Pharmacogenetic Studies Investigating the Adverse Effects of Antipsychotics

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0REVIEW ARTICLE0 Psychiatry Investig 2007;4:66-75 Print ISSN 1738-3684 / On-line ISSN 1976-3026

Heon-Jeong Lee, MD, PhD The pharmacogenetic study of antipsychotics has been developed along with the develop- Department of Psychiatry, ment of general techniques of genetic analysis. Because there are no significant differences Division of Brain Korea in the clinical efficacy of the various antipsychotics, it is important to prevent the adverse 21 for Biomedical Science, Korea University College of Medicine, effects of antipsychotics. Therefore, pharmacogenetic studies concerning antipsychotics have Seoul, Korea been primarily focused on their adverse effects. The most significant finding of the previous studies is the association between drug effects and drug metabolic polymorphisms, mainly in the cytochrome P450 (CYP) genes. Patients with genetically determined to be CYP poor metabolizers (PMs) may require lower doses of antipsychotic medications. On the other hand, CYP ultrarapid matabolizers (UMs) will need an increased dosage in order to obtain a therapeutic response. Genetic variations in the dopamine and serotonin receptor genes have been reported to be associated with the adverse effects of antipsychotics, reflecting the affinities that most antipsychotics have for these receptors. In particular, there is evidence to suggest an association between dopamine 2 receptor polymorphisms and a dopamine 3 receptor polymorphism and antipsychotic-induced tardive dyskinesia. Several studies were recently performed to determine the genetic susceptibility to antipsychotic-induced weight gain and metabolic syndrome. Adrenergic 2a receptor, leptin gene, and serotonin 2C receptor gene variants have been reported to be associated with drug-induced weight gain. Genetic tests before treatment will provide the necessary information on the patient’s metabolic status, which will aid in the appropriate adjustment of the therapeutic doses and the reduction of adverse reactions. Pharmacogenetic knowledge has obvious implications for the selection and improvement of antipsychotic treatment. These developments can be considered to be successes, but the objectives of bringing pharmacogenetic and pharmacogenomic research into psychiatric clinical practice are far from being realized. This review summarizes the findings of the previous research in the field. The current knowledge on the genetic prediction of drug metabolic status and drug-induced side effects will be reviewed and discussed.

KEY WORDS: Pharmacogenetics, Antipsychotics, Adverse effects, Tardive dyskinesia, Weight gain.

Psychiatry Investig 2007;4:66-75

Introduction

Pharmacotherapy is a primary mode of treatment for the various psychiatric symptoms of mental illnesses such as schizophrenia, bipolar disorder, major depression and organic mental disorders. The pharmacotherapy of psychiatric disorders is often Correspondence characterized by trial and error. Psychotropic drugs show a large variation in response Heon-Jeong Lee, MD, PhD Department of Psychiatry, and side effects. Genetic techniques seem to have a potential for use in the identifi- Korea University Anam Hospital, cation of biological predictors of drug response and side effects and may aid in the Korea University College of Medicine, establishment of tailored pharmacotherapy. The core hypothesis underlying pharma- 126-1 Anam-dong 5-ga, Seongbuk-gu, cogenetics is that genetic factors play a significant role in the differences between Seoul 136-705, Korea Tel +82-2-920-6721 individuals in response to medication and susceptibility to adverse effects. If these Fax +82-2-929-7679 genetic factors can be identified and understood, they may serve as predictors to E-mail [email protected] guide clinicians in tailoring medication to the individual patient.

