Clinical Implications of Pharmacogenomics for Tardive

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In this review, we retrieved literature Clinical implications of with the use of the computerized database MEDLINE (1966 to July pharmacogenomics for 2003), and abstracts that refer to patient samples that were included in tardive dyskinesia a pooled analysis on the dopamine D3 receptor gene by Lerer et al.6 We do not refer to findings published earlier than DJ Mu¨ller, T Shinkai, V De Luca and JL Kennedy 1995 related to the human leukocyte antigen (HLA) and TD, as we wish to Neurogenetics Section, Clarke Division, Department of Psychiatry, University of Toronto, focus on more recent findings. To be Centre for Addiction and Mental Health, Toronto, ON, Canada complete in our coverage of recent data, we refer to three study findings that have not been published yet, The Pharmacogenomics Journal (2004) 4, schizophrenia. A meta-analysis includ- which focus on the CYP1A2, NOS1 77–87. doi:10.1038/sj.tpj.6500233 ing 76 studies on 39 187 patients with and DBH genes (see Table 2). chronic antipsychotic treatment reported TD rates that ranged from 3 to DIAGNOSTIC ASSESSMENT OF TD INTRODUCTION 70% and an overall prevalence of One particular problem with studies Spontaneous dyskinetic (or abnormal) 24.2%.2 Prevalence rates are, however, on TD consists in the difficulties of movements have been associated with difficult to estimate because of the diagnostic assessment: First of all, schizophrenia (or to some subforms) fluctuating course of TD and hetero- dyskinetic movements are not specific independently of the use of antipsy- geneities across studies with respect to to TD and therefore, any other dis- chotics. It has been suggested that study population, diagnostic criteria order presenting with similar symp- some forms of dyskinesia may at least used, type and dose of (co-)medica- toms has to be ruled out by a thorough partially be intrinsic to the pathophy- tions, etc. Age, regardless of the dura- neuropsychiatric history and a physi- siology of schizophrenia, perhaps re- tion of treatment, is an important risk cal examination. Moreover, although flecting basal ganglia pathology. factor for TD, as TD is five to six times dyskinetic movements are visibly ob- However, up to 50% of patients af- more prevalent in the elder (445 vious signs, TD symptoms may fluc- fected with schizophrenia typically years) than in younger patients.3,4 tuate considerably over the course of develop dyskinesia in combination Even though newer (or ‘atypical’) the disorder or may be temporarily with long-term exposure (ie months antipsychotics have a lower or perhaps ‘masked’ by some antipsychotics, only to years) of traditional or ‘typical’ negligible risk to induce TD,5 classical to reappear after discontinuation of antipsychotics. The term tardive dys- (or typical) antipsychotics are, how- the drugs. In other cases, TD sympto- kinesia (TD) refers to this potentially ever, currently still prescribed for matology does not follow changes irreversible complication that is, by many reasons: Typical antipsychotics following reduction or increase of definition, caused by the long-term are less expensive than atypical anti- antipsychotics. However, it remains use of antipsychotic medication. TD psychotics, which may globally be one unclear whether this variability repre- consists of hyperkinetic involuntary leading reason. Moreover, some pa- sents etiologically or pathophysiologi- movements, most commonly charac- tients do not respond or tolerate cally distinct forms of TD. Therefore, terized by orofacial dyskinesia, but it treatment with atypical antipsychotics there are notable limitations to diag- may include tics, chorea and/or athe- that may cause side effects as weight nostic validity and reliability in TD tosis or a combination of these.1 For gain or diabetes mellitus. Finally, if studies. In order to overcome some of obvious reasons, TD may be extremely patients are treated by intramuscular these limitations, diagnosis of TD distressing to patients as it substan- application of antipsychotics (ie with should be based on at least two tially debilitates motor performances depot formula), this particular phar- examinations at different time points in normal life. Furthermore, TD may macopeia is mostly composed of clas- and ideally performed by the same lead to social stigmatization or to sical antipsychotics. Therefore, TD still investigator. Moreover, standardized difficulties in finding employment. represents a serious and prevalent symptom rating scales should be ap- The presence of schizophrenia is not adverse effect. The prevention of TD plied in TD studies to allow for necessary to develop antipsychotic and the detection of associated risk comparisons among studies. induced dyskinesias, as these occur factors are of great clinical importance In previous pharmacogenetic studies also in patients treated with antipsy- as no uniformly safe and effective on TD, dyskinetic movements have chotics for other conditions than treatment for TD is available yet. mostly been assessed with the Abnormal Genetics of tardive dyskinesia DJ Mu¨ller et al 78

