Genetic Determinants of Antidepressant Response

National Institute Of Mental Health

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Abstract

NCT00088699 In the first years of this project, candidate gene studies implicated a few genes in treatment outcome and other genes in adverse effects. We also participated in a meta-analysis of three genome-wide association studies of antidepressant outcome. Despite greater power of this combined sample to uncover association with common genetic markers, no genome-wide significant associations were found. We concluded that no common alleles of large effect on antidepressant outcome exist in these samples. In recent years, we have been using high-throughput sequencing methods to test for rarer genetic variants that may exert larger effects, at least in patients with treatment resistant depression (TRD). Sequencing of the coding regions of the genome (exome) has now been completed on over 250 treatment-resistant (TRD) or "typically responsive" patients drawn from the STAR*D, the Univ. Michigan Depression Center, and NIMH studies of novel antidepressants such as ketamine and scopolamine. Some exome sequencing was carried out at the NIH Intramural Sequencing Center with funds provided by the NIH Clinical Center Genomics Opportunity (CCGO) program, which also provided exome sequence from about 200 non-psychiatric patients for comparison. To increase power, we have obtained exome sequence data from over 2,000 healthy controls available through dbGAP. In the past year, we completed extensive data harmonization and quality control procedures and carried out analyses at the single variant, gene, and gene-set levels. . No individual variants were significantly associated with TRD. At the gene level, 5 genes carried an exome-wide significant excess burden of uncommon functional variants. Analysis of 41 pre-selected gene sets suggested an excess of uncommon, functional variants among genes involved in lithium response. These results implicate uncommon, functional alleles in TRD, and suggest promising novel targets for future research. In collaboration with Carlos Zarate and colleagues, and with the help of the NHLBI Stem Cell Core, we have also undertaken a series of studies aimed at characterizing the impact of antidepressant medication on gene expression and cellular morphology in human neurons derived from induced pluripotent stem cells. Early results from experiments with a metabolite of the novel antidepressant, ketamine, suggest that the drug changes expression of a large number of genes involved in regulation of cellular growth and development. We are currently carrying out similar assays using other novel antidepressants (such as psilocybin and scopolamine) in order to test the hypothesis that some novel antidepressants act through common, or overlapping, downstream mechanisms or signaling pathways. The long-term goal of all these studies is to identify genes and biological pathways robustly associated with resistance to anti-depressant treatment. Such genes could provide important clues about how to develop more effective antidepressant therapies in the future.