Review Article
The pharmacogenetic study of antipsychotics has been developed along with the development of general techniques of genetic analysis. Because there are no significant differences in the clinical efficacy of the various antipsychotics, it is important to prevent the adverse effects of antipsychotics. Therefore, pharmacogenetic studies concerning antipsychotics have 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.
Correspondence : Heon-Jeong Lee, MD, PhD, Department of Psychiatry, Korea University Anam Hospital, Korea University College of Medicine, 126-1 Anam-dong 5-ga, Seongbuk-gu, Seoul 136-705, Korea
Tel : +82-2-920-6721, Fax : +82-2-929-7679, E-mail : leehjeong@korea.ac.kr
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 characterized by trial and error. Psychotropic drugs show a large variation in response and side effects. Genetic techniques seem to have a potential for use in the identification of biological predictors of drug response and side effects and may aid in the establishment of tailored pharmacotherapy. The core hypothesis underlying pharmacogenetics is that genetic factors play a significant role in the differences between individuals in response to medication and susceptibility to adverse effects. If these genetic factors can be identified and understood, they may serve as predictors to guide clinicians in tailoring medication to the individual patient.
Antipsychotics are traditionally classified into two major groups: first generation (or typical) antipsychotics (F-GAs), with strong affinities for the dopamine D2 receptor (DRD2) among others, and the newer second generation (or atypical) antipsychotics (SGAs), with multiple receptor profiles.1,2 FGAs are usually associated with acute extrapyramidal symptoms (EPS), such as Parkinsonism, acute dystonic reactions, akathisia and long-lasting movement disorders such as tardive dyskinesia (TD). The newer SGAs are characterized by a lower incidence of EPS. Adherence (compliance) to medication is an important factor in the management of schizophrenia, and poor adherence has been directly linked to poor treatment outcomes.3 Adherence to therapy is often poor in schizophrenia, with up to 50% of patients with schizophrenia being non-compliant with treatment.4,5 Therefore, optimizing compliance with therapy offers considerable potential to improve disease management in many patients. Thus, pharmacogenetic research into the factors affecting the adverse effects of antipsychotics is very important.
Drug Metabolism-Related Genes
Drug metabolism is a critical determinant of the therapeutic and adverse effects of antipsychotics. There is strong evidence for the contribution of pharmacokinetic factors to the clinical outcome of antipsychotic treatment. Asians have been reported to require relatively low doses of antipsychotic drugs and appear to develop toxicity at lower doses than Caucasians. These inter-ethnic variations may be attributed to pharmacokinetic differences. Genetic variants in Phase I and II enzymes are known to reduce or increase their activity and subsequently to alter drug plasma level.6,7,8
Phase I enzymes (Cytochrome P450)
Phase I oxidation is a very important metabolic process for antipsychotics. All antipsychotics are subject to extensive metabolism by various enzymes of the cytochrome P450 (CYP) family, which play a pivotal role in the elimination of these drugs and therefore influence their efficacy and toxicity. Poor metabolizers (PMs), extensive metabolizers (EMs) and ultrarapid metabolizers (UMs) are phenotypic presentations of individuals carrying defective, normal or duplicate copies of the CYP genes, respectively. CYP2D6 is the main metabolic pathway of many classical antipsychotics. The gene coding for CY-P2D6 is highly variable. Out of 90 known mutations, four polymorphisms (*3, *4, *5 and *6) are responsible for the vast majority of inactive alleles (98%) in Caucasians.9 Some gene duplications (or multiplications) are responsible for the UM phenotype. The frequencies of CYP2D6 polymorphisms are subject to ethnic variation, with PMs representing 7-10% of Caucasians and only 1-2% of Asians.10 The metabolism of haloperidol was severely reduced by PMs, and a reduced therapeutic dose should be prescribed accordingly.11 It was recently observed that CYP2D6 did not predict the response to risperidone, but rather predicted the metabolic rate and adverse effects of the drug.12,13,14 CYP1A2 is the main metabolic pathway of clozapine and olanzapine.15,16 Among several CYP1A2 polymorphisms, three variants (*1C, *1K and *11) show decreased activity.17,18 However, polymorphisms in CYP1A2 did not significantly influence the metabolism of clozapine,19 although delayed responses have been reported in individuals with the UM pheno-type.20,21 The CYP3A4 enzyme variants are also involved in the metabolism of most antipsychotics. However, only CYP3A4*17 and *18A displayed functional variability with a decreased or increased activity, respectively.22 No connection between CYP3A5, CYP2C9 and CYP2C19 variants and the level of response or side effects to anti-psychotics has been reported.23,24,25 The world's first pharmacogenetic microarray-based test
(AmpliChip®) was recently approved for clinical use.26 The AmpliChip® provides comprehensive coverage of gene variations, including deletions and duplications, for the CYP2D6 and CYP2C19 genes, which play a major role in the meta-bolism of an estimated 25% of all prescription drugs.
