The effects of ondansetron on neural systems and symptoms associated with sensory phenomena

 描述(申请人提供)：这个R21/R33项目使用功能磁共振成像(FMRI)来研究恩丹西酮对强迫症(OCD)和抽动障碍(TD)患者神经功能和感觉症状的影响。尽管进行了广泛的研究，30%-60%的强迫症患者对一线治疗没有足够的反应，TD患者的比率也同样令人失望。强迫症和TD带来了治疗挑战，部分原因是它们是异质性疾病，其特征是一系列症状可能源于不同的神经病因。研究领域标准(RDoC)方法试图通过调查行为的跨诊断成分来解决这个问题，这些成分与大脑回路更紧密地一致。这项应用专注于感觉现象(SP)-强迫症和TD的强迫症之前的不适或厌恶感觉，以及以岛叶和躯体感觉皮层为中心的离散神经电路的这两种障碍的关键组成部分。恩丹西酮是一种作用于感觉通路的5-HT3受体拮抗剂，是调节与感觉现象相关的神经回路的一种很有前途的新候选药物。恩丹西酮可减少非精神疾病患者的感觉症状，并已被证明能降低强迫症和精神障碍患者的整体症状严重程度。我们的试验数据显示，单一16毫克剂量减少了岛叶和体感皮质的激活，增加了恩丹西酮可能通过直接靶向感觉回路来降低疾病严重程度的可能性。在这些有希望的发现的基础上，该应用程序使用双盲、安慰剂对照、混合设计来研究三种不同剂量的恩丹西酮对脑岛和躯体感觉皮质神经靶点激活的影响。在R21阶段结束时，里程碑驱动的评估将为药物与神经靶点的接触做出“通过/不进行”的决定提供明确的支持。如果靶点参与建立，R33阶段将寻求在患者样本中验证这些神经靶点，并测试靶点激活与临床症状之间的关系。采用双盲、安慰剂对照、平行分组设计，我们将测量4周最佳剂量恩丹西酮(从R21期确定)对强迫症和TD患者的脑功能和感觉现象的影响。R33阶段的结果预计将为第二个“通过/不通过”的决定提供支持，该决定涉及目标和干预的进一步临床开发。无论这两个阶段的结果如何，这个项目的结果都将增加对疾病机制和干预措施的了解。

 DESCRIPTION (provided by applicant): This R21/R33 project uses functional magnetic resonance imaging (fMRI) to investigate the effects of ondansetron on neural functioning and sensory symptoms in patients with obsessive-compulsive disorder (OCD) and tic disorders (TD). Despite extensive research, 30-60% of OCD patients do not respond adequately to first-line treatments, with similarly disappointing rates in TD. OCD and TD present a treatment challenge in part because they are heterogeneous disorders characterized by clusters of symptoms likely derived from differing neural etiologies. The Research Domain Criteria (RDoC) approach seeks to address this problem by investigating transdiagnostic components of behavior that more closely align with brain circuitry. This application focuses on sensory phenomena (SP) - uncomfortable or aversive sensations preceding compulsions in OCD and tics in TD - as a critical component of both disorders with a discrete neural circuitry centered on sensory regions in the insula and somatosensory cortex. Ondansetron, a 5-HT3 receptor antagonist acting on sensory pathways, is a promising novel candidate for the modulation of neural circuits related to sensory phenomena. Ondansetron reduces sensory symptoms in non-psychiatric conditions and has been shown to decrease overall symptom severity in both OCD and TD. Our pilot data show that single 16 mg doses decrease activation of the insula and somatosensory cortex, raising the possibility that ondansetron may reduce disorder severity by directly targeting sensory circuits. Building on these promising findings, this application uses a double blind, placebo-controlled, mixed design to investigate the effects of three different doses of ondansetron on the activation of neural targets in the insula and somatosensory cortex. Milestone- driven assessment at the end of the R21 phase will provide clear support for a "go/no-go" decision regarding the engagement of neural targets by the drug. If target engagement is established, the R33 phase will seek to validate these neural targets in a patient sample and test the relationship between target activation and clinical symptoms. Using a double blind, placebo-controlled, parallel group design, we will measure the effects of 4 weeks of optimal dose ondansetron (determined from the R21 phase) on brain functioning and sensory phenomena in a sample of OCD and TD patients. Results from the R33 phase are expected to provide support for a second "go/no-go" decision regarding further clinical development of the targets and intervention. Regardless of outcomes in either phase, results from this project will increase knowledge about mechanisms of disease as well as the intervention.