PHARMACOGENETICS OF ANTIDEPRESSANTS - CLINICAL ASPECTS

Plasma concentrations and response to antidepressants vary considerabl y between patients treated with similar dosages. Most antidepressants and also antipsychotics are metabolized by the polymorphic debrisoquin e/sparteine hydroxylase. i.e., cytochrome P450 (CYP)2D6. About 7% of C aucasians are poor metabolizers (PM), and such patients might develop adverse drug reactions when treated with recommended doses of for exam ple, tricyclic antidepressants. In contrast, ultrarapid metabolizers w ith multiple CYP2D6 genes might require high doses of such drugs for o ptimal therapy, The mean CYP2D6 activity is lower in Oriental than in Caucasian populations, because of a frequent mutation causing decrease d enzyme activity, Drugs metabolized by the same enzyme may interact w ith each other, For example. the potent CYP2D6 inhibitor fluoxetine in creases the plasma concentrations of tricyclic antidepressants. Anothe r enzyme catalyzing the metabolism of antidepressants is the polymorph ic S-mephenytoin hydroxylase, CYP2C19, which catalyses the metabolism of for example, citalopram. clomipramine and moclobemide. Various prob e drugs may be used for phenotyping CYP2D6 (debrisoquine, dextromethor phan and sparteine) and CYP2C19 (mephenytoin and omeprazole). Allele-s pecific polymerase chain reaction (PCR)-based methods are now availabl e for genotyping using leukocyte DNA. A major advantage of genotyping compared with phenotyping is that the former may be performed in blood samples from patients irrespective of treatment.