OVERVIEW

The biological mechanisms of action of the main classes of antidepressant compound involve the serotonin (5-HT) system. Consequently, genes of this system have been considered ideal candidates in pharmacogenetic studies of the antidepressant response. There are critical methodological issues created by the complexity of the definition of the phenotypes (i.e., categorical versus dimensional), the involvement of nongenetic factors in determining the clinical effect of antidepressants, and the different genetic strategies available to detect genetic susceptibility in complex traits (e.g., family-based association studies, transmission disequilibrium test for qualitative and quantitative traits). In this chapter, we present and discuss the most recent findings on genetic predictors of the response to antidepressants in mood and anxiety disorders. The need for a more homogeneous phenotype definition (e.g., including phenotypes related to the diagnosis such as rapid cycling course, psychotic symptoms, atypical features) is pointed out. We also propose and discuss the role of alternative phenotypes (side effects or non-desirable reactions) in pharmacogenetic studies focused on the prediction of the clinical effect of antidepressants. As an example, the phenomenon of antidepressant-induced mania, as an abnormal response to antidepressants, is described. The most recent data on the role of candidate genes (particularly for the 5-HT system, e.g., 5-HTT, 5HT1Dβ, 5HT2A) in contributing to the risk of developing this phenotype are presented and discussed.