Involuntary Movement Scale (AIMS). and clinical risk factors associated with Table 1 Possible risk factors associated AIMS scores were often used for TD are summarized in Table 1. Ad- with TD cross-sectional, continuous analyses vanced age (see introduction) and in TD studies or, alternatively, AIMS early manifestation of extrapyramidal Advanced age scores have been used to assign a symptoms are the risk factors which Female (or male) gender diagnosis of TD, most commonly have most consistently been re- Ethnicity (higher in African-Americans) Presence of (early) extrapyramidal according to the criteria for TD pro- ported.9 However, many other find- 7 symptoms posed by Schooler and Kane. Thus, ings related to risk factors for TD have Dose and duration of exposure to classical some authors only performed contin- often been inconsistent (eg gender). antipsychotics uous analysis, while others performed Therefore, validity of the assessment of Anticholinergic drugs, lithium solely categorical analyses. However, such risk factors remains limited in Organic brain dysfunctions and the co-existence of both forms of clinical practice since most of these neurological deficits analysis limits the comparisons among factors are ubiquitous (or appear to Affective symptoms/disorders different studies. confer only a small amount of risk) Negative symptoms Importantly, according to Schooler with respect to the occurrence of TD. Cognitive symptoms and Kane7 criteria, a diagnosis of Based on animal and clinical studies, a Alcohol/drug misuse Smoking persistent TD requires that TD is ob- genetic basis has been suggested in the Diabetes mellitus served for 3 months. If observed only pathophysiology of TD. In rats, occur- Menopause on one occasion, TD diagnosis remains rence of repetitive jaw movements and Family history of schizophrenia or affective ‘probable’. However, some studies did vacuous chewing following adminis- disorder not perform TD assessment twice or tration of antipsychotics showed con- Family history of TD did not specify whether TD assessment siderable interindividual variability has been done after more than one and varied significantly in different examination. This further limits inter- strains of selectively bred rats, suggest- pretation of the findings and compar- ing a genetic component in the man- PHARMACOGENETIC STUDIES OF isons among different studies. ifestation of TD.10,11 Human evidence TARDIVE DYSKINESIA In summary, one has to be aware of supporting genetic factors for TD de- Generally, each single adverse drug these characteristics related to TD rive from family studies reporting a reaction (ADR) is to be considered as diagnosis. Besides other confounding higher occurrence of TD in patients a complex gene-environment event. factors such as age, gender or samples with a family history of schizophre- Besides the potential influence of (size, duration of illness, antipsychotic nia12 and/or a significant concordance genetic factors, ADRs are determined treatment, etc), these factors may be of TD occurrence (or non-occurrence) by factors such as interactions with the major cause for considerable study in first-degree relatives.13,14 Finally, concomitant administered drugs, re- heterogeneity and nonreplication genetic factors have been reported to nal and liver function or lifestyle across studies. be involved in extrapyramidal disor- variables (smoking, alcohol consump- ders such as dystonia15 and Parkin- tion, diet, etc). In pharmacogenetics, son’s disease,16 both of which are three mechanisms may influence the RISK FACTORS FOR TARDIVE characterized by abnormal involun- occurrence of ADR: (1) gene variants DYSKINESIA tary movements and hypothetically associated with an altered metabolism Many efforts have been undertaken to may share common susceptibility of the drug (pharmacokinetic factors unravel the underlying mechanisms of pathways with TD. In summary, phase I and II), (2) gene variants that TD; however, the exact pathophysiol- although these findings in animals can induce an unexpected ADR (eg ogy remains largely unknown. Due to and humans do not directly prove long QT syndrome because of a muta- the antidopaminergic properties of the existence of a genetic component tion in the MinK-related peptide 1 classical antipsychotics, it has been in TD, they provide substantial sup- (MiRP1) gene)17 and (3) gene variants suggested that an overactivity of dopa- port. A causal relationship may of the drug target (eg, postsynaptic minergic neurotransmission, thought therefore only be proven by further receptors) can modulate efficacy of a to be secondary to chronic blockade of studies that reveal molecular genetic drug or ADRs18 (pharmacodynamic D2-like receptors in the basal ganglia, etiologies. Thus far, molecular genetic factors). In fact, the complexity of may play a crucial role in the manifes- findings do in fact support the hy- drug response in most cases probably tation of TD.8 From a clinical point of pothesis of a genetic basis of TD, as does not depend on one single factor view, detection of risk factors asso- will be highlighted in this review. In or on one single gene variant, but ciated with TD may be of particular addition, molecular genetic studies rather on a few or many gene variants, interest, as this may help to outweigh have reinforced the notion that TD similar to the polygenic mode of the benefit-to-risk ratio during treat- follows a polygenic mode of inheri- inheritance in complex disorders (eg, ment with antipsychotics and further tance, although this aspect is difficult schizophrenia, type I diabetes). Major point to specific mechanisms involved to prove and awaits confirmation results found over recent years are in TD. Potential socio-demographical through further studies. listed in Table 2.

