The CYP2D6 gene codes for human cytochrome P450 2D6 enzyme, which is responsible for the metabolism of many psychiatric drugs. In schizophrenic patients treated with neuroleptics, decreased or loss of function CYP2D6 alleles may contribute to the development of tardive dyskinesia (TD), a movement disorder that frequently occurs with chronic neuroleptic treatment. The goal of this study was to determine whether the occurrence of TD is associated with CYP2D6 genotype in a cohort of Korean schizophrenics by employing a CYP450 GeneChip® oligonucleotide microarray and PCR assays to screen for 19 CYP2D6 alleles. Our results revealed that males with at least one decreased or loss of function allele have a moderately greater chance of developing TD than males with only wild-type alleles. Female schizophrenics did not have a significantly greater chance of developing TD. Our results demonstrate the utility of CYP2D6 microarrays to assess genotype status in this Korean cohort.
Excessive levels of psychotropic drugs commonly used to treat schizophrenia have been linked to the development of extrapyramidal side effects and movement disorders. Tardive dyskinesia (TD), a frequently irreversible movement disorder characterized by stereotypical involuntary movement, often manifests after long-term antipsychotic therapy, with 23–43% of schizophrenic subjects becoming affected during the first five years of treatment.1 Since there is no accepted treatment for TD, preventing the occurrence of TD is an important aim when treating schizophrenics.2 However, predicting whether a patient will develop TD has been problematic since substantial heterogeneity in the occurrence and severity of TD exists and many risk factors such as age, gender, denture use, DSM IV diagnosis, drug disposition, current neuroleptic dose, and race are believed to influence its development.345 In addition, multiple biochemical pathways contribute to the catabolism of neuroleptic drugs, making it difficult to detect genotype/phenotype associations. In particular, it has yet to be resolved whether the polymorphic cytochrome P450 enzymes play a role in the development of TD.
The enzyme debrisoquine 4-hydroxylase, encoded by the cytochrome P450 CYP2D6 gene, catalyses the oxidative metabolism of a variety of drugs with narrow therapeutic range including tricyclic antidepressants, antiarrythmic agents and neuroleptics.6 Subjects can be classified into four phenotypes based on their CYP2D6 activity: poor metabolizers (PM), intermediate metabolizers (IM), extensive metabolizers (EM), and ultrarapid metabolizers (UM).7,8 IM individuals are commonly found among Asian populations, where a reduced activity CYP2D6*10B allele has a high frequency.91011 Over 70 allelic variants of CYP2D6 have been described to date, many of which reduce or eliminate enzyme activity and contribute to pronounced interindividual and interethnic differences in drug metabolism (http://www.imm.ki.se/cyp-alleles/cyp2d6.htm). Individuals with decreased or loss of activity CYP2D6 alleles may be at higher risk for certain adverse drug events and require careful therapeutic monitoring.12 In Caucasians, the CYP2D6 loss of function alleles have been shown to be moderately to significantly associated with TD and/or the total Abnormal Involuntary Movement Scale (AIMS) score, as well as related movement disorders.13-15 Armstrong et al16 concluded that CYP2D6 genotype does not play a major role in determining susceptibility to neuroleptic-induced movement disorders, but their study did reveal a trend among CYP2D6 heterozygotes towards increased risk for movement disorders. In contrast, Arthur et al reported no overrepresentation of PMs among subjects suffering from TD.17
In Asians, CYP2D6 lack of function alleles are rare and it has been postulated that decreased activity alleles may con-tribute to the occurrence of TD in these populations.181920 Demonstrating that these CYP2D6 variant alleles have a significant impact on the risk of developing TD, however, has been challenging. While several studies have shown that the decreased activity alleles affect the metabolism of haloperidol, a common neuroleptic used to treat schizophrenia,21222324 conflicting results have been reported concerning the association of CYP2D6 genotype and TD. Ohmori et al25 found a significant difference between the allelic distribution of the decreased activity allele CYP2D6*10B, an allele which codes for an unstable gene product,19,26 in subjects with and without TD. On the other hand, Lam et al27 found a significant association between the presence of CYP2D6*10B alleles and TD in Chinese schizophrenic women but not men. In most of these studies, the number of subjects examined was relatively small.
