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Pharmacodynamic gene polymorphism and adverse drug reactionsthen applying antipsychotic drugs


Application of antipsychotic drugs of both the first and subsequent generations quite often causes adverse side effects, which can reduce the compliance to the treatment of patients, reducing their quality of life. One of the most serious NLRs that occur during the period of application of antipsychotic disorders in patients are extrapyramidal disorders (acute dystonia, dyskinesia), malignant neuroleptic syndrome and tardive dyskinesia. During the year of therapy with the use of antipsychotic drugs of the first generation, signs of late dyskinesia appear in 3 to 5% of patients, and in elderly patients this figure is 5 times higher.

The achievement of recent years in medicine is the application of the pharmacogenetic approach for predicting the patient’s individual response to taking the drug.

Recent advances in medicine is the practice of pharmacogenetic approach to predict the patient’s individual response to receiving the drug. The pharmacogenetic approach to the prescription of medicines is based on the study of the effect of polymorphism of genes encoding the synthesis of isoenzymes of biotransformation and transport of xenobiotics, as well as the synthesis of elements responsible for the pharmacodynamic component.

In this article, we will attempt to describe the main adverse side effects arising from the use of antipsychotic drugs, as well as consider pharmacogenetic aspects of their appearance, to summarize the relevant information currently available. arisingfrom the use of antipsychotic drugs, as well as consider pharmacogenetic aspects of their appearance, to summarize the relevant information currently available.

About the Authors

Mikhail S. Zastrozhin

Russian Medical Academy of Continuous Professional Education; Moscow Research and Practical Centre for Narcology of the Department of Public Health

Russian Federation


Dmitry A. Sychev

Russian Medical Academy of Continuous Professional Education

Russian Federation

MD, PhD, Professor

Elena A. Grishina

Russian Medical Academy of Continuous Professional Education

Russian Federation

MD, PhD, professor associate

Ludmila M. Savchenko

Russian Medical Academy of Continuous Professional Education

Russian Federation

MD, PhD, professor associate

Evgeny A. Bryun

Russian Medical Academy of Continuous Professional Education; Moscow Research and Practical Centre for Narcology of the Department of Public Health

Russian Federation

MD, PhD, professor


1. Casey DE. Neuroleptic drug-induced extrapyramidal syndromes and tardive dyskinesia. Schizophr Res. 1991;4(2):109-120. doi: 10.1016/0920-9964(91)90029-q

2. Kane J, Woerner M, Lieberman J. Tardive Dyskinesia. Journal of ClinicalPsychopharmacology. 1988;8(SUPPLENENT):57S. doi:10.1097/00004714-198808001-00010.

3. Jeste DV, Caligiuri MP. Tardive Dyskinesia. Schizophr Bull. 1993;19(2):303-315. doi: 10.1093/schbul/19.2.303

4. Ascher-Svanum H, Zhu B, Faries D, et al. Tardive Dyskinesia and the 3-Year Course of Schizophrenia. The Journal of Clinical Psychiatry. 2008;69(10):1580-1588. doi: 10.4088/JCP.v69n1008.

5. Tandon R, Belmaker RH, Gattaz WF, et al. World Psychiatric Association Pharmacopsychiatry Section statement on comparative effectiveness of antipsychotics in the treatment of schizophrenia. Schizophr Res. 2008;100(1-3):20-38. doi: 10.1016/j.schres.2007.11.033

6. Lehman AF, Lieberman JA, Dixon LB, et al. Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry. 2004;161(2 Suppl):1-56.

7. Kane JM. Tardive dyskinesia rates with atypical antipsychotics in adults: prevalence and incidence.J Clin Psychiatry. 2004;65Suppl 9:16-20.

