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: 9127345
• 负责人: Emily R Stern
• 金额: $ 47.52万
• 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 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9127345
• 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; Health; 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; compulsion; design; experience; neural circuit; neuromechanism; novel; premonitory sensory phenomena; 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.



项目成果

Neural correlates of interoception: Effects of interoceptive focus and relationship to dimensional measures of body awareness.

• DOI: 10.1002/hbm.23811
• 发表时间: 2017-12
• 期刊: Human brain mapping
• 影响因子: 4.8
• 作者: Stern ER;Grimaldi SJ;Muratore A;Murrough J;Leibu E;Fleysher L;Goodman WK;Burdick KE
• 通讯作者: Burdick KE

High-dose ondansetron reduces activation of interoceptive and sensorimotor brain regions.

高剂量昂丹司琼可减少内感受和感觉运动大脑区域的激活。

• DOI: 10.1038/s41386-018-0174-x
• 发表时间: 2019
• 期刊: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
• 作者: Stern,EmilyR;Shahab,Rebbia;Grimaldi,StephanieJ;Leibu,Evan;Murrough,JamesW;Fleysher,Lazar;Parides,MichaelK;Coffey,BarbaraJ;Burdick,KatherineE;Goodman,WayneK
• 通讯作者: Goodman,WayneK