Advertisement

CNS Drugs

, Volume 16, Issue 5, pp 317–324 | Cite as

Genetic Predictors of Therapeutic Response to Clozapine

Current Status of Research
  • Dalu Mancama
  • Maria J. Arranz
  • Robert W. Kerwin
Review Article

Abstract

Clozapine is one of the most clinically potent drugs currently available for treating the symptoms of schizophrenia. Compared with conventional antipsychotics it surpasses its predecessors in its ability to treat a wider range of symptoms in otherwise refractory patients, while possessing a low propensity to produce extrapyramidal symptoms. Despite its significant advantages, not all patients benefit from treatment. Some patients react adversely to therapy while others fail to respond adequately. If those most likely to benefit from clozapine could be identified prior to treatment, this would significantly improve the clinical management of these patients.

Genetic alterations in drug-metabolising enzymes have previously been demonstrated to influence the efficacy of clinically relevant drugs. It is possible that similar alterations in these and other systems may influence the response variability of patients to clozapine. Pharmacogenetic studies are at present investigating genes encoding drug receptors, drug-metabolising enzymes and neurotransmitter transporters to identify genetic variants that may be important. To date polymorphisms within serotonergic and dopaminergic pathways have been implicated, though the involvement of similar variants in other candidate systems is also likely. This information will ultimately enable the genetic prediction of patients most likely to benefit from the drug, and in the process would alleviate the unnecessary exposure of predisposed individuals to potentially serious adverse effects.

Keywords

Major Histocompatibility Complex Clozapine Olanzapine Tardive Dyskinesia Bodyweight Gain 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

The authors have no conflicts of interest associated with the contents of this article.