The Pharmacogenomics Journal Table 2 Overview of genetic association studies with TD

Gene Polymorphisms (alleles) Rating 41 Rating Sample Ethnicity or nationality Main findings Ref. scales size

Association studies with TD and genes involved in the pharmacokinetics of antipsychotics CYP2D6 wt, A, B and D (or: alleles AIMS No 16 Caucasian No association, however, the only homozygous 27 *1, *3, *4 and *5) carrier of non-A alleles had the second highest AIMS score despite a very low dose of antipsychotics. Alleles *1, *3, *4, *5, *6 AIMS in 75 patients43 100 Scotland Tendency for poor metabolizers (ie non-presence of 22 and *7 ratings *1 alleles) to develop more severe TD and TD rating scores wt, A, B and D (or: alleles AIMS No 76 European Caucasian A tendency was noted for movement disorders, 23 *1, *3, *4 and *5) including TD, to be associated with *3, *4, or *5 alleles Alleles *1, *3, *4 and 10 AIMS No 99 Japanese Allele *10 significantly associated with total AIMS 24 scores and with ‘yes/no’ TD at trend level (total AIMS scores X6) Alleles *1, *3, *4 and *5 TDRS ? 45 Austrian Caucasian Heterozygous genotypes (*1/*3 or *1/*5) associated 19 with the presence of TD (P ¼ 0.03) Alleles *1 and *2 AIMS No 99 Japanese No significant association with TD or total AIMS scores 28 Alleles *1 and *10 AIMS No 76 Chinese *10/*10 genotype significantly associated with TD in 21 females (P ¼ 0.004), but not in males or in the total sample Alleles *1–*15, *17 and AIMS Yes 172 German Caucasian No significant association between CYP2D6 genotype 29 duplicates and TD Alleles *1, *3 and *4 AIMS No 37 US-Americans Heterozygous genotype (*1/*3 or *4) in smokers 20

significantly associated with TD (Po0.02) Mu DJ dyskinesia tardive of Genetics Alleles *1, *3 and *4 AIMS Yes 52 Estonian or Russian Nonsignificant tendency for carriers of alleles *3 and 25 ¨ *4 to develop TD as compared to extensive ller metabolizers (*1/*1) al et Alleles *1–*11, *10B, *14, AIMS Yes 202 Korean Nonsignificant tendency towards higher risk of TD in 26 *18, *19, *25, *26, *31, males carrying at least one of the variants as *36 and *41 compared to the wild-type form (*1/*1) Alleles *1, *3, *4, *5, *6 TDRS Yes 109 German Caucasian Nonsignificant association with CYPD26 genotype 30 and gene duplications and TD

CYP1A2 734C/A AIMS No 85 63: Caucasian; 22: African- C/C genotype associated with higher AIMS scores 33 American (P ¼ 0.0007), particularly in smokers (P ¼ 0.008; n ¼ 44) 734C/A AIMS Yes 119 German Caucasian No significant association with median AIMS scores or 34 with TD (regardless of smoking status) 734C/A AIMS Yes 103 Chinese No association with TD status regardless of smoking 35 status which was alone significantly associated with TD (P ¼ 0.01) 734C/A -2964G/A AIMS No 199 Japanese No significant association with either variant and 36 median AIMS scores with TD including haplotype www.nature.com/tpj analyses

CYP17 alpha- T-C polymorphism in AIMS No 113 Ashkenazi and non-Ashkenazi Nonsignificant, however, homozygosity for the A2 37 hydroxylase the promoter region and Jews allele was significantly associated with orofacial, distal and DRD3 DRD3 Ser9Gly and incapacitation scores of the AIMS in presence of the dopamine DRD3 Gly allele 79 h hraoeoisJournal Pharmacogenomics The 80 Table 2 (Continued)

Gene Polymorphisms (alleles) Rating 41 Rating Sample Ethnicity or nationality Main findings Ref. scales size

