How to dose a psychotropic drug: beyond therapeutic drug monitoring to genotyping the patient

The study of Davies et al. (1) published in this issue of the Acta Psychiatrica Scandinavica characterizes the drug metabolism pathways for an old firstgeneration antipsychotic zuclopenthixol that is still in widespread use inmany countries, both because it is relatively inexpensive and because it is available in a long-acting depot injection. Davies et al. (1) show that zuclopenthixol is inactivated essentially completely by only two enzymes, CYP 2D6 and CYP 3A4, that can be profoundly influenced by drugs and by inheritance. The impact of this findingwill be to cause revisions in the dosing and drug interaction recommendations for this agent in future prescribing guidelines and books including those of this editorialist (2). The report of Davies et al. (1) may even encourage others to look more carefully at the neglected drug metabolism pathways for older psychotropic drugs, particularly those in continued use today. First-generation antipsychotics were all developed prior to the careful characterization of cytochrome P 450 (CYP) drug metabolizing enzymes and their genes. The result is that clinicians have often been flying blind to the impact that drug interactions or hereditary variations in drug metabolism could have on dosing of many first-generation antipsychotics. Although the newer second-generation atypical antipsychotics are much better characterized in terms of their drug interactions (3), many older psychotropic agents still suffer from incomplete information about how they are metabolized, and thus how to dose them, particularly in patients receiving concomitant medications, who have unusually severe side effects, or who do not respond to standard doses.