Pharmacogenetic-Based Dose Adjustments in Psychopharmacology

For many psychotropic drugs, pharmacogenetic polymorphisms are known to affect biotransformation and clinical outcome. In antidepressant drug treatment, most drugs are metabolized via the polymorphic cytochrome P450 enzymes CYP2D6 and CYP2C19. Huge differences in pharmacokinetic parameters have been consistently shown for many tricyclics, some SSRIs, and other antidepressant drugs. However, the effects on therapeutic drug efficacy and adverse events have been described controversially. Pharmacokinetic differences caused by genetic polymorphisms can be overcome by adapting the drug dosages and dosing intervals. Similar to bioequivalence studies, the aim to achieve similar plasma concentration time courses of antidepressants might help to reduce side effects and therapeutic failure.

In the field of antipsychotic drug treatment, genetic polymorphisms in drug metabolizing enzymes as well influence pharmacokinetic parameters to a large part. In these kinds of drug therapy, a clearer dose dependency of side effects such as extrapyramidal side effects exists, and the consideration of genetic polymorphisms might be more beneficial. Recent studies showed a relationship between the occurrence of adverse antipsychotic drug effects and CYP2D6 genotype. A prospective evaluation of the cost-benefit of genotyping in this field would be very helpful for the aim of introducing pharmacogenetic diagnostic into drug therapy.

For candidates in pharmacodynamic pathways, many clinical studies on polymorphisms in logical candidate genes report an association between neurotransmitter receptor and transporter genotypes and therapy response or adverse drug reactions. In other studies these findings could not be replicated. For this reason, it is not yet possible to fully translate pharmacogenetic parameters into therapeutic recommendations. At present, antidepressant and antipsychotic drug responses can best be explained as the combinatorial outcome of complex systems that interact at multiple levels. In spite of these limitations, combinations of polymorphisms in pharmacokinetic and pharmacodynamic pathways of relevance might contribute to identify genotypes associated with best and worst responders as well as susceptibility to adverse drug reactions.