Off-Target Effects of Psychoactive Drugs Revealed by Genome-Wide Assays in Yeast

Abstract

To better understand off-target effects of widely prescribed psychoactive drugs, we performed a comprehensive series of chemogenomic screens using the budding yeast Saccharomyces cerevisiae as a model system. Because the known human targets of these drugs do not exist in yeast, we could employ the yeast gene deletion collections and parallel fitness profiling to explore potential off-target effects in a genome-wide manner. Among 214 tested, documented psychoactive drugs, we identified 81 compounds that inhibited wild-type yeast growth and were thus selected for genome-wide fitness profiling. Many of these drugs had a propensity to affect multiple cellular functions. The sensitivity profiles of half of the analyzed drugs were enriched for core cellular processes such as secretion, protein folding, RNA processing, and chromatin structure. Interestingly, fluoxetine (Prozac) interfered with establishment of cell polarity, cyproheptadine (Periactin) targeted essential genes with chromatin-remodeling roles, while paroxetine (Paxil) interfered with essential RNA metabolism genes, suggesting potential secondary drug targets. We also found that the more recently developed atypical antipsychotic clozapine (Clozaril) had no fewer off-target effects in yeast than the typical antipsychotics haloperidol (Haldol) and pimozide (Orap). Our results suggest that model organism pharmacogenetic studies provide a rational foundation for understanding the off-target effects of clinically important psychoactive agents and suggest a rational means both for devising compound derivatives with fewer side effects and for tailoring drug treatment to individual patient genotypes. Neuropsychiatric disorders such as depression and psychosis affect one-quarter of all individuals during their lifetime, and despite efforts to improve the selectivity of psychoactive drugs, all are associated with side effects. Drug efficacy and tolerance are known to be linked to an individual's genetic profile, but little is known about the nature of this correlation due, in part, to the current emphasis on screening compounds against targets in vitro. Here we present a comprehensive, genome-wide effort to understand drug effects on the cellular level using an unbiased genome-wide assay to determine the importance of every yeast gene for tolerance to 81 psychoactive drugs. We found that these medications perturbed many evolutionarily conserved genes and cellular pathways, such as those required for vesicle transport, establishment of cell polarity, and chromosome biology. The 500,000 drug–gene measurements obtained in this study increase our understanding of the mechanism of action of psychoactive drugs. Specifically, this study provides a framework to assess the next generation of psychoactive agents and to guide personalized medicine approaches that associate genotype and phenotype.