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; 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NIMH指导的以患者为导向的研究职业发展奖（K23）的申请 名为“氯氮平反应的神经生物标志物”。在此应用程序中，Deepak K. Sarpal博士提出了 转变为专注于理解的独立翻译研究人员的综合计划 精神疾病中治疗反应的神经机制并整合功能性神经影像学 带有临床算法。许多慢性精神病患者继续有症状 经过一线抗精神病药的试验失败。对于这些难治性精神病的患者 氯氮平始终显示出优异的功效。氯氮平经常被未充分利用和给药 在患者的治疗过程中，导致发病率增加，不必要的药物试验和 增加医疗保健支出。同时，氯氮平的新作用的作用机理 仍然未知，尚未使用现代神经影像学方法进行研究。识别神经 氯氮平施加其作用的机制可能会导致生物标志物，从而有助于有效利用 药物，并引入新的治疗靶标。在具有难治性精神病症状的患者中 拟议的研究将使用静止状态和基于任务的功能MRI（fMRI）检查 通过氯氮平试验有效治疗。患者将在12点之前和之后进行fMRI扫描 几周的治疗，以确定的目的：静止状态功能连接性的基线模式和 基于任务的激活预测对治疗的反应；以及静止状态和基于任务的变化 与有效治疗相关的功能电路。该提案的结果可能会导致生物标志物 将优化精神病的治疗算法并促进难治性药物开发 精神病。在受到公认专家的指导下，在追求这一研究的同时 精神分裂症的翻译研究（Anil K. Malhotra，M.D。，Todd Lencz，Ph.D。），临床试验（John M. Kane，John M. Kane， M.D.）和NeuroImaging（Katherine H. Karlsgodt，博士 参与神经心理学，转化神经影像学和 基于任务的fMRI方法。他还将获得执行和管理涉及研究的经验 精神病患者。拟议的指导职业奖的完成将支持 全面的，新颖的面向患者研究的计划，同时允许Sarpal博士获得基​​本技能 这将支持他成为独立翻译研究人员的发展。