Glutamatergic mechanisms of psychosis and target engagement

项目摘要/摘要： 精神分裂症(Sz)与部分或完全不符合标准的精神症状有关。 大多数患者服用抗精神病药物。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，但替代的谷氨酸能 治疗开发的方法尚未导致FDA批准的药物。一个主要障碍是 有效的谷氨酸能治疗发展是缺乏针对功能靶点的有效措施 能够识别有效化合物并指导剂量选择的参与。目前的项目试图改进 氯胺酮诱导的药物BOLD(PhBOLD)作为靶向结合生物标志物的研究 代谢性谷氨酸(mGluR2/3)激动剂。AIMS的组合将允许未来使用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 健康志愿者(HV)的PHBOLD。在最初的HV研究中，我们证明了氯胺酮诱导了一种强烈的， PhBOLD响应显著增加。最近，使用这种测试，我们已经证明了 先前临床研究中使用的mGluR2/3激动剂(POMA)剂量(80 Mg)并未导致显著 抑制氯胺酮诱导的phBOLD或HV的症状反应，表明先前临床阴性 结果可能是剂量不足造成的。相比之下，在剂量~4倍于在 阴性的临床试验，观察到行为靶点参与的证据，强调了在 活体临床生物标志物。在对最近开发的mGluR2/3激动剂(TS-134)的平行研究中，我们 演示显示了目标交战前的行为(和phBOLD)证据。此外，TS- 134抑制氯胺酮诱导的已知与多巴胺能功能积分有关的phBOLD。 本项目的目标如下。在目标1下，我们将向下滴定在高压下的氯胺酮剂量 以确定产生减少的精神分裂效应，但仍然足够强大的剂量 (D=1.5)phBOLD效应，以允许检测mGluR2/3激动剂效应。然后我们将对该程度进行评估 更低剂量的氯胺酮仍可产生足够的phBOLD反应(d=1.5)以使靶向 SZ患者的敬业度测试。最后，我们将评估不同剂量的氯胺酮的相对敏感性 为了确定未来在深圳进行目标交战研究的最佳目标效应尺寸，在高压区使用TS-134。在……里面 同时，我们评估了多巴胺系统对nmdar拮抗的敏感性，以及两者之间的关系。 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测量。

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.