The CYP2D6 poor metabolizer phenotype may be associated
with risperidone adverse drug reactions and discontinuation.
de Leon J, Susce MT, Pan RM, Fairchild M, Koch WH, Wedlund PJ.
University of Kentucky Mental Health Research Center at Eastern State Hospital,
Lexington, KY 40508, USA. jdeleon@uky.edu
OBJECTIVE: The cytochrome P450 2D6 (CYP2D6) enzyme metabolizes risperidone.
CYP2D6 poor metabolizers have no CYP2D6 activity (7% of whites and 1%-2% of
other races). This study tested whether the CYP2D6 poor metabolizer phenotype
was associated with adverse drug reactions (ADRs) and discontinuation due to
ADRs. METHOD: Adult inpatients and outpatients were recruited from July 2000 to
March 2003 including (1) 325 who were stabilized on risperidone therapy and
classified as either expressing moderate-to-marked ADRs (22%, 73/325) or not
(78%, 252/325) and (2) 212 who discontinued risperidone and were classified as
discontinued due to ADRs (38%, 81/212) or for other reasons (62%, 131/212).
Genetic tests were performed by allele-specific polymerase chain reaction and/or
by the AmpliChip CYP450 microarray system for up to 34 separate CYP2D6 alleles.
Two logistic regression models with dependent variables (moderate-to-marked ADRs
while taking risperidone and risperidone discontinuation due to ADRs) were
evaluated with respect to the CYP2D6 phenotype. RESULTS: The odds ratios (ORs)
and 95% confidence intervals (CIs) for the CYP2D6 poor metabolizer phenotype in
the univariate analyses and after correcting for clinical variables were (1) OR
= 3.1 (CI = 1.4 to 7.0) and 3.4 (CI = 1.5 to 8.0) for moderate-to-marked ADRs on
risperidone and (2) OR = 3.0 (CI = 0.85 to 10.6) and 6.0 (CI = 1.4 to 25.4) for
discontinuation due to ADRs.
CONCLUSIONS: The CYP2D6 poor metabolizer phenotype appears to be associated with risperidone ADRs and discontinuation due to ADRs; however, this finding requires further study in larger patient populations. The CYP3A5 and p-glycoprotein exon 21 and 26 genotypes were not significantly associated with risperidone response.
A pilot study on risperidone metabolism: the role of
cytochromes P450 2D6 and 3A.
Bork JA, Rogers T, Wedlund PJ, de Leon J.
University of Kentucky Mental Health Research Center at Eastern State Hospital
and College of Pharmacy, Lexington 40508, USA.
BACKGROUND: The limited available information on plasma risperidone levels shows
a stable relationship between daily doses of risperidone and total plasma
concentration (risperidone plus its active metabolite 9-hydroxyrisperidone). The
ratio between risperidone and 9-hydroxyrisperidone characterizes cytochrome P450
2D6 (CYP2D6) status. According to the manufacturer, the CYP2D6 genotype or drugs
that influence CYP2D6 or other cytochrome P450 isoenzyme activity are not
expected to be clinically significant. One case report suggests that CYP3A
participates in the metabolism of risperidone. METHOD: A case series of 13
risperidone patients (the initial case and 12 new cases) who were genotyped for
CYP2D6 were followed, and another 20 risperidone patients from a case-control
study for the CYP2D6 genotype were reviewed. RESULTS: The CYP2D6 poor
metabolizers, who are enzyme deficient (2/13 in the case series and 3/20 in the
case-control study), did not appear to tolerate risperidone well. Drugs
affecting CYP3A, in particular powerful inducers and inhibitors, resulted in at
least a 2-fold decrease or increase in plasma risperidone levels.
CONCLUSION: The anecdotal nature of this study is clearly a limitation. Drugs influencing CYP3A and CYP2D6 metabolic activity may significantly affect risperidone levels. Thus, plasma level monitoring of risperidone in a clinical setting may be useful, especially if patients are taking multiple medications or a CYP2D6 deficiency is suspected. New prospective studies under more controlled conditions are needed to verify these hypotheses.
Risperidone metabolism in relation to CYP2D6*10 allele in
Korean schizophrenic patients.
Roh HK, Kim CE, Chung WG, Park CS, Svensson JO, Bertilsson L.
Department of Medical Laboratory Sciences and Toxicology, Karolinska Institutet,
Huddinge University Hospital, Stockholm, Sweden. keunroh@inha.ac.kr
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 4.3 +/- 1.9, 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 identified
using allele-specific polymerase chain reaction amplification. 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
significant difference 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 significant
difference between the genotypes (P=0.54). The medians of the ratios between
risperidone and 9-hydroxyrisperidone 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 significantly different (P=0.004). The active
moieties (sum of the C/Ds of risperidone and 9-hydroxyrisperidone) were not
significantly different 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 significant differences in the plasma concentration of
parent drug plus its active metabolite between the genotypes. This suggests that
the clinical significance of this polymorphism is limited. Our study confirms
previous studies on risperidone metabolism in Caucasians.