Therefore, in this study, we examined the distribution and frequency of 19 CYP2D6 allelic variants in 110 TD+ and 92 TD− Korean schizophrenic subjects, and evaluated the association between CYP2D6 genotype and the manifestation of TD. By employing microarray technology, our report provides the most comprehensive genotypic analysis of CYP2D6 polymorphisms in any Asian population studied thus far.
MATERIALS AND METHODS
Recruitment of Subjects
Unrelated subjects of Korean origin ranging in age from 18 to 69 years were recruited from the Department of Psychiatry, Inje University Pusan Paik Hospital and Dongsuh Hospital, Pusan and Masan, Korea, and gave written informed consent to participate in the study. The protocol was approved by the Institutional Review Boards of both hospitals. Schizophrenic subjects were enrolled based on the following criteria: the patient must have fulfilled the DSM-IV criteria for clinical diagnosis of schizophrenia, received antipsychotics for at least three months, and maintained the same antipsychotic dosage regimen during the last three months expressed as the total dose in chlorpromazine (CPZ) equivalents.28 In this study, we recruited patients who were treated with conventional neuroleptics such as haloperidol, chlorpromazine, thioridazine, trifluperazine, fluphenazine, perphenazine, zuclopenthixol and pimozide; patients receiving atypical antipsychotics that are not believed to significantly impact the development of TD, such as risperidone, olanzapine and clozapine, were excluded from the study.6 Patient compliance with prescribed therapeutic regimens was confirmed by nursing staff records.
Schizophrenic patients with the following conditions were excluded from the study based on the following criteria: psychotic or neurological co-morbidity such as affective disorder, epilepsy, mental retardation, dementia, Parkinson's disease, organic brain syndrome, or substance abuse. In addition, patients with renal or hepatic dysfunction, patients with artificial teeth, or patients who received dental care recently were also excluded from the study. All subjects in this study were of Korean ancestry dating as far back as grandparents.
Diagnostic criteria for tardive dyskinesia was based on AIMS as described by Guy29 and Schooler and Kane.30 If a patient had at least two 2-point ratings or at least one 3-point rating among the seven movement categories that comprise the AIMS score, the patient was classified as suffering from TD. The AIMS evaluation was performed independently by two experienced psychiatrists, whose inter-rater reliability was previously established (r=0.90, P<0.001) in a blinded fashion prior to obtaining genotyping results. Two consecutive evaluations within a three month interval were performed for each patient who received a diagnosis of TD in order to confirm the presence of permanent TD.
Cytochrome P450 CYP2D6 Genotype Determinations
Three milliliters of venous blood was collected in heparinized tubes from 232 schizophrenic patients. Twenty-six patients failed to cooperate during the AIMS evaluation and were not evaluated for the presence of TD. Whole blood was stored at −70°C and transported to the Metabolic Core Laboratory, Division of Clinical Pharmacology, Georgetown University Medical Center, Washington, DC, for DNA extraction of peripheral leukocytes using the QIAamp® DNA Blood Mini Kit (QIAGEN, Inc., Valencia, CA, USA). For some samples, additional DNA extractions of thawed whole blood were performed at Roche Molecular Systems, Alameda, CA, USA.
In total, 202 genomic DNA samples were genotyped for 19 CYP2D6 variants using PCR methods and a newly designed oligonucleotide microarray based on the Affymetrix CYP450 GeneChip® system. Approximately 300 ng of sample DNA was subjected to multiplex PCR that generates seven amplicons encompassing the entire coding region and adjacent splice sites of CYP2D6 using primer sets and thermocycling profiles provided in the CYP450 GeneChip® Assay protocol (Affymetrix, Santa Clara, CA, USA). The 7-plex PCR products were separated and visualized by 2% SeaKem (LE) agarose gels stained with ethidium bromide. In some instances, PCR amplification appeared to be influenced by the amount of DNA, the integrity of DNA or the presence of inhibitors. Failure to amplify the longest 1125 bp product encompassing exon 1 and exon 2 of CYP2D6 was occasionally observed for problematic samples. By adjusting the amount of input DNA, sufficient 7-plex material was obtained for hybridization to the CYP450 GeneChip®.