Association studies with TD and genes of the dopaminergic or serotonergic system (pharmacodynamic factors) DRD2 NcoI AIMS ? 103 Japanese Nonsignificant 40 Ser311Cys AIMS Yes 317 Chinese Nonsignificant 42 TaqI A AIMS No 177 Taiwan Chinese A2/A2 genotype and A2 alleles significantly associated 38 with TD in females (P ¼ 0.002 and 0.001, respectively) Ser311Cys TaqIAÀ141C AIMS No 200 Japanese No significant association with the Ser311Cys or the 39 Ins/Del TaqI A variant. The –141 Ins/Del variant is associated with total AIMS scores (P ¼ 0.03), however, insignificant in regression analysis. Nine variants** AIMS Yes Up to German Caucasian No significant association of any DRD2 genotype or 41 584 haplotypes with the severity of AIMS eeiso adv dyskinesia tardive of Genetics DRD3 Ser9Gly Modified No 84 In majority Caucasian Nonsignificant, however, the global rating scores of 52 Rogers the Mod. Rogers Scale included catatonic and Scale Parkinsonian features Ser9Gly AIMS Yes 100 Caucasian Association with TD and the Gly-allele (P ¼ 0.03) and 43 with the Gly/Gly genotype (P ¼ 0.01) in cross- sectional analyses Mu DJ ¨

Ser9Gly AIMS Yes 105 Japanese Nonsignificant 40 ller

Ser9Gly Rockland No 93 North Italian Nonsignificant*** 48 al et Simpson Scale Ser9Gly AIMS No 112 85: Caucasian; Higher AIMS total scores associated with Gly/Gly 44 25: African-American genotype (P ¼ 0.0005) compared to Ser/Gly and Ser/ Ser genotype Ser9Gly AIMS No 116 Ashkenazi and non-Ashkenazi TD associated with Ser/Gly genotypes (P ¼ 0.0008); 47 total AIMS scores with genotypes carrying Gly alleles (P ¼ 0.02) Ser9Gly TDRS No 61 Austrian TD associated with Ser-allele and Ser-genotypes 49 (mainly) (P ¼ 0.02)*** Ser9Gly AIMS No 71 European Caucasian Tendency for an association between homozygosity 45 for the Gly-variant and TD, without statistical significance (P ¼ 0.20) Ser9Gly TDRS Yes 157 German Nonsignificant 46 Ser9Gly AIMS No 115 Taiwan Chinese Higher AIMS scores with Ser/Gly genotypes compared 50 to Ser/Ser and Gly–Gly genotypes (P ¼ 0.01) Ser9Gly AIMS No 131 Hong Kong Chinese Nonsignificant 51 Ser9Gly AIMS ? 113 Korean Gly/Gly genotype significantly associated with TD 53 (P ¼ 0.02), but no allelic association including continuous AIMS analysis Ser9Gly AIMS Yes 317 Chinese Nonsignificant; but Ser/Ser genotype significantly 42 associated with TD in logistic regression analysis (P ¼ 0.01)

DAT 40-bp VNTR AIMS Yes 105 Japanese Nonsignificant 40 DBH TaqI (intron 5) AIMS No 70 53: Caucasian; Nonsignificant (De Luca, unpublished) 17: African-American Table 2 (Continued)

Gene Polymorphisms (alleles) Rating 41 Rating Sample Ethnicity or nationality Main findings Ref. scales size

5-HTR2A T102C**** A-1438G**** AIMS No 121 Ashkenazi and non-Ashkenazi 102C (and À1438G) alleles and 102CC (and 56 His452Tyr Jews À1438GG) genotypes significantly associated with TD. No association with the his452tyr polymorphism T102C*** A-1437/8G*** AIMS No 136 109: Caucasian; Nonsignificant between allele, genotype or haplotype 58 His452Tyr 27: African-American frequencies of 5-HTR2A variants and patients with or without TD T102C AIMS No 221 Chinese Singaporeans T allele associated with non-occurrence of TD 57 (P ¼ 0.04); T/T genotypes associated with non- occurrence of TD (P ¼ 0.03) C102 T 1438G/A ESRS No 143 Turkish Nonsignificant 59

5-HTR2C and Cys23Ser & Ser9Gly AIMS No 115 Ashkenazi and non-Ashkenazi Ser allele, Cys/Ser and Ser/ser genotypes associated 61 DRD3 Jews with TD in females (P ¼ 0.01/0.02), Cys/Ser and Ser/ ser genotypes associated with orofacial dyskinesias. Additive effect for DRD3 Gly allele -759C/T-697G/C AIMS ? 92 Male Han Chinese À697C allele associated with TD (OR ¼ 2.80, CI ¼ 1.0– 62 7.2); no association with the À759 variant or with – 759/À697 haplotypes

5-HTR6 267C/T AIMS No 173 Japanese Nonsignificant 85

5-HTT 5-HTTLPR AIMS Yes 188 Chinese Nonsignificant 63 JMu DJ dyskinesia tardive of Genetics 5-HTTLPR VNTR (10/12) ESRS No 143 Turkish Nonsignificant for either variants 59 ¨ ller

