Association of CYP2D6 gene polymorphism and psychoactive drug therapy side effects

CYP2D6 (Debrisoquine 4-hydroxylase) is a cytochrome P450 isoenzyme involved in the metabolism of most neuroleptics, which are the drugs of choice for the treatment of psychotic symptoms. Greater than 100-fold variability in CYP2D6 activity has been observed within population and can be attributed to genetic polymorphism of CYP2D6 gene. Its six mutant alleles (null alleles *3, *4, *5, *6, *7 and *8) encode for inactive enzymatic molecules. A carrier of two mutant alleles is considered a poor metabolizer (PM) phenotype, while a carrier of only one damaged allele is considered an intermediate metabolizer (IM) phenotype. The aim of the study was to assess the association between CYP2D6 polymorphism and side effect in psychiatric patients suffer from schizophrenia (n=87) on the long term therapy with psychoactive drugs (> 5 years). The CYP2D6 genotype was determined using allele-specific multiplex PCR. The results indicated a significant allele (p=0.002), genotype (p=0.029) distribution between patients with (n=37) and without (n=47) side effect with considerably higher frequency of heterozygous (34.2%) and homozygous (13.2%) 2D6*4 allele in former. The odds ratio of 2.626 for 2D6*4 and of 5.333 for 2D6*6 alleles suggested a significant association of these alleles and side effect in schizophrenic patients on long-term therapy. The prevalence of PM and IM predicted phenotype was significantly higher in side effect group compared to the non-side effect group (p=0.002), and the odds ratio of 7.075 (2.010 to 24.908) suggested a strong association between the PM phenotype and side effects.