Journal of Molecular Neuroscience

, Volume 51, Issue 2, pp 380–388 | Cite as

Do Tardive Dyskinesia and l-Dopa Induced Dyskinesia Share Common Genetic Risk Factors? An Exploratory Study

  • Lior Greenbaum
  • Stefano Goldwurm
  • Polina Zozulinsky
  • Tzuri Lifschytz
  • Oren S. Cohen
  • Gilad Yahalom
  • Roberto Cilia
  • Silvana Tesei
  • Rosanna Asselta
  • Rivka Inzelberg
  • Yoav Kohn
  • Sharon Hassin-Baer
  • Bernard Lerer
Article

Abstract

Tardive dyskinesia (TD) in schizophrenia patients treated with antipsychotic medications and l-dopa induced dyskinesia (LID) among Parkinson's disease (PD) affected individuals share similar clinical features. Both conditions are induced by chronic exposure to drugs that target dopaminergic receptors (antagonists in TD and agonists in LID) and cause pulsatile and nonphysiological stimulation of these receptors. We hypothesized that the two motor adverse effects partially share genetic risk factors such that certain genetic variants exert a pleiotropic effect, influencing susceptibility to TD as well as to LID. In this pilot study, we focused on 21 TD-associated SNPs, previously reported in TD genome-wide association studies or in candidate gene studies. By applying logistic regression and controlling for relevant clinical risk factors, we studied the association of the SNPs with LID vulnerability in two independent pharmacogenetic samples. We included a Jewish Israeli sample of 203 PD patients treated with l-dopa for a minimum of 3 years and evaluated the existence or absence of LID (LID+ = 128; LID− = 75). An Italian sample was composed of early LID developers (within the first 3 years of treatment, N = 187) contrasted with non-early LID developers (after 7 years or more of treatment, N = 203). None of the studied SNPs were significantly associated with LID susceptibility in the two samples. Therefore, we were unable to obtain proof of concept for our initial hypothesis of an overlapping contribution of genetic risk factors to TD and LID. Further studies in larger samples are required to reach definitive conclusions.

Keywords

Tardive dyskinesia l-dopa induced dyskinesia Parkinson's disease Schizophrenia Genetics 

Supplementary material

12031_2013_20_MOESM1_ESM.doc (46 kb)
ESM 1(DOC 46 kb)

