Current Psychiatry Reports

, Volume 13, Issue 2, pp 156–165

Genetics of Antipsychotic-induced Side Effects and Agranulocytosis

  • Nabilah I. Chowdhury
  • Gary Remington
  • James L. Kennedy
Article

Abstract

Antipsychotic medication has been enormously helpful in the treatment of psychotic symptoms during the past several decades. Unfortunately, several important side effects that can cause significant morbidity and mortality. The two most common are abnormal involuntary movements (tardive dyskinesia) and weight gain progressing through diabetes to metabolic syndrome. A more rare and life-threatening adverse effect is clozapine-induced agranulocytosis (CIA), which has been linked to clozapine use. Clozapine itself has a unique position among antipsychotic medications, representing the treatment of choice in refractory schizophrenia. Unfortunately, the potential risk of agranulocytosis, albeit small, prevents the widespread use of clozapine. Very few genetic determinants have been clearly associated with CIA due to small sample sizes and lack of replication in subsequent studies. The HLA system has been the main hypothesized region of interest in the study of CIA, and several gene variants in this region have been implicated, particularly variants of the HLA-DQB1 locus. A preliminary genome-wide association study has been conducted on a small sample for CIA, and a signal from the HLA region was noted. However, efforts to identify key gene mechanisms that will be useful in predicting antipsychotic side effects in the clinical setting have not been fully successful, and further studies with larger sample sizes are required.

Keywords

Antipsychotics Agranulocytosis Clozapine-induced agranulocytosis Tardive dyskinesia Weight gain Genetics Association study Pharmacogenetics 

References

  1. 1.
    Lencz T, Malhotra AK. Pharmacogenetics of antipsychotic-induced side effects. Dialogues Clin Neurosci. 2009;11:405–15.PubMedGoogle Scholar
  2. 2.
    Gebhardt S, Theisen FM, Haberhausen M, et al. Body weight gain induced by atypical antipsychotics: an extension of the monozygotic twin and sib pair study. J Clin Pharm Ther. 2010;35(2):207–11.PubMedCrossRefGoogle Scholar
  3. 3.
    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):540–5.PubMedCrossRefGoogle Scholar
  4. 4.
    Zai CC, Romano-Silva MA, Hwang R, et al. Genetic study of eight AKT1 gene polymorphisms and their interaction with DRD2 gene polymorphisms in tardive dyskinesia. Schizophr Res. 2008;106(2–3):248–52.PubMedCrossRefGoogle Scholar
  5. 5.
    Thompson J, Thomas N, Singleton A. et al,: D2 dopamine receptor gene (DRD2) Taq1A polymorphism: reduced dopamine D2 receptor binding in the human striatum associated with the A1 allele. Pharmacogenetics. 1997;7:479–84.PubMedCrossRefGoogle Scholar
  6. 6.
    Pohjalainen T, Rinne JO, NÂgren K, et al. The A1 allele of the human D2 dopamine receptor gene predicts low D2 receptor availability in healthy volunteers. Mol Psychiatry. 1998;3:256–60.PubMedCrossRefGoogle Scholar
  7. 7.
    Schwartz JC, Diaz J, Pilon C, Sokoloff P. Possible implications of the dopamine D receptor in schizophrenia and in antipsychotic drug actions. Brain Res Brain Res Rev. 2000;31:277–87.PubMedCrossRefGoogle Scholar
  8. 8.
    Schwartz JC, Levesque D, Martres MP, et al. Dopamine D3 receptor: basic and clinical aspects. Clin Neuropharmacol. 1993;16:295–314.PubMedCrossRefGoogle Scholar
  9. 9.
    Badri F, Masellis M, Petronis A, et al. Dopamine and serotonin system genes may predict clinical response to clozapine. Proceedings of the 46th Annual Meeting of the American Society of Human Genetics, vol 59. San Francisco, American Journal of Human Genetics, 1996. p A247.Google Scholar
  10. 10.