Phase II enzymes
Phase II enzymes are responsible for the inactivation of drug metabolites via conjugation reactions. N-acetyltransferases (NATs), thiopurine S-methyltransferases, uridine diphosphate (UDP) glucuronosyltransferases (UGTs) and glutathione S-transferases (GSTs) are major enzymes involved in Phase II reactions. Some researchers have suggested that Phase II enzyme variants may contribute to treatment variability and disease pathogenesis, especially those related to toxic environmental compounds.27 Genetic differences in drug metabolic alterations have important implications for determination of the appropriate therapeutic dosage and may be related to the toxic side effects of the drugs. Pharmacogenetic studies of pharmacokinetic factors have shown the most informative and clinically useful results in clinical psychiatry. Genetic information on the metabolic status of the individual patient may be beneficial to antipsychotic treatment in clinical practice. It has been estimated that pretreatment metabolic determination may decrease adverse reactions by 10-20% and improve drug efficacy by 10-15%.28
Pharmacodynamic factors
Pharmacogenetic research into pharmacodynamic factors began as a strategy for the validation of therapeutic targets. Neurotransmitter systems in the brain have been thought to be altered in patients with schizophrenia and have been targets for antipsychotic therapy. Antipsychotics have a variety of affinities for neurotransmitter receptors, including dopamine, serotonin, histamine, muscarine, glutamate and adrenergic receptors. Therefore, the pharmacodynamic properties of antipsychotics are responsible for both their side effects and their therapeutic effects. The dopamine system has been regarded as an important neurotransmitter system in mediating the activity of antipsychotics. Dopamine alterations in the brain were the main pathological observations in schizophrenia research, and most antipsychotics had a preferential affinity for dopamine receptors. The serotonin system is also thought to be related to schizophrenia because of the hallucinogenic properties of a serotonin antagonist, lysergic acid diethylamide (LSD). Recent interest in the role of the serotonin system in the action of antipsychotic drugs has been primarily based upon the fact that antipsychotic drugs, such as clozapine, olanzapine, quetiapine, risperidone, and ziprasidone, are potent 5-Hydroxytryptamine (5-HT2A) receptor antagonists and relatively weaker dopamine D2 antagonists.29 Many of the pharmacogenetic studies on the adverse effects of antipsychotics have been focused on dopamine and serotonin-related genes.
Pharmacogenetics of Adverse Effects
Tardive dyskinesia
TD is one of the most serious adverse effects of treating schizophrenia with typical antipsychotics. The typical symptoms of TD are involuntary movements of the orofacial musculature, but the trunk and extremities may also be affected. Only a small proportion of patients who are exposed to long-term treatment with antipsychotics develop TD, which suggests that individual susceptibility such as genetic factors is important. Genetic vulnerability to the development of TD has been suggested based on the results of studies in both animals30 and families.31 Several biological mechanisms of TD have been hypothesized, including dopamine receptor supersensitivity,32 the dysfunction of the serotonergic system,33 gamma-aminobutyric acid insufficiency,34 and disturbances in antioxidative protection.35 However, the pathophysiological mechanisms of TD are not well understood. Additionally, the development of TD has been directly associated with increases in drug dosage and plasma levels, which may exacerbate the pathophysiological mechanisms.
