Most pharmaceutical treatments for major mental illnesses were discovered by trial and error and little is known about how they work. They are typically effective in only a minority of patients and are associated with severe side effects that discourage adherence. As a result most persons under treatment end up shifting drugs in a sometimes long and frustrating search for the most effective and least dangerous and debilitating treatment. Results from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) trial show that the discontinuation and switching of psychiatric medications is widespread. Overall, 74% discontinued one or more of the study medication during the 18 months of follow-up. Side-effects, such as weight gain, are a major contributor to the discontinuation and/or change of medications, and genetic factors contribute to the observed variability in treatment responses.
The goal of pharmacogenetics is to illuminate how genetic factors shape both beneficial and pernicious treatment responses. This enhanced understanding will facilitate the rational development of medicines that are tailored to individual patients. This project will establish a program in the Department of Mental Health that will bring together the existing technological and intellectual resources of the Johns Hopkins research community in genomics, epidemiology, statistics and psychopharmacology to carry out cutting-edge pharmacogenetic studies of psychiatric medications. These resources include the Genetics Resource Core Facility and Laboratory for the collection, processing and storage of biological materials from study participants; high-throughput genome facilities, including CIDR and the Johns Hopkins Microarray Core Facility, for rapid, low-cost genotyping and gene expression experiments; experts in genetic epidemiology and statistical genetics from the Departments of Mental Health, Epidemiology, and Biostatistics for study design and statistical analyses; and experts in psychopharmacology from the Department of Psychiatry for interpretation of substantive findings and translation to improved treatment strategies.
The Program in Pharmacoepidemiology will capitalize on the BMORE cohort established from the proposed East Baltimore and Johns Hopkins Community Psychiatry network in order to carry out nested pharmacogenetic studies of psychiatric treatments in a population-based setting. Blood will be collected from all participants enrolled in the East Baltimore cohort. Serum, plasma and DNA will be isolated and banked and immortal cell lines established. Participants will provide a history of medication use, and their responses to these medications will be recorded. DNA from the participants will be used for genotyping a panel of 500k SNPs to allow a range of nested genome-wide association studies with targeted pharmacogenetic outcomes. All genotypic and phenotypic data will be anonymized and databased for association analyses.
This research is sponsored by an anonymous donation to the Center for Mental Health Initiatives.
Peter Zandi, Ph.D., Primary Investigator
Co-Investigators: William Eaton, Ph.D. Anita Everett, MD, Bernadette Cullen, MD, and Katie Bonebrake, MA