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Lack of association between serotonin-2A receptor gene (HTR2A) polymorphisms and tardive dyskinesia in schizophrenia

Molecular Psychiatry volume 6, pages 230–234 (2001)Cite this article

Abstract

Tardive dyskinesia (TD) is a disabling neurological side effect associated with long-term treatment with typical antipsychotics. Family studies and animal models lend evidence for hereditary predisposition to TD. The newer atypical antipsychotics pose a minimal risk for TD which is in part attributed to their ability to block the serotonin-2A (5-HT2A) receptor. 5-HT2A receptors were also identified in the basal ganglia; a brain region that plays a critical role in antipsychotic-induced movement disorders. We tested the significance of variation in the 5-HT2A receptor gene (HTR2A) in relation to the TD phenotype. Three polymorphisms in HTR2A, one silent (C102T), one that alters the amino acid sequence (his452tyr) and one in the promoter region (A-1437G) were investigated in 136 patients refractory or intolerant to treatment with typical antipsychotics and with a DSM-IIIR diagnosis of schizophrenia. We did not find any significant difference in allele, genotype or haplotype frequencies of polymorphisms in HTR2A among patients with or without TD (P > 0.05). Further analysis using the ANCOVA statistic with a continuous measure of the TD phenotype (Abnormal Involuntary Movement Scale (AIMS) score) found that the AIMS scores were not significantly influenced by HTR2A polymorphisms, despite controlling for potential confounders such as age, gender and ethnicity (P > 0.05). Theoretically, central serotonergic function can be subject to genetic control at various other mechanistic levels including the rate of serotonin synthesis (tryptophane hydroxylase gene), release, reuptake (serotonin transporter gene) and degradation (monoamine oxidase gene). Analyses of these other serotonergic genes are indicated. In summary, polymorphisms in HTR2A do not appear to influence the risk for TD. Further studies evaluating in tandem multiple candidate genes relevant for the serotonergic system are warranted to dissect the genetic basis of the complex TD phenotype.

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References

  1. Simpson GM . The treatment of tardive dyskinesia and tardive dystonia J Clin Psychiatry 2000 61: (Suppl 4) 39–44

    Article  CAS  PubMed  Google Scholar 

  2. Bergen J, Kitchin R, Berry G . Predictors of the course of tardive dyskinesia in patients receiving neuroleptics Biol Psychiatry 1992 32: 580–594

    Article  CAS  PubMed  Google Scholar 

  3. Weinhold P, Wegner JT, Kane JM . Familial occurrence of tardive dyskinesia J Clin Psychiatry 1981 42: 165–166

    CAS  PubMed  Google Scholar 

  4. Yassa R, Ananth J . Familial tardive dyskinesia Am J Psychiatry 1981 138: 1618–1619

    Article  CAS  PubMed  Google Scholar 

  5. Waddington JL, Youssef HA . The expression of schizophrenia, affective disorder and vulnerability to tardive dyskinesia in an extensive pedigree Br J Psychiatry 1988 153: 376–381

    Article  CAS  PubMed  Google Scholar 

  6. Rosengarten H, Schweitzer JW, Friedhoff AJ . Possible genetic factors underlying the pathophysiology of tardive dyskinesia Pharmacol Biochem Behav 1994 49: 663–667

    Article  CAS  PubMed  Google Scholar 

  7. Basile VS, Ozdemir V, Masellis M, Walker ML, Meltzer HY, Lieberman JA, et al. A functional polymorphism of the cytochrome P450 1A2 (CYP1A2) gene: association with tardive dyskinesia in schizophrenia Mol Psychiatry 2000 5: 410–417

    Article  CAS  PubMed  Google Scholar 

  8. Hori H, Ohmori O, Shinkai T, Kojima H, Okano C, Suzuki T et al. Manganese superoxide dismutase gene polymorphism and schizophrenia. Relation to tardive dyskinesia Neuropsychopharmacology 2000 23: 170–177

    Article  CAS  PubMed  Google Scholar 

  9. Basile VS, Masellis M, Ozdemir V, Meltzer HY, Macciardi FM, Kennedy JL . Application of pharmacogenetics of schizophrenia: emerging insights from studies of clozapine response and tardive dyskinesia In: Brier A, Tran PV, Herrera J, Bymaster F, Tollefson G (eds). Current Issues in the Psychopharmacology of Schizophrenia Lippincott Williams & Wilkins, New York 2000 (in press

  10. Basile VS, Masellis M, Badri F, Paterson AD, Meltzer HY, Lieberman JA et al. Association of the Mscl polymorphism of the dopamine D3 receptor gene with tardive dyskinesia in schizophrenia Neuropsychopharmacology 1999 21: 17–27

    Article  CAS  PubMed  Google Scholar 

  11. Segman R, Neeman T, Heresco-Levy U, Finkel B, Karagichev L, Schlafman M et al. Genotypic association between the dopamine D3 receptor and tardive dyskinesia in chronic schizophrenia Mol Psychiatry 1999 4: 247–253