8. Correll CU, Leucht S, Kane JM. Lower risk for tardive dyskinesia associated with second-generation antipsychotics: a systematic review of 1-year studies. Am J Psychiatry. 2004;161(3):414-425. doi: 10.1176/appi.ajp.161.3.414

9. Kane JM, Fleischhacker WW, Hansen L, et al. Akathisia: an updated review focusing on second-generation antipsychotics. J Clin Psychiatry. 2009;70(5):627-643. doi: 10.4088/JCP.08r04210

10. Leucht S, Wahlbeck K, Hamann J, Kissling W. New generation antipsychotics versus low-potency conventional antipsychotics: a systematic review and meta-analysis. The Lancet. 2003;361(9369):1581-1589. doi: 10.1016/s0140-6736(03)13306-5

11. Miller DD, Caroff SN, Davis SM, et al. Extrapyramidal side-effects of antipsychotics in a randomised trial. Br J Psychiatry. 2008;193(4):279-288. doi: 10.1192/bjp.bp.108.050088

12. Leucht S, Corves C, Arbter D, et al. Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. The Lancet. 2009;373(9657):31-41. doi: 10.1016/s0140-6736(08)61764-x

13. Kapur S, Mamo D. Half a century of antipsychotics and still a central role for dopamine D2 receptors. Prog Neuropsychopharmacol Biol Psychiatry. 2003;27(7):1081-1090. doi: 10.1016/j.pnpbp.2003.09.004

14. Parsons B, Allison DB, Loebel A, et al. Weight effects associated with antipsychotics: A comprehensive database analysis. Schizophr Res. 2009;110(1-3):103-110. doi: 10.1016/j.schres.2008.09.025

15. Kane JM, Barrett EJ, Casey DE, et al. Metabolic Effects of Treatment With Atypical Antipsychotics. The Journal of Clinical Psychiatry. 2004;65(11):1447-1455. doi: 10.4088/JCP.v65n1102

16. Allison DB, Mentore JL, Heo M, et al. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry. 1999;156(11):1686-1696. doi: 10.1176/ajp.156.11.1686

17. Kahn RS, Fleischhacker WW, Boter H, et al. Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: an open randomised clinical trial. The Lancet. 2008;371(9618):1085-1097. doi: 10.1016/S0140-6736(08)60486-9

18. Correll CU. Balancing efficacy and safety in treatment with antipsychotics. CNS Spectr. 2007;12(10 Suppl 17):12-20, 35.

19. Correll CU. Monitoring and management of antipsychotic-related metabolic and endocrine adverse events in pediatric patients. Int Rev Psychiatry. 2008;20(2):195-201. doi: 10.1080/09540260801889179

20. Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353(12):1209-1223. doi: 10.1056/NEJMoa051688

21. Neville MJ, Johnstone EC, Walton RT. Identification and characterization of ANKK1: a novel kinase gene closely linked to DRD2 on chromosome band 11q23.1. Hum Mutat. 2004;23(6):540-545. doi: 10.1002/humu.20039

22. Thompson J, Thomas N, Singleton A, et al. D2 dopamine receptor gene (DRD2) Taql A polymorphism: reduced dopamine D2 receptor binding in the human striatum associated with the A1 allele. Pharmacogenetics. 1997;7(6):479-484. doi: 10.1097/00008571-199712000-00006

23. Pohjalainen T, Rinne JO, Någren K, et al. The A1 allele of the human D2 dopamine receptor gene predicts low D2 receptor availability in healthy volunteers. MolPsychiatry. 1998;3(3):256-260. doi: 10.1038/

24. Zai CC, De Luca V, Hwang RW, et al. Meta-analysis of two dopamine D2 receptor gene polymorphisms with tardive dyskinesia in schizophrenia patients. Mol Psychiatry. 2007;12(9):794-795. doi: 10.1038/

25. Bakker PR, van Harten PN, van Os J. Antipsychotic-induced tardive dyskinesia and polymorphic variations in COMT, DRD2, CYP1A2 and MnSOD genes: a meta-analysis of pharmacogenetic interactions. Mol Psychiatry. 2008;13(5):544-556. doi: 10.1038/

26. Schwartz JC, Diaz J, Pilon C, Sokoloff P. Possible implications of the dopamine D(3) receptor in schizophrenia and in antipsychotic drug actions. Brain Res Brain Res Rev. 2000;31(2-3):277-287.