    Steen VM, Løvlie R, MacEwan T, et al. Dopamine D3-receptor gene variant and susceptibility to tardive dyskinesia in schizophrenic patients. Mol Psychiatry. 1997;2(2):139–45.PubMedCrossRefGoogle Scholar
  11. 11.
    Basile V, Masellis M, Badri F, et al. Association of the MscI polymorphism of the dopamine D3 receptor gene with tardive dyskinesia in Schizophrenia. Neuropsychopharmacology. 1999;21(1):17–27.PubMedCrossRefGoogle Scholar
  12. 12.
    Lerer B, Segman RH, Fangerau H, et al. Pharmacogenetics of tardive dyskinesia: combined analysis of 780 patients supports association with dopamine D3 receptor gene Ser9Gly polymorphism. Neuropsychopharmacology. 2002;27(1):105–19.PubMedCrossRefGoogle Scholar
  13. 13.
    Szekeres G, Kéri S, Juhász A, et al. Role of dopamine D3 receptor (DRD3) and dopamine transporter (DAT) polymorphism in cognitive dysfunctions and therapeutic response to atypical antipsychotics in patients with schizophrenia. Am J Med Genet B Neuropsychiatr Genet. 2004;124B(1):1–5.PubMedCrossRefGoogle Scholar
  14. 14.
    Lane HY, Hsu SK, Liu YC, et al. Dopamine D3 receptor Ser9Gly polymorphism and risperidone response. J Clin Psychopharmacol. 2005;25(1):6–11.PubMedCrossRefGoogle Scholar
  15. 15.
    Tsai HT, North KE, West SL, et al. The DRD3 rs6280 polymorphism and prevalence of tardive dyskinesia: a meta-analysis. Am J Med Genet B Neuropsychiatr Genet. 2010;153B(1):57–66.PubMedGoogle Scholar
  16. 16.
    Zai CC, Tiwari AK, De Luca V, et al. Genetic study of BDNF, DRD3, and their interaction in tardive dyskinesia. Eur Neuropsychopharmacol. 2009;19(5):317–28.PubMedCrossRefGoogle Scholar
  17. 17.
    Männistö PT, Ulmanen I, Lundström K, et al. Characteristics of catechol O-methyl-transferase (COMT) and properties of selective COMT inhibitors. Prog Drug Res. 1992;39:291–350.PubMedGoogle Scholar
  18. 18.
    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):544–56.PubMedCrossRefGoogle Scholar
  19. 19.
    Hori H, Ohmori O, Shinkai T, et al. Manganese superoxide dismutase gene polymorphism and schizophrenia: relation to tardive dyskinesia. J Neuropsychopharmacology. 2000;23(2):170–7.CrossRefGoogle Scholar
  20. 20.
    Hitzeroth A, Niehaus DJ, Koen L, et al. Association between the MnSOD Ala-9 Val polymorphism and development of schizophrenia and abnormal involuntary movements in the Xhosa population. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31(3):664–72.PubMedCrossRefGoogle Scholar
  21. 21.
    Kang SG, Choi JE, An H, et al. Manganese superoxide dismutase gene Ala- 9Val polymorphism might be related to the severity of abnormal involuntary movements in Korean schizophrenic patients. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32(8):1844–7.PubMedCrossRefGoogle Scholar
  22. 22.
    Zai CC, Tiwari AK, Basile V, de Luca V, et al. Oxidative stress in tardive dyskinesia: genetic association study and meta-analysis of NADPH quinine oxidoreductase 1 (NQO1) and Superoxide dismutase 2 (SOD2, MnSOD) genes. Prog Neuropsychopharmacol Biol Psychiatry. 2010;34(1):50–6.PubMedCrossRefGoogle Scholar
  23. 23.
    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):411–25.PubMedCrossRefGoogle Scholar
  24. 24.
    Basile VS, Ozdemir V, Masellis M, et al. Lack of association between serotonin-2A receptor gene (HTR2A) polymorphisms and tardive dyskinesia in schizophrenia. Mol Psychiatry. 2001;6(2):230–4.PubMedCrossRefGoogle Scholar
  25. 25.
