Atypical Antipsychotics and Cardiovascular Risk in Schizophrenic Patients (original) (raw)
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Risperidone metabolism in relation to CYP2D6*10 allele in Korean schizophrenic patients
European Journal of Clinical Pharmacology, 2001
Objective: Risperidone is known to be biotransformed to its active metabolite, 9-hydroxyrisperidone, by the polymorphic CYP2D6 in Caucasians. This study aimed to investigate the relationship between the CYP2D6*10 allele and the plasma levels of risperidone and 9-hydroxyrisperidone in Korean schizophrenic patients. Methods: Eighty-two Korean schizophrenic patients in monotherapy with oral doses of risperidone from 1 mg/ day to 8 mg/day (mean SD 4.31.9, median 4) participated in this study. Plasma concentrations of risperidone and 9-hydroxyrisperidone were analyzed using high-performance liquid chromatography. The CYP2D6*10 allele, which contains C188T mutation in exon 1, was identi®ed using allele-speci®c polymerase chain reaction ampli®cation. Results: Seventeen of 82 patients were homozygous for CYP2D6*1, 22 for *10, while the remaining 43 patients were heterozygous for these alleles. The plasma levels of risperidone and 9-hydroxyrisperidone ranged from 1.0 nM to 168 nM and 6.2 nM to 235 nM, respectively. The median concentrations/dose (C/Ds) (range) of risperidone in CYP2D6*1/*1, *1/*10, and *10/*10 groups were 1.7 (0.2±7.9), 2.6 (0.3±27.1), and 6.7 nM/mg (2.4± 21.0), respectively. There was a statistically signi®cant dierence among the three genotypes (Kruskal-Wallis test, P<0.001). For 9-hydroxyriperidone, the corresponding median C/Ds were 13.1 (3.3±25.4), 11.9 (4.2± 30.8), and 13.6 nM/mg (6.5±52.8), respectively, with no signi®cant dierence between the genotypes (P=0.54). The medians of the ratios between risperidone and 9hydroxyrisperidone concentrations were 0.13 (0.01± 0.93), 0.28 (0.01±2.77), and 0.46 nM/mg (0.05±1.28) in *1/*1, *1/*10, and *10/*10 genotypes, respectively, and they were signi®cantly dierent (P=0.004). The active moieties (sum of the C/Ds of risperidone and 9-hydroxyrisperidone) were not signi®cantly dierent between the genotypes (P=0.063). Conclusion: In Korean schizophrenic patients, the metabolism of risperidone is dependent on CYP2D6, and the CYP2D6*10 allele is important for the regulation of the activity of this enzyme. There were no signi®cant dierences in the plasma concentration of parent drug plus its active metabolite between the genotypes. This suggests that the clinical signi®cance of this polymorphism is limited. Our study con®rms previous studies on risperidone metabolism in Caucasians.
Risperidone metabolic ratio as a biomarker of individual CYP2D6 genotype in schizophrenic patients
European Journal of Clinical Pharmacology, 2014
Purpose The purpose of the present study was to investigate the predictive value of the risperidone metabolic ratio for the individual CYP2D6 genotype. M e t h o d s T h e d e t e r m i n a t i o n o f r i s p e r i d o n e , 9-hydroxyrisperidone, and CYP2D6 genotype was performed in 89 schizophrenic patients. The receiver operator characteristic (ROC) method and the area under the ROC curve (AUC) were used to illustrate the predictive value of risperidone metabolic ratio for the individual CYP2D6 genotype. The area under the ROC curve (AUC) was used as a global measure of this predictive value. To evaluate the proposed cutoff levels of >1 and <0.1 to identify individuals with a poor or ultrarapid CYP2D6 genotype the sensitivity, specificity, positive predictive value and negative predictive were calculated. Results The area under the ROC curve (AUC) for poor and ultrarapid metabolisers was 0.85 and 0.86, respectively. The sensitivity, specificity, positive predictive value and negative predictive value of a risperidone/9-OH-risperidone ratio >1 to CYP2D6 poor metaboliser genotype were 75 %, 95 %, 60 % and 97 %, respectively. The corresponding measures for a metabolic ratio<0.1 to predict ultrarapid metabolisers were 80 %, 77 %, 18 % and 98 %. Conclusions A metabolic ratio>1 or<0.1 may be a useful therapeutic biomarker to recommend CYP2D6 genetic testing to guide the present or future treatment of patients in need of psychotropic drugs.
CYP2D6 poor metabolizer status might be associated with better response to risperidone treatment
Pharmacogenetics and Genomics, 2013
Risperidone non-compliance is often high due to undesirable side effects, whose development is in part genetically determined. Studies with genetic variants involved in the pharmacokinetics and pharmacodynamics of risperidone have yielded inconsistent results. Thus, the aim of this study was to investigate the putative association of genetic markers with the occurrence of four frequently observed adverse events secondary to risperidone treatment: sleepiness, weight gain, extrapyramidal symptoms and sexual adverse events. A series of 111 schizophrenia inpatients were genotyped for genetic variants previously associated with or potentially involved in risperidone response. Presence of adverse events was the main variable and potential confounding factors were considered. Allele 16Gly of ADRB2 was significantly associated with a higher risk of sexual adverse events. There were other non-significant trends for DRD3 9Gly and SLC6A4 S alleles. Our results, although preliminary, provide new candidate variants of potential use in risperidone safety prediction.
