THE CYTOCHROME-P450 2D6 (CYP2D6) ENZYME POLYMORPHISM - SCREENING COSTS AND INFLUENCE ON CLINICAL OUTCOMES IN PSYCHIATRY

Objectives: This study examined factors that affect cost, reliability, and the value of determining the cytochrome P450 2D6 (CYP2D6) polymor phism in clinical practice. Study design: The method of deoxyribonucle ic acid isolation, sample preparation, oligonucleotide primers, and po lymerase chain reaction procedures were scrutinized for their effect o n CYP2D6 genotyping efforts. The determination of the CYP2D6A, B, D, E , and T alleles was used to identify the deficiency in CYP2D6 expressi on in 161 individuals phenotyped for CYP2D6 activity with dextromethor phan. The CYP2D6 genotype was assessed in 74 outpatients who had recei ved diagnoses of depression. Eighteen of these patients were screened because of an adverse response to a tricyclic or antidepressant known or suspected to be a CYP2D6 substrate. Results: The CYP2D6 A, B, C, D, E, and T alleles could be detected in 13 hours at a cost of $84 per s ample by judicious selection of conditions and procedures. The genotyp e provided an accurate predictor of CYP2D6 expression in all 134 subje cts who expressed the enzyme and in all 27 unrelated individuals pheno typed as deficient in CYP2D6 activity. In the patient group that exper ienced adverse effects, 44% of all CYP2D6 gene copies contained the A, B, D, E, or T allele(s) associated with inactive CYP2D6 expression. T his was more than twice the rate for the occurrence of mutant alleles in the other 56 psychiatric patients (21%) and in 80 random subjects f rom the general population (20%; P < 0.05). Conclusions: Screening psy chiatric patients for CYP2D6 expression may distinguish metabolic-base d therapeutic problems from drug sensitivity caused by other mechanism s.