    Patsopoulos NA, Ntzani EE, Zintzaras E, et al. CYP2D6 polymorphisms and the risk of tardive dyskinesia in schizophrenia: a meta-analysis. Pharmacogenet Genomics. 2005;15(3):151–8.PubMedCrossRefGoogle Scholar
  26. 26.
    Allison DB, Mentore JL, Heo M, et al. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry. 1999;156(11):1686–96.PubMedGoogle Scholar
  27. 27.
    Müller DJ, Kennedy JL. Genetics of antipsychotic treatment emergent weight gain in schizophrenia. Pharmacogenomics. 2006;7(6):863–87.PubMedCrossRefGoogle Scholar
  28. 28.
    Reynolds GP, Zhang ZJ, Zhang XB. Association of antipsychotic drug-induced weight gain with a 5-HT2C receptor gene polymorphism. Lancet. 2002;359(9323):2086–7.PubMedCrossRefGoogle Scholar
  29. 29.
    De Luca V, Mueller DJ, de Bartolomeis A, et al. Association of the HTR2C gene and antipsychotic induced weight gain: a meta-analysis. Int J Neuropsychopharmacol. 2007;10(5):697–704.PubMedGoogle Scholar
  30. 30.
    Sicard MN, Zai CC, Tiwari AK, et al. Polymorphisms of the HTR2C gene and antipsychotic-induced weight gain: an update and meta-analysis. Pharmacogenomics. 2010;11(11):1561–71.PubMedCrossRefGoogle Scholar
  31. 31.
    Mammès O, Betoulle D, Aubert R, et al. Novel polymorphisms in the 59 region of the LEP gene: association with leptin levels and response to low-calorie diet in human obesity. Diabetes. 1998;47:487–9.PubMedCrossRefGoogle Scholar
  32. 32.
    Templeman LA, Reynolds GP, Arranz B, et al. 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.PubMedCrossRefGoogle Scholar
  33. 33.
    Zhang XY, Tan YL, Zhou DF, et al. Association of clozapine-induced weight gain with a polymorphism in the leptin promoter region in patients with chronic schizophrenia in a Chinese population. J Clin Psychopharmacol. 2007;27(3):246–51.PubMedCrossRefGoogle Scholar
  34. 34.
    Sickert L, Müller DJ, Tiwari AK, et al. Association of the alpha 2A adrenergic receptor -1291C/G polymorphism and antipsychotic-induced weight gain in European-Americans. Pharmacogenomics. 2009;10(7):1169–76.PubMedCrossRefGoogle Scholar
  35. 35.
    Risselada AJ, Vehof J, Bruggeman R, et al. Association between the 1291-C/G polymorphism in the adrenergic α-2a receptor and the metabolic syndrome. J Clin Psychopharmacol. 2010;30(6):667–71.PubMedCrossRefGoogle Scholar
  36. 36.
    Mosyagin I, Cascorbi I, Schaub R, et al. Drug-induced agranulocytosis: impact of different fcgamma receptor polymorphisms? J Clin Psychopharmacol. 2005;25(5):435–40.PubMedCrossRefGoogle Scholar
  37. 37.
    Flanagan RJ, Dunk L. Haematological toxicity of drugs used in psychiatry. Hum Psychopharmacol. 2008;1:27–41.CrossRefGoogle Scholar
  38. 38.
    Furst SM, Uetrecht JP. Carbamazepine metabolism to a reactive intermediate by the myeloperoxidase system of activated neutrophils. Biochem Pharmacol. 1993;45(6):1267–75.PubMedCrossRefGoogle Scholar
  39. 39.
    Baldessarini RJ, Frankenburg FR. Clozapine. A novel antipsychotic agent. N Engl J Med. 1991;324(11):746–54.PubMedCrossRefGoogle Scholar
  40. 40.
    Crilly J. The history of clozapine and its emergence in the US market: a review and analysis. Hist Psychiatry. 2007;18(1):39–60.PubMedCrossRefGoogle Scholar
  41. 41.