One-tenth of the multiplex PCR reaction products (10 μl) was treated with GeneChip® Fragmentation reagent (DNase I) for 20 min to generate low molecular weight fragments ranging in length from 25 to 100 bp, according to the manufacturer's instructions. The fragmented amplicons were labeled and hybridized to the CYP450 microarray under conditions recommended by the manufacturer using the Affymetrix GeneChip® Fluidics Station 400. A modified streptavidin–phycoerythrin staining procedure was employed to detect hybridized DNA fragments and to provide stronger intensity signals than those obtained with direct fluoresceination of fragmented DNA. Specifically, hybridized targets were stained in wash buffer consisting of 0.45 M NaCl, 0.3 M NaH2PO4, 0.003 M EDTA, pH 7.4, 1 mg/ml bovine serum albumin and 10 mg/ml of phycoerythrin-conjugated streptavidin (Molecular Probes, Eugene, OR, USA) for 10 min at 25°C and washed 28 times in 3 × SSC at 25°C. CYP450 microarrays were scanned with a Hewlett Packard GeneChip® Scanner (Hewlett Packard, Palo Alto, CA, USA) at an excitation wavelength of 570 nm to generate raw fluorescence intensity data files which were subsequently analysed by proprietary algorithms developed by Affymetrix to convert fluorescence hybridization intensity patterns into genotype determinations.
The expanded CYP2D6 microarray assay was designed to detect the presence of the CYP2D6*2, CYP2D6*3, CYP2D6*4, CYP2D6*6, CYP2D6*7, CYP2D6*8, CYP2D6*9, CYP2D6*10, CYP2D6*11, CYP2D6*14, CYP2D6*18, CYP2D6*19, CYP2D6*25, CYP2D6*26, and CYP2D6*31 alleles. Clinical samples found to harbor the CYP2D6*14 and CYP2D6*18 polymorphisms by the microarray assay were subsequently analysed by independent methods to confirm the presence of these mutations. Specifically, the allele-defining CYP2D6*14 mutation (G1846A) was confirmed by MspI restriction digestion31 and the CYP2D6*18 polymorphism was confirmed by a 9 bp length polymorphism assay.32 In addition, all putative homozygous samples were rescreened for the CYP2D6*5 deletion using a separate, long PCR approach to amplify a 3.5 kb product diagnostic for the CYP2D6 gene deletion allele.33 All PCR was performed on GeneAmp PCR System 9600 instrumentation (Applied Biosystems, Foster City, CA, USA) and PCR products were visualized by ethidium-bromide-stained 1% agarose gels. CYP2D6*10B/*10B homozygotes were also typed for the presence of the CYP2D6*36 allele using an RFLP-based assay26 that is diagnostic for the CYP2D6*36 gene conversion event in exon 9 of the CYP2D6*10B allele. Five nanogram of clinical DNA were subjected to PCR amplification using 20 pmol each of MN389 (5′-GAAGGAGTGTCAGGGCCGGAC-3′) and MN420 (5′-GCTCAGC CTCAA CGTACCCCT-3′) to produce a 1.3 kb product. Thermocycling conditions were as follows: Uracil N Glycosylase (UNG) digestion at 50°C for 2 min, denaturation at 95°C for 10 min, followed by 35 cycles of denaturation at 95°C for 15 s and annealing/extension at 68°C for 4 min with a final ramp to 4°C. NcoI digestion of the amplicon at C4243T resulted in the release of a 264 bp product for the wild-type allele, whereas the DNA representing the mutated allele remained intact. Finally, 43 samples harboring a CYP2D6*2 allele were genotyped for the presence of CYP2D6*41, a promoter polymorphism at position −1584, in which the C allele has been shown to co-segregate with an intermediate metabolizer phenotype.34 (Insufficient DNA was available to genotype for the presence of CYP2D6*41 in four samples, which were not included in the analysis.) Amplification with upf1434 and a CYP2D6*2 specific primer DMN 432 (5′-GTGGTGGGGCATCCTCAGG-3′) resulted in the production of a CYP2D6*2 specific 1.9 kb amplicon. Thermocycling conditions were as follows: 95°C for 2 min, followed by 33 cycles of denaturation at 95°C for 15 s, annealing at 61°C for 30 s and extension at 72°C for 2 min, followed by a final extension at 72°C for 10 min to a final ramp to 4°C. The 1.9 kb amplicon served as a template for nested PCR and BsrI restriction digestion as described by Claassen et al.35 Amplicon containing the C allele remained undigested giving rise to a 203 bp product, whereas the G allele yielded 177 and 26 bp fragments upon digestion with BsrI. All genotypic analyses were performed blinded to the patient's clinical TD status.