Many genetic case-control association studies have been performed. Chen et al. reported that the frequency of the TaqI A2/A2 genotype of the DRD2 gene was higher in Taiwanese female schizophrenic patients with TD than those without TD;36 however, this finding was not confirmed by other studies.37 Our group recently found a significant association between the DRD2 TaqI A polymorphism and TD in a Korean sample,38 which was similar to the result of Chen et al.36
The dopamine D3 receptor (DRD3) is localized the in brain areas involved in motor function, and it has been shown that DRD3 antagonism exacerbates locomotor activity in the brain.39 Additionally, antipsychotics with relatively low DRD3 affinity, such as clozapine, are reported to cause significantly fewer movement disorders.40 The DRD3 gene has been suggested as a susceptibility factor for TD,41,42,43 while negative results have also been reported.38,44 The Gly9 allele of the Ser9Gly polymorphism in DRD3 is reportedly associated with significantly higher dopamine activity, which in turn could explain its association with movement disorders.45 However, our group could not replicate this association in a Korean sample.38 Relatively few studies have been performed on the association of the dopamine D4 receptor (DRD4) with the development of TD in comparison to the number of studies on DRD2 and DRD3, with only four studies having been published. Lattuada et al. reported a marginally significant association between the short allele of the DRD4 variable number of tandem repeat (VNTR) polymorphisms in exon III and TD,46 while Segman et al. reported a complete lack of association between the two.47 Most recently, Srivastava et al. reported that a 120-bp duplication marker that is 1.2 kb upstream of the initiation codon of the DRD4 gene showed a significant genotypic association with TD.48 However, very recently, our group failed to find the association between the DRD4 -521 C/T polymorphism and TD.49
No association was found when investigating D1 polymorphisms and a polymorphism in the dopamine transporter (DAT) in relation to TD.48 Similarly, two monoamine oxidases (MAOA and MAOB) involved in dopamine degradation, have been investigated and were not found to contribute to TD,50 which suggests that factors controlling dopamine metabolism are not involved in TD.
The fact that serotonin inhibits dopamine function supports the suggestion that serotonin contributes to the pathogenesis of TD. Tan et al.51 and Segman et al.52 initially reported the association between 5-HT2A polymorphisms and TD; however, their findings were not replicated in independent studies.53,54 The association was later confirmed by Lerer et al. in combined analyses controlling for patient age, which is an important factor in the development of TD.56 A polymorphism in the 5-HT2C promoter was reported to be associated with TD,57 but finding was not replicated in other studies.55,58 Studies on serotonin transporter (5-HTT) polymorphisms failed to find any association with TD.53,59,60
Oxidative stress caused by the increased formation of reactive oxygen species by antipsychotic treatment may result in TD. Animal studies have proposed that oxidative stress may play a role in the pathogenetic mechanism of TD.61 The long-term administration of antipsychotics increases dopamine turnover, which leads to the excess production of oxidative metabolites, especially in dopamine-rich areas such as the basal ganglia. The oxidative metabolites are dopamine quinones and hydrogen peroxide
(H2O2). These, in turn, lead to the formation of reactive oxygen species (ROS). ROS can cause neuronal damage as a consequence of oxidative stress. The oxidative stress hypothesis comes from two studies that demonstrated the increased production of lipid peroxidation products in the cerebrospinal fluid of patients with TD.62,63 In addition, several studies have shown that Vitamin E, a free radical scavenger, has a positive effect on TD symptoms.64
Oxidative stress-mediated neuronal damage has been regarded as an important hypothesis for the development of TD. This hypothesis is supported by the finding of increased lipid peroxidation in the cerebrospinal fluid of TD patients and the finding that antioxidants, such as vitamin E, alleviated the symptoms of TD.64 GSTs represent an important family of phase II drug-metabolizing enzymes that catalyze the conjugation of a large variety of endogenous and exogenous compounds, including antipsychotics with reduced glutathione. In order to further investigate the oxidative stress hypothesis of TD development, we examined whether genetic variants of GSTM1, GSTT1, and GSTP1 were associated with anti-psychotic-induced TD. However, we did not