Genetics-Based Population Pharmacokinetics and Pharmacodynamics of Risperidone in a Psychiatric Cohort

Vandenberghe, Frederik; Guidi, Monia; Choong, Eva; Gunten, Armin von; Conus, Philippe; Csajka, Chantal; Eap, Chin B.

doi:10.1007/s40262-015-0289-8

Cited by 50 publications

(35 citation statements)

References 66 publications

(90 reference statements)

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“…Similar to the previous study, there were no association of reported side effects (neurologic, cardiovascular, psychic, and sexual side effects) with CYP2D6 -predicted phenotype. Only minimum active moiety concentration was found to be associated with neurologic symptoms, especially the severity of tremor 90. However, one study showed a trend of the association between CYP2D6 PM phenotype and the presence of tardive dyskinesia (TD).…”

Section: The Consequence Of Cyp2d6 Polymorphisms In Risperidone-assocmentioning

confidence: 99%

“…Using a population pharmacokinetic approach is a strategy to find out a suitable risperidone dosage. Vandenberghe et al reported that CYP2D6 but not NR1/2 , POR , PPAR α, ABCB1 , CYP3A plays an important role in risperidone, 9-hydroxyrisperidone, and active moiety plasma concentration 90. However, the CYP2D6 metabolizer subpopulation into PM, EM, IM, UM should be analyzed.…”

Section: Challenges Opportunities and Future Directions In The Clinmentioning

confidence: 99%

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CYP2D6 polymorphisms and their influence on risperidone treatment

Puangpetch

Vanwong

Nuntamool

et al. 2016

PGPM

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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.

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Section: The Consequence Of Cyp2d6 Polymorphisms In Risperidone-assocmentioning

confidence: 99%

Section: Challenges Opportunities and Future Directions In The Clinmentioning

confidence: 99%

CYP2D6 polymorphisms and their influence on risperidone treatment

Puangpetch

Vanwong

Nuntamool

et al. 2016

PGPM

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“…The activity score system provided a more detailed classification for the subjects." 192 Genetics-Based Population Pharmacokinetics and Pharmacodynamics of Risperidone in a Psychiatric Cohort http://www.ncbi.nlm.nih.gov/pubmed/26129906 193 "High interindividual variability in plasma concentrations of risperidone and its active metabolite, 9hydroxyrisperidone, may lead to suboptimal drug concentration… Genetic polymorphisms of CYP2D6 play an important role in risperidone, 9-hydroxyrisperidone and active moiety plasma concentration variability, which were associated with common side effects. These results highlight the importance of a personalized dosage adjustment during risperidone treatment."…”

Section: Impact Of Cyp1a2 and Cyp2d6 Polymorphisms On Drug Metabolismmentioning

confidence: 99%

“…These results highlight the importance of a personalized dosage adjustment during risperidone treatment." 193…”

Section: Impact Of Cyp1a2 and Cyp2d6 Polymorphisms On Drug Metabolismmentioning

confidence: 99%

Polymorphisms in Serotonergic Pathways Influence the Outcome of Antidepressant Therapy in Psychiatric Inpatients

Staeker

Leucht

Laika

et al. 2014

Genetic Testing and Molecular Biomarkers

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Serotonergic pathways are known to play an essential role in the effects generated by antidepressants. Polymorphisms in serotonin receptor and transporter genes have been identified as an important factor. To investigate which of these polymorphisms may be useful to predict clinical outcome, we assessed their effect in a naturalistic clinical study. We studied the influence of the 5-hydroxytryptamine transporter (5-HTT) variable number of tandem repeats (VNTR), 5-HTTLPR/rs25531 and a 5-HTR2A intron 2 SNP with regard to response and side effects in 273 psychiatric inpatients. Main clinical assessments included Clinical Global Impressions ratings, paranoid depression scale self-rating scale and Dosage Record, and Treatment Emergent Symptoms (DOTES) Scale. We found significant associations between 5-HTTLPR/rs25531 S/L(G) alleles and response and side effects in 100 patients with selective serotonin reuptake inhibitor (SSRI) treatment (p = 0.037, CGI-I ≤ 2: 0% vs. 19% and p = 0.0005, DOTES cluster c: 0.76 vs. 0.19). 5-HTT VNTR and 5-HTR2A intron 2 polymorphisms were associated significantly with adverse effects in patients with selective and nonselective SRI (5-HTT VNTR 12/12: n = 170, p = 0.0001, side effect rates: 51% vs. 19% and rs7997012 [A/A]: n = 50, p = 0.020, side effects rates: 43% vs. 11%). No impact of the polymorphisms on mirtazapine treatment was found. Our study confirms the influence of serotonergic polymorphisms at the receptor and transporter level on SSRI response and side effects, supporting previous reports based on various study designs. The effects were strong enough to be noticed clinically in this naturalistic setting. However, randomized controlled trials are warranted to provide unequivocal evidence of the clinical usefulness of pretherapeutic screening for these polymorphisms.

