Pharmacology - Neuromuscular

Increased incidence of CYP2D6 gene duplication in patients with persistent mood disorders: ultrarapid metabolism of antidepressants as a cause of nonresponse. A pilot study.

Kawanishi C et al., 2004. Eur J Clin Pharmacol 59:803.

OBJECTIVE: Recent studies have revealed that genetic polymorphisms of cytochrome P(450) 2D6 (CYP2D6) are among the factors that determine the interindividual differences in the metabolism and response to antidepressants. We investigated the relationship between persistent mood disorders and the duplication of the CYP2D6 gene, which encodes an enzyme with increased activity. METHODS: We screened the prevalence of the CYP2D6 genotypes in 108 patients with persistent mood disorders using long polymerase chain reaction (PCR) and the real-time PCR methods. Clinical correlates with the genotypes were also analyzed. RESULTS: Among the 108 patients, 81 had failed to respond to antidepressants shown to be metabolized by CYP2D6. Of those 81, 8 had a CYP2D6 gene duplication (9.9%, 95% confidence interval 3.4-16.4%) which was higher than the 0.8-1.0% incidence previously observed in healthy Nordic Caucasians. The worst week scores of the Hamilton Depression Rating Scale were higher in the patients with the duplication compared with those without the duplication ( P=0.026, student's t-test). CONCLUSION: These results suggest that the CYP2D6 gene duplication is a possible factor that influences the development of persistence in patients with mood disorders probably by ultrarapid drug metabolism.

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The influence of the CYP2D6 polymorphism on psychopathological and extrapyramidal symptoms in the patients on long-term antipsychotic treatment.

Plesnicar BK et al., 2006. J Psychopharmacol. 20(6):829-33.

Poor response to antipsychotics treatment and extrapyramidal side effects (EPS) are the most challenging problems in the treatment of schizophrenia. Several studies were investigating the impact of polymorphic cytochrome P450 2D6 gene (CYP2D6) on EPS but the results were conflicting. There are practically no clinical studies of long-term treatment of schizophrenia and CYP2D6 polymorphism. Our aim was to evaluate the influence of CYP2D6 genotype on psychopathological symptoms and the occurrence of EPS in Slovenian outpatients with schizophrenia or schizoaffective disorder in stable remission, receiving long-term maintenance antipsychotic treatment. In total 131 outpatients meeting the DSM IV criteria for schizophrenia or schizoaffective disorder and receiving maintenance therapy with haloperidol, fluphenazine, zuclopethixole or risperidone were genotyped for 14 polymorphic CYP2D6 alleles. Psychopathological symptoms were assessed with the Positive and Negative Symptom Scale for Schizophrenia (PANSS). EPS were assessed with the Simpson Angus Scale (SAS), the Barnes Akathisia Scale and the Abnormal Involuntary Movement Scale (AIMS). Six patients (4.6%) were genotyped as poor metabolizers (PMs). PMs scored significantly higher on the negative subscale for PANSS. There were no statistically significant differences between the group of PMs and the group of patients with at least one functional CYP2D6 allele in view of patient's characteristics or any of the items of the AIMS, the SAS or the Barnes Akathisia Scale. CYP2D6 genotype may not be the major factor that determines the susceptibility to antipsychotic-induced EPS in Slovenian patients in stable remission and on maintenance therapy with antipsychotics that are mainly CYP2D6 substrates. However, CYP2D6 genotype might be a factor contributing to the persistent negative symptoms of schizophrenia.

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