References

  1. 1.
    Kane JM, Honigfeld G, Singer J, et al. Clozapine in treatment-resistant schizophrenics. Psychopharmacol Bull 1988; 24(1): 62–7PubMedGoogle Scholar
  2. 2.
    Conley RR, Tamminga CA, Kelly DL, et al. Treatment-resistant schizophrenic patients respond to clozapine after olanzapine non-response. Biol Psychiatry 1999; 46(1): 73–7PubMedCrossRefGoogle Scholar
  3. 3.
    Lee MA, Thompson PA, Meltzer HY. Effects of clozapine on cognitive function in schizophrenia. J Clin Psychiatry 1994; 55 Suppl. B: 82–7PubMedGoogle Scholar
  4. 4.
    Purdon SE. Cognitive improvement in schizophrenia with novel antipsychotic medications. Schizophr Res 1999; 35: S51–60PubMedCrossRefGoogle Scholar
  5. 5.
    Reynolds G. What is an atypical antipsychotic? J Psychopharmacol 1997; 11(3): 195–9PubMedCrossRefGoogle Scholar
  6. 6.
    Meltzer HY. The role of serotonin in antipsychotic drug action. Neuropsychopharmacology 1999; 21(2): S106–15CrossRefGoogle Scholar
  7. 7.
    Gerlach J, Peacock L. New antipsychotics: the present status. Int Clin Psychopharmacol 1995; 10 Suppl. 3: 39–48PubMedCrossRefGoogle Scholar
  8. 8.
    Ellenbroek BA, Cools AR, editors. Atypical antipsychotics. Milestones in drug therapy (MDT). Basel: Birkhäuser Verlag AG, 2000Google Scholar
  9. 9.
    Lieberman J, Safferman AZ, Pollack S, et al. Clinical effects of clozapine in chronic schizophrenia -response to treatment and predictors of outcome. Am J Psychiatry 1994; 151(12): 1744–52PubMedGoogle Scholar
  10. 10.
    Vojvoda D, Grimmell K, Sernyak M. Monozygotic twins concordant for response to clozapine [letter]. Lancet 1996; 347(8993): 61PubMedCrossRefGoogle Scholar
  11. 11.
    Horacek J, Libiger J, Hoschl C, et al. Clozapine-induced concordant agranulocytosis in monozygotic twins. Int J Psychiatry Clin Pract 2001; 5(1): 71–3CrossRefGoogle Scholar
  12. 12.
    Mata I, Madoz V, Arranz MJ, et al. Olanzapine: concordant response in monozygotic twins with schizophrenia [letter]. Br J Psychiatry 2001; 178(1): 86PubMedCrossRefGoogle Scholar
  13. 13.
    Arranz MJ, Kerwin RW. Neurotransmitter-related genes and antipsychotic response: pharmacogenetics meets psychiatric treatment. Ann Med 2000; 32: 128–33PubMedCrossRefGoogle Scholar
  14. 14.
    Wong AHC, Buckle CE, Van Tol HHM. Polymorphisms in dopamine receptors: what do they tell us? Eur J Pharmacol 2000; 410: 183–203PubMedCrossRefGoogle Scholar
  15. 15.
    Malhotra AK, Buchanan RW, Kim S, et al. Allelic variation in the promoter region of the dopamine D2 receptor gene and clozapine response. Schizophr Res 1999; 36(1–3): 92–3Google Scholar
  16. 16.
    Arranz MJ, Li T, Munro J, et al. Lack of association between a polymorphism in the promoter region of the dopamine-2 receptor gene and clozapine response. Pharmacogenetics 1998; 8: 481–4PubMedCrossRefGoogle Scholar
  17. 17.
    Shaikh S, Collier D, Arranz M, et al. DRD2 Ser311/Cys311 polymorphism in schizophrenia. Lancet 1994; 343(8904): 1045–6PubMedGoogle Scholar
  18. 18.
    Shaikh S, Collier DA, Sham P, et al. Allelic association between a Ser-9-Gly polymorphism in the dopamine D3 receptor gene and schizophrenia. Hum Genet 1996; 97: 714–9PubMedCrossRefGoogle Scholar
  19. 19.
    Scharfetter J, Chaudhry HR, Hornik K, et al. Dopamine D3 receptor gene polymorphism and response to clozapine in schizophrenic Pakistani patients. Eur Neuropsychopharmacol 1998; 10(1): 17–20CrossRefGoogle Scholar
  20. 20.
    Sivagnanasundaram S, Morris AG, Gaitonde EJ, et al. A cluster of single nucleotide polymorphisms in the 5′-leader of the human dopamine D3 receptor gene (DRD3) and its relationship to schizophrenia. Neurosci Lett 2000; 279: 13–6PubMedCrossRefGoogle Scholar
