Genetics of Antipsychotic Metabolism

描述（研究者？摘要）：在本指导临床科学家 发展奖，Vicki L.埃林罗德寻求获得遗传学方面的专业知识， 精神药物代谢，治疗反应和不良反应 效果（即，精神药物遗传学（PPG）专业知识）。PPG的专业知识将 使她能够系统地研究非典型性 抗精神病药诱导的体重增加（AAP wt增加）和其他长期后遗症 AAP使用。她的长期职业目标是确定精神疾病的危险因素， 发病率，并制定干预措施，以减少或预防它。 希望成为这个国家少数几个专注于 药物代谢和发病率的发生。对于这项提议，博士。 Ellingrod开发了一个培训和研究计划， 爱荷华州大学药学院的各种资源， 医学院吗精神病学系和流行病学系。具体 指导和培训的领域包括分子遗传学方法， 药代动力学和动力学，用于精神分裂症的临床评估 研究、肥胖生理学、生物统计学和生物伦理学。的一部分 这次培训，候选人安排了访问，以满足她 导师/顾问，专门从事这些研究的各个领域。 为了加强她的训练，候选人已经制定了一项研究计划， 关注AAP wt增益的遗传学。超过50%的患者 AAP的增益大于其初始wt的10%，尽管有些增益大于40%。这 体重增加常常导致显著的医学发病率， 负担，增加药物不依从性。很少有人知道的 这种WT增益的潜在机制。识别风险因素可以防止 医疗和财务的发病率，疾病复发，提高综合素质 精神分裂症患者的生活质量。该领域目前的研究 不考虑遗传学，生理学，饮食和体育活动， 有节制的态度。根据候选人提供的试点数据，她 提出了一项关于精神分裂症患者AAP wt增加的PG研究，以检查两者的作用。 遗传和生理风险因素在这一现象背后的机制。 具体而言，本研究的目标是：1）确定的关系， 细胞色素P450多态性与wt测量和AAP血清水平的关系。患者 精神分裂症患者接受奎替鲁、利培酮和奥氮平治疗， 招募并对1A 2D 6、1A 2、3A 4、2C 9、2C 19和2 E1进行基因分型; 2） B3和5 HT受体多态性的基因型，以确定 这些多态性与WT测量之间的关系; 3）测量血清 瘦素、胰岛素、葡萄糖和同型半胱氨酸的水平， 它们与wt变化的关系; 4）连续测量wt、药物 依从性和QOL在接受AAP的患者中，并检查wt 生活质量和药物依从性的影响

DESCRIPTION (Investigator?s abstract): In this Mentored Clinical Scientist Development Award, Vicki L. Ellingrod seeks to gain expertise in the genetics of psychotropic medication metabolism, therapeutic response, and adverse effects (i.e., psychopharmacogenetics (PPG) expertise). This PPG expertise will allow her to systematically study the contributing factors for atypical antipsychotic induced weight gain (AAP wt gain) and other sequele of long-term AAP use. Her long-term career goal is to identify risk factors for psychotropic morbidity and develop interventions to reduce or prevent it. Dr. Ellingrod seeks to become one of the few pharmacogeneticists in this country focusing on drug metabolism and the occurrence of morbidity. For this proposal, Dr. Ellingrod has developed a program of training and research that utilizes a diverse array of resources at the University of Iowa College of Pharmacy and the College of Medicine?s Departments of Psychiatry and Epidemiology. Specific areas of mentorship and training include molecular genetic methods, pharmacokinetics and dynamics, clinical assessments used in schizophrenia research, the physiology of obesity, biostatistics, and bioethics. As part of this training, the candidate has arranged visits to meet with her mentors/consultants that specialize in these various areas of study. To augment her training, the candidate has developed a research proposal focusing on the genetics of AAP wt gain. More than 50 percent of patients on AAPs gain >10 percent of their initial wt, although some gain >40 percent. This wt gain often results in significant medical morbidity, substantial financial burden, and increased medication non-compliance. Little is known about the underlying mechanism for this wt gain. Identifying risk factors may prevent medical and financial morbidity, disease relapse, and improve overall quality of life (QOL) for patients with schizophrenia. Current research in this area does not take into account genetics, physiology, diet, and physical activity in a controlled manner. Based on pilot data provided by the candidate, she proposes a PG study of AAP wt gain in schizophrenia to examine the role of both genetic and physiologic risk factors in the mechanism behind this phenomenon. Specifically, the goals of this study are: 1) to determine the relationship of cytochrome P450 polymorphisms to wt measures and AAP serum levels. Patients with schizophrenia treated with quetiapine, risperidone, and olanzapine will be recruited and genotyped for CYP 2D6, 1A2, 3A4, 2C9, 2C19, and 2E1; 2) to genotype for polymorphisms of the B3 and 5HT receptors to determine the relationship between these polymorphisms and wt measures; 3) to measure serum levels of leptin, insulin, glucose, and homocystine over a year and examine their relationship to wt changes; 4) to serially measure wt, medication compliance, and QOL in patients receiving AAPs and examine the influence of wt on QOL and medication compliance.