Glutamatergic mechanisms of psychosis and target engagement

项目总结/摘要： 精神分裂症（Sz）与精神病症状有关，这些症状对标准治疗仍然部分或完全难治。 抗精神病药物对大多数病人来说。所有上市的抗精神病药物主要通过阻断 多巴胺D2受体尽管在临床前模型中具有强大的有效性，但替代的， 用于治疗开发的方法尚未导致FDA批准的药物。的主要障碍 有效的药物治疗开发是缺乏针对功能靶点的有效措施， 参与，可以确定有效的化合物和指导剂量选择。本项目旨在完善 氯胺酮诱导的pharmacoBOLD（phBOLD）作为开发的靶向结合生物标志物 代谢型谷氨酸（mGluR 2/3）激动剂。这些目标的结合将允许未来使用phBOLD进行研究 为了确定基于谷氨酸的干预措施的潜在候选者，允许在Sz内进行目标参与研究 探讨多巴胺和谷氨酸在精神病中的作用机制。 作为最近完成的NIMH多中心FAST-PS计划的一部分，我们评估了氯胺酮诱导的 健康志愿者（HV）中的phBOLD。在最初的HV研究中，我们证明了氯胺酮诱导了一个强大的， phBOLD响应的显著增加。最近，使用这种测定，我们已经证明， 在先前的临床研究中使用的mGluR 2/3激动剂（POMA）的剂量（80 mg）没有导致显著的 抑制氯胺酮诱导的phBOLD或HV中的症状反应，表明先前的阴性临床 结果可能是剂量不足所致。相比之下，在剂量比在本发明中使用的剂量高约4倍的情况下， 阴性临床试验，观察到行为目标参与的证据，强调需要在 体内临床生物标志物。在最近开发的mGluR 2/3激动剂（TS-134）的平行研究中，我们 显示了行为（和phBOLD前后目标参与的证据。此外，TS- 134抑制氯胺酮诱导的phBOLD已知是多巴胺能功能的组成部分。 本项目的目标如下。在目标1下，我们将在HV中向下滴定氯胺酮剂量， 为了确定产生降低的拟精神病效应但仍然足够稳健的剂量， （d=1.5）phBOLD效应，以允许检测mGluR 2/3激动剂效应。然后我们将评估程度， 尽管如此，仍然较低剂量的氯胺酮产生足够的phBOLD响应（d=1.5）， 在Sz患者中进行参与测试。最后，我们将评估不同剂量氯胺酮的相对敏感性 TS-134在HV，以确定最佳的目标效应大小为未来的目标参与研究在Sz。在 平行地，我们评估多巴胺系统对NMDAR拮抗作用的敏感性，沿着 氯胺酮phBOLD，1H MRS和使用神经黑色素的多巴胺合成能力的替代指标。

PROJECT SUMMARY/ABSTRACT: Schizophrenia (Sz) is associated with psychotic symptoms that remain partially or fully refractory to standard antipsychotic medications for most patients. All marketed antipsychotics primarily work through blocking dopamine D2 receptors. Despite robust effectiveness in preclinical models, alternative, glutamatergic approaches for treatment development have not yet led to FDA approved medications. A major barrier to effective glutamatergic treatment development is the absence of validated measures for functional target engagement that can identify effective compounds and guide dose selection. The present project seeks to refine ketamine-induced pharmacoBOLD (phBOLD) as target engagement biomarker for development of metabotropic glutamate (mGluR2/3) agonists. The combination of aims will permit future studies using phBOLD to identify potential candidates for glutamate-based interventions, permit target engagement studies within Sz and explore the mechanisms of dopamine and glutamate in psychosis. As part of the recently completed NIMH multicenter FAST-PS initiative, we have evaluated ketamine-induced phBOLD in healthy volunteers (HV). In an initial HV study, we demonstrated that ketamine induces a robust, highly significant increase in phBOLD response. More recently, using this assay we have demonstrated that the dose of an mGluR2/3 agonist (POMA) used in the prior clinical studies (80 mg) did not lead to significant inhibition of ketamine-induced phBOLD or symptomatic response in HV, suggesting that prior negative clinical results may have resulted from inadequate dosing. By contrast, at doses ~4x higher than those used in the negative clinical trials, evidence of behavioral target engagement was observed, underscoring the need for in vivo clinical biomarkers. In parallel studies of of a more recently developed mGluR2/3 agonist (TS-134), we demonstrated showed evidence of both behavioral ( and phBOLD pre-post target engagement. In addition, TS- 134 suppressed ketamine induced phBOLD known to be integral for dopaminergic function. Aims of the present project are as follows. Under Aim 1, we will titrate the ketamine dose downward in HV in order to identify doses that produce reduced psychotomimetic effects, but nevertheless sufficiently robust (d=1.5) phBOLD effects to permit detection of mGluR2/3 agonist effect. We will then evaluate the degree to which still-lower doses of ketamine nevertheless produce sufficient phBOLD response (d=1.5) to enable target engagement testing in Sz patients. Finally, we will evaluate the relative sensitivity of different doses of ketamine to TS-134 in HV in order to determine optimal target effect sizes for future target engagement studies in Sz. In parallel, we evaluate the sensitivity of the dopamine system to NMDAR antagonism, along with the relationship of ketamine phBOLD, 1H MRS and a proxy measure of dopamine synthesis capacity using neuromelanin.