  21. 21.
    Malhotra AK, Goldman D, Buchanan RW, et al. The dopamine D3 receptor (DRD3) Ser(9)Gly polymorphism and schizophrenia: a haplotype relative risk study and association with clozapine response. Mol Psychiatry 1998; 3(1): 72–5PubMedCrossRefGoogle Scholar
  22. 22.
    Sanyal S, Van Tol HHM. Review of the role of dopamine D4 receptors in schizophrenia and antipsychotic action. J Psychiatric Res 1997; 31(2): 219–32CrossRefGoogle Scholar
  23. 23.
    Rao PA, Pickar D, Gejman PV, et al. Allelic variation in the D4 dopamine receptor (DRD4) gene does not predict response to clozapine. Arch Gen Psychiatry 1994; 51(11): 912–7PubMedCrossRefGoogle Scholar
  24. 24.
    Shaikh S, Makoff A, Collier DA, et al. Dopamine D4 receptors: potential therapeutic implications in the treatment of schizophrenia. CNS Drugs 1997; 8: 1–11CrossRefGoogle Scholar
  25. 25.
    Rietschel M, Naber D, Oberlander H, et al. Efficacy and side-effects of clozapine: testing for association with allelic variation in the dopamine D4 receptor gene. Neuropsychopharmacology 1996; 15(5): 491–6PubMedCrossRefGoogle Scholar
  26. 26.
    Kohn Y, Ebstein RP, Heresco-Levy U, et al. Dopamine D4 receptor gene polymorphisms: relation to ethnicity, no association with schizophrenia and response to clozapine in Israeli subjects. Eur Neuropsychopharmacol 1997; 7(1): 39–43PubMedCrossRefGoogle Scholar
  27. 27.
    Kaiser R, Konneker M, Henneken M, et al. Dopamine D4 receptor 48-bp repeat polymorphisms: no association with response to antipsychotic treatment, but association with catatonic schizophrenia. Mol Psychiatry 2000; 5(4): 418–24PubMedCrossRefGoogle Scholar
  28. 28.
    Ozdemir V, Masellis M, Basile V, et al. Variability in response to clozapine: potential role of cytochrome P4501A2 and the dopamine D4 receptor gene. CNS Spectrums 1999; 4(6): 30–56Google Scholar
  29. 29.
    Ishiguro H, Okuyama Y, Toru M, et al. Mutation and association analysis of the 5′ region of the dopamine D3 receptor gene in schizophrenia patients: identification of the Ala38Thr polymorphism and suggested association between DRD3 haplotypes and schizophrenia. Mol Psychiatry 2000; 5(4): 433–8PubMedCrossRefGoogle Scholar
  30. 30.
    Steen VM, Lovlie R, MacEwan T, et al. Dopamine D3-receptor gene variant and susceptibility to tardive dyskinesia in schizophrenic patients. Mol Psychiatry 1997; 2(2): 139–45PubMedCrossRefGoogle Scholar
  31. 31.
    Basile VS, Masellis M, Badri F, et al. Association of the Msc I polymorphism of the dopamine D3 receptor gene with tardive dyskinesia in schizophrenia. Neuropsychopharmacology 1999; 21: 17–27PubMedCrossRefGoogle Scholar
  32. 32.
    Segman R, Neeman T, Heresco-Levy U, et al. Genotypic association between the dopamine D3 receptor and tardive dyskinesia in chronic schizophrenia. Mol Psychiatry 1999; 4(3): 247–53PubMedCrossRefGoogle Scholar
  33. 33.
    Rietschel M, Krauss H, Muller DJ, et al. Dopamine D3 receptor variant and tardive dyskinesia. Eur Arch Psychiatry Clin Neurosci 2000; 250(1): 31–5PubMedCrossRefGoogle Scholar
  34. 34.
    Arranz MJ, Collier DA, Sodhi M, et al. Association between clozapine response and allelic variation in the 5-HT2A receptor gene. Lancet 1995; 346: 281–2PubMedCrossRefGoogle Scholar
  35. 35.
    Masellis M, Paterson AD, Badri F, et al. Genetic variation of 5-HT2A receptor and response to clozapine [letter]. Lancet 1995; 346: 1108PubMedCrossRefGoogle Scholar
  36. 36.
    Nothen MM, Rietschel M, Erdmann J, et al. Genetic variation of the 5-HT2A receptor and response to clozapine. Lancet 1995; 346: 908–9PubMedCrossRefGoogle Scholar
