Genetics and the Pharmacokinetics and Pharmacodynamics of Psychiatric Drugs

Pharmacogenomic research shares with TDM the aim of improving drug therapy through a better understanding of treatment response. Since the 1950s, when pharmacogenetic research started with the discovery of gene mutations related to debrisoquine metabolic deficiency, a number of polymorphisms have been described with a direct effect on drug therapy (Weber, 1997). In particular, several functional genetic mutations in cytochrome P450 enzymes, responsible for the metabolism of the majority of psychiatric drugs, have been described with a direct relation to drug-induced side effects (Andreassen et al., 1997; Ellingrod et al., 2002). Further research has shown that plasma levels are related to drug dosage and genetically determined metabolic status, and that a threshold drug/metabolite plasma concentration is required for obtaining therapeutic efficacy. However, even when plasma therapeutic levels are achieved, individuals may fail to respond satisfactorily. Interindividual variability in clinical outcome is likely to be the product of genetically determined pharmacokinetic and pharmacodynamic factors as well as environmental factors. Evidence in support of the influence of pharmacodynamic factors has been provided by the associations observed between mutations in neurotransmitter systems and treatment response (Arranz et al., 2000). In addition, our investigations show that a combination of genetic information in metabolic enzymes and neurotransmitter systems can result in the correct prediction of response to commonly used atypical drugs in approximately 80% of cases. In summary, genetic information can be used to monitor the pharmacokinetic and pharmacodynamic status of individuals and help to improve pharmacotherapy.