs (NSAIDs) significantly improved psychopathology in relapsed patients, and serum cytokine levels predicted response to NSAIDs. The confluence of these findings provides important empirical support for a pathophysiological role of inflammation in relapse in some patients with schizophrenia. This application promotes the NIMH Strategic Plan by exploring a novel potential marker for relapse in schizophrenia that could be used to assess treatment effectiveness, inform and advance relapse prevention efforts, and even help pave the way for future immune-based therapeutic interventions.