Association studies with TD and oxidative stress-related genes al et MnSOD Ala-9Val AIMS No 192 Japanese Decreased –9Ala allele was found in subjects with TD 71 (P ¼ 0.02) Ala-9Val AIMS Yes 101 Male JiangSu Chinese Nonsignificant tendency in the same direction as the 72 study by Hori et al71 ApoE e2, e3 and e4 None Yes 333 Japanese Nonsignificant 73 NOS1 C-T variant in exon 29 AIMS No 171 Japanese Nonsignificant 77

Association studies with TD and other genes Opioid m (118A/G) d (921T/C) AIMS No 216 Japanese 118G allele of the m gene less present in TD using 78 receptor Glazer–Morgenstern criteria9 for TD (P ¼ 0.009). Estrogen Pvu II and XbaI AIMS Yes 246 Taiwan Han Chinese A trend was noted for the PvuII polymorphism to be 79 receptor a associated with TD (P ¼ 0.05), no sex-specific effects were noted ACE Ins/del (intron 16) AIMS No 113 Jewish Israeli Nonsignificant 81 COMT High/low activity ESRS No 143 Turkish Nonsignificant 59

www.nature.com/tpj Genes: DAT ¼ dopamine transporter, DBH ¼ dopamine beta hydroxylase, MnSOD ¼ manganese superoxide dismutase, ApoE ¼ apolipoprotein E, ACE ¼ angiotensin-converting enzyme, COMT ¼ catechol-O- methyltransferase, NOS1 ¼ neuronal nitric oxide synthase. Polymorphisms: **1–241A4G, À141C Ins/Del, TaqIB, TaqID, Val96Ala, Leu141Leu, Pro310Ser, Ser311Cys, TaqIA. ***Findings were published in abstract form, while results presented here are based on the data presented in the combined analysis performed by Lerer et al.6 ****These markers were found to be in complete or strong linkage disequilibrium. Rating scales: AIMS ¼ Abnormal Involuntary Movement Scale, TDRS ¼ Tardive Dyskinesia Rating Scale, ESRS ¼ Extrapyramidal Symptom Rating Scale. 81 Genetics of tardive dyskinesia DJ Mu¨ller et al 82

