Antipsychotic and Folate Pharmacogenetics

描述(由申请人提供)：我们的工作表明，叶酸可以改善精神分裂症患者的非典型抗精神病药物(AAP)的心血管效应，特别是改善内皮功能。减少与急性胰腺炎相关的代谢风险可能有助于减少这一人群失去的30年寿命。补充叶酸可能是降低AAP CVD发病率和死亡率的一种经济有效且低风险的方法。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和安慰剂对代谢综合征和心血管危险因素的影响。我们将评估接受AAPS治疗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，叶酸将减弱与使用AAP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))的变异调节了这些改善。我们根据我们在R01MH082784期间获得的试点数据提出了这一假设，这些数据表明，由于与MTHFR和COMT的相互作用，AAP增加了代谢综合征风险。我们进行了一项为期3个月的开放标签叶酸补充试验，发现代谢指标显著减少，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调节的。这项建议的具体目的是：1)评估叶酸补充剂(每天5毫克)与安慰剂16周对精神分裂症患者的治疗效果，并在停用补充剂8周后测量这种效果的可持续性；2)确定MTHFR和COMT变种在补充叶酸后对内皮功能和代谢改善的作用。这一创新的方法利用了一种新的战略，利用一种新的非侵入性内皮功能测量作为生物标记物来降低AAP的代谢风险。与单纯关注体重减轻和血糖调节相比，这可以对整体心血管疾病风险进行评估。药物基因组学的纳入使个性化药物结果的潜在创新转化为实践。我们的预期结果将通过随机双盲纵向治疗设计证明叶酸在减轻代谢综合征措施和改善AAP用户的内皮功能方面的有效性。我们的后续访问将允许测量任何持续的叶酸影响，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有望提供对AAP代谢风险的更大的机械性理解。我们预期的发现的主要积极影响将是为AAP代谢并发症的叶酸干预开发一个基于证据的科学框架，这可以直接转化为临床实践。

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.