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

 描述（由申请人提供）：本R21/R33项目使用功能性磁共振成像（fMRI）研究昂丹司琼对强迫症（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，但30-60%的强迫症患者对一线治疗没有充分的反应，TD患者的反应率也同样令人失望。强迫症和TD提出了治疗挑战，部分原因是它们是异质性疾病，其特征在于可能源自不同神经病因的症状簇。研究领域标准（RDoC）方法试图通过研究与大脑回路更密切相关的行为的transdiagnosis组件来解决这个问题。这种应用程序的重点是感觉现象（SP）-强迫症和抽搐在TD强迫之前的不舒服或厌恶的感觉-作为两种疾病的关键组成部分，以离散的神经回路为中心的感觉区域在大脑皮层和体感皮层。昂丹司琼是一种作用于感觉通路的5-HT 3受体拮抗剂，是一种很有前途的新型候选药物，用于调节与感觉现象相关的神经回路。昂丹司琼可减轻非精神疾病的感觉症状，并已被证明可降低强迫症和TD的总体症状严重程度。我们的试点数据显示，单次16 mg剂量降低了脑皮层和体感皮层的激活，提高了昂丹司琼通过直接靶向感觉回路降低疾病严重程度的可能性。基于这些有希望的发现，本申请使用双盲、安慰剂对照、混合设计来研究三种不同剂量的昂丹司琼对脑皮层和体感皮层中神经靶点激活的影响。在R21阶段结束时的里程碑驱动的评估将为关于药物对神经靶点的参与的“进行/不进行”决定提供明确的支持。如果建立了靶点参与，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。使用双盲、安慰剂对照、平行组设计，我们将测量4周最佳剂量昂丹司琼（从R21阶段确定）对强迫症和TD患者样本的脑功能和感觉现象的影响。预计R33阶段的结果将为关于靶点和干预措施的进一步临床开发的第二个“进行/不进行”决定提供支持。无论这两个阶段的结果如何，该项目的结果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.