References

  1. Ahlskog JE, Muenter MD (2001) Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature. Mov Disord 16:448–458PubMedCrossRefGoogle Scholar
  2. Al Hadithy AF, Ivanova SA, Pechlivanoglou P et al (2009) Tardive dyskinesia and DRD3, HTR2Aand HTR2Cgene polymorphisms in Russian psychiatric inpatients from Siberia. Prog Neuropsychopharmacol Biol Psychiatry 33:475–481PubMedCrossRefGoogle Scholar
  3. Al Hadithy AF, Ivanova SA, Pechlivanoglou P et al (2010) Missense polymorphisms in three oxidative-stress enzymes (GSTP1, SOD2, and GPX1) and dyskinesias in Russian psychiatric inpatients from Siberia. Hum Psychopharmacol 25:84–91PubMedCrossRefGoogle Scholar
  4. Aubert I, Guigoni C, Håkansson K et al (2005) Increased D1 dopamine receptor signaling in levodopa-induced dyskinesia. Ann Neurol 57:17–26PubMedCrossRefGoogle Scholar
  5. Bakker PR, van Harten PN, van Os J (2006) Antipsychotic-induced tardive dyskinesia and the Ser9Gly polymorphism in the DRD3 gene: a meta analysis. Schizophr Res 83:185–192PubMedCrossRefGoogle Scholar
  6. Bakker PR, van Harten PN, van Os J (2008) Antipsychotic-induced tardive dyskinesia and polymorphic variations in COMT, DRD2, CYP1A2 and MnSOD genes: a meta-analysis of pharmacogenetic interactions. Mol Psychiatry 13:544–556PubMedCrossRefGoogle Scholar
  7. Blanchet PJ (2003) Antipsychotic drug-induced movement disorders. Can J Neurol Sci 30:S101–S107PubMedGoogle Scholar
  8. Boke O, Gunes S, Kara N et al (2007) Association of serotonin 2A receptor and lack of association of CYP1A2 gene polymorphism with tardive dyskinesia in a Turkish population. DNA Cell Biol 26:527–531Google Scholar
  9. Crowley JJ, Sullivan PF, McLeod HL (2009) Pharmacogenomic genome-wide association studies: lessons learned thus far. Pharmacogenomics 10:161–163PubMedCrossRefGoogle Scholar
  10. de Lau LM, Verbaan D, Marinus J, Heutink P, van Hilten JJ (2012) Catechol-O-methyltransferase Val158Met and the risk of dyskinesias in Parkinson's disease. Mov Disord 27:132–135PubMedCrossRefGoogle Scholar
  11. Del Sorbo F, Albanese A (2008) Levodopa-induced dyskinesias and their management. J Neurol 255(Suppl 4):32–41PubMedCrossRefGoogle Scholar
  12. Delfs JM, Ellison GD, Mercugliano M, Chesselet MF (1995) Expression of glutamic acid decarboxylase mRNA in striatum and pallidum in an animal model of tardive dyskinesia. Exp Neurol 133:175–188PubMedCrossRefGoogle Scholar
  13. Egan MF, Apud J, Wyatt RJ (1997) Treatment of tardive dyskinesia. Schizophr Bull 23:583–609PubMedCrossRefGoogle Scholar
  14. Fabbrini G, Brotchie JM, Grandas F, Nomoto M, Goetz CG (2007) Levodopa-induced dyskinesias. Mov Disord 22:1379–1389PubMedCrossRefGoogle Scholar
  15. Fisone G, Bezard E (2011) Molecular mechanisms of l-dopa-induced dyskinesia. Int Rev Neurobiol 98:95–122PubMedCrossRefGoogle Scholar
  16. Foltynie T, Cheeran B, Williams-Gray CH et al (2009) BDNF val66met influences time to onset of levodopa induced dyskinesia in Parkinson's disease. J Neurol Neurosurg Psychiatry 80:141–144PubMedCrossRefGoogle Scholar
  17. Greenbaum L, Alkelai A, Rigbi A, Kohn Y, Lerer B (2010) Evidence for association of the GLI2 gene with tardive dyskinesia in patients with chronic schizophrenia. Mov Disord 25:2809–2817PubMedCrossRefGoogle Scholar
  18. Greenbaum L, Alkelai A, Zozulinsky P, Kohn Y, Lerer B (2012) Support for association of HSPG2 with tardive dyskinesia in Caucasian populations. Pharmacogenomics J 12:513–20Google Scholar
  19. Guigoni C, Doudnikoff E, Li Q, Bloch B, Bezard E (2007) Altered D(1) dopamine receptor trafficking in parkinsonian and dyskinetic non-human primates. Neurobiol Dis 2007(26):452–463CrossRefGoogle Scholar
  20. Haddad PM, Dursun SM (2008) Neurological complications of psychiatric drugs: clinical features and management. Hum Psychopharmacol 23(Suppl):15–26PubMedCrossRefGoogle Scholar
  21. Hassin-Baer S, Molchadski I, Cohen OS et al (2011) Gender effect on time to levodopa-induced dyskinesias. J Neurol 258:2048–2053PubMedCrossRefGoogle Scholar
  22. Hely MA, Morris JG, Reid WG, Trafficante R et al (2005) Sydney Multicenter Study of Parkinson's disease: non-L-dopa-responsive problems dominate at 15 years. Mov Disord 20:190–199Google Scholar
