sign in sign up
<<
Home , Tardive dyskinesia

The Pharmacogenomics Journal (2009) 9, 168–174 & 2009 Nature Publishing Group All rights reserved 1470-269X/09 $32.00 www.nature.com/tpj ORIGINAL ARTICLE

Association study of tardive and five DRD4 polymorphisms in patients

CC Zai1, AK Tiwari1, V Basile1, Tardive dyskinesia (TD) is a side effect of chronic 1 1 1 exposure. Abnormalities in dopaminergic activity in the nigro-striatal system V De Luca ,DJMu¨ller , N King , have been most often suggested to be involved because the agents that 1 1 AN Voineskos , G Remington , cause TD share in common potent antagonism of D2 receptors HY Meltzer2, JA Lieberman3, (DRD2). Thus, a number of studies have focused on the association of SG Potkin4 and JL Kennedy1 dopamine system gene polymorphisms and TD, with the most consistent findings being an association between TD and the Ser9Gly polymorphism of 0 1Neurogenetics Section, Centre for Addiction and the DRD3 gene and the TaqIA site 3 of the DRD2 gene. The DRD4 gene Mental Health, Toronto, Ontario, Canada; codes for the third member of the D -like dopamine receptor family, and the 2 2 Psychiatric Hospital, Vanderbilt University, variable number tandem-repeat polymorphism in exon 3 of DRD4 has been Nashville, TN, USA; 3Columbia University Medical Centre, New York State Psychiatric associated with TD. However, other polymorphisms have not been Institute, New York City, NY, USA and 4Brain thoroughly examined. In this study, we investigated five polymorphisms Imaging Center, University of California, Irvine, spanning the DRD4 gene and their association with TD in our European CA, USA Caucasian sample (N ¼ 171). Although the exon 3 variable number tandem repeat was not associated with TD, haplotypes consisting of four tag Correspondence: Dr JL Kennedy, Neurogenetics, Centre for polymorphisms were associated with TD in males. This study suggests that Addiction and Mental Health, 250, College DRD4 may be involved in TD in the Caucasian population, although further Street, R-30, Toronto, Ontario, Canada M5T replication studies are needed. 1R8. The Pharmacogenomics Journal (2009) 9, 168–174; doi:10.1038/tpj.2009.2; E-mail: [email protected] published online 24 February 2009

Keywords: schizophrenia; tardive dyskinesia; genetics; DRD4; abnormal involuntary movement scale

Introduction

Tardive dyskinesia (TD) is a potentially irreversible motor side effect that develops in approximately 25% of schizophrenia patients on long-term medication (reviewed by Margolese et al.1 and Tarsy and Baldessarini2). The disfiguring and sometimes disabling involuntary movements can interfere with daily functioning and treatment adherence, resulting in reduced quality of life.3,4 The notion that the atypical are the clear choice over their conventional counterparts has more recently been tempered by evidence challenging their clinical superiority, as well as growing concerns regarding the increased liability for weight gain and metabolic abnormalities associated with these newer drugs.5,6 Moreover, although the atypical agents may have a lower risk for TD, none are without risk.2,7–10 Thus, TD remains a real concern in clinical practice and strategies that may assist in predicting those patients who are vulnerable remains a high priority. Unfortunately, the etiology of TD is complex and remains unclear. Older age11–14 Received 23 September 2008; revised 11 15 16 November 2008; accepted 8 January 2009; and female gender have both been associated with increased TD risk. Jeste published online 24 February 2009 and co-workers reported higher rates of TD in African-Americans compared with Study of TD and DRD4 gene in schizophrenia patients CC Zai et al 169

