Pharmacogenomics of antidepressant treatment effects

Abstract

There has been considerable promise and hope that pharmacogenomics will optimize existing treatments for major depression, as well as identify novel targets for drug discovery. Immediately after the sequencing of the human genome, there was much hope that tremendous progress in pharmacogenomics would rapidly be achieved. In the past 10 years this initial enthusiasm has been replaced by a more sober optimism, as we have gone a long way towards the goal of guiding therapeutics based on genomics. While the effort to translate discovery to clinical applications is ongoing, we now have a vast body of knowledge as well as a clear direction forward. This article will provide a critical appraisal of the state of the art in the pharmacogenomics of depression, both in terms of pharmacodynamics and pharmacokinetics.

Figure 1.. CYP2D6-mediated quantitative influences on pharmacokinetics of antidepressant drugs expressed as percent dose adjustments: CYP2D6 poor metabolizers (PM, white), intermediate metabolizers (IM, gray), extensive metabolizers (EM, dark gray), ultrarapid metabolizers (UM, black) Dose adjustments were calculated according to the data given in Table II. If data on active drug moiety (consisting on active principle metaboite+parent drug of active enantiomers of a racemic drug) were given, dose recommendations were based on these data only (other studies not providing so detailed information were not incorporated). If more than one study was integrated, the weighted mean for the dose adjustment was taken according to the number of poor metabolizers in each study. Data on mirtazapine, moclobemide, fluoxetine, and maprotiline were not shown in the figure, since no dose adjustment based on CYP2D6 can be recommended at present. Reproduced from ref 43: Kirchheiner J, Nickchen K, Bauer M, et al. Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response. Mol Psychiatry. 2004;9:442-473. Copyright © Nature Publishing Group 2004

Figure 2.. CYP2C19-mediated quantitative influences on pharmacokinetics of antidepressant drugs expressed as percentage dose adaptations: CYP2C19 poor metabolizers (PM, white), intermediate metabolizers (IM, gray), extensive metabolizers (EM, dark gray). Reproduced from ref 43: Kirchheiner J, Nickchen K, Bauer M, et al. Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response. Mol Psychiatry. 2004;9:442-473. Copyright © Nature Publishing Group 2004