27. Schwartz JC, Levesque D, Martres MP, Sokoloff P. Dopamine D3 receptor: basic and clinical aspects. ClinNeuropharmacol. 1993;16(4):295-314.

28. Lundstrom K, Turpin MP. Proposed schizophrenia-related gene polymorphism: expression of the Ser9Gly mutant human dopamine D3 receptor with the Semliki Forest virus system. Biochem Biophys Res Commun. 1996;225(3):1068-1072. doi: 10.1006/bbrc.1996.1296

29. Jeanneteau F, Funalot B, Jankovic J, et al. A functional variant of the dopamine D3 receptor is associated with risk and age-at-onset of essential tremor. Proc Natl Acad Sci U S A. 2006;103(28):10753-10758. doi: 10.1073/pnas.0508189103

30. Malhotra AK, Goldman D, Buchanan RW, et al. The dopamine D3 receptor (DRD3) Ser9Gly polymorphism and schizophrenia: a haplotype relative risk study and association with clozapine response. Mol Psychiatry. 1998;3(1):72-75.

31. Xuan J, Zhao X, He G, et al. Effects of the dopamine D3 receptor (DRD3) gene polymorphisms on risperidone response: a pharmacogenetic study. Neuropsychopharmacology. 2008;33(2):305-311. doi: 10.1038/sj.npp.1301418

32. Xiao R, Boehnke M. Quantifying and correcting for the winner’s curse in genetic association studies. Genet Epidemiol. 2009;33(5):453-462. doi: 10.1002/gepi.20398

33. Tsai HT, Caroff SN, Miller DD, et al. A candidate gene study of Tardive dyskinesia in the CATIE schizophrenia trial. Am J Med Genet B Neuropsychiatr Genet. 2010;153B(1):336-340. doi: 10.1002/ajmg.b.30981

34. Mannisto PT, Ulmanen I, Lundstrom K, et al. Characteristics of catechol O-methyl-transferase (COMT) and properties of selective COMT inhibitors. Prog Drug Res. 1992;39:291-350.

35. Lachman HM, Papolos DF, Saito T, et al. Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics. 1996;6(3):243-250.

36. Farde L, Nyberg S, Oxenstierna G, et al. Positron Emission Tomography Studies on D2 and 5-HT2 Receptor Binding in Risperidone-Treated Schizophrenic Patients. J Clin Psychopharmacol. 1995;15(1):19S-23S.

37. Kapur S, Zipursky RB, Remington G, et al. 5-HT2 and D2 receptor occupancy of olanzapine in schizophrenia: a PET investigation. Am J Psychiatry. 1998;155(7):921-928. doi: 10.1176/ajp.155.7.921

38. Rasmussen K, Aghajanian GK. Potency of antipsychotics in reversing the effects of a hallucinogenic drug on locus coeruleus neurons correlates with 5-HT2 binding affinity. Neuropsychopharmacology. 1988;1(2):101-107.

39. Trichard C, Paillere-Martinot ML, Attar-Levy D, et al. Binding of antipsychotic drugs to cortical 5-HT2A receptors: a PET study of chlorpromazine, clozapine, and amisulpride in schizophrenic patients. Am J Psychiatry. 1998;155(4):505-508. doi: 10.1176/ajp.155.4.505

40. Arranz MJ, Munro J, Sham P, et al. Meta-analysis of studies on genetic variation in 5-HT2A receptors and clozapine response. Schizophr Res. 1998;32(2):93-99.