Caucasians, but socioeconomic factors could have contrib- ys) C uted to these findings. Alcohol/substance abuse and smok- 90 s2 17–20 R y T 2 C 6 ing might further increase the risk for TD. Concordance 3 N 0 , 2 5 57 V 5 0C 2 6 4 3 2 7 46 8 6 n 76 8 2 for the presence or absence of TD among first-degree 75 1 o s T 1 3 s9 x r ( 1 relatives has provided evidence for a genetic component as rs r E rs well.21 A number of biological mechanisms have been implicated 5’ 3’ in the pathophysiology of TD. The hypothesis of hypersen- sitivity of dopamine receptors secondary to chronic dopa- 1 2 3 4 mine receptor blockade by antipsychotics is one of the most 3.4kb popular models, as reflected by the number of genetic studies investigating dopamine system genes.22–26 This Figure 1 Schematic diagram of the DRD4 gene with its exons and introns. The positions of the five polymorphisms used for this study are hypothesis is based on several observations. Antipsychotic indicated within the gene. treatment results in persistent dyskinesia in non-human primates, with significantly decreased dopamine turnover in 27 the caudate and substantia nigra. The dopamine D2 receptor is most densely expressed in the , an In this investigation, we tested for the presence of an area of the central nervous system that regulates move- association between the DRD4 gene and TD, using five ments.28 Clinical studies29–32 and rodent vacuous chewing polymorphisms spanning the DRD4 gene. TD was assessed TD models33,34 have shown that, compared with atypical by means of both continuous (Abnormal Involuntary antipsychotics, TD is more likely to develop after treatment Movement Scale (AIMS)) and dichotomous (TD occurrence) with typical agents that generally have higher affinities for measures in relatively large samples of Caucasian patients the D2 receptor. It has been noted that antipsychotic drugs with schizophrenia. with high affinities for D2 have a lower risk of TD, for example , and ziprasidone, although Results several mechanisms have been proposed to account for this, 35 including potent concomitant 5HT2A antagonism and Sample characteristics 36,37 rapid D2 dissociation. Antipsychotic drugs with D4 The genotype distributions of all the DRD4 gene poly- affinity may protect against TD. The most notable example morphisms in the European Caucasian samples did not is with high D4 affinity and reports of reduction of deviate significantly from Hardy–Weinberg equilibrium 38 TD symptoms after starting clozapine. Also the rat model (P40.10). An increase in frequency of TD was found in 34 of TD shows amelioration with clozapine treatment. females compared with males (P ¼ 0.084), although the Summarizing, DNA variations in the genes coding for the difference did not reach statistical significance. No signifi- D2-like receptors may contribute to the risk of TD develop- cant association was found between gender and genotype ment. We have previously found polymorphisms associated frequencies (Table 1). As expected, we also found a with genes coding for the D2 and D3 receptors to influence significant positive correlation between AIMS scores and 14,39 TD risk and severity. D4, the other member of the D2-like age (r ¼ 0.306; Po0.001). Because the DRD4 gene is situated 40 receptor family, is expressed in the striatum, and transient in a chromosomal region containing CpG islands and a increases of D4 in the caudate and putamen have been number of imprinted genes, we also analyzed the poly- reported following lesion by 6-hydroxydopamine in neona- morphisms in males and females separately. 41 tal rats. In addition, the period of D4 increase was correlated with a period of observed motor hyperactivity.41 Association study of individual polymorphisms and haplotypes with AD4 agonist exacerbated the hyperactivity, although it was TD occurrence and AIMS 42 reversed with a D4 antagonist. None of the four tested SNPs was associated with TD or AIMS The D4 receptor belongs to the G-protein coupled receptor scores in our Caucasian schizophrenia sample. Four-marker family and activates intracellular signaling by inhibiting the haplotype analysis of DRD4 showed a significant association synthesis of cyclic AMP. DRD4, the D4 encoding gene on (global P ¼ 0.056), wherein the haplotype TCCA was under- chromosome 11p15.5, consists of four exons and spans represented in TD cases (Table 2) (haplotype-specific approximately 6 kb (Figure 1). The polymorphic repeat P ¼ 0.008). Carriers of this haplotype also had the lowest sequence in exon 343 of DRD4 has been shown to affect average total AIMS scores compared with other haplotypes RNA stability in luciferase assay.44 Specifically, the 7-repeat (global P ¼ 0.082; haplotype-specific P ¼ 0.058). When we 44 variant was reported to give rise to lower D4 expression analyzed males and females separately, we found that the and thereby weaker inhibition of cAMP synthesis45 com- TCCA haplotype was absent in male TD cases, but present in pared with 2- and 4-repeat variants. Four association studies 11 male patients without TD (global P ¼ 0.002; haplotype- have been reported between DRD4 and TD,46–49 with two specific P ¼ 0.008; Figures 2 and 3). We also tested the noting positive results, each with a different polymorphism. variable number tandem repeat in exon 3 of DRD4, and we However, the DRD4 association with TD could not be did not find a significant difference in the distribution of replicated in other studies.46,48,49 alleles between patients with and without TD (Fisher’s Exact

The Pharmacogenomics Journal Study of TD and DRD4 gene in schizophrenia patients CC Zai et al 170

Table 1 Statistical analyses on demographics (gender, age) as well as total AIMS scores and TD diagnoses with genotypes and alleles of the five polymorphisms in DRD4

DRD4 markers Genotypes N (M/F) Age (years) Total AIMS score TD Alleles TD

Yes No Yes No rs3758653 1/1 (T/T) 109 (74/35) 38.0±10.1 6.12±7.36 42 67 1 (T) 109 167 5’ near gene 1/2 (T/C) 57 (34/23) 37.5±10.2 6.65±8.11 25 33 2 (C) 31 35 2/2 (C/C) 4 (2/2) 46.0±2.94 8.50±6.46 3 1 P 0.486a 0.269 0.788 0.357a P 0.267 rs916457 1/1 (T/T) 1 (1/0) 49.00 13.00 1 0 1 (T) 12 10 5’ near gene 1/2 (T/C) 20 (13/7) 39.7±9.9 5.06±4.55 10 10 2 (C) 128 192 2/2 (C/C) 149 (96/53) 37.8±10.1 6.48±7.88 59 91 P 0.999a 0.408 0.520b 0.326a P 0.180

