A Translational and Neurocomputational Evaluation of a D1R Partial Agonist for Schizophrenia

项目摘要 此UO 1应用程序是对NIMH计划公告的响应，旨在加速开发一个高性能的 通过确定其对生物标志物的剂量相关药效学效应， quent临床开发。多巴胺D1受体（D1 R）激动剂是最优先的连续治疗之一 精神分裂症的发病机制目前，所有D1 R激动剂也是D5 R激动剂。D1 R/D5 R激动剂具有促认知作用， 和抗精神病药样作用，反映了它们稳定前额叶皮层网络活动的能力， 干扰物的面孔，并通过增强空间工作记忆（sWM）的抑制性调谐来提高空间工作记忆（sWM）的精度。 前额叶皮层（PFC）功能连接（FC）。然而，D1 R/D5 R激动剂在患者中的剂量相关益处不能 在之前的试点研究中得到证实。本申请提出，D1 R/D5 R激动剂的测试需要更多的 直接翻译/计算神经科学框架（即，最合适的生物标志物）和精准医学 策略（即，适当的患者亚群）。为了加速最佳剂量的选择，我们提出了多剂量 一项密集绘制D1 R/D5 R部分激动剂PF-06412562速释（IR）剂量相关效应的中心研究， 三种信息性翻译功能性神经成像（fMRI）生物标志物作为主要结果指标：i）sWM相关 激活; ii）基于任务的FC;和iii）在早期病程精神分裂症患者的静息状态FC。主要目标1将应用穆尔- 对这三种结果测量（sWM相关激活，基于任务的FC和静息状态FC）进行变量分析策略， 检测PF-06412562是否产生剂量相关效应。这种多变量翻译神经标记物被设计和供电， 告知关于进行全面临床试验的明确的进行/不进行决定。如果出现以下情况，将指示执行决定 通过任务诱发的多变量组合测量的神经信号上存在显著的剂量相关的药物效应， sWM任务期间的激活和FC以及休息期间的FC。相反，如果存在以下情况，则将做出不通过决定： 对多变量指数无剂量相关影响。次要目的2将量化药物对sWM的剂量相关影响 精确度基于功能性磁共振成像期间收集的行为数据。探索性目标3将模拟PF的生物物理特性， 06412562在能够进行sWM模拟的皮质回路模型中，其将模拟假设的分子机制 控制PF-06412562对sWM的促认知作用。反过来，我们将检测PF-06412562的剂量相关模式是否 对患者静息FC的影响映射到源自艾伦的人体D1 R和D5 R受体转录组学谱 人脑图谱。最后，探索性目的4将研究PF-06412562 ef的潜在临床预测因子和调节因子。 影响神经影像学生物标志物。总的来说，这项翻译生物标志物研究为最高优先级的实验提供了信息。 NIMH MATRICS计划使用针对特定的精确医学策略确定的治疗机制 可能对D1 R/D5 R激动剂有前认知应答的早期病程精神分裂症患者亚群。

PROJECT SUMMARY This UO1 application is a response to the NIMH Program Announcement intended to accelerate the development of a high priority therapeutic agent by establishing its dose-related pharmacodynamic effects on biomarkers designed to inform subse- quent clinical development. Dopamine D1 receptor (D1R) agonism is among the most highly prioritized adjunctive treatment mechanisms for schizophrenia. Currently, all D1R agonists are also D5R agonists. D1R/D5R agonists have pro-cognitive and antipsychotic-like effects in preclinical studies, reflecting their ability to stabilize prefrontal cortical network activity in the face of distractors, and to enhance the precision of spatial working memory (sWM) by enhancing inhibitory tuning of prefrontal cortical (PFC) functional connectivity (FC). Yet, dose-related benefits of D1R/D5R agonism in patients could not be demonstrated in prior pilot studies. This application proposes that the testing of D1R/D5R agonists requires both a more direct translational/computational neuroscience framework (i.e., the most appropriate biomarkers) and a precision medicine strategy (i.e., the appropriate subpopulation of patients). To accelerate the selection of an optimal dose, we propose a multi- center study that densely maps the dose-related effects of the D1R/D5R partial agonist, PF-06412562 immediate release (IR), on three informative translational functional neuroimaging (fMRI) biomarkers as primary outcome measures: i) sWM-related activation; ii) task-based FC; and iii) resting-state FC in early course schizophrenia patients. Primary Aim 1 will apply a mul- tivariate analytic strategy to these three outcome measures (sWM-related activation, task-based FC and resting-state FC) to test if PF-06412562 produces a dose-related effect. This multivariate translational neural marker is designed and powered to inform a clear Go/No-Go decision with regards to proceeding to a full-scale clinical trial. A Go decision will be indicated if there is a significant dose-related drug effect on the neural signal measured via the multivariate combination of task-evoked activation and FC during the sWM task and FC during rest. Conversely, a No-Go decision will be reached if there is an absence of a dose-related effect on the multivariate index. Secondary Aim 2 will quantify dose-related drug effects on sWM precision based on behavioral data collected during fMRI. Exploratory Aim 3 will model the biophysical properties of PF- 06412562 in a cortical circuit model capable of sWM simulations, which will simulate hypothesized molecular mechanisms governing pro-cognitive PF-06412562 effects on sWM. In turn, we will will test if the dose-related pattern of PF-06412562 effects on resting FC in patients maps onto D1R and D5R receptor transcriptomic profiles in humans derived from from Allen Human Brain Atlas. Finally, Exploratory Aim 4 will study potential clinical predictors and moderators of PF-06412562 ef- fects on neuroimaging biomarkers. Collectively, this translational biomarker study informs the highest priority experimental treatment mechanism identified by the NIMH MATRICS Initiative using a precision medicine strategy that targets a specific subpopulation of early course schizophrenia patients who may pro-cognitively respond to D1R/D5R agonism.