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（由适用提供）：该R21/R33项目使用功能磁共振成像（fMRI）来研究Ondansetron对痴迷性强迫症（OCD）和TIC疾病（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的反应不当，而TD的率也令人失望。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，其特征是可能来自区分神经病因的症状簇。研究领域标准（RDOC）方法试图通过调查与脑电路更紧密一致的行为的转诊成分来解决这一问题。该应用的重点是感官现象（SP） - 在强迫症和TD中的强迫症之前，不舒服或厌恶感 - 作为两种疾病的关键组成部分，具有离散的神经元电路，以岛状和体感皮质的感觉区域为中心。 Ondansetron是作用于感觉途径的5-HT3受体拮抗剂，是调节与感觉现象相关的神经元电路的新颖候选者。 Ondansetron在非精神病疾病中降低了感觉症状，并已被证明会降低OCD和TD的总体症状严重程度。我们的飞行员数据表明​​，单一16 mg剂量减少了岛状和体感皮质的激活，从而提高了Ondansetron可以通过直接靶向感觉电路来降低障碍严重程度的可能性。在这些承诺的发现的基础上，该应用程序使用了双盲，安慰剂对照的混合设计，研究了三种不同剂量的ondansetron对岛状和体感皮质中神经靶标的激活的影响。 R21阶段结束时的里程碑驱动评估将为对药物的神经靶标参与“ GO/No-Go”决定提供明确的支持。如果建立目标参与，R33阶段将寻求在患者样本中验证这些中性靶标，并测试目标激活和临床症状之间的关系。使用双盲，安慰剂对照的平行组设计，我们将测量4周最佳剂量Ondansetron（根据R21期确定）对OCD和TD患者样本中脑功能和感觉现象的影响。 R33阶段的结果有望为目标和干预的进一步临床发展提供第二个“ GO/No-Go/no-Go”决定。无论在任何一个阶段的结果如何，该项目的结果都将增加有关疾病机制以及干预措施的知识。