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

昂丹司琼对神经系统和与感觉现象相关的症状的影响

• 批准号: 9488694
• 负责人: Emily R Stern
• 金额: $ 21.49万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-14 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9488694
• 关键词: Address; Adult; Behavior; Blinking; Brain; Brain region; Clinical; Conscious; Data; Development; Disease; Distress; Dose; Double-Blind Method; Drug Targeting; Ensure; Esthesia; Etiology; FDA approved; Functional Magnetic Resonance Imaging; Individual; Insula of Reil; Intervention; Investigational Therapies; Knowledge; Link; Measures; Mediating; Motor; Nausea; Neurophysiology - biologic function; Obsessive-Compulsive Disorder; Ondansetron; Outcome; Pathway interactions; Patients; Perception; Pharmaceutical Preparations; Phase; Placebo Control; Placebos; Research; Research Domain Criteria; Rest; Sampling; Sensory; Serotonin Receptors 5-HT-3; Severities; Somatosensory Cortex; Symptoms; System; Testing; Tic disorder; Variant; Visceral; associated symptom; brain circuitry; clinical development; compulsion; design; experience; neural circuit; neuromechanism; novel; premonitory sensory phenomena; public health relevance; relating to nervous system; standard care; symptom cluster

 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.

 描述（由申请人提供）：该 R21/R33 项目使用功能磁共振成像（fMRI）来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 OCD 患者对一线治疗没有充分反应，TD 患者的反应率同样令人失望。 OCD 和 TD 提出了治疗挑战，部分原因是它们是异质性疾病，其特征是可能源自不同神经病因的一系列症状。研究领域标准（RDoC）方法旨在通过研究与大脑回路更紧密相关的行为的跨诊断成分来解决这个问题。该应用重点关注感觉现象（SP）——强迫症中的强迫症和TD中的抽动之前的不舒服或厌恶的感觉——作为这两种疾病的关键组成部分，具有以岛叶和体感皮层感觉区域为中心的离散神经回路。 Ondansetron 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有前途的新型候选药物。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。我们的试验数据显示，单次 16 mg 剂量会减少岛叶和体感皮层的激活，这提高了昂丹司琼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。基于这些有希望的发现，本申请采用双盲、安慰剂对照、混合设计来研究三种不同剂量的昂丹司琼对岛叶和体感皮层神经靶标激活的影响。 R21 阶段结束时的里程碑驱动的评估将为有关药物参与神经靶标的“进行/不进行”决策提供明确的支持。如果建立了目标参与，R33 阶段将寻求验证患者样本中的这些神经目标，并测试目标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 期确定）对 OCD 和 TD 患者样本的大脑功能和感觉现象的影响。 R33 阶段的结果预计将为有关目标和干预措施的进一步临床开发的第二个“进行/不进行”决策提供支持。无论任一阶段的结果如何，该项目的结果都将增加有关疾病机制和干预措施的知识。