Pharmacokinetic Factors Besides the CYP2D6 enzyme, other plication in larger samples; however, The pharmacokinetic properties of P450 enzymes are very active partici- the approach to detect interactive drugs are determined by drug-metabo- pants in the metabolism of many effects among different gene variants lizing phase 1 enzymes (drug oxida- antipsychotics as well. The CYP1A2 appears promising. tion, like P450 cytochromes, CYP) and gene has received attention in this phase 2 enzymes (drug conjugation context as two single-nucleotide poly- The Dopaminergic System allowing for subsequent excretion). morphisms (SNPs) have been reported Due to the postsynaptic dopamine TheCYP2D6enzymeisinvolvedin to be associated with reduction of the supersensitivity hypothesis of TD, the the metabolism of many antipsycho- CYP1A2 enzyme activity in smokers: dopaminergic system has received tics and is known to be highly poly- Smoking usually induces CYP1A2 ac- marked attention in TD studies. morphic as more than 70 allelic variants tivity, which in turn reduces the The underlying hypothesis in phar- have been reported (www.imm.ki.se/ plasma concentration of antipsychotic macogenetic studies is based on a CYPalleles/cyp2d6.htm). By definition, drugs and may therefore limit adverse pharmacodynamic principle, in that the *1/*1 genotype refers to the usual effects. However, smokers carrying the dopamine receptor variants may mod- wild-type condition and subjects with C/C genotype of the 734C/A variant or ulate the signaling pathways of anti- this genotype represent ‘extensive me- the A-allele of the À2964 variant show psychotics that may lead to tabolizers’. In subjects carrying one or a significant lower CYP1A2 induc- susceptibility for TD. However, studies two gene variants (eg allele *2, *3, and tion.31,32. One study by Basile et al33 related to DRD2 have been inconclu- so on) or a duplication of the CYP2D6 could demonstrate a significant asso- sive. Only Chen et al38 found an gene, the enzyme activity is altered ciation between higher AIMS scores association between the TaqI A poly- towards ‘poor’, ‘intermediate’ or ‘ul- (more severe TD) and the C/C geno- morphism with TD in females, and trarapid’ metabolizers. These altera- type of the 734C/A variant with an Hori et al39 found a weak association tions may be importantly associated even more pronounced effect in smo- with the À141C Ins/del variant and with the efficacy or adverse effect of kers. However, the significant predic- TD, which did not remain significant antipsychotics. Consequently, many tive finding for the 734C/A variant with subsequent regression analysis. studies have focused on CYP2D6 gene could not be replicated in three larger Three other studies did not reveal a variants and their relationship to TD. samples of German,34 Chinese35 and significant association.40–42 Interestingly, most studies reported Japanese36 patients, all of which in- As for the dopamine D3 receptor that alterations from the normal 1*/ cluded patients’ smoking status in gene, DRD3 knockout mice show 1* genotype (ie intermediate or poor their analyses. Inspection of the geno- locomotor hyperactivation similar to metabolizers) are associated with a type data, however, reveals a trend in those in TD, thus implicating a poten- higher risk for TD or higher TD rating each of the three studies in the same tial role for the DRD3 in the etiology scale scores. This relationship was direction as the finding of Basile et of TD. In contrast to the findings on reported to be significant in several al.33 Furthermore, the frequency of DRD2, one polymorphism of the studies19–21 and to be observed as a homozygous C/C patients was too DRD3 gene (Ser9Gly) has more con- trend in other studies;22–26 however, low (B9–12%) in the three subsequent sistently been shown to be associated some have failed to detect this studies,34–36 to have power to detect with TD, although results were mixed trend.27–30 These mixed results are the size of effect observed by Basile et among studies (see Table 2). In order to likely due to considerable study het- al,33 who found a higher frequency of shed light on these controversial re- erogeneity with regard to the gene the C/C genotype (B18%). In this sults, recently, Lerer et al6 performed a variants examined, type and amount study of Basile et al,33 the frequency combined analysis including data of medication, study sample (ie age, of the C/C homozygotes was highest from 780 patients from six research ethnicity), use of different rating in the African-American subpopula- centers, dividing patients into eight scales for the assessment of dyskinetic tion, thus providing a likely explana- groups based on their population movements, etc. Another shortcoming tion as to why the C/C rate was higher origin. Most of the data have been is the limited sample size of most in that sample. The study by Matsu- published previously either in peer studies: For example, some CYPD26 moto et al36 combined their analyses reviewed journals43–47 or in abstract variants were observed only at low of the 734C/A variant with the – form48,49 (see Table 2 for more details). frequencies and therefore many find- 2694G/A variant, in order to perform The authors applied stepwise logistic ings may have only limited statistical haplotype analyses. However, they regression, and confounding effects of power, leading to type II errors. De- could not detect any association with group, age and gender were taken into spite these limitations, it seems that TD. Finally, Segman et al37 found an account. In a subset of patients, AIMS allelic variation leading particularly to association between homozygosity for scores were used as a continuous poor metabolism of antipsychotics a gene variant in the CYP17a-hydro- variable as opposed to a dichotomous might confer an increased risk for TD, xylase in presence of the DRD3Gly one (TD-yes vs TD-no). Overall, the although the effect size is small and allele and the highest orofacial, distal DRD3 Gly allele carrier status and the likely depends on particular co-factors and incapacitation AIMS scores. This Gly/Gly genotype were found to be such as ethnicity or smoking. exploratory finding merits further re- significantly associated with TD or