Exon 3 VNTR 2-repeat 11 19 3-repeat 1 4 4-repeat 86 123 5-repeat 2 5 6-repeat 2 1 7-repeat 37 46 8-repeat 1 2 P 0.862a rs762502 1/1 (T/T) 57 (38/19) 38.9±10.2 6.27±6.40 25 32 1 (T) 82 116 Exon 3 Cys290Cys 1/2 (T/C) 84 (50/34) 37.3±10.2 6.07±7.98 32 52 2 (C) 50 78 T870C 2/2 (C/C) 21 (16/5) 38.8±10.2 8.39±9.40 9 13 P 0.322 0.609 0.509 0.791 P 0.673 rs11246226 1/1 (A/A) 38 (28/10) 37.2±10.1 6.94±8.30 15 23 1 (A) 64 103 3’ near gene 1/2 (A/C) 90 (53/37) 37.8±9.6 5.37±6.33 34 57 2 (C) 76 97 2/2 (C/C) 41 (28/13) 39.4±11.5 8.21±9.08 21 20 P 0.235 0.605 0.330b 0.317 P 0.294

Abbreviations: AIMS, abnormal involuntary movement scale; TD, tardive dyskinesia. aWith at least 1 expected cell count o5; Fisher Exact Test used. bVariances among comparison groups differ significantly; Kruskel–Wallis test used.

Test P ¼ 0.862; CLUMP P ¼ 0.956; Table 1). Because we did have yielded mixed results with regard to the DRD4 gene not find the variable number tandem repeat to be significant and TD, with several possible explanations. First, different as an individual marker, and to reduce the degrees of polymorphisms were used in many of the studies, and in freedom, we have excluded the variable number tandem most cases only a few polymorphisms were tested without repeat from the haplotype analyses. haplotype analyses. Second, populations with different ethnic backgrounds were used in the studies, making Copy-number variations at the DRD4 locus findings difficult to compare due to potential stratification Because DRD4 is located in a region with copy-number effects. Further, in some studies, the sample sizes were small, variations, we counted the number of patients homozygous limiting the power to detect an association. The aim of our for all genotyped markers and compared the frequencies study was to investigate polymorphisms spanning the DRD4 between the group with TD and the group without. Runs of gene for association with TD in a relatively large sample homozygosity may give an indication of potential hemi- involving haplotype analyses. zygosity due to deletion at the copy-number variation. We This study encourages further examination of DRD4 did not find a significant difference in the frequency of runs haplotypes and TD, especially in males. It does not appear of homozygosity between the two groups (P ¼ 0.69). to be related to the variable number tandem repeat in exon 3. As DRD4 is located in a CpG island, investigating for sex- Discussion specific changes in methylation status may help illuminate a mechanism underlying the haplotypic association observed We report here about a significant association between in our study. Nonetheless, our study has several limitations. haplotypes consisting of four markers in DRD4 and TD in First, not all clinical data were available for each patient our male Caucasian schizophrenia patients. Previous studies in our study, including detailed information regarding

The Pharmacogenomics Journal Study of TD and DRD4 gene in schizophrenia patients CC Zai et al 171

Table 2 Global P-values from sliding-window analyses of DRD4 haplotypes for association with TD occurrence using COCAPHASE, and AIMS using QTPHASE with two, three and four markers rs3758653 rs916457 rs762502 rs11246226 Polymorphisms P-value (TD+/À)/AIMS rs3758653 0.80 0.27 0.17 0.56-0.92 0.03-0.58 0.01-0.44 2-marker 3-marker 4-marker rs916457 0.23 0.039 0.02-0.75 0.01-0.55 (a) rs3758653 rs762502 0.58 0.43-0.70 0.113/0.813 0.023/0.128 rs916457 rs11246226 0.215/0.404 0.056/0.082 rs762502 0.085/0.573 0.048/0.605 Figure 2 Linkage disequilibrium plot among the four DRD4 gene rs11246226 polymorphisms used in this study. The numbers represents D0 values and the 95% confidence intervals of D0, while the color darkness within (b) each box corresponds to strength of linkage. rs3758653 0.11/0.88 50 rs916457 0.11/0.26 30 p(Males)=0.002 0.38/0.38 0.002/0.01 48 28 rs762502 0.02/0.13 40 0.01/0.14 rs11246226 30 (c) 28 rs3758653 0.71/0.78 22 20 rs916457 0.63/0.81 % patients (n) 0.94/0.80 0.19/0.75 rs762502 11 5 0.92/0.83 10 0.86/0.73 7 rs11246226 3 0 Abbreviations: AIMS, abnormal involuntary movement scale; TD, tardive 0 dyskinesia. TCTA TCTC TCCA TCCC CCTC Haplotypes with frequencies of less than 0.05 were excluded from the analyses. (a) Summary of results from the combined sample of males and females. 50 (b) Summary of results from the male sample. (c) Summary of results from the p(Females)=0.189 TD (+) female sample. 22 Bold numbers indicate 0.05oPo0.10; bold and italicized numbers indicate 40 TD (-) Po0.05.