Antipsychotic-induced extrapyramidal syndromes and
cytochrome P450 2D6 genotype: a case-control study.
Schillevoort I, de Boer A, van der Weide J, Steijns LS, Roos RA, Jansen PA,
Leufkens HG.
Department of Pharmacoepidemiology & Pharmacotherapy, Utrecht Institute for
Pharmaceutical Sciences (UIPS), Utrecht University, The Netherlands.
i.e.r.m.schillevoort@pharm.uu.nl
To study the association between polymorphism of the cytochrome P450 2D6 gene
(CYP2D6) and the risk of antipsychotic-induced extrapyramidal syndromes, as
measured by the use of antiparkinsonian medication.Data for this case-control
study were obtained from a psychiatric hospital where newly admitted patients
are routinely screened for several CYP2D6 mutant alleles. Cases were patients
prescribed antiparkinsonian medication during oral antipsychotic drug treatment
in the period September 1994 to August 2000. They were divided into those using
an antipsychotic drug the metabolic elimination of which depends on the activity
of the CYP2D6 enzyme ('CYP2D6-dependent') and those using other antipsychotic
drugs. We formed a control group of antipsychotic drug users for both case
groups using a matching ratio of 3 : 1 (controls : cases). Control patients were
matched on whether or not their prescribed antipsychotic drug was
CYP2D6-dependent. Odds ratios for patients who were slow metabolizers versus
patients who were extensive metabolizers were calculated using conditional
logistic regression and were adjusted for age, gender, dose and other potential
confounding factors.We identified 77 case patients who were prescribed a
CYP2D6-dependent antipsychotic drug and 54 case patients who were prescribed non
CYP2D6-dependent antipsychotic drugs. Among the case- and control-patients using
a CYP2D6-dependent antipsychotic drug, the poor metabolizers were more than four
times more likely to start with antiparkinsonian medication than the extensive
metabolizers (odds ratio 4.44; 95% confidence interval 1.11-17.68). An increased
risk was not observed for patients using non CYP2D6-dependent antipsychotic
drugs (odds ratio 1.20; 95% confidence interval 0.21-6.79).Genetically impaired
CYP2D6 activity can increase the risk of antipsychotic-induced extrapyrimidal
syndromes. Poor metabolizers should have their antipsychotic drug dosage reduced
when the metabolism of the prescribed drug depends on CYP2D6 activity or should
receive an antipsychotic drug that is not CYP2D6-dependent.
Cytochrome P-450 2D6*10 C188T polymorphism is associated
with antipsychotic-induced persistent tardive dyskinesia in Chinese
schizophrenic patients.
Liou YJ, Wang YC, Bai YM, Lin CC, Yu SC, Liao DL, Lin MW, Chen JY, Lai IC.
Department of Psychiatry, Yuli Veterans Hospital, Hualien, Taiwan, ROC.
Typical antipsychotic treatment had been postulated to be a risk factor for the
susceptibility to tardive dyskinesia (TD). The cytochrome P-450 debrisoquine/sparteine
hydroxylase (CYP2D6) metabolizes a majority of antipsychotics and exhibits
various phenotypes on enzymatic activities from poor metabolizers to ultrarapid
metabolizers. The various phenotypes are encoded by polymorphic genetic variants
on the CYP2D6 gene. Although several studies had explored the association
between the CYP2D6*10 C188T polymorphism, which encodes the phenotype
intermediate metabolizers, and TD in Orientals, the findings were inconclusive.
In the present study, we examined the relationship between the CYP2D6*10 C188T
polymorphism and the TD occurrence in 216 Chinese schizophrenic patients (113
patients with TD and 103 patients without TD) and explored the correlation
between the TD severity assessed by the Abnormal Involuntary Movement Scale
(AIMS) and each C188T genotype in the 113 TD patients. Using logistic regression
analysis, we found a modest association (p = 0.045) between TD and C188T
genotypes. This positive finding was only observed in male patients (p = 0.001),
but not in females. Our findings also support the correlation between AIMS
scores and C188T polymorphism within the TD group after adjusting for
confounding effects with the multiple regression analysis (p = 0.033). We
concluded that the CYP2D6*10 C188T polymorphism may be associated with the
susceptibility to the occurrence of TD induced by typical antipsychotics,
especially in male patients, and may also be correlated with AIMS scores in TD
patients.