A Potential State and Relapse Predictive Marker in Schizophrenia

描述（由申请人提供）：我的职业发展目标在这个指导以患者为导向的研究职业发展奖（K23）是获得所需的技能和培训，成为一个独立的医生，科学家在精神分裂症的免疫学以患者为导向的研究。职业发展计划将侧重于：1）增加我对单核细胞和辅助性T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）增加我在纵向研究的设计，实施和分析方面的知识和技能，4）发展对精神分裂症研究中复发的更多理解和经验，5）磨练我在批判性思维、科学写作和演讲方面的技能。我将把这些知识应用到以病人为中心的研究中，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。我的研究目标是评估血清白细胞介素-6（IL-6）水平作为一个潜在的临床状态和复发的预测标志物精神分裂症使用新的，互补的横截面和纵向的方法。项目#1是一项在NIMH资助的PROACTIVE（预防复发口服抗精神病药与注射剂相比评估疗效）研究中参与者血清IL-6水平的纵向研究，该研究是一项为期30个月的复发预防试验，定期抽取血液样本，复发是主要结局指标。主要目的是确定血清IL-6水平的变化是否预测复发。项目#2是一项对复发和稳定的门诊精神分裂症患者和对照组的血清IL-6水平、色氨酸catalysts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志物。免疫异常在精神分裂症（包括炎症）中的病理生理作用于1967年首次被假设，并且一直是该领域中更持久的发现之一。最近，对其他慢性疾病中炎症与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，一些随机双盲试验发现，非甾体抗炎药（NSAID）的连续治疗显着改善复发患者的精神病理学，血清细胞因子水平预测对NSAID的反应。这些研究结果的汇合为炎症在某些精神分裂症患者复发中的病理生理作用提供了重要的经验支持。该应用程序通过探索精神分裂症复发的新的潜在标志物来促进NIMH战略计划，该标志物可用于评估治疗有效性，告知和推进复发预防工作，甚至有助于为未来基于免疫的治疗干预铺平道路。 公共卫生相关性：精神分裂症通常是一种慢性的、使人衰弱的疾病，对受影响的个人和家庭具有终身的后果，并且临床过程通常是 其特征在于复发性复发，其与不良结果相关，包括增加的耐药症状、认知下降和功能残疾。这个指导以患者为导向的研究职业发展奖（K23）将使布赖恩米勒博士通过探索精神分裂症的新的潜在临床状态和复发预测标志物，进一步发展他在精神分裂症研究中的职业轨迹。更好地理解和预测精神分裂症复发的能力是一个引人注目的机会，也是公共卫生的优先事项。

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. PUBLIC HEALTH RELEVANCE: Schizophrenia is commonly a chronic, debilitating disorder with life-long consequences for affected individuals and families, and the clinical course is often characterized by recurrent relapses, which are associated with adverse outcomes, including increased treatment-resistant symptoms, cognitive decline, and functional disability. This Mentored Patient-Oriented Research Career Development Award (K23) will enable Dr. Brian Miller to further develop his career trajectory in schizophrenia research by exploring a novel potential clinical state and relapse predictive marker in schizophrenia. A better ability to understand and predict relapse in schizophrenia is a compelling opportunity and a public health priority.