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

项目摘要 精神病的治疗进展受到现象学定义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。 中间表型躁郁症-精神分裂症网络(B-SNIP)使用生物标记物来定义 精神病亚组，目标是测试B-Snip生物标记物用于诊断和治疗的优势 治疗决定，与NIMH战略计划(NSP)中的原则一致。具有&gt；3000表型 精神病先证者、亲属和健康对照(HC)，B-SNIP有一个多水平的生物标志物文库 并使用该库将精神病亚群重新概念化为生物标记物定义的生物类型(B1， B2、B3)，其中B1和B2为低认知/高症状组，B3为低症状和高症状组 相对正常的认知。我们在一个新的样本中复制了Biotype，“打造一个衡量 个人的…神经和生理状态将形成一个越来越具体和信息量越来越大的基础 诊断“(Diagnosis”)。在这项研究中，我们提出，认知能力较低、皮层活动较低的B1将会做出反应 氯氮平是独一无二的，氯氮平是一种药物，它将在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(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，反应明显好于B1/利培酮组，也好于 两组中任一组。我们的假设是大脑皮层吸引子网络将被归一化，它们的功能 随着脑电活动的增加而增加。

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.