Background: In the human population, CYP2D6 is highly polymorphic group of
genes involved in metabolizing ~25% of all clinically used neuroleptic and antidepressant
drugs. The CYP2D6*4 and CYP2D6*10 variants are prevalent in Asian population exhibiting
variable drug metabolizing ability thereby affecting drug therapeutic responses.
Objective: To determine the genotypic frequencies of CYP2D6*1 (Normal metabolizer), *4
(Poor metabolizer) and *10 (Intermediate metabolizer) variants among schizophrenic subjects
and control group from a sub-set of Karachi population.
Method: Genomic Deoxyribonucleic Acid (gDNA) was extracted and amplified with
CYP2D6*4 and *10 primers using Polymerase Chain Reaction (PCR) and digested by Bacillus
stereothermophilus (BstN1) and Hemophilus parahemolyticus (Hph1) restriction enzymes. The
digested gDNA bands were identified as wild type or mutants and their genotypic frequencies
were estimated by Hardy-Weinberg Equation (HWE).
Results: In normal subjects, frequencies of CYP2D6*1 wild allele (57%) coded functional enzyme,
CYP2D6*4 variant (9%) producing non-functional enzyme and CYP2D6*10 allele (70%)
producing altered enzyme with reduced activity that was most prevalent in schizophrenic patients.
Discussion: Drug response is a complex phenomenon that is governed by genetic and environmental
factors. Antipsychotic drug metabolism among schizophrenic patients with variable drug
responsesis related to CYP2D6 polymorphism. Clinically, it is imperative to differentiate between
responders and non-responders using the treatment, otherwise the drug will be either nonefficacious
or toxic to the patients. Therefore, a gene testing system needs to be established to
identify patient’s genotype(s) predicting whether they are normal, poor, intermediate or ultrarapid
drug metabolizer thereby allowing clinicians to adjust dose(s) of antipsychotic drug(s).
Conclusion: Genotyping of CYP2D6 alleles among schizophrenic patients indicated prevalence
of *4 and *10 variants in Karachi population producing non-functional (poor metabolizer)
and reduced functional (intermediate metabolizer) drug metabolizing enzymes phenotypes,
respectively. Hence, dose adjustment is crucial otherwise schizophrenia condition will not be
improved satisfactorily. Therefore, CYP2D6 gene screening program should be included in
clinical practice to help clinicians to prescribe appropriate doses according to patient’s genotype
and minimize sufferings of schizophrenics including side effects of drug that might occur
at high drug concentrations.