Genetics of Antipsychotic Metabolism

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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.