Genetics of Antipsychotic Metabolism

描述(研究员？S摘要)：在这位临床科学家的指导下 发展奖，Vicki L.Ellingrod寻求获得遗传学方面的专业知识 精神药物新陈代谢、治疗反应和不良反应 影响(即，精神药物遗传学(PPG)专业知识)。这项PPG专业知识将 让她系统地研究非典型肺炎的致病因素 抗精神病药物引起的体重增加(AAP体重增加)和其他长期后遗症 AAP使用。她的长期职业目标是确定精神药物的风险因素 并制定干预措施，以减少或预防发病率。艾林罗德博士 寻求成为这个国家为数不多的专注于 药物代谢与发病率的发生。对于这项提议，Dr。 Ellingrod开发了一个培训和研究计划，利用 爱荷华大学药学院的各种资源 医学院？S精神病学和流行病学系。特定的 指导和培训的领域包括分子遗传学方法， 精神分裂症的药代动力学和临床评价 研究、肥胖生理学、生物统计学和生物伦理学。作为以下内容的一部分 在这次培训中，应聘者已经安排了与她见面的机会 专门从事这些不同研究领域的导师/顾问。 为了加强她的训练，这位候选人制定了一项研究计划 关注AAP wt增益的遗传学。超过50%的患者服用 AAPS的收益是他们最初重量的10%，尽管有些人增长了40%。这 WT的增加通常会导致重大的医疗发病率、大量的经济 负担，以及更多的用药不依从。人们对此知之甚少 这一重量收益的潜在机制。识别风险因素可能会防止 医疗和经济方面的发病率、疾病复发和整体素质的提高 精神分裂症患者的生活质量(QOL)。这一领域的研究现状 没有考虑遗传学、生理学、饮食和体力活动 有节制的方式。根据候选人提供的飞行员数据，她 提出了一项精神分裂症患者AAP wt增益的PG研究，以检验两者的作用 遗传和生理风险因素是这一现象背后的机制。 具体地说，本研究的目标是：1)确定两者之间的关系 细胞色素P450基因多态性对WT测定和AAP血清水平的影响。病人 使用奎硫平、利培酮和奥氮平治疗精神分裂症 2D6、1A2、3A4、2C9、2C19和2E1的招募和基因分型；2)至 B3和5-羟色胺受体基因多态性检测 这些基因多态与体重指数的关系；3)测定血清 一年内的瘦素、胰岛素、血糖和同型半胱氨酸水平，并检查 它们与wt变化的关系；4)连续测量wt、用药 AAPS患者的依从性、生活质量及WT对其的影响 关于生活质量和服药依从性。

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.