12 12 13 15 antipsychotic dose/duration, as well as illness history for 30 example, age of onset, clinical subtype, symptomatology and co-morbidities. Each of these factors or variables have been previously associated with TD (reviewed by Mu¨ller 20

% patients (n) 7 50 7 et al. ). taken by patients for other adverse 5 4 effects, such as parkinsonism, could have masked the TD 4 10 phenotype.51–53 Moreover, we did not have information on tobacco, alcohol or substance use for our entire sample. Finally, the marginally significant association could be due 0 to the possibility that the polymorphisms have only a small TCTA TCTC TCCA TCCC CCTC contributing effect to the risk for TD, as expected in complex Figure 3 Haplotype analysis of the four DRD4 polymorphisms phenotypes. Our reported P-values have not been corrected (rs3758653, rs916457, rs762502, rs11246226) with tardive dyskinesia for multiple testing, and would not have survived correction (TD) occurrence, separately for males (top) and females (bottom). The for all of the single polymorphisms and their haplotypes. numbers above the bars correspond to the number of patients with the The sample size in this study had limited power to detect a respective haplotypes. significant difference in AIMS scores between the genotypes. Under reasonable assumptions (a set at 0.05, marker allele If DRD4 gene is associated with TD, it is unlikely to be the frequency set at 0.2), the sample used for this study has 80% only genetically determined factor, as other genes have also power to detect an odds ratio of as low as 2.1.54 been associated. Genetic studies have identified DRD3,

The Pharmacogenomics Journal Study of TD and DRD4 gene in schizophrenia patients CC Zai et al 172