  37. 37.
    Malhotra AK, Goldman D, Ozaki N, et al. Lack of association between polymorphisms in the 5-HT2A receptor gene and the antipsychotic response to clozapine. Am J Psychiatry 1996; 153(8): 1092–4PubMedGoogle Scholar
  38. 38.
    Nimgaonkar VL, Zhang XR, Brar JS, et al. 5-HT2 receptor gene locus: association with schizophrenia or treatment response not detected. Psychiatr Genet 1996; 6(1): 23–7PubMedCrossRefGoogle Scholar
  39. 39.
    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: 93–9PubMedCrossRefGoogle Scholar
  40. 40.
    Masellis M, Basile V, Meltzer HY, et al. Serotonin subtype 2 receptor genes and clinical response to clozapine in schizophrenia patients. Neuropsychopharmacology 1998; 19(2): 123–32PubMedCrossRefGoogle Scholar
  41. 41.
    Masellis M, Basile VS, Ozdemir V, et al. Pharmacogenetics of antipsychotic treatment: lessons learned from clozapine. Biol Psychiatry 2000; 7(3): 252–66CrossRefGoogle Scholar
  42. 42.
    Lin CH, Tsai SJ, Yu YW, et al. No evidence for association of serotonin-2A receptor variant (102T/C) with schizophrenia or clozapine response in a Chinese population. Neuroreport 1999; 10(1): 57–60PubMedCrossRefGoogle Scholar
  43. 43.
    Arranz MJ, Collier DA, Munro J, et al. Analysis of a structural polymorphism in the 5-HT2A receptor and clinical response to clozapine. Neurosci Lett 1996; 217: 177–8PubMedCrossRefGoogle Scholar
  44. 44.
    Badri F, Masellis M, Petronis A, et al. Dopamine and serotonin system genes may predict clinical response to clozapine [abstract]. Am J Hum Genet 1996; 59(4): A247Google Scholar
  45. 45.
    Sodhi M, Arranz MJ, Curtis D, et al. Association between clozapine response and allelic variation in the 5-HT2C receptor gene. Neuroreport 1995; 7: 169–72PubMedGoogle Scholar
  46. 46.
    Rietschel M, Naber D, Fimmers R, et al. Efficacy and side-effects of clozapine not associated with variation in the 5-HT2C receptor. Neuroreport 1999; 8(8): 1999–2003CrossRefGoogle Scholar
  47. 47.
    Birkett JT, Arranz MJ, Munro J, et al. Association analysis of the 5-HT5A gene in depression, psychosis and antipsychotic response. Neuroreport 2000; 11(9): 2017–20PubMedCrossRefGoogle Scholar
  48. 48.
    Yu YWY, Tsai S-J, Lin C-H, et al. Serotonin-6 receptor variant (C267T) and clinical response to clozapine. Neuroreport 1999; 10: 1231–3PubMedCrossRefGoogle Scholar
  49. 49.
    Huezo-Diaz P, Demspter D, Gutierrez B, et al. Serotonin-6 (5-HT6) receptor variant association study with clozapine and olanzapine response [abstract]. Schizophr Res 2001; 49: 71Google Scholar
  50. 50.
    Masellis M, Basile VS, Meltzer HY, et al. Lack of association between the T-C267 serotonin 5-HT6 receptor gene (HTR6) polymorphism and prediction of response to clozapine in schizophrenia. Schizophr Res 2001; 47: 49–58PubMedCrossRefGoogle Scholar
  51. 51.
    Tsai SJ, Hong CJ, Yu YW, et al. Association study of a functional serotonin transporter gene polymorphism with schizophrenia, psychopathology and clozapine response. Schizophr Res 2000; 44(3): 177–81PubMedCrossRefGoogle Scholar
  52. 52.
    Mancama D, Arranz MJ, Munro J, et al. The histamine 1 and histamine 2 receptor genes — candidates for schizophrenia and clozapine response. GeneScreen 2000; 1: 29–34CrossRefGoogle Scholar
  53. 53.
    Arranz MJ, Munro J, Birkett J, et al. Pharmacogenetic prediction of clozapine response. Lancet 2000; 355: 1615–6PubMedCrossRefGoogle Scholar
  54. 54.
    Bolonna AA, Arranz MJ, Munro J, et al. No influence of adrenergic receptor polymorphisms on schizophrenia and antipsychotic response. Neurosci Lett 2000; 280: 65–8PubMedCrossRefGoogle Scholar