41. Lerer B, Segman RH, Tan EC, et al. Combined analysis of 635 patients confirms an age-related association of the serotonin 2A receptor gene with tardive dyskinesia and specificity for the non-orofacial subtype. Int J Neuropsychopharmacol. 2005;8(3):411-425. doi: 10.1017/S1461145705005389

42. Waeber C, Palacios JM. Binding sites for 5-hydroxytryptamine-2 receptor agonists are predominantly located in striosomes in the human basal ganglia. Brain Res Mol Brain Res. 1994;24(1-4):199-209.

43. Bishop C, Tessmer JL, Ullrich T, et al. Serotonin 5-HT2A receptors underlie increased motor behaviors induced in dopamine-depleted rats by intrastriatal 5-HT2A/2C agonism. J PharmacolExpTher. 2004;310(2):687-694. doi: 10.1124/jpet.104.066365

44. Caccia S. New antipsychotic agents for schizophrenia: pharmacokinetics and metabolism update. Curr OpinInvestig Drugs. 2002;3(7):1073-1080.

45. Bertilsson L, Dahl ML, Dalen P, Al-Shurbaji A. Molecular genetics of CYP2D6: clinical relevance with focus on psychotropic drugs. Br J ClinPharmacol. 2002;53(2):111-122. PMC1874287

46. Kobylecki CJ, Jakobsen KD, Hansen T, et al. CYP2D6 genotype predicts antipsychotic side effects in schizophrenia inpatients: a retrospective matched case-control study. Neuropsychobiology. 2009;59(4):222-226. doi: 10.1159/000223734

47. Gunes A, Scordo MG, Jaanson P, Dahl ML. Serotonin and dopamine receptor gene polymorphisms and the risk of extrapyramidal side effects in perphenazine-treated schizophrenic patients. Psychopharmacology (Berl). 2007;190(4):479-484. doi: 10.1007/s00213-006-0622-x

48. Guzey C, Scordo MG, Spina E, et al. Antipsychotic-induced extrapyramidal symptoms in patients with schizophrenia: associations with dopamine and serotonin receptor and transporter polymorphisms. Eur J Clin Pharmacol. 2007;63(3):233-241. doi: 10.1007/s00228-006-0234-8

49. Gasso P, Mas S, Bernardo M, et al. A common variant in DRD3 gene is associated with risperidone-induced extrapyramidal symptoms. Pharmacogenomics J. 2009;9(6):404-410. doi: 10.1038/tpj.2009.26

50. Greenbaum L, Strous RD, Kanyas K, et al. Association of the RGS2 gene with extrapyramidal symptoms induced by treatment with antipsychotic medication. Pharmacogenet Genomics. 2007;17(7):519-528. doi: 10.1097/FPC.0b013e32800ffbb4

51. Greenbaum L, Smith RC, Rigbi A, et al. Further evidence for association of the RGS2 gene with antipsychotic-induced parkinsonism: protective role of a functional polymorphism in the 3’-untranslated region. Pharmacogenomics J. 2009;9(2):103-110. doi: 10.1038/tpj.2008.6

52. Al Hadithy AF, Wilffert B, Bruggeman R, et al. Lack of association between antipsychotic-induced Parkinsonism or its subsymptoms and rs4606 SNP of RGS2 gene in African-Caribbeans and the possible role of the medication: the Curacao extrapyramidal syndromes study X. Hum Psychopharmacol. 2009;24(2):123-128. doi: 10.1002/hup.997

53. Compton MT, Miller AH. Antipsychotic-induced hyperprolactinemia and sexual dysfunction. Psychopharmacol Bull. 2002;36(1):143-164.

54. Eichhammer P, Albus M, Borrmann-Hassenbach M, et al. Association of dopamine D3-receptor gene variants with neuroleptic induced akathisia in schizophrenic patients: a generalization of Steen’s study on DRD3 and tardive dyskinesia. Am J Med Genet. 2000;96(2):187-191.

