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CYP2D6 polymorphism and side effects in schizophrenic patients

Introduction: The genetic polymorhism of drug-metabolizing enzymes is responsible for inter-individual differences in the therapeutic effects and toxicity of many drugs and an important contributor to individual responses to the pharmaceutical drug treatment. Many reports suggest that prescribing of drugs would be more effective and less hazardous when an assessment of this genetic variability is carried out for the relevant enzymes. CYP2D6 (debrisoquine 4-hydroxylase) is a cytochrome P450 isoenzyme involved in the metabolism of most psychoactive drugs, which are the drugs of choice for the treatment of psychotic symptoms. Greater than 100-fold variability in CYP2D6 activity has been observed within the population and can be attributed to the 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. Aim: The aim of the study was to assess the association between CYP2D6 polymorphism and side effects in psychiatric patients suffering from schizophrenia (n=64). Method: CYP2D6 wt, *3, *4, *6, *7, *8 alleles were directly detected on DNA isolated from EDTA-blood by multiplex allele specific PCR. The genotypes were confirmed using quality control samples containing known genotypes. By this method it is possible to exclude the subjects having homozygous CYP2D6*5 genotype since *5 allele represents complete deletion of CYP2D6 gene. Results:The results indicated a significant allele (p=0.002), and genotype (p=0.029) distribution between patients with (n=27) and without (n=37) side effects with a considerably higher frequency of heterozygous (34.2%) and homozygous (13.2%) 2D6*4 allele in the former. The odds ratio of 2.626 for 2D6*4 and of 5.333 for 2D6*6 allele suggested a significant association of these alleles with side effects in schizophrenic patients on long-term therapy. The prevalence of PM and IM predicted phenotype was significantly higher in the side effects group compared to the non-side effects group (p=0.002), while the odds ratio of 7.075 (2.010 to 24.908) suggested a strong association between PM phenotype and therapeutic side effects. Conclusion: These preliminary results suggest the association of CYP2D6 polymorphism with side effects and underline the importance of pre-treatment genotyping, which could recognize the subjects prone to develop adverse drug reaction. However, prospective studies are needed to prove the value of genotyping or phenotyping in patients with schizophrenia.

CYP2D6; side effects; schizophrenia

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