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

项目摘要 精神病的治疗进展可能会受到基于以下因素的现象学定义诊断的限制： 症状的结果，而不是通过定量特征监测的神经生物学结构。的 中间表型双极-精神分裂症网络（B-SNIP）使用生物标志物来定义精神病 亚组的目标是测试B-SNIP生物标志物用于诊断和治疗决策的优势， 符合NIMH战略计划（NSP）的原则。有超过3000个精神病先证者， 亲属和健康对照，B-SNIP有一个多层次的精神病生物标志物库，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/高症状组和B3表现出较低的症状和相对正常的认知。我们 在一个新的样本中复制了生物型，“锻造一个未来，在这个未来， 生理状态将形成越来越具体和信息丰富的诊断的基础”（NSP）。在这份赠款中， 我们认为，B1的认知能力低，皮质活动低，将对药物氯氮平产生独特的反应 这将在B1中产生活跃的皮质吸引子网络以支持症状改善。 氯氮平是目前最有效的抗精神病药物，具有独特的临床疗效。它是使用最少的APD 因为它的副作用很严重（中性粒细胞减少症、心肌炎、癫痫发作），而且给药复杂。一 预测性生物标志物将允许靶向最有可能响应的病例并改善精神病的预后。 B-SNIP已经表明，氯氮平与α/θ功率EEG测量值的增加有关，我们 将没有刺激处理要求的时间段的这种增加识别为固有EEG活动（IEA）， 在所有的生物类型中。由于B_1组表现为低IEA，故氯氮平增加脑电功率的作用将是 正常化为这个精神病亚组，增加皮质吸引子状态。因为B2快车 加强IEA，氯氮平与B2中更偏离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），6周交叉滴定（至治疗剂量） 血浆水平）和9周稳定剂量扩展，预测B1/氯氮平组将响应 用总PANSS测量，显著优于B1/利培酮组，也优于B2 组我们的假设是，皮层吸引子网络将被正常化，并且它们的功能将被增强。 内在脑电活动的增加

Project Summary Treatment advances in psychosis may be 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, 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.