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“…[2] Therapeutic plasma concentrations of risperidone and its active moiety are directly influenced by genetic variations in metabolic CYP 450 enzymes (CYP2D6 and slightly CY-P3A4/5) and transporter (ABCB1) enzymes, and are influenced by environment. Particularly drug interactions associated with intake of inducers or inhibitor may influence CYP or P-gp and alter the pharmacological profile of risperidone and its active metabolite, and their therapeutic effect [3,4]. The metabolic transformation of risperidone is determined by the genetic variations in CYP2D6 enzyme, and depending on the number of active copies of the gene patients are classified as extensive metabolizers (EM), intermediate metabolizers (IM), ultrarapid metabolizers (UM) and poor metabolizers (PM).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Correlation Between the Pharmacogenetic Profiles of Risperidone Treated Psychiatry Patients with Plasma and Urine Concentration of Risperidone and its Active Moiety 9-OH Risperidone Determined with Optimized Bioanalytical LC Method

Filipce

Naumovska

Nestorovska

et al. 2018

Prilozi

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Atypical antipsychotic risperidone is widely used first-line monotherapy in schizophrenia and combined therapy in bipolar disorders. Therapeutic plasma concentrations of risperidone and its active moiety are directly influenced by genetic variations in metabolic CYP450 enzymes (CYP2D6 and CYP3A4/5) and transporter (ABCB1) protein and additional environmental factors. Since active metabolite 9-OH risperidone has a greater percentage of the pharmacologically active fraction and is equipotent to the parent drug risperidone, it is assumed that it contributes significantly to therapeutic and adverse effects. Unpredictable dose/concentration ratio, narrow therapeutic index, number of interactions, along with serious adverse reactions (ADR), raises the need for individualization of risperidone treatment and establishing of good therapeutic regime using TDM. A simple and reliable validated bioanalytical liquide-liquide extraction HPLC/UV method was applied for the simultaneous determination of risperidone and its active metabolite, 9-OH risperidone, in human plasma and urine of 52 hospitalized schizophrenia/bipolar disorder patients treated with risperidone as monotherapy and in polytherapy. All the patients were previously genotyped for CYP2D6 (EM=30, EM/IM=14, IM=4 IM/PM=1 and PM=3) and ABCB1 using Real-Time PCR methods with TaqMan SNP genotyping suitable assays according to the guidelines of the manufacturer (Life Technologies, USA).The influence of CYP2D6 phenotype on metabolic ratio MR (Ris/9-OHRis) in plasma (p=0.012) and in urine (p=0.048) was confirmed. Statistically significant correlation (R2=55.53%, Rho=0.844, p<0,0001) for MR in both plasma and urine indicates that urine may be utilized as appropriate media for initial CYP2D6 phenotype identification and selection of patients on risperidone treatment with high risk for ADR.

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Genetics-Based Population Pharmacokinetics and Pharmacodynamics of Risperidone in a Psychiatric Cohort

Abstract: Background: There is a high inter-individual variability in risperidone and its active

Cited by 50 publications

References 66 publications

CYP2D6 polymorphisms and their influence on risperidone treatment

CYP2D6 polymorphisms and their influence on risperidone treatment

Polymorphisms in Serotonergic Pathways Influence the Outcome of Antidepressant Therapy in Psychiatric Inpatients

Evaluation of Correlation Between the Pharmacogenetic Profiles of Risperidone Treated Psychiatry Patients with Plasma and Urine Concentration of Risperidone and its Active Moiety 9-OH Risperidone Determined with Optimized Bioanalytical LC Method

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