Continuous variables were compared between TD+ and TD− patients using the Wilcoxon two-sample test. The association of the continuous variables with the total AIMS score was evaluated using the Spearman rank correlation coefficient. Hardy–Weinberg equilibrium was tested using a χ2 goodness-of-fit test. Associations between TD and the genotypes and alleles were tested using a χ2 test or the Freeman–Halton exact test, as appropriate. Association between TD and genotype after adjusting for cpz equivalents, days in hospital, age, gender, and gender*age was tested using logistic regression. The association of total AIMS score and genotype was tested using the Kruskal–Wallis test and, after adjusting for cpz equivalents, days in hospital, age, gender, and gender*age, with an ANOVA. P-values less than 0.05 were considered significant. Alleles were categorized as wild type, decreased activity, or loss of activity and, due to the low representation of some of the genotypes, as wild type or mutant. Additionally, to test whether gender modified the impact of genotype on the development of TD, gender*genotype interaction terms were placed into the models if sample sizes allowed; if not, the data were stratified by gender.
Descriptive statistics for patients are given in Table 1. There was no significant difference in the percentage of males and females, cpz equivalents, days in the hospital, or age between TD+ and TD− patients (P-values: 0.3543, 0.1992, 0.1077, and 0.0801, respectively). The total AIMS score was significantly correlated with cpz equivalents and age (P-value: 0.0092 and 0.0182, respectively), and moderately but not significantly associated with days in the hospital (P-value: 0.0629). Since TD and total AIMS score reflect the cumulative effect of neuroleptic drugs given over time,it would be expected that cpz equivalents and days in the hospital would be correlated with these endpoints. Moreover, age is a well-established risk factor for TD(4,25)
Association Between CYP2D6 Alleles and Tardive Dyskinesia
CYP2D6 allelic frequencies for TD+ and TD− patients are listed in Table 2. The reduced activity allele CYP2D6*10B was the most common allele identified in this cohort and occurred at frequencies similar to those previously reported for other Asian populations.19,25,26 CYP2D6*41, another decreased activity allele found in this cohort, occurred at frequencies of 1.36 and 2.17% in TD+ and TD− subjects, respectively, which is considerably less than the estimated frequency reported by Raimundo et al for a European population.34 The loss of function alleles occurred at very low frequencies in this cohort, less than 5% in both TD+ and TD− subjects, and consisted of CYP2D6*5 and CYP2D6*14 alleles. Allelic frequencies between TD+ and TD− patients did not differ significantly, regardless of whether alleles were categorized as wild type, decreased activity, or loss of activity (P-value: 0.3786), or as wild type or mutant (P-value: 0.5849). None of the remaining CYP2D6 mutant alleles screened for on the microarray were detected among Korean schizophrenics in this study.
Association Between CYP2D6 Genotype and Tardive Dyskinesia
CYP2D6 genotypic frequencies for TD+ and TD− Korean patients are given in Table 3. The CYP2D6*10B allele occurs in 70.65% and 74.54% of the TD− and TD+ genotypes, respectively. CYP2D6 genotypic frequencies for TD− subjects were in Hardy–Weinberg equilibrium when alleles were coded as wild type, decreased activity, or loss of activity (P-value: 0.8117) and as wild type or mutant (P-value: 1.000). CYP2D6 genotypic frequencies for TD+ subjects were just barely in Hardy–Weinberg equilibrium, regardless of whether alleles were coded as wild type, decreased activity, or loss of activity (P-value: 0.0791) or as wild type and mutant (P-value: 0.0800), with a larger than expected number of mutant heterozygotes.