HJ Lee

Antipsychotics are traditionally classified into two major casians.9 Some gene duplications (or multiplications) groups: first generation (or typical) antipsychotics (F- are responsible for the UM phenotype. The frequencies GAs), with strong affinities for the dopamine D2 recep- of CYP2D6 polymorphisms are subject to ethnic varia- tor (DRD2) among others, and the newer second gener- tion, with PMs representing 7-10% of Caucasians and ation (or atypical) antipsychotics (SGAs), with multiple only 1-2% of Asians.10 The metabolism of haloperidol receptor profiles.1,2 FGAs are usually associated with was severely reduced by PMs, and a reduced therapeutic acute extrapyramidal symptoms (EPS), such as Parkin- dose should be prescribed accordingly.11 It was recently sonism, acute dystonic reactions, akathisia and long- observed that CYP2D6 did not predict the response to lasting movement disorders such as tardive dyskinesia risperidone, but rather predicted the metabolic rate and (TD). The newer SGAs are characterized by a lower adverse effects of the drug.12-14 CYP1A2 is the main met- incidence of EPS. Adherence (compliance) to medication abolic pathway of clozapine and olanzapine.15,16 Among is an important factor in the management of schizophrenia, several CYP1A2 polymorphisms, three variants (*1C, and poor adherence has been directly linked to poor *1K and *11) show decreased activity.17,18 However, treatment outcomes.3 Adherence to therapy is often poor polymorphisms in CYP1A2 did not significantly influence in schizophrenia, with up to 50% of patients with schiz- the metabolism of clozapine,19 although delayed responses ophrenia being non-compliant with treatment.4,5 There- have been reported in individuals with the UM pheno- fore, optimizing compliance with therapy offers consid- type.20,21 The CYP3A4 enzyme variants are also involved erable potential to improve disease management in many in the metabolism of most antipsychotics. However, only patients. Thus, pharmacogenetic research into the factors CYP3A4*17 and *18A displayed functional variability affecting the adverse effects of antipsychotics is very with a decreased or increased activity, respectively.22 No important. connection between CYP3A5, CYP2C9 and CYP2C19 variants and the level of response or side effects to anti- Drug Metabolism-Related Genes psychotics has been reported.23-25 The world’s first pharmacogenetic microarray-based test (AmpliChip®) was Drug metabolism is a critical determinant of the thera- recently approved for clinical use.26 The AmpliChip® peutic and adverse effects of antipsychotics. There is provides comprehensive coverage of gene variations, in- strong evidence for the contribution of pharmacokinetic cluding deletions and duplications, for the CYP2D6 and factors to the clinical outcome of antipsychotic treatment. CYP2C19 genes, which play a major role in the meta- Asians have been reported to require relatively low doses bolism of an estimated 25% of all prescription drugs. of antipsychotic drugs and appear to develop toxicity at lower doses than Caucasians. These inter-ethnic variations Phase II enzymes may be attributed to pharmacokinetic differences. Genetic Phase II enzymes are responsible for the inactivation variants in Phase I and II enzymes are known to reduce of drug metabolites via conjugation reactions. N-ace- or increase their activity and subsequently to alter drug tyltransferases (NATs), thiopurine S-methyltransferases, plasma level.6-8 uridine diphosphate (UDP) glucuronosyltransferases (UGTs) and glutathione S-transferases (GSTs) are major Phase I enzymes (Cytochrome P450) enzymes involved in Phase II reactions. Some researchers Phase I oxidation is a very important metabolic process have suggested that Phase II enzyme variants may con- for antipsychotics. All antipsychotics are subject to ex- tribute to treatment variability and disease pathogenesis, tensive metabolism by various enzymes of the cytochrome especially those related to toxic environmental com- P450 (CYP) family, which play a pivotal role in the pounds.27 Genetic differences in drug metabolic alterations elimination of these drugs and therefore influence their have important implications for determination of the efficacy and toxicity. Poor metabolizers (PMs), extensive appropriate therapeutic dosage and may be related to the metabolizers (EMs) and ultrarapid metabolizers (UMs) toxic side effects of the drugs. Pharmacogenetic studies of are phenotypic presentations of individuals carrying de- pharmacokinetic factors have shown the most informative fective, normal or duplicate copies of the CYP genes, re- and clinically useful results in clinical psychiatry. Genetic spectively. CYP2D6 is the main metabolic pathway of information on the metabolic status of the individual many classical antipsychotics. The gene coding for CY- patient may be beneficial to antipsychotic treatment in P2D6 is highly variable. Out of 90 known mutations, clinical practice. It has been estimated that pretreatment four polymorphisms (*3, *4, *5 and *6) are responsible metabolic determination may decrease adverse reactions for the vast majority of inactive alleles (98%) in Cau- by 10-20% and improve drug efficacy by 10-15%.28