find any significant association between GST gene variants and TD in our Korean sample, and there was no significant difference in the mean Abnormal Involuntary Movement Scale (AIMS) scores of the different genotypes.65 Several studies previously investigated the association between phase II antioxidant enzyme gene variants and TD. Although the most of these studies failed to show a relationship between the antioxidant enzyme gene and TD,66,67,68,69,70 several studies have reported a positive association between the two.71 Especially, de Leon et al. reported an association between TD and the GSTM1 polymorphism, but failed to find associations between TD and GSTT1, DRD2 and MDR1 polymorphisms.72 A novel brain-targeted antioxidant, N-acetyl cysteine amide, has recently been reported to reduce haloperidol-induced vacuous chewing movements in rats.73 Most recently, Thelma et al. performed a genetic association study for the several oxidative stress-related gene (SOD2, UCP2, NOS1, NOS1, NOS3, GSTM1, GSTT1, GSTP1, and NQO1) variants with the development of TD in Indian patients with schizophrenia.74 None of the polymorphisms tested were associated with the development of TD. However, they found the tendency for an association between the NOS3 variant and the severity of TD.74 Therefore, the relationships between the ROS-related genes and TD are still controversial.
Genetically determined dysfunctions of the CYP enzymes and the subsequent accumulation of drug meta-bolites significantly contribute to the development of TD. The impaired activity of the CYP2D6 enzyme was found to be associated with the adverse reactions induced by antipsychotics.13,75 CYP2D6 PM variants have been found to be associated with TD and EPS in several studies, including those in different ethnic groups.76,77,78 CYP1A2 variants also have been reported to be related to the genetic risk factors for the development of TD, as suggested by a number of positive findings.76,79 However, investigations on the CYP3A4 and CYP3A5 genes failed to find any association between these genes and TD.80,81 Our group recently evaluated the candidate functional polymorphisms of the G protein beta 3 subunit (GNB3) gene and their association with drug-induced TD in Korean patients with schizophrenia, but we could not find any association.82 Figure 1 shows the possible candidate genes for pharmacogenetic studies of antipsychotic-induced TD.
Weight gain and metabolic syndrome
Atypical antipsychotic-induced weight gain is well-recognized and has important physical and psychological consequences. Weight gain is a major reason for discontinuation or noncompliance with atypical antipsychotics. The use of antipsychotics might result in not only excessive weight gain but also metabolic sequelae, such as dyslipidemia, glucose dysregulation, and the metabolic syndrome. Obesity and weight gain in adulthood have been associated with significant health complications, such as type II diabetes, coronary heart disease, stroke, sleep apnea, and some types of cancer.83 Substantial weight gain may also adversely affect the patient's self-esteem, social functioning and physical activity.84
Clozapine and olanzapine, in particular, may induce profound weight gain, although among other classical and atypical antipsychotics, few are free of this effect.83 One meta-analysis of antipsychotic use and weight gain found that clozapine and olanzapine use were associated with an average increase in body weight of 9.9 pounds and 9.2 pounds, respectively, while those treated with risperidone or ziprasidone gained an average of 4.7 and 0.9 pounds, respectively.85
The underlying mechanisms by which these medications cause weight gain remain unclear. However, there appears to be considerable variability among patients in the propensity to gain weight due to the use of an antipsychotic. It is likely that this variability in weight gain is influenced by biological susceptibility, including genetic factors. Serotonin and histamine receptors play important roles in eating behavior and are promising candidate genes for these studies. The adrenergic system is also thought to play an important role in regulating energy balance via thermogenesis and lipid mobilization in adipose tissue. Genetic variation in these receptors could alter lipolytic activity and contribute to weight alterations during antipsychotic treatment. The candidate genes that are proposed to be related to antipsychotic-induced weight gain are the 5-HT2C receptor gene,86,87 histamine receptor gene,88 and leptin gene.89,90