The Pharmacogenomics Journal Genetics of tardive dyskinesia DJ Mu¨ller et al 83

higher AIMS scores (P-values ranging 5), which has previously been reported males) with the 5-HT2C promoter from o0.0001 to 0.04). Furthermore, to be associated with attention deficit variant À697C allele, but not with Lerer et al6 performed a meta-analysis hyperactivity disorder (ADHD).55 How- the À759C/T variants or with haplo- with seven out of eight groups, includ- ever, no association could be detected type analyses. No association has been ing additional studies.40,50,51 DRD3 (De Luca and Kennedy, unpublished reported between the 5-HT6 receptor, Gly allele carrier status was found to data). or the serotonin transporter59,63 and increase susceptibility to TD with a TD. pooled odds ratio (OR) of 1.33 (95% CI The Serotonergic System 1.04–1.70). Thus, the results of these As many antipsychotics are thought to Oxidative Stress-Related Genes analyses support a small, but signifi- modulate serotonergic (5-HT) recep- Oxidative stress has been implicated in cant contribution of the DRD3 Ser9Gly tors interacting with dopaminergic the pathophysiology of TD. Long-term polymorphism to TD susceptibility. neurotransmission, 5-HT receptor administration of antipsychotics, by One early study by Gaitonde et al,52 genes have been considered as reason- blocking dopamine receptors, is reporting no association between able candidates as well. An initial known to increase dopamine turnover movement disorders (including TD, finding by Segman et al56 suggested and to produce free radicals. The latter catatonic and Parkinsonian features) that, for the 5-HT2A gene, the 102C may be involved in the development and the DRD3 Ser9Gly polymorphism allele and 102CC genotype are asso- of TD through neuronal damage in- in schizophrenia patients, was not ciated with TD, specifically with high- duced by lipid peroxidation.64,65 This included in the meta analysis by Lerer er AIMS trunk dyskinesia scores. hypothesis is supported by the finding et al.6 However, the lack of a thorough Although Tan et al57 found a much that increased markers of oxidative TD assessment may be one major lower frequency of the C-allele in their stress such as lipid peroxidation pro- cause for this negative finding and sample, their findings were consistent ducts have been found in the cere- suggests that the polymorphism is with Segman et al,56 as they reported brospinal fluid (CSF) of patients with rather associated with TD per se and a significant excess of the T allele and TD.66,67 In addition, chronic treat- not in a wider array of unspecific T/T genotype with non-occurrence of ment with antipsychotics caused sig- movement disorders. More recently, TD. Basile et al58 and Herken et al59 nificant decreased antioxidant enzyme Woo et al53 found a significant associa- were unable to replicate these findings activities in rat brain.68 Furthermore, tion between the Gly/Gly genotype and, therefore, the role of the T102C several studies have shown the bene- and TD, thus also supporting the role variant in the 5-HT2A gene cannot be ficial effect of vitamin E, a free radical of the DRD3 Ser9Gly variant in the unambiguously associated with the scavenger, on TD symptoms.69 Addi- Korean population. However, Chong occurrence of TD. Segman et al,60 tionally, increased oxidative stress et al42 found no significant association however, could demonstrate by with cumulative free radical damage with the Ser9Gly variant in a Chinese further analysis that the effect of 5- is a well-known feature of the aging sample, but found an opposite finding HT2A in TD is age related: The 5-HT2A brain,70 which is relevant to the pre- in logistic regression analysis for the variant seems to confer risk for TD in dominant risk factor of TD, namely, Ser/Ser genotype being associated with older patients (449 years) but not in aging. TD. Possible explanations may include younger patients, which may explain Based on the above findings, mole- that the Ser9Gly polymorphism is not the inconsistent findings. Of note, the cular genetic study of TD has also the causative genetic site, but may be T102 C and the A-1438G variants were focused on oxidative stress-related in linkage disequilibrium with the found to be in linkage disequilibrium genes. Hori et al71 have investigated causative risk allele only in certain in the studies of Segman et al56 and the genetic association between a ethnic groups, not including Chinese Basile et al;58 therefore, similar results functional polymorphism (AlaÀ9Val) patients. Finally, the DRD3 gene may with both variants were obtained. in the manganese superoxide dismu- be associated with a subgroup of Another variant of the 5-HT2A gene tase (MnSOD) gene and TD in Japanese schizophrenia presenting with a subset did not reveal any significant finding patients with schizophrenia. In their of specific symptoms and predisposi- (His452Tyr).56,58 study, they found decreased À9Ala tion to TD, as suggested by Segman The Ser allele of the X-linked allele frequency in patients with TD and Lerer.54 Further analyses are 5-HT2C Cys23Ser variant was found compared to patients without TD, and needed to elucidate the role of the to be associated with TD in females.61 that the À9Ala allele might play a DRD3 gene in TD with respect to By using stepwise multiple regression protective role against TD. Zhang et clinical features. analyses, the inclusion of DRD3 geno- al72 have failed to replicate the find- One gene variant in the dopamine types revealed an additive contribu- ings by Hori et al.71 Nevertheless, they transporter was analyzed for TD in a tion of the 5-HT2C Ser allele and the found a significant positive correlation Japanese population, yielding negative DRD3 Gly allele, respectively, of 4.2 between total AIMS score and MnSOD results.40 Recently, our group has in- and 4.7% to the variance of orofacial activity, which may imply MnSOD’s vestigated the potential relationship dyskinesia (OFD) scores in the overall role in pathogenesis of TD. between the dopamine beta-hydroxy- sample.61 Zhang et al62 found a sig- Kimura et al73 examined the allelic lase (DBH) gene (TaqI variant in intron nificant association (including only frequencies in apolipoprotein E (ApoE)

