One Tablet or Two? Towards the Development of Pharmacogenomically Informed Drug Dose Individualization

Over 50 years of pharmacogenetic research have produced many examples of how inherited variability in drug metabolism can influence individual responses to psychotropic drugs. However, this knowledge has largely failed to be translated into broadly applicable strategies for improvements in individual drug treatment in psychiatry. One important argument brought against the widespread adoption of pharmacogenetics as a clinical tool is the lack of available evidence showing its influence on contemporary clinical praxis and its potential role in improving the risk/benefit ratio for the patients. Individual drug-metabolizing capacity is assessed by genotyping drug-metabolizing enzymes. The information gained from genotyping patients may be used to adjust initial and maintenance drug doses according to genotype. However, even where the consequences of genotype on pharmacokinetics are significant and well-known, as in the case of many tricyclic antidepressants and several selective serotonin reuptake inhibitors, there is still considerable controversy as to whether the adjustment of dosage (based upon genetic information) to improve therapeutic efficacy and/or to reduce the occurrence of adverse events is of any practical importance in clinical practice. Pharmacogenetic studies can improve our understanding of the functional consequence of a genetic variant in the clinical setting, and the use of intermediate phenotypes instead of broad outcome parameters (such as drug response or remission) might improve our knowledge regarding the clinical response of an individual with a specific genotype to a specific drug. Here, we review the potential impact of adopting an integrated approach to patient treatment, which combines the use of intermediate phenotypes that arise from common genetic polymorphisms in drug metabolism enzymes, the monitoring of the therapy progress, and the possibility of pharmacogeneticbased response prediction in depression.