Yuan et al. reported that the -759C/T polymorphism of the HTR2C gene was related to late-onset diabetes and obesity in a normal population.87 Reynolds et al. was the first to show a protective effect of the variant T allele of the -759C/T polymorphism of the HTR2C gene in patients with schizophrenia receiving chlorpromazine and risperidone for 6 weeks.86 They also reported that the T allele was more prevalent in schizophrenic patients who received clozapine for 6 months but did not gain significant weight.91 This variant has been reported to influence transcriptional activity, with the -759 C allele showing comparatively less activity.92 Although many studies replicated this finding in different population groups,90,93 a number of studies failed to replicate this finding.94,95,96,97 Very recently, De Luca et al. used meta-analytical techniques to investigate the association between the -759C/T polymorphism and weight gain resulting from the use of various antipsychotics.98 From 10 published reports they found a slight association between the -759C/T polymorphism and weight gain, but also found significant heterogeneity between the studies. Therefore, this relationship remains controversial. In Korea, Ryu et al. reported that the -759C/T polymorphism of the HTR2C gene and only the early-phase (4-weeks) weight gain were associated with antipsychotic use (including olanzapine) in subjects who were receiving many types of antipsychotics (risperidone, olanzapine, quetiapine, amisulpride, haloperidol, and trifluoperazine).99 However, our group found no evidence of an association between the -759C/T polymorphism of the HTR2C gene and weight gain after long-term treatment with olanzapine in Korean patients with schizophrenia.100
The leptin gene, which is located at chromosome 7q31.3, encodes a 3.5 kb cDNA and has three exons and two introns.101,102 Many single nucleotide polymorphisms (SNPs) of the leptin gene have been extensively studied. In recent studies of French,103 North American,104 and Asian105 populations, a polymorphism in the promoter region (-2548A/G) of the leptin gene was associated with obesity. The -2548G allele was more frequent in the overweight group in both studies. There were three previous studies that examined the association of the -2548A/G SNP of the leptin gene with antipsychotic-induced weight gain. Zhang et al. reported that the -2548 AA genotype may be a genetic risk factor for the development of weight gain in 128 Chinese Han patients with schizophrenia during treatment with antipsychotics.89 However, Templeman et al. investigated the same association in 73 Spanish Caucasian patients and reported that patients with the GG genotype of the -2548A/G SNP tended to exhibit greater changes in body mass index (BMI) than those with the AA or AG genotypes.90 They suggested that racial variations could affect the relationship between leptin gene polymorphisms and weight gain. Ryu et al. recently examined the association in 71 Korean patients with schizophrenia and reported that no association was found after 4 and 8 weeks of treatment with various antipsychotics.106 However, the duration of exposure to antipsychotics was too short to evaluate the genetic effects on drug-induced weight gain. Our group recently found that the AG genotype of the -2548A/G SNP of the leptin gene was associated with body weight gain during olanzapine treatment.107 However, the functional effect of this polymorphism has yet to be determined.
Wang et al. reported that the G variant of the -1291 C/G promoter polymorphism in the alpha-2 adrenergic receptor gene (ADRA2A) was significantly associated with clozapine-induced weight gain.108 Our group also reported that this SNP of ADRA2A was associated with olanzapine-induced weight gain.109 As the functional effect of this polymorphism is currently unknown, it is only possible to hypothesize that this polymorphism influences the adrenergic-mediated thermogenetic and lipolityc activity. Although the beta 3 adrenergic receptor gene has been regarded as a good candidate gene, its polymorphism did not contribute to clozapine-induced weight gain in a previous study.110 There is no strong evidence to suggest a connection between other serotonin (5-HT2A, 5-HT6) variants and antipsychotic-related weight gain. Although there were several reports of a relationship between the GNB3 gene and drug-induced weight gain,111,112 our group could not replicate this finding in a sample receiving long-term treatment with olanzapine.113
A linkage study of weight change in patients undergoing treatment with classical antipsychotics identified a suggestive linkage (Lod score=2.74) at 12q24.114 The pro-melanin-concentrating hormone gene, which is involved in the control of eating behavior and energy regulation, is located near this locus. Therefore, it may be a potential candidate gene for antipsychotic-induced weight gain.