DRD2, MnSOD, CYP2D6, CYP1A2, HTR2A to be reproducibly and African (YRI) samples using single-nucleotide polymorph- associated with TD,39,55–59 although studies in other genes, ism (SNP) tagger on the HapMap website (www.hapmap. such as HTR2C, NQO1 and GABRB2, require further org68). After genotyping these five polymorphisms in our own investigation.60–62 As nearly all antipsychotics target more Caucasian TD sample, we ran SNP tagger on the Haploview than one receptor, it is more likely that TD is not related to software and rs936465 was not tagged in our sample using r2 one receptor gene, but instead represents a polygenic threshold of 0.80, and was excluded from further analysis. The condition with each gene contributing a small proportion remaining tag polymorphisms and their locations are shown of the risk to this disorder. Gene–gene interaction in Figure 1. The SNPs were genotyped using the Illumina SNP studies may help to identify and clarify pathways that platform.69 The exon 3 VNTR was genotyped using PCR with contribute to TD. TD risk is also more likely to be influenced conditions described previously,43 and resolved on 3% high- by environmental factors;50 acquiring this information resolution agarose gels. All ambiguous genotypes were retyped will help in increasing the statistical power and limiting and if they remained ambiguous, they were excluded from the the effects of potential confounders in genetic studies analysis. of TD. Statistics Statistical analyses were conducted using the Statistical Materials and methods Package for the Social Sciences version 15, Haploview 68,70–72 Patients version 4.0, and UNPHASED version 2.402. Odds Patients were recruited from four clinical sites in North ratio calculations were conducted using Program 2BY2 America: Center for Addiction and Mental Health in version 2 written by Jurg Ott. Genotype frequency distribu- Toronto, Ontario (Dr G Remington, N ¼ 88); Case Western tion was tested for fitness to Hardy–Weinberg equilibrium Reserve University in Cleveland, Ohio (Dr HY Meltzer, using Haploview. The association of genotype frequencies N ¼ 42); Hillside Hospital in Glen Oaks, New York (Dr JA with age and AIMS scores was assessed using analysis of Lieberman, N ¼ 38); University of California at Irvine, variance, and where the variances of AIMS scores among California (Dr SG Potkin, N ¼ 3). Patients were selected genotypes differed significantly using the Levene Test for based on their diagnoses of schizophrenia or schizoaffective homogeneity of variance, AIMS scores were examined with disorder according to DSM-III-R or DSM-IV.63 All patients the Kruskal–Wallis test on SPSS. Gender differences in w2 had received a cumulative treatment exposure of at least 1 genotype frequencies were assessed using the -test on year with typical antipsychotics. For the Meltzer, Lieberman SPSS. The differences in allele and genotype frequencies and Potkin samples, the presence or absence of TD was between patients with and without TD were analyzed by w2 evaluated before any administration, -test. For contingency tables with at least one expected cell although patients were on both typical and atypical count of less than five, two-tailed Fisher’s Exact Tests were antipsychotics when TD was evaluated in the Remington performed (http://home.clara.net/sisa/fiveby2.htm). Haplo- sample. The presence of TD was assessed using the type analyses and linkage disequilibrium calculations were Abnormal Involuntary Movement Scale (AIMS) or the conducted using UNPHASED and Haploview, respectively. The exon 3 VNTR was analyzed with Fisher’s Exact Test, and modified Hillside Simpson Dyskinesia Scale (HSDS) for 38 73 patients recruited from the Hillside Hospital.64–66 The seven the Monte Carlo test in CLUMP. body area items and the overall global item of the HSDS match those of the AIMS; thus, assessment for presence of Ethical considerations TD was equivalent for all four sites. All four clinicians (GR, HYM, JAL, SGP) are highly experienced in TD severity The scientific work described in this article complies measurements, and consistency was further enhanced by with the current laws of Canada and the United States, exchange visits across sites. In all, 171 Caucasian patients as well as the ethical standards established in the 1964 were studied and AIMS scores were available for 144 Declaration of Helsinki. Informed consent was obtained patients, of which 70 were positive for TD. before patients’ participation, and this study was approved by the Ethics Committee of the Centre for Addiction and Gene polymorphism analysis Mental Health. Genomic DNA was purified from whole blood samples using high-salt method described previously.67 Genotyping was Acknowledgments done after the patients completed the follow-up, with all laboratory staff blind to AIMS scores. The variable number We thank the Canadian Institute for Health Research (CIHR) tandem-repeat polymorphism in exon 3 that changes the MOP79525, CHIR postdoctoral fellowship to AKT the CR Younger Foundation, the Bebensee Foundation, the Prentiss Foundation amino-acid sequence of the receptor protein has been used in 46–48 and the Ritter Foundation for funding this study. CIHR, the CR previous TD studies and the remaining five polymorph- Younger Foundation, the Bebensee Foundation, the Prentiss isms, rs3758653, rs916457, rs762502, rs11246226, rs936465, Foundation and the Ritter Foundation had no further role in study were selected based on their position within the DRD4 gene design; in the collection, analysis and interpretation of data; in the and the presence of sufficiently high minor allele frequencies writing of the report; and in the decision to submit the article for with genotype information available for the Caucasian (CEU) publication.

The Pharmacogenomics Journal Study of TD and DRD4 gene in schizophrenia patients CC Zai et al 173

