Neural Biomarkers of Clozapine Response

氯氮平反应的神经生物标志物

• 批准号: 9310411
• 负责人: Deepak K Sarpal
• 金额: $ 18.08万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-26 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9310411
• 关键词: Address; Affect; Aftercare; Algorithms; Antipsychotic Agents; Award; Biological Assay; Biological Markers; Brain; Chronic; Chronic Disease; Clinical; Clinical Trials; Clozapine; Corpus striatum structure; Cross-Sectional Studies; Data; Development; Doctor of Medicine; Doctor of Philosophy; Drug Psychoses; Drug Utilization; Evidence based treatment; Functional Imaging; Functional Magnetic Resonance Imaging; Generations; Goals; Health Expenditures; Incentives; Lead; Measures; Mentored Patient-Oriented Research Career Development Award; Mentors; Methodology; Methods; Modernization; Morbidity - disease rate; National Institute of Mental Health; Patients; Pattern; Pharmaceutical Preparations; Pharmacology; Positive Valence; Prefrontal Cortex; Principal Investigator; Process; Prognostic Marker; Psychotic Disorders; Punishment; Refractory; Research; Research Domain Criteria; Rest; Rewards; Schizophrenia; Sensitivity and Specificity; Structure; Symptoms; Task Performances; Training; Training Programs; Work; base; biomarker development; biomarker identification; career; drug development; experience; experimental study; functional MRI scan; improved; indexing; mortality; neural circuit; neuroimaging; neuroimaging marker; neuromechanism; neuropsychopharmacology; novel; patient oriented research; phenomenological models; precision medicine; predicting response; programs; psychotic symptoms; relating to nervous system; responders and non-responders; response; skills; symptomatology; translational scientist; translational study; treatment responders; treatment response

PROJECT SUMMARY This is an application for an NIMH Mentored Patient-Oriented Research Career Development Award (K23) entitled "Neural Biomarkers of Clozapine Response." In this application, Dr. Deepak K. Sarpal, proposes a comprehensive plan for transitioning into an independent translational researcher focused on understanding the neural mechanisms of treatment response in psychotic disorders and integrating functional neuroimaging with clinical algorithms. A large number of patients with chronic psychotic disorders continue to have symptoms following unsuccessful trials with first-line antipsychotic drugs. For these patients with refractory psychosis, clozapine has consistently demonstrated superior efficacy. Clozapine is often underutilized and administered late in a patient's course of treatment, which leads to increased morbidity, unnecessary medication trials, and increased health care expenditure. Meanwhile, the mechanism of action underlying clozapine's novel effects remains unknown and has not been studied with modern neuroimaging methods. Identifying the neural mechanisms by which clozapine exerts its effects may lead to biomarkers that will facilitate efficient utilization of the drug, and introduce novel treatment targets. In patients with refractory psychotic symptoms, the proposed study will use resting-state and task-based functional MRI (fMRI) to examine the neural circuitry of efficacious treatment with a trial of clozapine. Patients will undergo fMRI scanning both before and after 12 weeks of treatment, with the aims of determining: baseline patterns of resting-state functional connectivity and task-based activation that predict response to treatment; and changes in resting-state and task-based functional circuitry associated with efficacious treatment. Results of this proposal may lead to biomarkers that will optimize treatment algorithms for psychotic disorders and facilitate drug development for refractory psychosis. While pursuing this line of research under the guidance of mentors who are recognized experts in translational studies in schizophrenia (Anil K. Malhotra, M.D., Todd Lencz, Ph.D.), clinical trials (John M. Kane, M.D.) and neuroimaging (Katherine H. Karlsgodt, Ph.D., Michael P. Milham, M.D., Ph.D.), Dr. Sarpal will engage in a comprehensive training program in neuropsychopharmacology, translational neuroimaging, and task-based fMRI methodology. He will also gain experience in executing and managing studies involving psychiatrically ill patients. The completion of the proposed Mentored Career Award will support a comprehensive, novel program of patient-oriented research, while allowing Dr. Sarpal to acquire essential skills that will support his development into an independent translational researcher.

项目摘要 这是一个NIMH指导病人为导向的研究职业发展奖（K23）的应用程序 名为“氯氮平反应的神经生物标志物。“在本申请中，Deepak K. Sarpal提出， 全面的计划，过渡到一个独立的翻译研究人员专注于理解 精神障碍治疗反应的神经机制与整合功能神经影像学 临床算法。大量慢性精神病患者持续出现症状 在一线抗精神病药物试验失败后对于这些难治性精神病患者， 氯氮平一直显示出上级功效。氯氮平通常未被充分利用， 在患者治疗过程的后期，这导致发病率增加，不必要的药物试验， 增加医疗保健支出。与此同时，氯氮平新作用的作用机制 目前尚不清楚，也没有用现代神经影像学方法进行研究。识别神经 氯氮平发挥其作用的机制可能导致生物标志物，这将有助于有效利用 并引入新的治疗靶点。在难治性精神病症状患者中， 一项拟议的研究将使用静息状态和基于任务的功能性MRI（fMRI）来检查大脑的神经回路。 一个有效的治疗与试验的氯氮平。患者将在12小时之前和之后接受fMRI扫描。 治疗周，目的是确定：静息状态功能连接的基线模式， 预测对治疗反应的基于任务的激活;以及静息状态和基于任务的激活的变化。 与有效治疗相关的功能回路。这一提议的结果可能导致生物标志物， 将优化精神障碍的治疗算法，并促进难治性精神障碍的药物开发。 精神病在导师的指导下进行这一研究的同时，导师是公认的专家， 精神分裂症的转化研究（Anil K.马尔霍特拉医学博士，托德伦茨博士），临床试验（John M.凯恩， （医学博士）和神经影像学（凯瑟琳H. Karlsgodt博士Michael P. Milham，医学博士，Ph.D.），萨尔帕博士会 从事神经精神药理学，转化神经影像学的综合培训计划， 基于任务的fMRI方法。他还将获得执行和管理研究的经验， 精神病患者完成拟议的辅导职业奖将支持 全面，新颖的以患者为导向的研究计划，同时允许Sarpal博士获得基本技能 这将有助于他成为一名独立的翻译研究人员。