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CYP2D6 genotype and antipsychotic-induced extrapyramidal side effects in schizophrenic patients
1Department of Medical Laboratory Sciences and Technology, Karolinska Institutet, Huddinge University Hospital, Sweden. gabriella-s@usa.net
Objective:
In order to evaluate whether poor metabolizers (PM) of debrisoquine are overrepresented among patients with acute dystonic reactions and chronic movement disorders associated with the administration of antipsychotic drugs, the CYP2D6 genotype was determined in schizophrenic patients.
Methods:
Allele status for CYP2D6*3, CYP2D6*4, CYP2D6*5, and CYP2D6*6 as well as gene duplication was determined by allele-specific PCR, long-PCR and restriction fragment length polymorphism analysis (RFLP) in 119 schizophrenic patients (99 males and 20 females). All subjects were treated with antipsychotics metabolized, at least partially, by this isozyme. Sixty-three of the patients (52.9%) had a history of extrapyramidal side effects (EPS), while 56 (47.1%) had not experienced such problems (controls).
Results:
Sixty-five patients (54.6%) were homozygous for a functional CYP2D6*1 allele, 44 (37.0%) were heterozygous for detrimental alleles, and 4 (3.4%), who carried two detrimental alleles, were classified as PM. In six patients (5.0%) duplication of a functional CYP2D6 gene was found, and they were consequently classified as ultrarapid metabolizers (UM). Homo- and heterozygous extensive metabolizers (EM) as well as UM were equally distributed between patients with and without EPS, whereas all the PM had a history of EPS. No significant differences in allele frequencies between the two groups were found.
Conclusion:
Although the results cannot be considered conclusive due to the small number of PM patients in our study, the PM genotype may be a predisposing factor for antipsychotic-induced EPS. Knowledge of the CYP2D6 genotype, before starting antipsychotic therapy, might be useful in identifying subjects at risk of developing EPS.
Insights
Poor metabolizers (PM) of debrisoquine, identified by CYP2D6 genotype, may be predisposed to antipsychotic-induced extrapyramidal side effects (EPS). Genotyping before treatment could identify patients at higher risk for these adverse drug reactions.
Area of Science:
- Pharmacogenetics
- Neuroscience
- Psychiatry
Background:
- Antipsychotic medications are commonly used to treat schizophrenia.
- Extrapyramidal side effects (EPS) are a significant concern with antipsychotic use.
- Individual variability in drug metabolism, particularly via CYP2D6, can influence drug efficacy and safety.
Purpose of the Study:
- To investigate the association between CYP2D6 genotype and the occurrence of EPS in schizophrenic patients treated with antipsychotics.
- To determine if poor metabolizers (PM) of debrisoquine are overrepresented in patients experiencing EPS.
Main Methods:
- CYP2D6 genotyping was performed on 119 schizophrenic patients using allele-specific PCR, long-PCR, and RFLP.
- Patients were categorized based on their CYP2D6 genotype, including poor metabolizers (PM) and ultrarapid metabolizers (UM).
- History of EPS was recorded for all patients, and genotype frequencies were compared between patients with and without EPS.
Main Results:
- Four patients (3.4%) were classified as PM, and all had a history of EPS.
- Six patients (5.0%) were identified as UM.
- No significant differences in allele frequencies were found between patients with and without EPS, apart from the PM group.
Conclusions:
- The study suggests a potential link between the PM CYP2D6 genotype and an increased risk of antipsychotic-induced EPS.
- While not conclusive due to the small sample size of PM patients, CYP2D6 genotyping may aid in identifying individuals at risk.
- Pre-treatment CYP2D6 genotyping could personalize antipsychotic therapy and mitigate EPS risk.