References 26 Arranz MJ, de Leon J. Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research. Mol 2007; 1 Margolese HC, Chouinard G, Kolivakis TT, Beauclair L, Miller R, Annable 12: 707–747. L. Tardive dyskinesia in the era of typical and atypical antipsychotics. 27 Gunne LM, Haggstrom JE, Sjoquist B. Association with persistent Part 2: Incidence and management strategies in patients with neuroleptic-induced dyskinesia of regional changes in brain gaba schizophrenia. Can J Psychiatry 2005; 50: 703–714. synthesis. Nature 1984; 309: 347–349. 2 Tarsy D, Baldessarini RJ. Epidemiology of tardive dyskinesia: is risk 28 Hall H, Sedvall G, Magnusson O, Kopp J, Halldin C, Farde L. Distribution declining with modern antipsychotics? Mov Disord 2006; 21: 589–598. of D1- and D2-dopamine receptors, and dopamine and its metabolites 3 Marsalek M. Tardive drug-induced extrapyramidal syndromes. Pharma- in the human brain. Neuropsychopharmacol 1994; 11: 245–256. copsychiatry 2000; 33(S1): 14–33. 29 Kane JM, Woerner MG, Pollack S, Safferman AZ, Lieberman JA. Does 4 Gerlach J. Improving outcome in schizophrenia: the potential impor- clozapine cause tardive dyskinesia? J Clin Psychiatry 1993; 54: 327–330. tance of EPS and neuroleptic dysphoria. Ann Clin Psychiatry 2002; 14: 30 Beasley Jr CM, Dellva M, Tamura RN, Morgenstern H, Glazer WM, 47–57. Ferguson K et al. Randomized double-blind comparison of the 5 Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins incidence of tardive dyskinesia in patients with schizophrenia during DO, et al., Clinical Antipsychotic Trials of Intervention Effectiveness long-term treatment with olanzapine or . Br J Psychiatry (CATIE) Investigators. Effectiveness of antipsychotic drugs in patients 1999; 174: 23–30. with chronic schizophrenia. N Engl J Med 2005; 353: 1209–1223. 31 Jeste DV, Rockwell E, Harris MG, Lohr JB, Lacro J. Conventional vs. 6 Jones PB, Barnes TR, Davies L, Dunn G, Lloyd H, Hayhurst KP et al. newer antipsychotics in elderly patients. Am J Geriatric Psychiatry 1999a; Randomized controlled trial of the effect on Quality of Life of second- vs 7: 70–76. first-generation antipsychotic drugs in schizophrenia: Cost Utility of the 32 Jeste DV, Lacro JP, Bailey A, Rockwell E, Harris MJ, Caligiuri MP. Lower Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1). Arch incidence of tardive dyskinesia with risperidone compared with Gen Psychiatry 2006; 63: 1079–1087. haloperidol in older patients. J Am Geriatric Soc 1999b; 47: 716–719. 7 Correll CU, Leucht S, Kane JM. Lower risk of tardive dyskinesia 33 Johansson P, Casey DE, Gunne LM. Dose-dependent increases in rat associated with second-generation antipsychotics: a systematic review spontaneous chewing rates during long-term administration of halo- of 1-year studies. Am J Psychiatry 2004; 161: 414–425. peridol but not clozapine. Psychopharmacol Bull 1986; 22: 1017–1019. 8 Kane JM. Tardive dyskinesia circa 2006. Am J Psychiatry 2006; 163: 34 Gao X, Sakai K, Tamminga CA. Chronic olanzapine or 1316–1318. treatment results in reduced oral chewing movements in rats compared 9 Remington G. Tardive dyskineisa: eliminated, forgotten, or over- to haloperidol. Neuropsychopharmacol 1998; 19: 428–433. shadowed? Curr Opin Psychiatry 2007; 20: 130–137. 35 Meltzer HY, Li Z, Kaneda Y, Ichikawa J. Serotonin receptors: their key 10 Correll CU, Schank EM. Tardive dyskinesia and new antipsychotics. Curr role in drugs to treat schizophrenia. Prog Neuropsychopharmacol Biol Opin Psychiatry 2008; 21: 151–156. Psychiatry 2003; 27: 1159–1172. 11 Woerner MG, Alvir JMJ, Saltz BL, Lieberman JA, Kane JM. Prospective 36 Seeman P, Tallerico T. Antipsychotic drugs which elicit little or no study of tardive dyskinesia in the elderly: rates and risk factors. Am J Parkinsonism bind more loosely than dopamine D2 receptors, yet Psychiatry 1998; 155: 1521–1528. occupy high levels of these receptors. Mol Psychiatry 1998; 3: 123–134. 12 Kane JM, Woerner M, Lieberman J. Epidemiological aspects of tardive 37 Kapur S, Seeman P. Does fast dissociation from the dopamine D2 dyskinesia. L’Encephale 1988; 14S: 191–194. receptos explain the action of atypical antipsychotics: a new hypothesis. 