4/5: Antipsychotic Response to Clozapine in B-SNIP Biotype-1 (CLOZAPINE)

项目摘要 精神病的治疗进展受到基于以下因素的现象学定义的诊断的限制： 症状的结果，而不是通过定量特征监测的神经生物学结构。 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，目的是测试B-SNIP生物标志物用于诊断和治疗的优势。 治疗决定，符合NIMH战略计划（NSP）的原则。表型>3000 精神病先证者，亲属和健康对照（HC），B-SNIP具有多层次的生物标志物库， 并使用该文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， 相对正常的认知。我们在一个新的样本中复制了生物型，“打造一个未来， 个人的.神经和生理状态将形成一个越来越具体和翔实的基础 诊断”（NSP）。在这项研究中，我们提出，B1，其低认知和低皮层活动，将作出反应， 氯氮平是一种独特的药物，它会在B1中产生活跃的皮质吸引子网络， 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 治疗血浆水平）和9周稳定剂量延长，预测B1/氯氮平组将 用总PANSS测量，B1/利培酮组的反应明显优于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，它们的功能 增加了内在的脑电图活动。

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.