2/5-Clozapine Response and Biomarker Correlates in Low-IEA Biotype-1

2/5-氯氮平反应与低 IEA Biotype-1 中的生物标志物相关

基本信息

批准号：
10397395
负责人：
Elliot S Gershon
金额：
$ 36.45万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10397395
关键词：
Antidepressive Agents Antipsychotic Agents Bacterial Artificial Chromosomes Biological Markers Blinded Blood Characteristics Chemistry Clinical Clinical Trials Clinical Trials Cooperative Group Clinical Trials Design Clinical assessments Clozapine Cognition Communities Complex Consent Custom Diagnosis Diagnostic Dose Double-Blind Method Dropout Drug Monitoring Electrocardiogram Electroencephalography Future Goals Grant Individual Libraries Measures Monitor Myocarditis National Institute of Mental Health Neurobiology Neutropenia Outcome Participant Patients Pharmaceutical Preparations Pharmacotherapy Phenotype Physicians Physiological Plasma Preparation Prognosis Psychoses Randomized Regimen Resistance Risperidone Saccades Safety Sampling Schedule Schizophrenia Seizures Site Specific qualifier value Strategic Planning Subgroup Symptoms Testing Therapeutic Time Titrations Work base clinical efficacy deviant forging improved phenomenological models phenotypic biomarker predictive marker proband recruit relating to nervous system research clinical testing response response biomarker side effect specific biomarkers stimulus processing symptomatic improvement treatment duration volunteer

项目摘要

Project Summary Treatment advances in psychosis are limited by the use of phenomenology-defined diagnoses based on symptomatic outcomes, rather than by neurobiological constructs monitored by quantitative characteristics. The Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP) uses biomarkers to define psychosis subgroups with the goal of testing the advantages of B-SNIP biomarkers for diagnostic and therapeutic decisions, consistent with principles in the NIMH Strategic Plan (NSP). With >3000 phenotyped psychosis probands, relatives and healthy controls (HC), B-SNIP has a multilevel biomarker library for psychosis and used that library to re-conceptualize psychosis subgroups as biomarker-defined Biotypes (B1, B2, B3), where B1 and B2 are the low cognition/high symptom groups and B3 shows lower symptoms and relatively normal cognition. We replicated Biotypes in a new sample, “forging a future where measures of an individual's … neural and physiological state will form the basis of an increasingly specific and informative diagnosis” (NSP). In this grant we propose that B1, with its low cognition and low cortical activity, will respond uniquely to clozapine, a drug which will generate active cortical attractor networks in B1 to support symptomatic improvement. Clozapine is the most effective antipsychotic drug (APD) with unique clinical efficacy. It is the least used APD because its side effects are serious (neutropenia, myocarditis, seizures) and its administration complex. A predictive biomarker would allow targeting of cases most likely to respond and improve prognosis in psychosis. B-SNIP has shown that clozapine is associated with increases in EEG measures of alpha/theta power, and we identify this increase in time periods without stimulus processing requirements as intrinsic EEG activity (IEA), across all Biotypes. Because B1 cases express low IEA, clozapine's action to increase EEG power will be normalizing for this psychosis subgroup, with increased cortical attractor states. Because B2 express accentuated IEA, clozapine is associated with more deviant IEA in B2. We propose to test B1 psychosis cases with clozapine vs. risperidone (n=40/group clinical trial completers), over a 6 week cross-titration (to therapeutic plasma levels) and a 9 week stable dose extension, predicting that the B1/clozapine group will respond significantly better, as measured with total PANSS, than the B1/risperidone group and also better than either B2 group. It is our hypothesis that the cortical attractor networks will be normalized and their function increased by the increase in intrinsic EEG activity.

项目概要精神病治疗的进展受到使用基于现象学定义的诊断的限制症状结果，而不是通过定量特征监测的神经生物学结构。双相精神分裂症中间表型网络 (B-SNIP) 使用生物标志物来定义精神病亚组，目的是测试 B-SNIP 生物标志物在诊断和治疗方面的优势治疗决策，符合 NIMH 战略计划 (NSP) 中的原则，具有 >3000 个表型。精神病先证者、亲属和健康对照 (HC)，B-SNIP 拥有一个多级生物标志物库，可用于精神病并使用该库将精神病亚组重新概念化为生物标志物定义的生物型（B1， B2、B3)，其中 B1 和 B2 是低认知/高症状组，B3 显示较低症状，我们在一个新样本中复制了生物型，“打造一个未来的衡量标准”。个人的……神经和生理状态将构成日益具体和信息丰富的基础诊断”（NSP），在这项资助中，我们建议 B1 因其低认知和低皮质活动而做出反应。氯氮平是独一无二的，这种药物会在 B1 中产生活跃的皮质吸引子网络，以支持症状改善。氯氮平是最有效的抗精神病药物（APD），具有独特的临床疗效，也是使用最少的APD。因为它的副作用很严重（中性粒细胞减少、心肌炎、癫痫）并且其给药复杂。预测性生物标志物将能够针对最有可能做出反应的病例并改善精神病的预后。 B-SNIP 表明氯氮平与脑电图 α/θ 功率测量值的增加有关，我们将这种没有刺激处理要求的时间段的增加识别为内在脑电图活动（IEA），由于 B1 病例表达低 IEA，氯氮平增加 EEG 功率的作用将是该精神病亚组正常化，皮质吸引子状态增加，因为 B2 表达。强调 IEA，氯氮平与 B2 中更异常的 IEA 相关，我们建议测试 B1 精神病病例。氯氮平与利培酮（n=40/组临床试验完成者），经过 6 周的交叉滴定（至治疗血浆水平）和 9 周稳定剂量延长，预测 B1/氯氮平组将根据总 PANSS 测量，反应明显优于 B1/利培酮组，也优于我们假设皮质吸引子网络及其功能将被标准化。随着内在脑电图活动的增加而增加。