CYP2D6 mutations and therapeutic outcome in schizophrenic patients

Study Objective. To investigate whether a relationship exists between the m ost common known cytochrome P450 (CYP) isozyme 2D6 mutations and schizophre nia. Because most antipsychotic and antidepressant agents interact with CYP 2D6, we also investigated clinical outcomes in schizophrenic poor metaboliz ers (PMs) and extensive metabolizers (EMs). Design. Prospective, observational study. Setting. Two psychiatric hospitals and a university-affiliated nonpsychiatr ic hospital. Subjects. Thirty-nine consecutive schizophrenic patients (POP 1), 89 schizo phrenics of French Canadian origin (POP 2), and 384 healthy French Canadian s (POP 3). Intervention. All study subjects were genotyped for CYP2D6 mutant alleles. POP 1 patients were evaluated before and after 21 or more days of treatment with antipsychotic drugs metabolized at least in part by CYP2D6. Measurements and Main Results. Whole blood was collected to determine CYP2D 6 alleles *1, *3, *4, *5, *6, and *7 using standard restriction fragment le ngth polymorphisms and polymerase chain reaction techniques. In comparison, CYP2D6 genotypes were determined in POP 2 and POP 3. Twenty-three (59.0%) of 39 patients in POP 1 were genotypically EM homozygotes, 15 (38.4%) were EM heterozygotes, and 1 (2.6%) was a PM. Similar genotype distributions wer e determined in POP 2 and in POP 3. Genotype distributions for all three, p opulations were in Hardy-Weinberg equilibrium (p>0.05),and there was no sig nificant difference among them (p=0.857). In POP 1, no differences were see n among genotypes in disease symptom severity, number and severity of adver se drug effects, or attitudes toward drug treatment at baseline and at the end of the study. In fact, all patients improved significantly during their hospital stay (all p<0.05), although independent of the CYP2D6 genotype. Conclusion. Common CYP2D6 mutant alleles were not associated with schizophr enia or with disease symptoms, antipsychotic-related adverse effects, or at titudes toward treatment.