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受到现象学定义的基于以下方面的诊断的使用的限制 有症状的结果，而不是通过量化特征监测的神经生物学结构。这个 双相精神分裂症中间表型网络(B-SNIP)使用生物标记物来定义精神病 以测试B-SNIP生物标记物在诊断和治疗决策中的优势为目标的小组， 与NIMH战略计划(NSP)中的原则一致。有3000名表型精神病先证者， 亲属和健康对照，B-SNIP有一个多层次的精神病生物标志物文库，并利用该文库 将精神病亚群重新定义为生物标记物定义的生物型(B1、B2、B3)，其中B1和B2是 低认知/高症状组和B3表现为低症状和相对正常的认知。我们 在新的样本中复制生物型，“打造一个衡量个人…的未来神经性和 生理状态将构成日益具体和信息丰富的诊断的基础“(NSP)。在这笔赠款中 我们认为，具有低认知和低皮质活性的B1对药物氯氮平具有独特的反应 这将在B1中产生活跃的皮质吸引器网络，以支持症状改善。 氯氮平是最有效的抗精神病药物，具有独特的临床疗效。这是最少使用的警察局 因为其副作用严重(中性粒细胞减少、心肌炎、癫痫发作)，且给药复杂。一个 预测性生物标记物将使最有可能做出反应的病例成为靶点，并改善精神病患者的预后。 B-SNIP已经表明，氯氮平与脑电α/θ功率测量的增加有关，我们 将这种没有刺激处理要求的时间段的增加识别为固有的脑电活动(IEA)， 所有的生物类型。由于B1例表达低IEA，氯氮平增加脑电功率的作用将是 对这一精神病亚组进行正常化，皮质吸引子状态增加。因为B2快递 强化的IEA中，氯氮平与B2中更多的IEA异常有关。我们建议对B1例精神病病例进行测试 氯氮平与利培酮(n=40/组临床试验完成者)，超过6周的交叉滴定(治疗 血浆水平)和9周的稳定剂量延长，预测B1/氯氮平组将有反应 用总PANSS衡量，显著优于B1/利培酮组，也好于B2 一群人。我们的假设是，大脑皮层吸引器网络将被归一化，其功能将增加 内源性脑电活动的增加。

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.