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Pharmacogenetics of Antipsychotics

Pharmacodynamic factors been performed. Chen et al. reported that the frequency Pharmacogenetic research into pharmacodynamic fac- of the TaqI A2/A2 genotype of the DRD2 gene was tors began as a strategy for the validation of therapeutic higher in Taiwanese female schizophrenic patients with targets. Neurotransmitter systems in the brain have been TD than those without TD;36 however, this finding was thought to be altered in patients with schizophrenia and not confirmed by other studies.37 Our group recently found have been targets for antipsychotic therapy. Antipsychotics a significant association between the DRD2 TaqI A poly- have a variety of affinities for neurotransmitter receptors, morphism and TD in a Korean sample,38 which was sim- including dopamine, serotonin, histamine, muscarine, glu- ilar to the result of Chen et al.36 tamate and adrenergic receptors. Therefore, the pharma- The dopamine D3 receptor (DRD3) is localized the in codynamic properties of antipsychotics are responsible brain areas involved in motor function, and it has been for both their side effects and their therapeutic effects. shown that DRD3 antagonism exacerbates locomotor The dopamine system has been regarded as an important activity in the brain.39 Additionally, antipsychotics with neurotransmitter system in mediating the activity of relatively low DRD3 affinity, such as clozapine, are re- antipsychotics. Dopamine alterations in the brain were the ported to cause significantly fewer movement disorders.40 main pathological observations in schizophrenia research, The DRD3 gene has been suggested as a susceptibility and most antipsychotics had a preferential affinity for factor for TD,41-43 while negative results have also been dopamine receptors. The serotonin system is also thought reported.38,44 The Gly9 allele of the Ser9Gly polymorphism to be related to schizophrenia because of the hallucino- in DRD3 is reportedly associated with significantly higher genic properties of a serotonin antagonist, lysergic acid dopamine activity, which in turn could explain its asso- diethylamide (LSD). Recent interest in the role of the ciation with movement disorders.45 However, our group serotonin system in the action of antipsychotic drugs has could not replicate this association in a Korean sample.38 been primarily based upon the fact that antipsychotic Relatively few studies have been performed on the as- drugs, such as clozapine, olanzapine, quetiapine, risperi- sociation of the dopamine D4 receptor (DRD4) with the done, and ziprasidone, are potent 5-Hydroxytryptamine development of TD in comparison to the number of studies (5-HT2A) receptor antagonists and relatively weaker on DRD2 and DRD3, with only four studies having been dopamine D2 antagonists.29 Many of the pharmacogenetic published. Lattuada et al. reported a marginally signifi- studies on the adverse effects of antipsychotics have been cant association between the short allele of the DRD4 focused on dopamine and serotonin-related genes. variable number of tandem repeat (VNTR) polymorphisms in exon III and TD,46 while Segman et al. reported Pharmacogenetics of Adverse Effects a complete lack of association between the two.47 Most recently, Srivastava et al. reported that a 120-bp duplica- Tardive dyskinesia tion marker that is 1.2 kb upstream of the initiation codon TD is one of the most serious adverse effects of treat- of the DRD4 gene showed a significant genotypic as- ing schizophrenia with typical antipsychotics. The typical sociation with TD.48 However, very recently, our group symptoms of TD are involuntary movements of the oro- failed to find the association between the DRD4 -521 facial musculature, but the trunk and extremities may also C/T polymorphism and TD.49 be affected. Only a small proportion of patients who are No association was found when investigating D1 exposed to long-term treatment with antipsychotics de- polymorphisms and a polymorphism in the dopamine velop TD, which suggests that individual susceptibility transporter (DAT) in relation to TD.48 Similarly, two mon- such as genetic factors is important. Genetic vulnerability oamine oxidases (MAOA and MAOB) involved in do- to the development of TD has been suggested based on pamine degradation, have been investigated and were the results of studies in both animals30 and families.31 not found to contribute to TD,50 which suggests that fac- Several biological mechanisms of TD have been hypo- tors controlling dopamine metabolism are not involved thesized, including dopamine receptor supersensitivity,32 in TD. the dysfunction of the serotonergic system,33 gamma- The fact that serotonin inhibits dopamine function sup- aminobutyric acid insufficiency,34 and disturbances in ports the suggestion that serotonin contributes to the pa- antioxidative protection.35 However, the pathophysiol- thogenesis of TD. Tan et al.51 and Segman et al.52 initially ogical mechanisms of TD are not well understood. Addi- reported the association between 5-HT2A polymorphisms tionally, the development of TD has been directly asso- and TD; however, their findings were not replicated in ciated with increases in drug dosage and plasma levels, independent studies.53,54 The association was later con- which may exacerbate the pathophysiological mechanisms. firmed by Lerer et al. in combined analyses controlling Many genetic case-control association studies have for patient age, which is an important factor in the de-

