Pharmacogenomics and antidepressants: efficacy and adverse drug reactions

Pharmacogenetics has gained increasing interest among both clinicians and investigators as a potentially useful tool for gauging psychotropic drug trial outcomes. Strides have been made in identifying polymorphic loci associated with poor metabolizer genotypes of Phase I (i.e., cytochrome P450) hepatic enzymes, which, in turn, may account for some proportions of adverse drug effects or poor conversion of prodrugs or parent compounds to active metabolites; or ultrarapid metabolizer genotypes for whom standard drug dosages may be subtherapeutic. Particular adverse drug effects also have been linked with unique susceptibility genes, such as an increased risk for Stevens Johnson syndrome following carbamazepine treatment in Southeast Asians who carry the HLA*B1502 gene. Less well established are the use of functional polymorphisms of candidate genes associated with neurotransmitter function (such as the serotonin transporter gene, locus SLC6A4), or combinatorial pharmacogenetic groupings of genes, in order to predict pharmacodynamic efficacy of antidepressants. Herein we review current evidence for the practical application of psychiatric pharmacogenetic testing at the bedside, noting strengths, weaknesses, areas of uncertainty, and directions for future work.