Genotype was not significantly associated with TD (P-value: 0.3128), even after adjusting for cpz equivalents, age, gender, age*gender, and days in the hospitial (P-value: 0.5061) when CYP2D6 alleles were categorized as wild type, decreased activity, or loss of activity. Additionally, when data were stratified by gender, genotype was not associated with TD in either males or females in the unadjusted (P-values: 0.3777 and 0.2343, respectively) or in the adjusted (P-values: 0.4665 and 0.2506, respectively) analyses. However, when the CYP2D6 alleles were categorized as wild type and mutant, the impact of genotype on TD differed moderately in males and females (P-values for genotype and genotype*gender were 0.6899 and 0.0703, respectively) after adjusting for cpz equivalents, age, gender, age*gender, and days in the hospital. Parameter estimates for the logistic model are given in Table 4. Odds ratios comparing each genotype to the wild-type homozygote for each gender are given in Table 5. Both mutant heterozygous and homozygous males have a moderately higher odds of developing TD than homozygous wild-type males (OR: 2.06 and 2.26, respectively; 95% CI: 0.88–4.83 and 0.82–6.23, respectively; P-values: 0.0962 and 0.1132, respectively). In general, the odds of developing TD for males with at least one mutant allele was 2.10 times that of a wild-type homozygous male (95% CI: 0.93–4.74; P-value: 0.0704). In contrast, heterozygous and homozygous mutant females did not have a significantly higher odds of developing TD than homozygous wild-type females (OR: 0.44 and 0.20, respectively; 95% CI: 0.09–2.06 and 0.03–1.27, respectively; P-values: 0.2978 and 0.0876, respectively).
Association Between CYP2D6 Genotype and Total AIMS Score
When CYP2D6 alleles were categorized as wild type, decreased activity, or loss of activity, genotype was not significantly associated with total AIMS score in either the unadjusted or adjusted analyses (P-values: 0.3102 and 0.2314, respectively). Furthermore, gender did not significantly impact total AIMS score (P-values for genotype and genotype*gender were 0.2708 and 0.3298, respectively). Genotype was also not associated with total AIMS score when alleles were categorized as wild type or mutant in the unadjusted and adjusted analyses (P-values: 0.1451 and 0.1660, respectively), nor did gender influence the impact of genotype on total AIMS score (P-value: 0.3117). However, for the sake of completeness, we present the average total AIMS scores by genotype and gender in Table 5.
Predicting adverse effects to antipsychotic treatment has been confounded by large interindividual variability in the metabolism and detoxification of antipsychotic medications. In addition to gender, age, concurrent medication and environmental factors, genetic factors appear to play a role in the incidence of adverse drug effects. Previous studies have reported that subjects harboring non-functional and decreased function CYP2D6 alleles tend to be at risk for developing drug-induced movement disorders, although the number of individuals examined was quite low.1314151617 Hence, the goal of our study was to elucidate the association between CYP2D6 genotype and the occurrence of TD in a cohort of Korean schizophrenics. We hypothesized that Korean schizophrenic patients harboring CYP2D6 reduced activity alleles may exhibit impaired metabolism of antipsychotic drugs.
In this study, decreased activity and loss of function CYP2D6 alleles were moderately associated with TD in male Korean schizophrenics, but did not appear to be associated with TD in female Korean schizophrenics. Total AIMS score also appeared to be higher in Korean schizophrenic males with at least one decreased or loss of function allele, although not significantly so.
There are two possible reasons why CYP2D6 genotype was associated with TD in males but not in females in our study. First, males in our study had been hospitalized slightly longer than females, although not significantly so (P-value: 0.1105). Given that TD is believed to be caused by the cumulative effect of neuroleptic drugs, the effect of reduced CYP2D6 activity may have been apparent only in subjects who had been hospitalized for longer periods of time. Secondly, there were 143 males and only 59 females in our study. Consequently, our power to detect associations in females is significantly lower than in males.