  55. 55.
    Tsai SJ, Wang YC, Yu Younger WY, et al. Association analysis of polymorphism in the promoter region of the alpha2a-adrenoceptor gene with schizophrenia and clozapine response. Schizophr Res 2001; 49(1–2): 53–8PubMedCrossRefGoogle Scholar
  56. 56.
    Prior TI, Chue PS, Tibbo P, et al. Drug metabolism and atypical antipsychotics. Eur Neuropsychopharmacol 1999; 9(4): 301–9PubMedCrossRefGoogle Scholar
  57. 57.
    Weber WW. Pharmacogenetics. 1st ed. New York: Oxford University Press, 1997Google Scholar
  58. 58.
    Arranz MJ, Dawson E, Shaikh S, et al. Cytochrome P4502D6 genotype does not determine response to clozapine. Br J Clin Pharmacol 1995; 39: 417–20PubMedCrossRefGoogle Scholar
  59. 59.
    Dettling M, Sachse C, Muller-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): 218–20PubMedCrossRefGoogle Scholar
  60. 60.
    Reznik I, Mester R. Genetic factors in clozapine-induced agranulocytosis. Isr Med Assoc J 2000; 2(11): 857–8PubMedGoogle Scholar
  61. 61.
    Yunis JJ, Corzo D, Salazar M, et al. HLA associations in clozapine-induced agranulocytosis. Blood 1995; 86(3): 1177–83PubMedGoogle Scholar
  62. 62.
    Turbay D, Lieberman J, Alper CA, et al. Tumor necrosis factor constellation polymorphism and clozapine-induced agranulocytosis in two different ethnic groups. Blood 1997; 89(11): 4167–74PubMedGoogle Scholar
  63. 63.
    Wetterling T, Mubigbrodt H. Weight gain: side effect of atypical neuroleptics? J Clin Psychopharmacol 1999; 19(4): 316–21PubMedCrossRefGoogle Scholar
  64. 64.
    McIntyre RS, Mancini DA, Basile VS. Mechanisms of antipsychotic-induced weight gain. J Clin Psychiatry 2001; 62 Suppl. 23: 23–9PubMedGoogle Scholar
  65. 65.
    De Vry J, Schreiber R. Effects of selected serotonin 5-HT(1) and 5-HT(2) receptor agonists on feeding behavior: possible mechanisms of action. Neurosci Biobehav Rev 2000; 24(3): 341–53CrossRefGoogle Scholar
  66. 66.
    Meguid MM, Fetissov SO, Varma M, et al. Hypothalamic dopamine and serotonin in the regulation of food intake. Nutrition 2000; 16(10): 843–57PubMedCrossRefGoogle Scholar
  67. 67.
    Tecott LH, Sun LM, Akana SF, et al. Eating disorder and epilepsy in mice lacking 5-HT2C serotonin receptors. Nature 1995; 374: 542–6PubMedCrossRefGoogle Scholar
  68. 68.
    Hong CJ, Lin CH, Yu YW, et al. Genetic variants of the serotonin system and weight change during clozapine treatment. Pharmacogenetics 2001; 11(3): 265–8PubMedCrossRefGoogle Scholar
  69. 69.
    Basile VS, Masellis M, McIntyre RS, et al. Genetic dissection of atypical antipsychotic-induced weight gain: novel preliminary data on the pharmacogenetic puzzle. J Clin Psychiatry 2001; 62 Suppl. 23: 45–66PubMedGoogle Scholar
  70. 70.
    Jibson MD, Tandon R. New atypical antipsychotic medications. J Psychiatr Res 1998; 32(3–4): 215–28PubMedCrossRefGoogle Scholar
  71. 71.
    Rietschel M, Kennedy JL, Macciardi F, et al. Application of pharmacogenetics to psychotic disorders: the first consensus conference. The Consensus Group for Outcome Measures in Psychoses for Pharmacological Studies. Schizophr Res 1999; 37(2): 191–6PubMedCrossRefGoogle Scholar
  72. 72.
    Cichon S, Nöthen MM, Rietschel M, et al. Pharmacogenetics of schizophrenia. Am J Med Genet 2000; 97(1): 98–106PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 2002

Authors and Affiliations

  • Dalu Mancama
    • 1
  • Maria J. Arranz
    • 1
  • Robert W. Kerwin
    • 1
  1. 1.Clinical NeuropharmacologyInstitute of PsychiatryDenmark Hill, LondonUK

Personalised recommendations