Journal of Pharmaceutical Health Care and Sciences, 2018
Background: Risperidone 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. Methods: Schizophrenia 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). Results: A 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). Conclusion: Special attentions should be paid to the onset of extrapyramidal symptoms in schizophrenia patients identified as CYP2D6 IM undergoing risperidone therapy.
Atypical antipsychotics are widely used and have been shown to be effective against both positive and negative symptoms of schizophrenia. Through this study we intended to bring to the forefront attention the implications of pharmacogenetics for obtaining the optimum results after antipsychotic treatment in a very sensitive category of patients: children and adolescents. This study was performed between 2009 and 2013 and includes children and adolescents with a diagnosis of schizophrenia or bipolar disorder. 81 patients, aged between 9 and 20 years were included in this study (median age was 15.74±4). The efficacy of the therapy was evaluated through the mean change in the PANSS total scores from baseline-T0, through every timepoint -T1=after 3 months, T2=after 6 months, T3=after 12 months, till endpoint -T4=after 18 months. Genotypes were determined by measuring allele-specific fluorescence using the software for allelic discrimination. Our results, showing statistically significant differences of the clinical score between the groups classified based on the genotype, sustain the use of the pharmacogenetic screening in clinical practice for the personalization of the therapy.
European Journal of Clinical Pharmacology, 2010
Purpose: To evaluate the role of cytochrome 450 2D6 (CYP2D6) and ABCB1 variants on plasma risperidone concentrations and treatment response in 83 drug naive patients with first episode of psychosis. Methods: All patients were treated with risperidone for 8 weeks. The CYP2D6 genotyping was performed by allele-specific PCR-RFLP (for *3,*4,*6) and long PCR (for duplications and *5), while real-time PCR method was used for ABCB1 G2677T/A and C3435T. Plasma concentrations of risperidone and 9-OH risperidone were measured by high-preformance liquid chromatography. Results: The number of patients with the CYP2D6 wild type (wt/wt), wt/mutation (mut) and mut/mut genotype
Semi-quantitative CYP2D6 gene doses in relation to metabolic ratios of psychotropics
European Journal of Clinical Pharmacology, 2008
Purpose Genetic polymorphisms in cytochrome P450 (CYP) enzyme CYP2D6 have a substantial effect on the success of pharmacotherapy. Different models, including a predicted-phenotype model and a semi-quantitative gene dose (SGD) model, have been developed based on CYP genotype. The objective of this study was to investigate the surplus value of the SGD model in predicting the metabolic ratios (MRs) of the psychotropics venlafaxine, fluoxetine and risperidone. Methods Phenotype prediction and semi-quantitative gene doses were conducted after genotyping for CYP2D6 *3, *4, *5, *6, *9, *10, *41 and gene multiplication. Results The predicted-phenotype and SGD model showed increasing mean MRs with increasing predicted metabolic activity and decreasing SGD values, respectively, for all three psychotropics. The reliability of MR prediction was higher for the SGD model. Conclusions Both models are suitable for venlafaxine, fluoxetine and risperidone. In this study, a surplus value of semi-quantitative gene dose model was present, but small, for all three psychotropics.
The Pharmacogenomics Journal, 2010
The aim of this study is to evaluate whether the quantitative prescription of risperidone (dosage) is related to the patient's metabolic status. Metabolic status was defined in terms of the most relevant polymorphisms of CYP2D6 (*3, *4, *5, *6 and *1xN), CYP3A5 (*3A) and ABCB1 (G2677T) determined a posteriori and blinded to the clinicians. This prospective and observational study includes a cohort of 151 Caucasian psychiatric patients treated with risperidone. Significant differences (Kruskal-Wallis test p ¼ 0.01) among the doses administered were observed to correlate (Spearman's r ¼ 1, p ¼ 0.02) with the different CYP2D6 groups. Poor metabolizers received the lowest doses and ultra rapid metabolizers the highest. No significant correlations were observed with regard to CYP3A5 and ABCB1. We find that, despite not knowing patients' metabolic status, clinicians modify risperidone dosage in order to obtain the best therapeutic option.
CYP2D6 polymorphisms and their influence on risperidone treatment
Pharmacogenomics and Personalized Medicine, 2016
Cytochrome P450 enzyme especially CYP2D6 plays a major role in biotransformation. The interindividual variations of treatment response and toxicity are influenced by the polymorphisms of this enzyme. This review emphasizes the effect of CYP2D6 polymorphisms in risperidone treatment in terms of basic knowledge, pharmacogenetics, effectiveness, adverse events, and clinical practice. Although the previous studies showed different results, the effective responses in risperidone treatment depend on the CYP2D6 polymorphisms. Several studies suggested that CYP2D6 polymorphisms were associated with plasma concentration of risperidone, 9-hydroxyrisperidone, and active moiety but did not impact on clinical outcomes. In addition, CYP2D6 poor metabolizer showed more serious adverse events such as weight gain and prolactin than other predicted phenotype groups. The knowledge of pharmacogenomics of CYP2D6 in risperidone treatment is increasing, and it can be used for the development of personalized medication in term of genetic-based dose recommendation. Moreover, the effects of many factors in risperidone treatment are still being investigated. Both the CYP2D6 genotyping and therapeutic drug monitoring are the important steps to complement the genetic-based risperidone treatment.