  23. Jenner P (2008) Molecular mechanisms of l-DOPA-induced dyskinesia. Nat Rev Neurosci 9:665–677PubMedCrossRefGoogle Scholar
  24. Kaiser R, Hofer A, Grapengiesser A et al (2003) l-dopa-induced adverse effects in PD and dopamine transporter gene polymorphism. Neurology 60:1750–1755PubMedCrossRefGoogle Scholar
  25. Kane JM (1995) Tardive dyskinesia: epidemiological and clinical presentation. In: Bloom FE, Kupfer DJ (eds) Psychopharmacology: the 4th generation of progress. Raven, New YorkGoogle Scholar
  26. Kang SG, Lee HJ, Choi JE, An H, Rhee M, Kim L (2009) Association study between glutathione S-transferase GST-M1, GST-T1, and GST-P1 polymorphisms and tardive dyskinesia. Hum Psychopharmacol 24:55–60PubMedCrossRefGoogle Scholar
  27. Lee HJ, Kang SG (2011) Genetics of tardive dyskinesia. Int Rev Neurobiol 98:231–264PubMedCrossRefGoogle Scholar
  28. Lerer B, Segman RH (2006) Pharmacogenetics of antipsychotic therapy: pivotal research issues and the prospects for clinical implementation. Dialogues Clin Neurosci 8:85–94PubMedGoogle Scholar
  29. Lerer B, Segman RH, Fangerau H et al (2002) Pharmacogenetics of tardive dyskinesia: combined analysis of 780 patients supports association with dopamine D3 receptor gene Ser9Gly polymorphism. Neuropsychopharmacology 27:105–119PubMedCrossRefGoogle Scholar
  30. Lerer B, Segman RH, Tan EC et al (2005) 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 8(3):411–425PubMedCrossRefGoogle Scholar
  31. Lin JJ, Yueh KC, Lin SZ, Harn HJ, Liu JT (2007) Genetic polymorphism of the angiotensin converting enzyme and L-dopa-induced adverse effects in Parkinson's disease. J Neurol Sci 252:130–134PubMedCrossRefGoogle Scholar
  32. Linazasoro G (2005) New ideas on the origin of L-dopa-induced dyskinesias: age, genes and neural plasticity. Trends Pharmacol Sci 26:391–397PubMedCrossRefGoogle Scholar
  33. Margolese HC, Chouinard G, Kolivakis TT, Beauclair L, Miller R (2005) Tardive dyskinesia in the era of typical and atypical antipsychotics. Part 1: pathophysiology and mechanisms of induction. Can J Psychiatry 50:541–547PubMedGoogle Scholar
  34. Mercuri NB, Bernardi G (2005) The ‘magic’ of L-dopa: why is it the gold standard Parkinson's disease therapy? Trends Pharmacol Sci 26:341–344PubMedCrossRefGoogle Scholar
  35. Molchadski I, Korczyn AD, Cohen OS et al (2011) The role of apolipoprotein E polymorphisms in levodopa-induced dyskinesia. Acta Neurol Scand 123:117–121PubMedCrossRefGoogle Scholar
  36. Naidu PS, Singh A, Kulkarni SK (2002) Carvedilol attenuates neuroleptic-induced orofacial dyskinesia: possible antioxidant mechanisms. Br J Pharmacol 136:193–200PubMedCrossRefGoogle Scholar
  37. Olanow CW, Obeso JA, Stocchi F (2006) Continuous dopamine-receptor treatment of Parkinson's disease: scientific rationale and clinical implications. Lancet Neurol 5:677–687PubMedCrossRefGoogle Scholar
  38. Oliveri RL, Annesi G, Zappia M et al (1999) Dopamine D2 receptor gene polymorphism and the risk of levodopa-induced dyskinesias in PD. Neurology 53:1425–1430PubMedCrossRefGoogle Scholar
  39. Paus S, Gadow F, Knapp M, Klein C, Klockgether T, Wüllner U (2009) Motor complications in patients form the German Competence Network on Parkinson's disease and the DRD3 Ser9Gly polymorphism. Mov Disord 24:1080–1084PubMedCrossRefGoogle Scholar
  40. Prashanth LK, Fox S, Meissner WG (2011) l-Dopa-induced dyskinesia-clinical presentation, genetics, and treatment. Int Rev Neurobiol 98:31–54PubMedCrossRefGoogle Scholar
  41. Purcell S, Neale B, Todd-Brown K et al (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81:559–575PubMedCrossRefGoogle Scholar
  42. Rascol O, Brooks DJ, Korczyn AD et al (2000) A five-year study of the incidence of dyskinesia in patients with early Parkinson's disease who were treated with ropinirole or levodopa. 056 Study Group. N Engl J Med 342:1484–1491PubMedCrossRefGoogle Scholar
  43. Remington G (2007) Tardive dyskinesia: eliminated, forgotten, or overshadowed? Curr Opin Psychiatry 20:131–137PubMedCrossRefGoogle Scholar
  44. Sagara Y (1998) Induction of reactive oxygen species in neurons by haloperidol. J Neurochem 71:1002–1012PubMedCrossRefGoogle Scholar
