online © ML Comm 0REVIEW ARTICLE0 Psychiatry Investig 2007;4:66-75 Print ISSN 1738-3684 / On-line ISSN 1976-3026 Pharmacogenetic Studies Investigating the Adverse Effects of Antipsychotics 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 predic- tion 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 symp- toms 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. 66 www.psychiatryinvestigation.org ⓒ 2007 Official Journal of Korean Neuropsychiatric Association 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 phar- macogenetic 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 www.psychiatryinvestigation.org 67 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