3/5 Selective Antipsychotic Response to Clozapine in B-SNIP Biotype-1 (CLOZAPINE)

B-SNIP Biotype-1 (CLOZAPINE) 中氯氮平的选择性抗精神病反应为 3/5

• 批准号: 10396432
• 负责人: GODFREY D PEARLSON
• 金额: $ 35.95万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 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/10396432
• 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; side effect; specific biomarkers; stimulus processing; symptomatic improvement; treatment duration; volunteer

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.

项目摘要 精神病的治疗进展受到基于现象学定义的诊断的限制 有症状的结果，而不是通过定量特征监测的神经生物学结构。这 用于中间表型（B-SNIP）的双极 - 奇异性网络使用生物标志物来定义精神病 亚组的目标是测试B-SNIP生物标志物在诊断和治疗决定中的优势， 与NIMH战略计划（NSP）中的原则一致。具有> 3000个表型精神病概率， 亲戚和健康对照（HC），B-SNIP具有用于精神病的多级生物标志物库，并使用了该图书馆 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/高症状组和B3表现出较低的症状和相对正常的认知。我们 在新样本中复制生物型，“锻造一个个人的神经和神经和 生理状态将构成越来越具体且内容丰富的诊断”（NSP）。 我们建议B1具有低认知和低皮质活性，将对氯氮平（一种药物）做出独特的反应 这将在B1中产生主动皮质吸引力网络，以支持症状改善。 氯氮平是具有独特临床有效性的最有效的抗精神病药（APD）。它是最不使用的APD 因为它的副作用是严重的（中性粒细胞减少症，心肌炎，癫痫发作）及其给药络合物。一个 预测生物标志物将允许针对最有可能响应并改善精神病的预后的病例。 B-SNIP表明，氯氮平与α/theta功率的脑电图测量值的增加有关，而我们 在没有刺激处理要求的情况下确定这种增加的时间段，作为内在的脑电图活动（IEA）， 在所有生物型中。因为B1案例表达了低IEA，因此氯氮平增加脑电图的动力将是 该精神病亚组的标准化，皮质吸引子态增加。因为B2表示 强调IEA，氯氮平与B2中更异常的IEA有关。我们建议测试B1精神病病例 与氯氮平与利培酮（n = 40/组临床试验完成者）的使用，在6周的交叉术中（用于治疗 血浆水平）和9周稳定的剂量扩展，预测B1/氯氮平组将做出反应 与B1/利培酮组相比，用总PANS测量的要好得多，并且比任何一个B2更好 团体。我们的假设是，皮层吸引子网络将被标准化，其功能通过 内在脑电图活性的增加。