  45. Sakai K, Gao XM, Hashimoto T, Tamminga CA (2001) Traditional and new antipsychotic drugs differentially alter neurotransmission markers in basal ganglia-thalamocortical neural pathways. Synapse 39:152–160PubMedCrossRefGoogle Scholar
  46. Segman RH, Heresco-Levy U, Finkel B et al (2000) Association between the serotonin 2C receptor gene and tardive dyskinesia in chronic schizophrenia: additive contribution of 5-HT2Cser and DRD3gly alleles to susceptibility. Psychopharmacology (Berl) 152:408–413CrossRefGoogle Scholar
  47. Segman RH, Heresco-Levy U, Finkel B et al (2001) Association between the serotonin 2A receptor gene and tardive dyskinesia in chronic schizophrenia. Mol Psychiatry 6:225–229PubMedCrossRefGoogle Scholar
  48. Sharma JC, Macnamara L, Hasoon M, Vassallo M, Ross I (2006) Cascade of levodopa dose and weight-related dyskinesia in Parkinson's disease (LD-WD-PD cascade). Parkinsonism Relat Disord 12:499–505PubMedCrossRefGoogle Scholar
  49. Sharma JC, Bachmann CG, Linazasoro G (2010) Classifying risk factors for dyskinesia in Parkinson's disease. Parkinsonism Relat Disord 16:490–497PubMedCrossRefGoogle Scholar
  50. Shulman JM, De Jager PL, Feany MB (2011) Parkinson's disease: genetics and pathogenesis. Annu Rev Pathol 28:193–222CrossRefGoogle Scholar
  51. Strong JA, Dalvi A, Revilla FJ et al (2006) Genotype and smoking history affect risk of levodopa-induced dyskinesias in Parkinson's disease. Mov Disord 21:654–659PubMedCrossRefGoogle Scholar
  52. Syu A, Ishiguro H, Inada T et al (2010) Association of the HSPG2 gene with neuroleptic-induced tardive dyskinesia. Neuropsychopharmacology 35:1155–1164PubMedCrossRefGoogle Scholar
  53. Tanaka S, Syu A, Ishiguro H et al (2011) DPP6 as a candidate gene for neuroleptic-induced tardive dyskinesia. Pharmacogenomics J. doi:10.1038/tpj.2011.36 Google Scholar
  54. Tenback DE, van Harten PN (2011) Epidemiology and risk factors for (tardive) dyskinesia. Int Rev Neurobiol 98:211–230PubMedCrossRefGoogle Scholar
  55. Tenback DE, van Harten PN, van Os J (2009) Non-therapeutic risk factors for onset of tardive dyskinesia in schizophrenia: a meta-analysis. Mov Disord 24:2309–2315PubMedCrossRefGoogle Scholar
  56. van Harten PN, Tenback DE (2011) Tardive dyskinesia: clinical presentation and treatment. Int Rev Neurobiol 98:187–210PubMedCrossRefGoogle Scholar
  57. Watanabe M, Harada S, Nakamura T et al (2003) Association between catechol-O-methyltransferase gene polymorphisms and wearing-off and dyskinesia in Parkinson's disease. Neuropsychobiology 48:190–193PubMedCrossRefGoogle Scholar
  58. Zai CC, De Luca V, Hwang RW et al (2007) Meta-analysis of two dopamine D2 receptor gene polymorphisms with tardive dyskinesia in schizophrenia patients. Mol Psychiatry 12:794–795PubMedCrossRefGoogle Scholar
  59. Zappia M, Annesi G, Nicoletti G et al (2005) Sex differences in clinical and genetic determinants of levodopa peak-dose dyskinesias in Parkinson disease: an exploratory study. Arch Neurol 62:601–605PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Lior Greenbaum
    • 1
    • 2
  • Stefano Goldwurm
    • 3
  • Polina Zozulinsky
    • 1
  • Tzuri Lifschytz
    • 1
  • Oren S. Cohen
    • 2
    • 4
    • 5
  • Gilad Yahalom
    • 2
    • 4
  • Roberto Cilia
    • 3
  • Silvana Tesei
    • 3
  • Rosanna Asselta
    • 6
  • Rivka Inzelberg
    • 2
    • 4
    • 5
  • Yoav Kohn
    • 7
  • Sharon Hassin-Baer
    • 2
    • 4
    • 5
  • Bernard Lerer
    • 1
  1. 1.Biological Psychiatry Laboratory, Department of PsychiatryHadassah-Hebrew University Medical CenterJerusalemIsrael
  2. 2.Department of NeurologyChaim Sheba Medical CenterTel HashomerIsrael
  3. 3.Parkinson InstituteIstituti Clinici di PerfezionamentoMilanItaly
  4. 4.Parkinson’s Disease and Movement Disorders ClinicChaim Sheba Medical CenterTel HashomerIsrael
  5. 5.Sackler Faculty of MedicineTel Aviv UniversityTel AvivIsrael
  6. 6.Dipartimento di Biologia e Genetica per le Scienze MedicheUniversità degli Studi di MilanoMilanItaly
  7. 7.Jerusalem Mental Health Center, Eitanim Psychiatric HospitalJerusalemIsrael

Personalised recommendations