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HJ Lee velopment of TD.56 A polymorphism in the 5-HT2C pro- chewing movements in rats.73 Most recently, Thelma et moter was reported to be associated with TD,57 but find- al. performed a genetic association study for the several ing was not replicated in other studies.55,58 Studies on oxidative stress-related gene (SOD2, UCP2, NOS1, NOS1, serotonin transporter (5-HTT) polymorphisms failed to NOS3, GSTM1, GSTT1, GSTP1, and NQO1) variants find any association with TD.53,59,60 with the development of TD in Indian patients with Oxidative stress caused by the increased formation of schizophrenia.74 None of the polymorphisms tested were reactive oxygen species by antipsychotic treatment may associated with the development of TD. However, they result in TD. Animal studies have proposed that oxida- found the tendency for an association between the NOS3 tive stress may play a role in the pathogenetic mechanism variant and the severity of TD.74 Therefore, the relation- of TD.61 The long-term administration of antipsychotics ships between the ROS-related genes and TD are still increases dopamine turnover, which leads to the excess controversial. production of oxidative metabolites, especially in dopa- Genetically determined dysfunctions of the CYP en- mine-rich areas such as the basal ganglia. The oxidative zymes and the subsequent accumulation of drug meta- metabolites are dopamine quinones and hydrogen per- bolites significantly contribute to the development of TD. oxide (H2O2). These, in turn, lead to the formation of The impaired activity of the CYP2D6 enzyme was found reactive oxygen species (ROS). ROS can cause neuronal to be associated with the adverse reactions induced by damage as a consequence of oxidative stress. The oxi- antipsychotics.13,75 CYP2D6 PM variants have been found dative stress hypothesis comes from two studies that de- to be associated with TD and EPS in several studies, monstrated the increased production of lipid peroxida- including those in different ethnic groups.76-78 CYP1A2 tion products in the cerebrospinal fluid of patients with variants also have been reported to be related to the TD.62,63 In addition, several studies have shown that genetic risk factors for the development of TD, as sug- Vitamin E, a free radical scavenger, has a positive effect gested by a number of positive findings.76,79 However, on TD symptoms.64 investigations on the CYP3A4 and CYP3A5 genes failed Oxidative stress-mediated neuronal damage has been to find any association between these genes and TD.80,81 regarded as an important hypothesis for the develop- Our group recently evaluated the candidate functional ment of TD. This hypothesis is supported by the finding polymorphisms of the G protein beta 3 subunit (GNB3) of increased lipid peroxidation in the cerebrospinal fluid gene and their association with drug-induced TD in of TD patients and the finding that antioxidants, such as Korean patients with schizophrenia, but we could not vitamin E, alleviated the symptoms of TD.64 GSTs re- find any association.82 Figure 1 shows the possible can- present an important family of phase II drug-metaboliz- ing enzymes that catalyze the conjugation of a large variety Long-term antipsychitic DRD1-5, 5-HTRs of endogenous and exogenous compounds, including exposure (Monoamine DAT, SERT antipsychotics with reduced glutathione. In order to receptors blockade) & CYPs further investigate the oxidative stress hypothesis of TD Alternation on signal development, we examined whether genetic variants of GNB3, PAR-4 transduction GSTM1, GSTT1, and GSTP1 were associated with antipsychotic-induced TD. However, we did not find any GAD1-2, GABAnergic and Free radicals GSTs, MnSOD significant association between GST gene variants and GABRB1-2, glutamatergic Oxidative stress NOS, etc TD in our Korean sample, and there was no significant etc neurotransmission difference in the mean Abnormal Involuntary Movement 65 Scale (AIMS) scores of the different genotypes. Several Apototic neuronal injury BDNF, TNFα, GSK-3 etc studies previously investigated the association between phase II antioxidant enzyme gene variants and TD. Al- though the most of these studies failed to show a relation- Tardive dyskinesia ship between the antioxidant enzyme gene and TD,66-70 FIGURE 1. Suggested pathophysiologic process of tardive dys- several studies have reported a positive association be- kinesia and related candidate genes for pharmacogenetic study. tween the two.71 Especially, de Leon et al. reported an DRD: dopamine receptor, 5-HTR: serotonin receptor, DAT: do- association between TD and the GSTM1 polymorphism, pamine transporter, SERT: serotonin transporter, CYP: cytochrome P450, GNB3: G-proteisn beta subunit, PAR: prostate apoptosis but failed to find associations between TD and GSTT1, response, GAD: glutamic acid decarboxylase, GABRB: GABA DRD2 and MDR1 polymorphisms.72 A novel brain- receptor B, GST: glutathione S-transferase, MnSOD: manganase superoxide dismutase, NOS: nitric oxide synthase, BDNF: brain targeted antioxidant, N-acetyl cysteine amide, has recently derived neurotrophic factor, TNF: tumor necrotic factor, GSK: gly- been reported to reduce haloperidol-induced vacuous cogen synthase kinase.

