Development of a Pharmacodynamic Biomarker of Opioid Antagonism in Adolescents with Eating Disorders

青少年饮食失调阿片类药物拮抗药效生物标志物的开发

• 批准号: 10662801
• 负责人: Stephani L Stancil
• 金额: $ 18.75万
• 依托单位: CHILDREN'S MERCY HOSP (KANSAS CITY, MO)
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10662801
• 关键词: Active Learning; Address; Adolescence; Adolescent; Adult; Affect; Anorexia Nervosa; Anterior; Award; Binge Eating; Binge eating disorder; Biological Markers; Brain; Bulimia; Cardiac; Central Nervous System Agents; Child; Childhood; Clinical; Clinical Pharmacology; Clinical Sciences; Clinical Trials; Cross-Over Studies; Cross-Over Trials; Data; Development; Development Plans; Dorsal; Dose; Drug Design; Drug Exposure; Drug Kinetics; Eating Behavior; Eating Disorders; Environment; Enzymes; Food; Functional Magnetic Resonance Imaging; Functional disorder; Future; Genetic Variation; Goals; Hour; Individual; Intervention; Joints; K-Series Research Career Programs; Link; Malnutrition; Medical center; Mental Health; Mental disorders; Mentors; Modeling; Morbidity - disease rate; Naltrexone; National Institute of Mental Health; Neuropharmacology; Obesity; Opioid; Opioid Antagonist; Opioid Receptor; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Placebo Control; Plasma; Play; Positioning Attribute; Precision therapeutics; Randomized; Randomized, Controlled Trials; Recommendation; Research Institute; Research Personnel; Rewards; Risk; Role; Sampling; Site; Structure; Substance Use Disorder; System; Taste Perception; Teenagers; Therapeutic; Training; Translational Research; Visualization; Vomiting; Vulnerable Populations; aged; alternative treatment; antagonist; binge type behavior; biomarker development; biomarker validation; brain reward regions; career; career development; cingulate cortex; craving; design; drug action; drug development; drug discovery; drug repurposing; efficacy trial; frontier; imaging facilities; interest; male; medical schools; model development; mortality; neuroimaging; neuroimaging marker; neuropsychopharmacology; pediatric department; pharmacodynamic biomarker; pharmacologic; pleasure; practical application; psychopharmacologic; purge; purging behavior; randomized, clinical trials; research and development; response; response biomarker; skill acquisition; substance use; translational scientist

Project Summary The overall goal of this 4-year K23 proposal is to support Dr. Stephani Stancil to become an independent investigator in the field of pharmacodynamic biomarker development to support quantitative early-stage drug development in pediatric neuropsychopharmacology, specifically eating disorder therapeutics. This proposal aligns with NIMH’s prioritization of and the National Advisory Mental Health Council workgroup recommendations for quantitative pharmacologic early-stage trials, particularly in vulnerable populations. Eating disorders (ED), including Bulimia Nervosa, Anorexia Nervosa-Binge/Purge and Binge Eating Disorder, are characterized by binge eating and purge behaviors (e.g., vomiting), typically begin in adolescence, and affect up to 5% of teens. EDs are associated with significant morbidity (e.g., malnutrition, cardiac compromise, development of substance use disorder), have the highest mortality rate of any psychiatric illness and are not responsive to current pharmacotherapy. This career development proposal will leverage Dr. Stancil’s clinical pharmacology expertise in drug exposure inquiry and expand her career focus to clinical neuropsychopharmacology to enable her to define central nervous system drug action in children and adolescents. The comprehensive career development plan (CDP) contains three training objectives: 1) neuroimaging, 2) pediatric randomized clinical trials, and 3) exposure-response modeling, to transition Dr. Stancil into a successful, independent investigator. The CDP’s structured mentoring, didactic training and experiential learning will be applied to a randomized, placebo-controlled crossover trial in adolescents with Binge/Purge ED to accomplish the following aims: Aim 1) Determine the sensitivity of a neuroimaging biomarker to reward system modulation by opioid antagonism, Aim 2) Develop an Exposure-Response Model for naltrexone. Dr. Stancil’s career development and research will take place in a highly favorable and well- suited environment that includes a tertiary academic children’s medical center, children’s research institute, joint department of pediatrics shared by two regional medical schools, an outstanding imaging center and the Frontiers CTSA. After completing this project, Dr, Stancil will have advanced the field of pharmacodynamic biomarker development in pediatric mental health and generated data to support an R01 application to establish the validity of the proposed pharmacodynamic biomarker. She will be well-positioned to become a leader in the field of pharmacodynamic biomarker development and exposure-response linkage to de-risk early-stage drug development and facilitate a precision therapeutics approach to pediatric neuropsychopharmacology.

项目摘要 这项为期4年的K23提案的总体目标是支持斯蒂芬尼·斯坦西博士成为一名独立的 药效学生物标记物开发领域的研究人员支持定量早期药物 儿童神经精神药理学的发展，特别是进食障碍的治疗。这项建议 与NIMH的优先事项和国家咨询精神卫生委员会工作组保持一致 关于定量药理学早期试验的建议，特别是在脆弱人群中。 饮食障碍(ED)，包括暴食症、神经性厌食症--暴饮暴食/暴饮暴食、暴饮暴食， 以暴饮暴食和大便行为(如呕吐)为特征，通常始于青春期，以及 影响多达5%的青少年。EDS与严重的发病率有关(例如营养不良、心脏受损、 物质使用障碍)，在所有精神疾病中死亡率最高，而不是 对当前的药物治疗有反应。这项职业发展提案将利用斯坦西博士的临床 在药物暴露调查方面的药理学专业知识，并将其职业生涯重点扩展到临床 神经精神药理学，使她能够确定儿童中枢神经系统药物的作用 青少年。综合职业发展计划(CDP)包含三个培训目标：1) 神经成像，2)儿科随机临床试验，3)暴露-反应模型，以过渡博士。 斯坦西成为一名成功的、独立的调查员。CDP的结构化指导、教学培训和 体验式学习将应用于一项随机、安慰剂对照的交叉试验，研究对象为患有 狂欢/清除ED以实现以下目标：目标1)确定神经成像的灵敏度 阿片类拮抗剂调节奖赏系统的生物标记物，目的2)建立暴露-反应模型 纳曲酮。斯坦塞尔博士的职业发展和研究将在一个非常有利的和良好的- 适宜的环境，包括高等学府儿童医学中心、儿童研究所、 由两所地区医学院、一个杰出的影像中心和 边疆CTSA。完成这个项目后，斯坦西博士将在药效学领域取得进展。 儿科心理健康中的生物标记物开发和生成的数据支持R01应用于 确定所提出的药效学生物标志物的有效性。她将处于有利地位，成为一名 在药效生物标记物开发和暴露-反应联动降风险领域处于领先地位 早期药物开发和促进儿科精确治疗方法 神经精神药理学。

项目成果

Potential biomarker of brain response to opioid antagonism in adolescents with eating disorders: a pilot study.

• DOI: 10.3389/fpsyt.2023.1161032
• 发表时间: 2023
• 期刊: FRONTIERS IN PSYCHIATRY
• 影响因子: 4.7
• 作者: Stancil, Stephani L.;Yeh, Hung-Wen;Brucks, Morgan G.;Bruce, Amanda S.;Voss, Michaela;Abdel-Rahman, Susan;Brooks, William M.;Martin, Laura E.
• 通讯作者: Martin, Laura E.