55. Reynolds GP, Zhang ZJ, Zhang XB. Association of antipsychotic drug-induced weight gain with a 5-HT2C receptor gene polymorphism. Balancing efficacy and safety in treatment with antipsychotics. The Lancet. 2002;359(9323):2086-2087. doi: 10.1016/S0140-6736(02)08913-4

56. Adan RA, Vanderschuren LJ, la Fleur SE. Anti-obesity drugs and neural circuits of feeding. Trends Pharmacol Sci. 2008;29(4):208-217. doi: 10.1016/

57. Davis R, Faulds D. Dexfenfluramine. Drugs. 1996;52(5):696-724. doi: 10.2165/00003495-199652050-00007

58. Reynolds GP, Zhang Z-J, Zhang X-B. Association of antipsychotic druginduced weight gain with a 5-HT2C receptor gene polymorphism. The Lancet. 2002;359(9323):2086-2087. doi: 10.1016/s0140-6736(02)08913-4

59. Miller DD, Ellingrod VL, Holman TL, et al. Clozapine-induced weight gain associated with the 5HT2C receptor -759C/T polymorphism. Am J Med Genet B Neuropsychiatr Genet. 2005;133B(1):97-100. doi: 10.1002/ajmg.b.30115

60. Reynolds GP, Zhang Z, Zhang X. Polymorphism of the promoter region of the serotonin 5-HT(2C) receptor gene and clozapine-induced weight gain. Am J Psychiatry. 2003;160(4):677-679. doi: 10.1176/appi.ajp.160.4.677

61. Ellingrod VL, Perry PJ, Ringold JC, et al. Weight gain associated with the -759C/T polymorphism of the 5HT2C receptor and olanzapine. Am J Med Genet B Neuropsychiatr Genet. 2005;134B(1):76-78. doi: 10.1002/ajmg.b.20169

62. Lane HY, Liu YC, Huang CL, et al. Risperidone-related weight gain: genetic and nongenetic predictors. J ClinPsychopharmacol. 2006;26(2):128-134. doi: 10.1097/

63. Ryu S, Cho EY, Park T, et al. -759 C/T polymorphism of 5-HT2C receptor gene and early phase weight gain associated with antipsychotic drug treatment. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31(3):673-677. doi: 10.1016/j.pnpbp.2006.12.021

64. Reynolds GP, Templeman LA, Zhang ZJ. The role of 5-HT2C receptor polymorphisms in the pharmacogenetics of antipsychotic drug treatment. Prog Neuropsychopharmacol Biol Psychiatry. 2005;29(6):1021-1028. doi: 10.1016/j.pnpbp.2005.03.019

65. Rosskopf D, Busch S, Manthey I, Siffert W. G protein beta 3 gene: structure, promoter, and additional polymorphisms. Hypertension. 2000;36(1):33-41.

66. Siffert W. G-protein beta3 subunit 825T allele and hypertension. Curr Hypertens Rep. 2003;5(1):47-53.

67. Souza RP, De Luca V, Muscettola G, et al. Association of antipsychotic induced weight gain and body mass index with GNB3 gene: a meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32(8):1848-1853. doi: 10.1016/j.pnpbp.2008.08.014

68. Perlis RH, Ganz DA, Avorn J, et al. Pharmacogenetic testing in the clinical management of schizophrenia: a decision-analytic model. J Clin Psychopharmacol. 2005;25(5):427-434.

69. Conley RR, Kelly DL. Management of treatment resistance in schizophrenia. Biol Psychiatry. 2001;50(11):898-911.

70. Templeman LA, Reynolds GP, Arranz B, San L. Polymorphisms of the 5-HT2C receptor and leptin genes are associated with antipsychotic drug-induced weight gain in Caucasian subjects with a first-episode psychosis. Pharmacogenet Genomics. 2005;15(4):195-200.


For citations:

Zastrozhin M.S., Sychev D.A., Grishina E.A., Savchenko L.M., Bryun E.A. Pharmacodynamic gene polymorphism and adverse drug reactionsthen applying antipsychotic drugs. World Journal of Personalized Medicine. 2017;1(1):5-12. (In Russ.)

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