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

项目概要 精神病治疗的进展可能会受到基于现象学定义的诊断的限制 症状结果，而不是通过定量特征监测的神经生物学结构。的 双相精神分裂症中间表型网络 (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 生物标志物在诊断和治疗决策中的优势， 符合 NIMH 战略计划 (NSP) 中的原则。拥有超过 3000 名表型精神病先证者， 亲属和健康对照，B-SNIP 拥有一个针对精神病的多级生物标志物库，并使用该库来 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 在新样本中复制了生物型，“打造一个未来，测量个人的......神经和 生理状态将构成日益具体和信息丰富的诊断的基础”（NSP）。在这笔补助金中 我们认为 B1 具有低认知和低皮质活性，因此对氯氮平（一种药物）有独特的反应 这将在 B1 中产生活跃的皮质吸引子网络，以支持症状改善。 氯氮平是最有效的抗精神病药物（APD），具有独特的临床疗效。它是最少使用的 APD 因为它的副作用很严重（中性粒细胞减少、心肌炎、癫痫发作）并且给药复杂。一个 预测性生物标志物将能够针对最有可能做出反应的病例并改善精神病的预后。 B-SNIP 表明氯氮平与脑电图 α/θ 功率测量值的增加有关，我们 将没有刺激处理要求的时间段的增加识别为内在脑电图活动（IEA）， 跨越所有生物型。由于 B1 病例表现出低 IEA，因此氯氮平增加 EEG 功率的作用将是 该精神病亚组正常化，皮质吸引子状态增加。因为B2快递 强调 IEA，氯氮平与 B2 中更异常的 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），经过 6 周的交叉滴定（至治疗效果） 血浆水平）和 9 周稳定剂量延长，预测 B1/氯氮平组将有反应 根据总 PANSS 测量，明显优于 B1/利培酮组，也优于 B2 组 组。我们的假设是，皮质吸引子网络将正常化，其功能将增加 内在脑电图活动的增加。

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.