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Pharmacogenetics of Antipsychotics didate genes for pharmacogenetic studies of antipsycho- significant weight.91 This variant has been reported to tic-induced TD. influence transcriptional activity, with the -759 C allele showing comparatively less activity.92 Although many Weight gain and metabolic syndrome studies replicated this finding in different population Atypical antipsychotic-induced weight gain is well- groups,90,93 a number of studies failed to replicate this recognized and has important physical and psycholog- finding.94-97 Very recently, De Luca et al. used meta-an- ical consequences. Weight gain is a major reason for alytical techniques to investigate the association between discontinuation or noncompliance with atypical antipsy- the -759C/T polymorphism and weight gain resulting chotics. The use of antipsychotics might result in not only from the use of various antipsychotics.98 From 10 pub- excessive weight gain but also metabolic sequelae, such lished reports they found a slight association between as dyslipidemia, glucose dysregulation, and the metabolic the -759C/T polymorphism and weight gain, but also syndrome. Obesity and weight gain in adulthood have found significant heterogeneity between the studies. There- been associated with significant health complications, fore, this relationship remains controversial. In Korea, such as type II diabetes, coronary heart disease, stroke, Ryu et al. reported that the -759C/T polymorphism of sleep apnea, and some types of cancer.83 Substantial weight the HTR2C gene and only the early-phase (4-weeks) gain may also adversely affect the patient’s self-esteem, weight gain were associated with antipsychotic use social functioning and physical activity.84 (including olanzapine) in subjects who were receiving Clozapine and olanzapine, in particular, may induce many types of antipsychotics (risperidone, olanzapine, profound weight gain, although among other classical quetiapine, amisulpride, haloperidol, and trifluopera- and atypical antipsychotics, few are free of this effect.83 zine).99 However, our group found no evidence of an One meta-analysis of antipsychotic use and weight gain association between the -759C/T polymorphism of the found that clozapine and olanzapine use were associated HTR2C gene and weight gain after long-term treatment with an average increase in body weight of 9.9 pounds with olanzapine in Korean patients with schizophrenia.100 and 9.2 pounds, respectively, while those treated with The leptin gene, which is located at chromosome 7q31.3, risperidone or ziprasidone gained an average of 4.7 and encodes a 3.5 kb cDNA and has three exons and two 0.9 pounds, respectively.85 introns.101,102 Many single nucleotide polymorphisms The underlying mechanisms by which these medications (SNPs) of the leptin gene have been extensively studied. cause weight gain remain unclear. However, there ap- In recent studies of French,103 North American,104 and pears to be considerable variability among patients in Asian105 populations, a polymorphism in the promoter the propensity to gain weight due to the use of an region (-2548A/G) of the leptin gene was associated antipsychotic. It is likely that this variability in weight with obesity. The -2548G allele was more frequent in gain is influenced by biological susceptibility, including the overweight group in both studies. There were three genetic factors. Serotonin and histamine receptors play previous studies that examined the association of the important roles in eating behavior and are promising -2548A/G SNP of the leptin gene with antipsychotic-in- candidate genes for these studies. The adrenergic system duced weight gain. Zhang et al. reported that the -2548 is also thought to play an important role in regulating AA genotype may be a genetic risk factor for the develop- energy balance via thermogenesis and lipid mobilization ment of weight gain in 128 Chinese Han patients with in adipose tissue. Genetic variation in these receptors schizophrenia during treatment with antipsychotics.89 could alter lipolytic activity and contribute to weight However, Templeman et al. investigated the same as- alterations during antipsychotic treatment. The candidate sociation in 73 Spanish Caucasian patients and reported genes that are proposed to be related to antipsychotic-in- that patients with the GG genotype of the -2548A/G duced weight gain are the 5-HT2C receptor gene,86,87 his- SNP tended to exhibit greater changes in body mass index tamine receptor gene,88 and leptin gene.89,90 (BMI) than those with the AA or AG genotypes.90 They Yuan et al. reported that the -759C/T polymorphism suggested that racial variations could affect the relation- of the HTR2C gene was related to late-onset diabetes ship between leptin gene polymorphisms and weight gain. and obesity in a normal population.87 Reynolds et al. Ryu et al. recently examined the association in 71 Korean was the first to show a protective effect of the variant T patients with schizophrenia and reported that no asso- allele of the -759C/T polymorphism of the HTR2C gene ciation was found after 4 and 8 weeks of treatment with in patients with schizophrenia receiving chlorpromazine various antipsychotics.106 However, the duration of ex- and risperidone for 6 weeks.86 They also reported that posure to antipsychotics was too short to evaluate the the T allele was more prevalent in schizophrenic patients genetic effects on drug-induced weight gain. Our group who received clozapine for 6 months but did not gain recently found that the AG genotype of the -2548A/G