13 Morgenstern H, Glazer WM. Identifying risk factors for tardive Am J Psychiatry 2001; 158: 36–369. dyskinesia among long-term outpatients maintained with neuroleptic 38 Bassitt DP, Louza˜ Neto MR. Clozapine efficacy in tardive dyskinesia in medications. Results of the Yale Tardive Dyskinesia Study. Arch Gen schizophrenic patients. Eur Arch Psychiatry Clin Neurosci 1998; 248: Psychiatry 1993; 50: 723–733. 209–211. 14 Zai CC, Hwang RW, De Luca V, Mu¨ller DJ, King N, Zai GC et al. 39 Zai CC, De Luca V, Hwang RW, Voineskos AN, Mu¨ller DJ, Remington G Association study of tardive dyskinesia and twelve DRD2 polymorph- et al. Meta-analysis of two Dopamine D2 receptor gene polymorphisms isms in schizophrenia patients. Int J Neuropsychopharmacol 2007a; 10: with tardive dyskinesia in schizophrenia patients. Mol Psychiatry 2007b; 639–651. 12: 794–795. 15 Smith JM, Dunn DD. Sex differences in the prevalence of severe tardive 40 Rivera A, Cue´llar B, Giro´n FJ, Grandy DK, de la Calle A, Moratalla R. dyskinesia. Am J Psychiatry 1979; 136: 1080–1082. Dopamine D4 receptors are heterogeneously distributed in the 16 Jeste DV, Rockwell E, Harris MJ, Lohr JB, Lacro J. Conventional vs. striosomes/matrix compartments of the striatum. J Neurochem 2002; newer antipsychotics in elderly patients. Am J Geriatr Psychiatry 1999; 7: 80: 219–229. 70–76. 41 Zhang K, Davids E, Tarazi FI, Baldessarini RJ. Effects of dopamine D4 17 Menza MA, Grossman N, Van Horn M, Cody R, Forman N. Smoking and receptor-selective antagonists on motor hyperactivity in rats with movement disorders in psychiatric patients. Biol Psychiatry 1991; 30: neonatal 6-hydroxydopamine lesions. Psychopharmacology (Berl) 109–115. 2002; 161: 100–106. 18 Bailey LG, Maxwell S, Brandabur MM. Substance abuse as a risk factor 42 Zhang K, Tarazi FI, Baldessarini RJ. Role of dopamine D(4) receptors in for tardive dyskinesia: a retrospective analysis of 1,027 patients. motor hyperactivity induced by neonatal 6-hydroxydopamine lesions in Psychopharmacol Bull 1997; 33: 177–181. rats. Neuropsychopharmacology 2001; 25: 624–632. 19 Dixon L, Weiden PJ, Haas G, Sweeney J, Frances AJ. Increased tardive 43 Van Tol HH, Bunzow JR, Guan HC, Sunahara RK, Seeman P, Niznik HB et dyskinesia in alcohol-abusing schizophrenic patients. Compr Psychiatry al. Cloning of the gene for a human dopamine D4 receptor with high 1992; 33: 121–122. affinity for the antipsychotic clozapine. Nature 1991; 350: 610–614. 20 Stoessl AJ. Effects of ethanol in a putative rodent model of tardive 44 Schoots O, Van Tol HH. The human dopamine D4 receptor repeat dyskinesia. Pharmacol Biochem Behav 1996; 54: 541–546. sequences modulate expression. Pharmacogenomics J 2003; 3: 343– 21 Mu¨ller DJ, Schulze TG, Knapp M, Held T, Krauss H, Weber T et al. 348. Familial occurrence of tardive dyskinesia. Acta Psychiatr Scand 2001; 45 Asghari V, Sanyal S, Buchwaldt S, Paterson A, Jovanovic V, Van Tol HH. 104: 375–379. Modulation of intracellular cyclic AMP levels by different human 22 Tarsy D, Baldessarini RJ. The pathophysiologic basis of tardive dopamine D4 receptor variants. J Neurochem 1995; 65: 1157–1165. dyskinesia. Biol Psychiatry 1977; 12: 431–450. 46 Segman RH, Goltser T, Heresco-Levy U, Finkel B, Shalem R, Schlafman 23 Klawans HL, Goetz CG, Perlik S. Tardive dyskinesia: review and update. M et al. Association of dopaminergic and serotonergic genes with Am J Psychiatry 1980; 137: 900–908. tardive dyskinesia in patients with chronic schizophrenia. Pharmacoge- 24 Gerlach J, Casey DE. Tardive dyskinesia. Acta Psychiatrica Scand 1988; nomics J 2003; 3: 277–283. 77: 369–378. 47 Lattuada E, Cavallaro R, Serretti A, Lorenzi C, Smeraldi E. Tardive 25 Abilio VC, Vera Jr JAR, Ferreira LSM, Duarte CRM, Martins CR, Torres- dyskinesia and DRD2, DRD3, DRD4, 5-HT2A variants in schizophrenia: Leite D et al. Effects of on behavioral dopaminergic an association study with repeated assessment. Int J Neuropsychophar- supersensitivity. Life Sciences 2003; 72: 3003–3015. macol 2004; 7: 489–493.