    Meltzer H. Atypical antipsychotic drugs, Psychopharmacology: the Fourth Generation of Progress. New York: Raven; 1995.Google Scholar
  42. 42.
    Kane J, Honigfeld G, Singer J, et al. Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry. 1988;45(9):789–96.PubMedGoogle Scholar
  43. 43.
    Alvir JM, Lieberman JA, Safferman AZ, et al. Clozapine-induced agranulocytosis. Incidence and risk factors in the United States. N Engl J Med. 1993;329(3):162–7.PubMedCrossRefGoogle Scholar
  44. 44.
    Ibáñez L, Vidal X, Ballarín E, et al. Population-based drug-induced agranulocytosis. Arch Intern Med. 2005;165(8):869–74.PubMedCrossRefGoogle Scholar
  45. 45.
    Meltzer HY, Davidson M, Glassman AH, et al. Assessing cardiovascular risks versus clinical benefits of atypical antipsychotic drug treatment. J Clin Psychiatry. 2002;9:25–9.Google Scholar
  46. 46.
    Meltzer HY, Bastani B, Kwon KY, et al. A prospective study of clozapine in treatment-resistant schizophrenic patients. I. Preliminary report. Psychopharmacology. 1989;99(Suppl):S68–72.PubMedCrossRefGoogle Scholar
  47. 47.
    Davis JM, Chen N, Glick ID. A meta-analysis of the efficacy of second-generation antipsychotics. Arch Gen Psychiatry. 2003;60(6):553–64.PubMedCrossRefGoogle Scholar
  48. 48.
    Brenner HD, Dencker SJ, Goldstein MJ, et al. Defining treatment refractoriness in schizophrenia. Schizophr Bull. 1990;16(4):563–5.Google Scholar
  49. 49.
    Chung WH, Hung SI, Hong HS, et al. Medical genetics: a marker for Stevens-Johnson syndrome. Nature. 2004;428(6982):486.PubMedCrossRefGoogle Scholar
  50. 50.
    Pereira A, Dean B. Clozapine bioactivation induces dose-dependent, drug-specific toxicity of human bone marrow stromal cells: a potential in vitro system for the study of agranulocytosis. Biochem Pharmacol. 2006;72(6):783–93.PubMedCrossRefGoogle Scholar
  51. 51.
    Pirmohamed M, Kitteringham NR, et al. Polymorphism in gene for microsomal epoxide hydrolase and lung disease. Lancet. 1997;350(9090):1553–4.PubMedCrossRefGoogle Scholar
  52. 52.
    Dettling M, Sachse C, Müller-Oerlinghausen B, et al. Clozapine-induced agranulocytosis and hereditary polymorphisms of clozapine metabolizing enzymes: no association with myeloperoxidase and cytochrome P4502D6. Pharmacopsychiatry. 2000;33(6):218–20.PubMedCrossRefGoogle Scholar
  53. 53.
    Gardner I, Popović M, Zahid N, et al. A comparison of the covalent binding of clozapine, procainamide, and vesnarinone to human neutrophils in vitro and rat tissues in vitro and in vivo. Chem Res Toxicol. 2005;18(9):1384–94.PubMedCrossRefGoogle Scholar
  54. 54.
    Hsuanyu Y, Dunford HB. Oxidation of clozapine and ascorbate by myeloperoxidase. Arch Biochem Biophys. 1999;368(2):413–20.PubMedCrossRefGoogle Scholar
  55. 55.
    Mosyagin I, Dettling M, Roots I, et al. Impact of myeloperoxidase and NADPH-oxidase polymorphisms in drug-induced agranulocytosis. J Clin Psychopharmacol. 2004;24(6):613–7.PubMedCrossRefGoogle Scholar
  56. 56.
    Husain Z, Almeciga I, Delgado JC, et al. Increased FasL expression correlates with apoptotic changes in granulocytes cultured with oxidized clozapine. Toxicol Appl Pharmacol. 2006;214(3):326–34.PubMedCrossRefGoogle Scholar
  57. 57.
    de la Chapelle A, Kari C, Nurminen M, et al. Clozapine-induced agranulocytosis. A genetic and epidemiologic study. Hum Genet. 1977;37(2):183–94.PubMedCrossRefGoogle Scholar
  58. 58.