    Article  CAS  PubMed  Google Scholar 

  12. Steen VM, Lovlie R, MacEwan T, McCreadie RG . Dopamine D3-receptor gene variant and susceptibility to tardive dyskinesia in schizophrenic patients Mol Psychiatry 1997 2: 139–145

    Article  CAS  PubMed  Google Scholar 

  13. Armstrong M, Daly AK, Blennerhassett R, Ferrier N, Idle JR . Antipsychotic drug-induced movement disorders in schizophrenics in relation to CYP2D6 genotype Br J Psychiatry 1997 170: 23–26

    Article  CAS  PubMed  Google Scholar 

  14. Meltzer HY . The role of serotonin in antipsychotic drug action Neuropsychopharmacology 1999 21: 106S–115S

    Article  CAS  PubMed  Google Scholar 

  15. Nedergaard S, Bolam JP, Greenfield SA . Facilitation of a dendritic calcium conductance by 5-hydroxytryptamine in the substantia nigra Nature 1988 333: 174–177

    Article  CAS  PubMed  Google Scholar 

  16. Roth BL, Berry SA, Kroeze WK, Willins DL, Kristiansen K . Serotonin 5-HT2A receptors: molecular biology and mechanisms of regulation Crit Rev Neurobiol 1998 12: 319–338

    Article  CAS  PubMed  Google Scholar 

  17. Meltzer HY, Matsubara S, Lee JC . Classification of typical and atypical antipsychotic drugs on the basis of dopamine-D-1, -D-2, and serotonin-2 pKi values J Pharmacol Exp Ther 1989 251: 238–246

    CAS  PubMed  Google Scholar 

  18. Schooler NR, Kane JM . Research diagnoses for tardive dyskinesia Arch Gen Psychiatry 1982 39: 486–487

    CAS  PubMed  Google Scholar 

  19. Masellis M, Basile VS, Meltzer HY et al. Serotonin subtype 2 receptor genes and clinical response to clozapine in schizophrenia patients Neuropsychopharmacology 1998 19: 123–132

    Article  CAS  PubMed  Google Scholar 

  20. Lander ES, Schork NJ . Genetic dissection of complex traits Science 1994 265: 2037–2048

    Article  CAS  PubMed  Google Scholar 

  21. Petronis A . The genes for major psychosis Aberrant sequence or regulation? Neuropsychopharmacology 2000 23: 1–12

    CAS  PubMed  Google Scholar 

  22. Lahiri DK, Nurnberger JI Jr . A rapid nonenzymatic method for the preparation of HMW DNA from blood for RFLP studies Nucleic Acids Res 1991 19: 5444

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Warren JT, Jr, Peacock ML, Rodriguez LC, Fink JK . An Mspl polymorphism in the human serotonin receptor gene (HTR2): detection by DGGE and RFLP analysis Hum Mol Genet 1993 2: 338

    Article  CAS  PubMed  Google Scholar 

  24. Ozaki N, Manji H, Lubierman V, Lu SJ, Lappalainen J, Rosenthal NE et al. A naturally occurring amino acid substitution of the human serotonin 5-HT2A receptor influences amplitude and timing of intracellular calcium mobilization J Neurochem 1997 68: 2186–2193

    Article  CAS  PubMed  Google Scholar 

  25. Nothen MM, Rietschel M, Erdmann J, Oberlander H, Moller HJ, Naber D et al. Genetic variation of the 5-HT2A receptor and response to clozapine Lancet 1995 346: 908–909

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

V Ozdemir is supported by a postdoctoral fellowship from the Ontario Mental Health Foundation and a NARSAD Young Investigator Award. A Petronis is supported by grants from the Ontario Mental Health Foundation and NARSAD. JL Kennedy is supported by operating grants from the Ontario Mental Health Foundation and the Medical Research Council of Canada (MT15007) and a NARSAD Independent Investigator Award.

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Authors and Affiliations

  1. Neurogenetics Section, Clarke Institute of Psychiatry, Centre for Addiction and Mental Health (CAMH), University of Toronto, Toronto, Canada

    V S Basile, V Ozdemir, M Masellis, F M Macciardi, A Petronis & J L Kennedy

  2. Department of Pharmacology, University of Toronto, Toronto, Canada

    V Ozdemir

  3. Department of Psychiatry, Vanderbilt University, Nashville, USA

    H Y Meltzer

  4. Department of Psychiatry, University of North Carolina, Chapel Hill, USA

    J A Lieberman

  5. Department of Psychiatry, University of California, Irvine, USA

    S G Potkin

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  1. V S Basile
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  2. V Ozdemir
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Correspondence to J L Kennedy.

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Basile, V., Ozdemir, V., Masellis, M. et al. Lack of association between serotonin-2A receptor gene (HTR2A) polymorphisms and tardive dyskinesia in schizophrenia. Mol Psychiatry 6, 230–234 (2001). https://doi.org/10.1038/sj.mp.4000847

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