Interestingly, a recent study found differences in genetic patterns associated with weight gain in olanzapine and risperidone treatment. The weight profiles of patients treated with olanzapine were significantly associated with peripheral lipid homeostatic axes genes, whereas the weight profiles in patients treated with risperidone were significantly associated with the genes in the brain appetite peptide regulation.115 This report suggests that there may be drug-specific factors contributing to weight gain in addition to the common factors shared by all antipsychotics.
Restless legs syndrome
Restless legs syndrome (RLS) is characterized by an unpleasant leg sensation and urge to move that is often undiagnosed or misdiagnosed as a psychiatric, other neurological, muscular, or orthopedic condition. A recent survey from Europe and the USA showed the correct diagnosis of RLS by general physicians to be less than 7% of the cases diagnosed by specialists.116,117 RLS is also frequently observed in schizophrenic patients who take antipsychotics. Our group found that the prevalence of RLS was 21.4% and was more than two times higher in the schizophrenics than in the control group.118 RLS has been known to have a genetic cause. Five susceptibility loci (12q, 14q, 9p, 2q, and 20p) for RLS have been identified by linkage studies.119,120,121,122,123,124,125
Only a small proportion of patients who are exposed to treatment with antipsychotics develop RLS, which suggests that the susceptibility to RLS differs between individuals. The difference in susceptibility could be attributed to biological factors, including genetic vulnerability. Although RLS is considered to have a significant genetic etiology, very few association studies have been performed on this subject. Desautels et al. investigated eight genes coding for receptors and enzymes related to the neurotransmission-related genes,126 and they found that the monoamine oxidase A (MAOA) gene might only be involved in the severity of RLS in females.127 Very recently, our group performed genetic studies for antipsychotic-induced RLS. We investigated several gene variants of the dopamine D1-4 (DRD1-DRD4), dopamine transporter gene, monoamine oxidase A and B, and G protein beta3 subunit gene (GNB3). We found significant results only in the GNB3, DRD1, and DRD4 gene variants, but they were very weak.128,129
Agranulocytosis
Clozapine, an atypical antipsychotic used in the treatment of refractory schizophrenia, causes agranulocytosis in 0.7% of patients.130 The risk factors and underlying mechanisms of clozapine-induced agranulocytosis remain unclear. Although only a small percentage of clozapine-treated patients develop this adverse effect, agranulocytosis is a great barrier to the prescription of this drug due to its potentially lethal effect. Immune-mediated toxicity is one of the possible causes of agranulocytosis by clozapine. Several studies have reported that agranulocytosis was associated with the major histocompatibility complex.131,132,133 Oxidative stress also has been suggested a potential cause of agranulocytosis. A genetic variant of the Myeloperoxidase (MPO) gene was found to be related to clozapine-induced agranulocytosis.134 Varients of NOQ1, the oxidative gene involved in the detoxification of drugs, were associated with clozapine-induced agranulocytosis.135 Cytokine gene polymorphisms were also found in higher frequencies in patients presenting with agranulocytosis.136
Conclusion
Pharmacogenetic study findings constitute a great advance towards the future tailoring of antipsychotic treatment to the individual patient. Although they are still at early stages, preliminary studies have proven that the prediction of antipsychotic-related side effects using genetic information may be feasible, and prototype tests, such as the
AmpliChip®, are currently underway. In addition to candidate gene approaches, pharmacogenomic approach studies to identify novel proteins and pathways that intervene during antipsychotic treatment are needed. Furthermore, epigenetic approaches are also necessary and are expected to be associated with antipsychotic response variability. Epigenetic alterations of response-related genes, such as dopamine and serotonin, have been previously suggested.137,138 and differences in DNA methylation in the regulatory regions of the D2 and COMT genes have been identified.139 Some studies have shown that clozapine and haloperidol induce distinct patterns of phosphorylation of gene expression controlling kinases in the dorsal striatum, indicating a possible explanation for their difference in antipsychotic activity.140 Those kinds of novel approaches to pharmacogenomic studies will undoubtedly improve our knowledge on the determinants of the variability in antipsychotic-related side effects.
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