Antipsychotic and Folate Pharmacogenetics - Gender Supplement

抗精神病药和叶酸药物遗传学 - 性别补充剂

• 批准号: 8797754
• 负责人: VICKI L ELLINGROD
• 金额: $ 10万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8797754
• 关键词: Accounting; Address; Antipsychotic Agents; Attenuated; Biological Markers; Body Weight decreased; Cardiovascular Diseases; Cardiovascular system; Catechols; Cessation of life; Clinical; Data; Development; Diet; Dose; Double-Blind Method; Effectiveness; Folate; Folic Acid; Future; Gender; General Population; Genes; Goals; Healthcare Systems; Intervention; Intervention Studies; Knowledge; Laboratories; Lead; Length; Life; Link; Maintenance; Measurement; Measures; Medicine; Mental Health; Mental disorders; Metabolic; Metabolic syndrome; Metabolism; Methods; Methylenetetrahydrofolate reductase (NADPH); Morbidity - disease rate; Outcome; Patients; Pharmaceutical Preparations; Pharmacogenetics; Pharmacogenomics; Placebos; Population; Quality of life; Randomized; Research; Risk; Risk Factors; Role; Schizophrenia; Strategic Planning; Supplementation; Symptoms; Testing; Time; Transferase; Translating; Translations; Variant; Visit; Withdrawal; Work; attenuation; atypical antipsychotic; base; blood glucose regulation; cardiovascular disorder risk; clinical practice; cost; cost effective; endothelial dysfunction; evidence base; expectation; folic acid metabolism; follow-up; improved; innovation; meetings; mortality; novel; novel strategies; open label; primary outcome; public health relevance; response; severe mental illness; therapeutic effectiveness; therapy design; therapy development; years of life lost

DESCRIPTION (provided by applicant): Our work shows folate improves atypical antipsychotic (AAP) CV effects in schizophrenia specifically improving endothelial functioning. Reducing AAP linked metabolic risks may help cut the 30 years of life lost within this population. Supplemental folate may be a cost effective and low risk method to reduce AAP CVD morbidity and mortality. Folate pharmacogenetics, allows us to mechanistically study AAP metabolic complications and develop personalized medicine within clinical practice. The objective of this project is to compare the effect of folate versus placebo on measures of the metabolic syndrome and CVD risk factors. We will evaluate metabolic laboratory components, and endothelial functioning, in schizophrenia patients receiving AAPs, taking into account pharmacogenetic differences related to folate metabolism. Our primary hypothesis is that folate will attenuate metabolic changes associated with AAP use, thereby contributing to improve endothelial functioning. Variation within the genes facilitating folate metabolism (methylenetetrahydrofolate reductase (MTHFR) and catechol-o-methyl transferase (COMT)) modulate these improvements. We have formulated this hypothesis based on our pilot data obtained during R01MH082784 showing AAPs increase metabolic syndrome risk due to an interaction with MTHFR and COMT. We performed an open-label 3-month folate supplement trial and found significant reductions in metabolic measures and significantly reduced the number of subjects meeting endothelial dysfunction criteria. These improvements were modulated through MTHFR and COMT. The specific aims for this proposal are: 1) Evaluate the therapeutic effectiveness of folic acid supplementation (5mg/day) versus placebo for 16 weeks in schizophrenia subjects and measure sustainability of this effect 8 weeks after supplementation withdrawal, 2) Determine the role of MTHFR and COMT variants on endothelial functioning and metabolic improvements seen with folate supplementation. The innovative approach capitalizes upon a novel strategy to reduce AAP metabolic risks using a novel non-invasive endothelial functioning measurement as a biomarker. This allows for an overall CVD risk estimation compared to focusing on solely weight loss and glucose regulation. The inclusion of pharmacogenomics allows for potential innovative translation of personalized medicine outcomes into practice. Our expected outcomes will demonstrate folate's effectiveness in attenuating metabolic syndrome measures and improvements in endothelial functioning in AAP users with a randomized double blind longitudinal treatment design. Our follow up visit will allow for measurement of any sustained folate effects leading to future dose ranging studies. Successful completion of our pharmacogenetic analyses can be expected to provide a greater mechanistic understanding of AAP metabolic risks. The primary positive impact of our anticipated findings will be an evidence-based scientific framework for folate intervention development for AAP metabolic complications, which can be directly translated into clinical practice.

描述（由申请人提供）：我们的工作表明叶酸改善精神分裂症中的非典型抗精神病药（AAP）CV效应，特别是改善内皮功能。减少AAP相关的代谢风险可能有助于减少这一人群中30年的寿命损失。补充叶酸可能是降低AAP CVD发病率和死亡率的成本效益和低风险方法。叶酸药物遗传学使我们能够机械地研究AAP代谢并发症，并在临床实践中开发个性化药物。本项目的目的是比较叶酸与安慰剂对代谢综合征和CVD危险因素的影响。我们将评估接受AAP的精神分裂症患者的代谢实验室成分和内皮功能，同时考虑到与叶酸代谢相关的药物遗传学差异。我们的主要假设是，叶酸将减弱与AAP使用相关的代谢变化，从而有助于改善内皮功能。促进叶酸代谢的基因（亚甲基四氢叶酸还原酶（MTHFR）和儿茶酚-O-甲基转移酶（COMT））内的变异调节这些改善。我们根据R 01 MH 082784期间获得的初步数据制定了这一假设，这些数据显示AAP与MTHFR和COMT相互作用会增加代谢综合征风险。我们进行了一项为期3个月的开放标签叶酸补充试验，发现代谢指标显著降低，符合内皮功能障碍标准的受试者数量显著减少。这些改善是通过MTHFR和COMT调制的。该提案的具体目的是：1）评价叶酸补充剂（5 mg/天）与安慰剂相比在精神分裂症受试者中持续16周的治疗效果，并在补充剂停药后8周测量该效果的可持续性，2）确定MTHFR和COMT变体对叶酸补充剂所观察到的内皮功能和代谢改善的作用。该创新方法利用了一种新的策略，使用一种新的非侵入性内皮功能测量作为生物标志物来降低AAP代谢风险。这允许整体CVD风险估计相比，专注于单独的体重减轻和血糖调节。包括药物基因组学允许潜在的创新翻译个性化医疗成果付诸实践。我们的预期结果将证明叶酸在减轻代谢综合征指标和改善AAP使用者的内皮功能方面的有效性，采用随机双盲纵向治疗设计。我们的后续访问将允许测量任何持续的叶酸作用，导致未来的剂量范围研究。我们的药物遗传学分析的成功完成，可以预期提供一个更大的机制AAP代谢风险的理解。我们预期研究结果的主要积极影响将是AAP代谢并发症叶酸干预开发的循证科学框架，可直接转化为临床实践。