Pharmacogenetics of antidepressants: clinical aspects.
Plasma concentrations and response to antidepressants vary considerably between patients treated with similar dosages. Most antidepressants and also antipsychotics are metabolized by the polymorphic debrisoquine/sparteine hydroxylase, i.e., cytochrome P450 (CYP)2D6. About 7% of Caucasians are poor metabolizers (PM), and such patients might develop adverse drug reactions when treated with recommended doses of, for example, tricyclic antidepressants. In contrast, ultrarapid metabolizers with multiple CYP2D6 genes might require high doses of such drugs for optimal therapy. The mean CYP2D6 activity is lower in Oriental than in Caucasian populations, because of a frequent mutation causing decreased enzyme activity. Drugs metabolized by the same enzyme may interact with each other. For example, the potent CYP2D6 inhibitor fluoxetine increases the plasma concentrations of tricyclic antidepressants. Another enzyme catalyzing the metabolism of antidepressants is the polymorphic S-mephenytoin hydroxylase. CYP2C19, which catalyses the metabolism of, for example, citalopram, clomipramine and moclobemide. Various probe drugs may be used for phenotyping CYP2D6 (debrisoquine, dextromethorphan and sparteine) and CYP2C19 (mephenytoin and omeprazole). Allele-specific polymerase chain reaction (PCR)-based methods are now available 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.
Bertilsson
L
L
Department of Medical Laboratory Sciences and Technology, Karolinska Institute, Huddinge University Hospital, Sweden.
Dahl
M L
ML
Tybring
G
G
D000328:Adult; D000368:Aged; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000929:Antidepressive Agents, Tricyclic / Q000493:pharmacokinetics / Q000627:therapeutic use; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D003863:Depression / Q000188:drug therapy* / Q000208:ethnology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000235:genetics; D017891:Pharmacoepidemiology; D011110:Polymorphism, Genetic; D011619:Psychotropic Drugs / Q000493:pharmacokinetics; D044469:Racial Groups / Q000235:genetics
D000928:Antidepressive Agents; D000929:Antidepressive Agents, Tricyclic; D011619:Psychotropic Drugs; D003577:Cytochrome P-450 Enzyme System; D019389:Cytochrome P-450 CYP2D6