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gene in 333 Japanese schizophrenic TD studies in a study by Herken et al,59 be highly associated with TD (P ¼ patients with TD, since ApoE e4 has but an association between the 0.00007) in an additive, co-recessive decreased anti-oxidant activity as mea- Val158Met variant and TD could not model of interaction which accounted sured by cytotoxicity.74 Although no be detected, suggesting that this en- for 450% of the variance in risk for significant differences in ApoE allelic zyme does not play a major role in TD. TD.83 This prediction was for the frequency were found between TD and This is also consistent with the finding patients’ AIMS score. The overall mod- non-TD groups, ApoE e4 was signifi- that COMT plays little role in dopa- el also included the covariates, age, cantly lower in the female TD group mine turnover in the striatum.82 sex, ethnicity and smoking. For com- than in the male TD group. parison, this model has similar pre- Nitric oxide (NO) has been identi- dictive power to the traditional test of fied as a nonconventional neurotrans- OUTLOOK: CLINICAL IMPLICATIONS cardiac enzymes in the emergency mitter as well as one of the free radicals This review has summarized most room for detecting myocardial infarc- in the CNS. Hence, NO may play a role pharmacogenetic studies on TD and tion. Thus, the question arises: When in the pathophysiology of TD.75,76 highlighted major findings. We have is a genetic test ready for clinical Production of neuronal NO from L- emphasized the marked study hetero- application? A test for TD risk, even if arginine is catalyzed by neuronal NO geneity with regard to many factors only explaining part of the risk, may synthase (NOS1). Shinkai et al77 have such as age, ethnicity, antipsychotic be very valuable to psychiatrists world- investigated the genetic association treatment and varying sample sizes, wide. Clinicians frequently face the between a C/T polymorphism of exon etc. This heterogeneity limits direct decision as to whether to treat a 29 in the NOS1 gene and TD in 171 comparisons among studies, since patient on a newer atypical antipsy- Japanese patients with schizophrenia many factors likely play a substantial chotic, which is almost exclusively including 41 patients with TD. role in complex phenotypes such as administered orally, vs a traditional Although the results were negative, TD. A number of studies used smaller antipsychotic in depot formulation more investigations on other popula- sample sizes, and thus had limited that facilitates compliance particularly tions are warranted. statistical power. Despite these limita- in disorganized patients. If the clin- tions, several interesting findings have ician could administer a genetic test Other Studies of Genes Potentially emerged: the most robust finding that provided information suggesting Related to TD being perhaps the DRD3 and, in older higher risk for TD in a given patient, Opioid receptors were hypothesized to patients, the 5-HT2A gene effects. then the clinician might shift toward be associated with TD according to Other interesting results include find- use of atypical antipsychotics. If the findings in animal studies. The m and d ings with the 5-HT2C gene, and genes genetic test indicated low risk for TD, opioid receptor gene variants were related to both oxidative stress and then the decision might shift toward investigated without detecting signifi- pharmacokinetics. Future studies use of traditional depot antipsychotics cant results,78 according to Schooler should ideally use large, ethnically which would have greatly increased and Kane criteria.7 However, with the homogeneous, well-characterized sam- compliance, lower price and decreased more permissive Glazer and Morgen- ples. Covariates such as age, gender, risk for the serious adverse affects of stern criteria,9 Ohmori et al found a duration of treatment, amount of weight gain and diabetes. protective effect with the 118G allele exposure to antipsychotics and smok- However, as there are likely several of the m receptor gene.78 ing status should be included, as well genes involved in prediction of risk for TD risk was found to be higher in as testing several polymorphisms in TD, these genes will need to be defined females and after the menopause. In each gene and performing haplotype in terms of their individual as well as addition, estrogens interact with the analyses. Furthermore, there is need to interactive effects before an optimal dopaminergic system and thus Lai et investigate novel candidate genes aris- diagnostic test can be developed. In al79 drew their attention towards two ing out of advances in genomics and addition, the frequencies of the risk polymorphisms in the estrogen recep- the promising field of microarray alleles in various ethnic subgroups will tor a. However, only a trend was noted studies. need to be ascertained. The sensitivity in the overall sample. No specific With regard to clinical practice, gene and specificity of the test needs to be effect was found in females alone.79 variants conferring susceptibility to established, and typically this involves The angiotensin-converting enzyme TD will have to be placed in context piloting the test on thousands of has been found to modulate dopamine with other nongenetic risk factors in individuals. turnover in the striatum.80 Segman et order to perform an individual ‘risk If, however, a clinical genetic test for al81 examined the role of a functional profile’ for patients receiving antipsy- TD is deemed appropriate, then a Ins/Del variant, however, yielding no chotic treatment. Only recently have problem immediately arises. The two significant results. studies begun to investigate the addi- genetic variants DRD3 Ser9Gly (Steen The catechol-o-methyltransferase tive or interactive effects among dif- et al43) and CYP1A2 C734A (presented (COMT) gene is involved in dopami- ferent risk alleles.37,61,83. In our in our additive, co-recessive model of nergic turnover and thus has been sample, the risk alleles of the DRD3 interaction as mentioned above) were hypothesized to be a candidate for and CYP1A2 genes were found to published (Basile et al33,44) without

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