Abstract
BackgroundRisperidone is mainly metabolized by cytochrome P450 (CYP) 2D6 in the liver. The gene encoding CYP2D6 is highly polymorphic. The average steady-state plasma concentration of risperidone active moiety is higher in the CYP2D6 intermediate metabolizers (IMs) compared with that in the extensive metabolizers (EMs). An association between drug-induced extrapyramidal symptoms scale (DIEPSS) score and CYP2D6 polymorphisms has not been reported to date. This study investigates the association of CYP2D6 polymorphisms with the severity of extrapyramidal symptoms in schizophrenia patients receiving risperidone therapy.MethodsSchizophrenia patients undergoing risperidone treatment were recruited for the study in the Kobe University Hospital. We evaluated extrapyramidal symptoms of schizophrenia using the DIEPSS. CYP2D6*10 and CYP2D6*14 were analyzed using TaqMan® assays, and CYP2D6*5 was analyzed using the long-PCR method. Patients with CYP2D6*1/*5, *1/*14, *5/*10, *10/*10, and *10/*14 were classified as IMs, and patients with CYP2D6*1/*1 and *1/*10 were classified as EMs. Patients with CYP2D6*5/*5, *5/*14, and *14/*14 were classified as poor metabolizers (PMs).ResultsA total of 22 patients were included in the study. No patients were classified as PMs. The dose of risperidone (mg/day) was not significantly different between EMs (n = 15) and IMs (n = 7) (median with the interquartile range: 4.0 (2.0–6.0) vs. 4.0 (2.0–7.0) mg, p = 0.31). The age and disease duration of schizophrenia were not significantly different between the EMs and IMs. The DIEPSS score in the IMs was significantly higher than that in the EMs (median with the interquartile range: 5.0 (3.5–6.5) vs. 0.0 (0.0–3.0), p < 0.001). The multiple regression analysis showed that CYP2D6 IMs is a significant risk factor for the DIEPSS (p < 0.05).ConclusionSpecial attentions should be paid to the onset of extrapyramidal symptoms in schizophrenia patients identified as CYP2D6 IM undergoing risperidone therapy.
Highlights
Risperidone is mainly metabolized by cytochrome P450 (CYP) 2D6 in the liver
CYP2D6 genotyping might be useful in personalizing risperidone therapy in patients with schizophrenia to reduce the incidence of adverse extrapyramidal symptoms
Patients Patients with schizophrenia defined according to the Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV criteria [19] who received risperidone treatment were recruited for the study between February 2011 and July 2013 from the Kobe University Hospital
Summary
Risperidone is mainly metabolized by cytochrome P450 (CYP) 2D6 in the liver. The gene encoding CYP2D6 is highly polymorphic. This study investigates the association of CYP2D6 polymorphisms with the severity of extrapyramidal symptoms in schizophrenia patients receiving risperidone therapy. Atypical antipsychotics developed after 1960s showed a relatively low frequency of extrapyramidal symptoms. The atypical antipsychotics such as clozapine and risperidone that relatively had low frequency of extrapyramidal symptoms are used, many patients develop serious acute adverse effects, such as akathisia, dystonia, and parkinsonism, leading to an impaired quality of life of these patients [3,4,5]. Higher plasma concentrations of risperidone plus 9-hydroxy-risperidone, the active moiety of risperidone, are associated with higher incidence of adverse effects [14]. CYP2D6 genotyping might be useful in personalizing risperidone therapy in patients with schizophrenia to reduce the incidence of adverse extrapyramidal symptoms
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