    Amsler HA, Teerenhovi L, Barth E, et al. Agranulocytosis in patients treated with clozapine. A study of the Finnish epidemic. Acta Psychiatr Scand. 1977;56(4):241–8.PubMedCrossRefGoogle Scholar
  59. 59.
    Lieberman JA, Yunis J, Egea E, et al. HLA-B38, DR4, DQw3 and clozapine-induced agranulocytosis in Jewish patients with schizophrenia. Arch Gen Psychiatry. 1990;47(10):945–8.PubMedGoogle Scholar
  60. 60.
    Yunis JJ, Corzo D, Salazar M, Lieberman, et al. HLA associations in clozapine-induced agranulocytosis. Blood. 1995;86(3):1177–83.PubMedGoogle Scholar
  61. 61.
    Valevski A, Klein T, Gazit E, et al. HLA-B38 and clozapine-induced agranulocytosis in Israeli Jewish schizophrenic patients. European Journal of Immunogenetics: Official Journal of the British Society for Histocompatibility and Immunogenetics. 1998;25(1):11–3.Google Scholar
  62. 62.
    Amar A, Segman RH, Shtrussberg S, et al. An association between clozapine-induced agranulocytosis in schizophrenics and HLA-DQB1*0201. Int J Neuropsychopharmacol. 1998;1(1):41–4.PubMedCrossRefGoogle Scholar
  63. 63.
    Dettling M, Schaub RT, Mueller-Oerlinghausen B, et al. Further evidence of human leukocyte antigen-encoded susceptibility to clozapine-induced agranulocytosis independent of ancestry. Pharmacogenetics. 2001;11(2):135–41.PubMedCrossRefGoogle Scholar
  64. 64.
    Dettling M, Cascorbi I, Opgen-Rhein C, et al. Clozapine-induced agranulocytosis in schizophrenic Caucasians: confirming clues for associations with human leukocyte class I and II antigens. Pharmacogenomics J. 2007;7(5):325–32.PubMedCrossRefGoogle Scholar
  65. 65.
    Miretti MM, Walsh EC, Ke X, et al. A high-resolution linkage-disequilibrium map of the human major histocompatibility complex and first generation of tag single-nucleotide polymorphisms. Am J Hum Genet. 2005;76(4):634–46.PubMedCrossRefGoogle Scholar
  66. 66.
    Opgen-Rhein C, Dettling M. Clozapine-induced agranulocytosis and its genetic determinants. Pharmacogenomics. 2008;9(8):1101–11.PubMedCrossRefGoogle Scholar
  67. 67.
    Yokoyama T, Hyodo M, Hosoya Y, et al. Aggressive G-CSF-producing gastric cancer complicated by lung and brain abscesses, mimicking metastases. Gastric Cancer. 2005;8(3):198–201.PubMedCrossRefGoogle Scholar
  68. 68.
    Hägg S, Rosenius S, Spigset O. Long-term combination treatment with clozapine and filgrastim in patients with clozapine-induced agranulocytosis. Int Clin Psychopharmacol. 2003;18(3):173–4.PubMedCrossRefGoogle Scholar
  69. 69.
    Lamberti JS, Bellnier TJ, Schwarzkopf SB. Filgrastim treatment of three patients with clozapine-induced agranulocytosis. J Clin Psychiatry. 1995;56(6):256–9.PubMedGoogle Scholar
  70. 70.
    Nielsen H. Recombinant human granulocyte colony-stimulating factor (rhG-CSF; filgrastim) treatment of clozapine-induced agranulocytosis. J Intern Med. 1993;234(5):529–31.PubMedCrossRefGoogle Scholar
  71. 71.
    Athanasiou MC, Cascorbi I, Mosyagin, et al. Candidate gene analysis identifies a polymorphism in HLA-DQB1 associated with clozapine-induced agranulocytosis. J Clin Psychiatry. doi:10.4088/JCP.09m05527yel.
