CYP2D6 genotype: impact on adverse effects and nonresponse during treatment with antidepressants-a pilot study

Treatment with antidepressants is frequently associated with adverse effects or insufficient clinical response. Several antidepressants are metabolized by cytochrome P450 (CYP) 2D6. The activity of this enzyme markedly varies among individuals from poor to ultrarapid metabolism on the basis of the polymorphism of the CYP2D6 gene. This association study investigated whether the CYP2D6 genotype distribution differs from that of the German white population either in patients with marked adverse effects or in nonresponders during treatment with antidepressants metabolized by CYP2D6.

By use of a retrospective, naturalistic approach, outpatient practices and hospitals in southern Germany were asked to report on patients who either had had adverse drug effects or were nonresponsive during treatment with CYP2D6-dependent antidepressants. CYP2D6 genotyping was performed by a panel of polymerase chain reaction techniques. Poor and intermediate metabolizer alleles, as well as allelic duplications of CYP2D6, were detected.

Of 28 patients with adverse effects during treatment with a CYP2D6-dependent antidepressant, 8 (29%) had 2 inactive alleles and thus were poor metabolizers. This is a 4-fold increase as compared with the German population (P <.0001). Amplification of fully functional alleles (associated with ultrarapid metabolism) was found in 3 (19%) of the 16 nonresponders (approximately 5.0-fold higher in nonresponders than in the population) (P =.0012).

The results suggest that the CYP2D6 genotype is associated with the occurrence of adverse effects and clinical nonresponse in psychiatric patients treated with CYP2D6-dependent antidepressants.