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HJ Lee

SNP of the leptin gene was associated with body weight of RLS was 21.4% and was more than two times higher gain during olanzapine treatment.107 However, the func- in the schizophrenics than in the control group.118 RLS tional effect of this polymorphism has yet to be determined. has been known to have a genetic cause. Five suscepti- Wang et al. reported that the G variant of the -1291 bility loci (12q, 14q, 9p, 2q, and 20p) for RLS have C/G promoter polymorphism in the alpha-2 adrenergic been identified by linkage studies.119-125 receptor gene (ADRA2A) was significantly associated Only a small proportion of patients who are exposed with clozapine-induced weight gain.108 Our group also to treatment with antipsychotics develop RLS, which reported that this SNP of ADRA2A was associated with suggests that the susceptibility to RLS differs between olanzapine-induced weight gain.109 As the functional effect individuals. The difference in susceptibility could be at- of this polymorphism is currently unknown, it is only tributed to biological factors, including genetic vulnera- possible to hypothesize that this polymorphism influences bility. Although RLS is considered to have a significant the adrenergic-mediated thermogenetic and lipolityc ac- genetic etiology, very few association studies have been tivity. Although the beta 3 adrenergic receptor gene has performed on this subject. Desautels et al. investigated been regarded as a good candidate gene, its polymorphism eight genes coding for receptors and enzymes related to did not contribute to clozapine-induced weight gain in a the neurotransmission-related genes,126 and they found previous study.110 There is no strong evidence to suggest that the monoamine oxidase A (MAOA) gene might a connection between other serotonin (5-HT2A, 5-HT6) only be involved in the severity of RLS in females.127 variants and antipsychotic-related weight gain. Although Very recently, our group performed genetic studies for there were several reports of a relationship between the antipsychotic-induced RLS. We investigated several gene GNB3 gene and drug-induced weight gain,111,112 our group variants of the dopamine D1-4 (DRD1-DRD4), dopa- could not replicate this finding in a sample receiving long- mine transporter gene, monoamine oxidase A and B, and term treatment with olanzapine.113 G protein beta3 subunit gene (GNB3). We found signif- A linkage study of weight change in patients undergo- icant results only in the GNB3, DRD1, and DRD4 gene ing treatment with classical antipsychotics identified a variants, but they were very weak.128,129 suggestive linkage (Lod score=2.74) at 12q24.114 The pro-melanin-concentrating hormone gene, which is in- Agranulocytosis volved in the control of eating behavior and energy reg- Clozapine, an atypical antipsychotic used in the treat- ulation, is located near this locus. Therefore, it may be a ment of refractory schizophrenia, causes agranulocytosis potential candidate gene for antipsychotic-induced weight in 0.7% of patients.130 The risk factors and underlying gain. mechanisms of clozapine-induced agranulocytosis remain Interestingly, a recent study