Our findings differ from those of Lam et al,27 who reported that only female CYP2D6*10B homozygotes showed an association with TD, although the sample size was relatively small. In this Korean cohort, the females' odds ratio estimates do not support an association between CYP2D6 variant genotypes and TD; however, due to the small number of women in this cohort, these estimates are probably unreliable (Table 5). For example, the 95% confidence intervals for the odds ratios of female mutant homozygotes and heterozygotes not developing TD, which gives a better sense of the uncertainty in the estimates than the confidence intervals for the odds ratio for developing TD do, are (0.79–31.62) and (0.49–10.57); these confidence intervals are quite broad, and reflect the large degree of uncertainty in these estimates. Furthermore, results for males and females may be more similar than what the odds ratios suggest. In males, the mean total AIMS score was slightly higher in subjects who had at least one mutant allele (w/w: 2.81, w/m: 3.77, and m/m: 3.70; Table 5). This pattern was also observed in female wild-type homozygotes and heterozygotes (w/w: 2.73 and w/m: 3.58; Table 5), although unexpectedly, the average total AIMS score in female mutant homozygotes was somewhat lower than the average score in female and male wild-type homozygotes (m/m: 1.87; Table 5). Again, because the number of female mutant homozygotes is quite small (n=15), the low average total AIMS score observed among these female mutant homozygotes is probably a fluke.
In our study, a variety of neuroleptics were administered for the treatment of schizophrenia. Before atypical antipsychotics were introduced into Korea, haloperidol, chlorpromazine, thioridazine, trifluperazine, fluphenazine, perphenazine and zuclopenthixol have been the drugs of choice to treat schizophrenia. While CYP2D6 participates in the metabolism of many of these neuroleptics, it is not uncommon for physicians to switch or alter the dose of an antipsychotic during treatment based on patient responsiveness. Such practices in the clinical setting often present challenges in study design or interpretation of genotype/phenotype associations. Moreover, schizophrenics admitted for hospitalization often bring a complex treatment history and may be taking numerous medications concurrently. Since TD develops in a cumulative manner over time, it is unlikely that monitoring the current medication accurately reflects any genotype/phenotype association. Yet in a recent study, Murphy et al36 reported CYP2D6 genotype/phenotype associations in geriatric subjects who were receiving the antidepressant nortripyline concurrently with a variety of other drugs. Concurrent medications did not appear to mask the effects of CYP2D6 genotype in this study, and thus lends credence to CYP2D6 genotyping in the clinical setting.
To date, our report represents the most comprehensive genotypic analysis of Asian CYP2D6 polymorphisms and TD. The microarray-based genotyping system offered several advantages over traditional allele-specific PCR/RFLP-based genotyping systems.37 First, the CYP450 GeneChip® microarray system is rapid and semi-automated, allowing us to assess allelic and genotypic distributions in larger clinical populations easily. Secondly, the expanded CYP450 GeneChip® microarray supported the inclusion and identification of many rare CYP2D6 mutations, providing the most extensive evaluation and accurate assessment of CYP2D6 status developed thus far. Thirdly, while current genotyping methodologies such as allele-specific PCR/RFLP analysis are straightforward and reliable, these tools assign mutations in a deductive, serial manner, which can provide incomplete genotypic information.37 The CYP450 GeneChip® microarray directly queries for the presence of multiple mutations simultaneously in a parallel fashion. For instance, CYP2D6*10 genotypes are frequently determined by detecting the defining C100T polymorphism in the absence of the CYP2D6*4 allele defining polymorphism, rather than the presence of all four mutations: C100T, C1039T, G1661C and G4180C.9 Finally, even with the identification of putative CYP2D6*10B haplotypes, the existence of an underlying CYP2D6*36 allele, which has reduced activity compared to the CYP2D6*10B allele, would not have been identified by traditional methods.
To conclude, our results suggest that Korean schizophrenic males who harbor loss of function or reduced activity CYP2D6 alleles may be at increased risk for developing TD. Our results demonstrate the utility of oligonucleotide microarrays for CYP2D6 genotype analyses.
Duality of Interest
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We gratefully acknowledge Tom Ryder for advice in designing the new CYP450 GeneChip® microarray. This study was supported in part by a grant-in-aid from Research Foundation of Inje University (1999).
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Nikoloff, D., Shim, J., Fairchild, M. et al. Association between CYP2D6 genotype and tardive dyskinesia in Korean schizophrenics. Pharmacogenomics J 2, 400–407 (2002) doi:10.1038/sj.tpj.6500138
- tardive dyskinesia
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