  72. 72.
    Corzo D, Yunis JJ, Salazar M, et al. The major histocompatibility complex region marked by HSP70-1 and HSP70-2 variants is associated with clozapine-induced agranulocytosis in two different ethnic groups. Blood. 1995;86(10):3835–40.PubMedGoogle Scholar
  73. 73.
    Turbay D, Lieberman J, Alper CA, Delgado JC, Corzo D, Yunis JJ, et al. Tumor necrosis factor constellation polymorphism and clozapine-induced agranulocytosis in two different ethnic groups. Blood. 1997;89(11):4167–74.PubMedGoogle Scholar
  74. 74.
    Daëron M. Fc receptor biology. Annu Rev Immunol. 1997;15:203–34.PubMedCrossRefGoogle Scholar
  75. 75.
    Husain Z, Almeciga I, Delgado JC, et al. Increased FasL expression correlates with apoptotic changes in granulocytes cultured with oxidized clozapine. Toxicol Appl Pharmacol. 2006;214(3):326–34.PubMedCrossRefGoogle Scholar
  76. 76.
    Liles WC, Dale DC, Klebanoff SJ. Glucocorticoids inhibit apoptosis of human neutrophils. Blood. 1995;86(8):3181–8.PubMedGoogle Scholar
  77. 77.
    Nagata S, Golstein P. The Fas death factor. Science. 1995;267(5203):1449–56.CrossRefGoogle Scholar
  78. 78.
    Ostrousky O, Meged S, Loewenthal R, et al. NQO2 gene is associated with clozapine-induced agranulocytosis. Tissue Antigens. 2003;62(6):483–91.PubMedCrossRefGoogle Scholar
  79. 79.
    xDettling M, Sachse C, Müller-Oerlinghausen B, et al. Clozapine-induced agranulocytosis and hereditary polymorphisms of clozapine metabolizing enzymes: no association with myeloperoxidase and cytochrome P4502D6. Pharmacopsychiatry. 2000;33(6):218–20.PubMedCrossRefGoogle Scholar
  80. 80.
    Mosyagin I, Dettling M, Roots I, et al. Impact of myeloperoxidase and NADPH-oxidase polymorphisms in drug-induced agranulocytosis. J Clin Psychopharmacol. 2004;24(6):613–7.PubMedCrossRefGoogle Scholar
  81. 81.
    Esposito D, Aouillé J, Rouillon F, et al. Two-year follow-up of a patient with successful continuation of clozapine treatment despite morning pseudoneutropenia. J Clin Psychiatry. 2004;65(9):1281.PubMedCrossRefGoogle Scholar
  82. 82.
    Gründer G, Hippius H, Carlsson A. The ‘atypicality’ of antipsychotics: a concept re-examined and re-defined. Nat Rev Drug Discov. 2009;8(3):197–202.PubMedCrossRefGoogle Scholar
  83. 83.
    Remington G, Kapur S. Atypical antipsychotics: are some more atypical than others? Psychopharmacology. 2000;148(1):3–15.PubMedCrossRefGoogle Scholar
  84. 84.
    Opgen-Rhein C, Dettling M. Clozapine-induced agranulocytosis and its genetic determinants. Pharmacogenomics. 2008;9(8):1101–11.PubMedCrossRefGoogle Scholar
  85. 85.
    Dettling M, Cascorbi I, Roots I, et al. Genetic determinants of clozapine-induced agranulocytosis: recent results of HLA subtyping in a non-jewish caucasian sample. B Arch Gen Psychiatry. 2001;58(1):93–4.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Nabilah I. Chowdhury
    • 1
  • Gary Remington
    • 2
  • James L. Kennedy
    • 1
  1. 1.Neurogenetics Section, Neuroscience DepartmentCentre for Addiction and Mental HealthTorontoCanada
  2. 2.Schizophrenia Program, Centre for Addiction and Mental HealthTorontoCanada

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