found differences in genetic unclear. Although only a small percentage of clozapine- patterns associated with weight gain in olanzapine and treated patients develop this adverse effect, agranulocy- risperidone treatment. The weight profiles of patients tosis is a great barrier to the prescription of this drug due treated with olanzapine were significantly associated to its potentially lethal effect. Immune-mediated toxicity with peripheral lipid homeostatic axes genes, whereas is one of the possible causes of agranulocytosis by clo- the weight profiles in patients treated with risperidone zapine. Several studies have reported that agranulocytosis were significantly associated with the genes in the brain was associated with the major histocompatibility com- appetite peptide regulation.115 This report suggests that plex.131-133 Oxidative stress also has been suggested a there may be drug-specific factors contributing to weight potential cause of agranulocytosis. A genetic variant of the gain in addition to the common factors shared by all Myeloperoxidase (MPO) gene was found to be related to antipsychotics. clozapine-induced agranulocytosis.134 Varients of NOQ1, the oxidative gene involved in the detoxification of drugs, Restless legs syndrome were associated with clozapine-induced agranulocytosis.135 Restless legs syndrome (RLS) is characterized by an Cytokine gene polymorphisms were also found in higher unpleasant leg sensation and urge to move that is often frequencies in patients presenting with agranulocytosis.136 undiagnosed or misdiagnosed as a psychiatric, other neu- rological, muscular, or orthopedic condition. A recent Conclusion survey from Europe and the USA showed the correct diagnosis of RLS by general physicians to be less than Pharmacogenetic study findings constitute a great ad- 7% of the cases diagnosed by specialists.116,117 RLS is vance towards the future tailoring of antipsychotic treat- also frequently observed in schizophrenic patients who ment to the individual patient. Although they are still at take antipsychotics. Our group found that the prevalence early stages, preliminary studies have proven that the

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Pharmacogenetics of Antipsychotics prediction of antipsychotic-related side effects using effects. Eur Arch Psychiatry Clin Neurosci 2005;255:261-268. genetic information may be feasible, and prototype tests, 13. de Leon J, Susce MT, Pan RM, Fairchild M, Koch WH, Wedlund PJ. ® The CYP2D6 poor metabolizer phenotype may be associated with such as the AmpliChip , are currently underway. In ad- risperidone adverse drug reactions and discontinuation. J Clin Psychi- dition to candidate gene approaches, pharmacogenomic atry 2005;66:15-27. approach studies to identify novel proteins and pathways 14. Kakihara S, Yoshimura R, Shinkai K, Matsumoto C, Goto M, Kaji K, that intervene during antipsychotic treatment are needed. et al. Prediction of response to risperidone treatment with respect to plasma concencentrations of risperidone, catecholamine metabolites, Furthermore, epigenetic approaches are also necessary and polymorphism of cytochrome P450 2D6. 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