The Pharmacogenomics Journal Study of TD and DRD4 gene in schizophrenia patients CC Zai et al 174

48 Srivastava V, Varma PG, Prasad S, Semwal P, Nimgaonkar VL, Lerer B et 61 Thelma BK, Tiwari AK, Deshpande SN, Lerer B, Nimgaonkar VL. al. Genetic susceptibility to tardive dyskinesia among schizophrenia Genetic susceptibility to tardive dyskinesia in chronic schizophrenia subjects: IV. Role of dopaminergic pathway gene polymorphisms. subjects: role of oxidative stress pathway genes. Schizophr Res 2007; 92: Pharmacogenet Genomics 2006; 16: 111–117. 278–279. 49 Lee HJ, Kang SG, Choi JE, Paik JW, Kim YK, Kim SH et al. No association 62 Inada T, Koga M, Ishiguro H, Horiuchi Y, Syu A, Yoshio T et al. Pathway- between dopamine D4 receptor gene -521 C/T polymorphism and based association analysis of genome-wide screening data suggest that tardive dyskinesia in schizophrenia. Neuropsychobiology 2007; 55: 47–51. genes associated with the gamma-aminobutyric acid receptor signaling 50 Mu¨ller DJ, Shinkai T, De Luca V, Kennedy JL. Clinical implications of pathway are involved in neuroleptic-induced, treatment-resistant pharmacogenomics for tardive dyskinesia. Pharmacogenomics J 2004; 4: tardive dyskinesia. Pharmacogenet Genomics 2008; 18: 317–323. 77–87. 63 American Psychiatric Association (1994) Diagnostic and Statistical 51 Shale H, Tanner C. Pharmacological options for the management of Manual of Mental Disorders, (4th edn). American Psychiatric Association: dyskinesia. Drugs 1996; 52: 849–860. Washington, DC. 52 Egan MF, Apud J, Wyatt RJ. Treatment of tardive dyskinesia. Schizophr 64 Guy W (1976) Abnormal involuntary movement scale. In: ECDEU Bull 1997; 23: 583–609. Assessment Manual for Psychopharmacology (Revised edn). Department 53 Glazer WM. Extrapyramidal side effects, tardive dyskinesia, and the of Health, Education and Welfare: Washington, DC pp 534–537. concept of atypicality. J Clin Psychiatry 2000; 61(Suppl 3): 16–21. 65 Schooler NR, Kane JM. Research diagnoses for tardive dyskinesia. Arch 54 Purcell S, Cherny SS, Sham PC. Genetic Power Calculator: design of Gen Psychiatry 1982; 39: 486–487. linkage and association genetic mapping studies of complex traits. 66 Basile VS, Masellis M, Badri F, Paterson AD, Meltzer HY, Lieberman JA et Bioinformatics 2003; 19: 149–150. al. Association of the MscI polymorphism of the dopamine D3 receptor 55 Lerer B, Segman RH, Fangerau H, Daly AK, Basile VS, Cavallaro R et al. gene with tardive dyskinesia in schizophrenia. Neuropsychopharmacol Pharmacogenetics of tardive dyskinesia: combined analysis of 780 1999; 21: 17–27. patients supports association with dopamine D3 receptor gene ser9gly 67 Lahiri DK, Nurnburger Jr JI. A rapid non-enzymatic method for the polymorphism. Neuropsychopharmacol 2002; 27: 105–119. preparation of HMV DNA from blood for RFLP analysis. Nucleic Acids Res 56 Bakker PR, van Harten PN, van Os J. Antipsychotic-induced tardive 1991; 19: 5444. dyskinesia and the Ser9Gly polymorphism in the DRD3 gene: a meta- 68 Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization analysis. Schizophr Res 2006; 83: 185–192. of LD and haplotype maps. Bioinformatics 2005; 21: 263–265. 57 Patsopoulos NA, Ntzani EE, Zintzaras E, Ioannidis JPA. CYP2D6 69 Hodgkinson CA, Xu K, Yuan Q, Shen P-H, Heinz E, Lobos EA et al. polymorphisms and the risk of tardive dyskinesia in schizophrenia: a Addictions biology: haplotype based analysis for 130 candidate genes meta-analysis. Pharmacogenet Genomics 2005; 15: 151–158. on a single array. Alcohol Alcohol 2008; 43: 505–515. 58 Bakker PR, van Harten PN, van Os J. Antipsychotic-induced tardive 70 Statistical Package for the Social Sciences (2000) SPSS for Windows, Rel. dyskinesia and polymorphic variations in COMT, DRD2, CYP1A2 and 10.0.7. SPSS Inc.: Chicago. MnSOD genes: a meta-analysis of pharmacogenetic interactions. Mol 71 Dudbridge F. Pedigree disequilibrium tests for multilocus haplotypes. Psychiatry 2008; 13: 544–556. Genet Epidemiol 2003; 25: 115–121. 59 Lerer B, Segman RH, Tan E-C, Basile VS, Cavallaro R, Aschauer HN et al. 72 Hwang R, Shinkai T, Deluca V, Mueller DJ, Ni X, Macciardi F et al. Combined analysis of 635 patients confirms an age-related association of Association study of 12 polymorphisms spanning the dopamine D2 the serotonin 2A receptor gene with tardive dyskinesia and specificity for receptor gene and clozapine treatment response in two treatment the non-orofacial subtype. Int J Neuropsychopharmacol 2005; 8:411–425. refractoryintolerant populations. Psychopharmacol (Berl) 2005; 181: 60 Gunes A, Dahl ML, Spina E, Scordo MG. Further evidence for the 179–187. association between 5-HT2C receptor gene polymorphisms and 73 Sham PC, Curtis D. Monte Carlo tests for associations between disease extrapyramidal side effects in male schizophrenic patients. Eur J Clin and alleles at highly polymorphic loci. Ann Hum Genet 1995; 59: Pharmacol 2008; 64: 477–482. 97–105.

The Pharmacogenomics Journal