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Dopamine D4 receptor 48-bp repeat polymorphism: no association with response to antipsychotic treatment, but association with catatonic schizophrenia

Molecular Psychiatry volume 5, pages 418–424 (2000)Cite this article

Abstract

The dopamine D4 receptor (DRD4) may play a role in the pathogenesis of neuropsychiatric disease and in the action of dopaminergic drugs. The 48-bp repeat polymorphism (48-bp VNTR) coding for a 16-amino acid segment in the third cytoplasmatic loop of the DRD4 was studied as a predictor of the therapeutic response to antipsychotics and as susceptibility factor for schizophrenia. We included 638 in-patients with acute schizophrenic, schizoaffective (mainly schizophrenic), and other nonaffective psychoses, as well as two reference groups: one with 278 in-patients with non-psychiatric diseases, and one with 474 healthy volunteers. Catatonic patients (DSM-IV 295.2) more frequently carried the DRD4 D4.2 and D4.3 allele than did all other schizophrenic cases (P < 0.001; or: 2.7; ci: 1.5–4.9) and controls (P < 0.004; or: 2.3; ci: 1.3–4.2). We found no significant difference in the drd4 allele or in genotype frequencies in our comparison of all schizophrenic patients and controls. The subgroups with affected family members, and the subgroups with early or late onset of disease, also did not differ from the controls in drd4 allele frequencies. The 48-bp vntr was not a predictor for therapeutic outcome measured by the positive and negative symptoms scale. A total of 1390 subjects showed between 1 and 10 repeats (d4.1 and D4.10), with 25 different genotypes. These data exclude a major role of DRD4 48-bp VNTR in response to antipsychotic therapy and as susceptibility factor for schizophrenia, but catatonic schizophrenia may be associated with the D4.2 and D4.3 alleles.

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References

  1. Hartmann D, Monsma F, Civelli O . Interaction of Antipsychotics Drugs with Dopamine Receptor Subtypes Springer Verlag: Berlin, Heidelberg, New York 1996

    Book  Google Scholar 

  2. Kramer MS, Last B, Getson A, Reines SA . The effects of a selective D4 dopamine receptor antagonist (L-745,870) in acutely psychotic inpatients with schizophrenia. D4 antagonist group Arch Gen Psychiatry 1997; 54: 567–572

    Article  CAS  Google Scholar 

  3. Truffinet P, Tamminga CA, Fabre LF, Meltzer HY, Rivière M-E, Papillon-Downey C . Placebo controlled study of the D4/5HT2A antagonist fananserin in the treatment of schizophrenia Am J Psychiatry 1999; 156: 419–425

    CAS  PubMed  Google Scholar 

  4. van Tol HHM, Bunzow JR, Guan HC, Sunahara RK, Seeman P, Niznik HB et al. Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine Nature 1991; 350: 610–614

    Article  CAS  Google Scholar 

  5. Nöthen MM, Cichon S, Hemmer S, Hebebrand J, Remschmidt H, Lehmkuhl G et al. Human dopamine D4 receptor gene: frequent occurrence of a null allele and observation of homozygosity Hum Mol Genet 1994; 3: 2207–2212

    Article  Google Scholar 

  6. Lichter JB, Barr CL, Kennedy JL, Van Tol HHM, Kidd KK, Livak KJ . A hypervariable segment in the human dopamine receptor D4 (DRD4) gene Hum Mol Genet 1993; 2: 767–773

    Article  CAS  Google Scholar 

  7. van Tol HHM, Wu CM, Guan HC, Ohara K, Bunzow JR, Civelli O et al. Multiple dopamine D4 receptor variants in the human population Nature 1992; 358: 149–152

    Article  CAS  Google Scholar 

  8. Asghari V, Schoots O, Van Kats S, Ohara K, Jovanovic V, Guan HC et al. Dopamine D4 receptor repeat: analysis of different native and mutant forms of the human and rat genes Mol Pharmacol 1994; 46: 364–373

    CAS  PubMed  Google Scholar 

  9. Asghari V, Sanyal S, Buchwaldt S, Paterson A, Jovanovic V, Van Tol HHM . Modulation of intracellular cyclic AMP levels by different human dopamine D4 receptor variants J Neurochem 1995; 65: 1157–1165

    Article  CAS  Google Scholar 

  10. Hwu HG, Hong CJ, Lee PC, Lee SF . Dopamine D4 receptor gene polymorphisms and neuroleptic response in schizophrenia Biol Psychiatry 1998; 44: 483–487

    Article  CAS  Google Scholar 

  11. Cohen BM, Ennulat DJ, Centorrino F, Matthysse S, Konieczna H, Chu HM et al. Polymorphisms of the dopamine D4 receptor and response to antipsychotic drugs Psychopharmacology 1999; 141: 6–10

    Article  CAS  Google Scholar 

  12. Rao PA, Pickar D, Gejman PV, Ram A, Gershon ES, Gelernter J . Allelic variation in the D4 dopamine receptor (DRD4) gene does not predict response to clozapine Arch Gen Psychiatry 1994; 51: 912–917

    Article  CAS  Google Scholar 

  13. Shaikh S, Collier DA, Kerwin RW, Pilowsky LS, Gill M, Zu WM et al. Dopamine D4 receptor subtypes and response to clozapine Lancet 1993; 341: 116

    Article  CAS  Google Scholar 

  14. Rietschel M, Naber D, Oberlander H, Holzbach R, Fimmers R, Eggermann K et al. Efficacy and side-effects of clozapine: testing for association with allelic variation in the dopamine D4 receptor gene Neuropsychopharmacology 1996; 15: 491–496

    Article  CAS  Google Scholar 

  15. Seeman P, Guan HC, Van Tol HHM . Dopamine D4 receptors elevated in schizophrenia Nature 1993; 365: 441–445

    Article  CAS  Google Scholar 

  16. Catalano M, Nobile M, Novelli E, Nöthen MM, Smeraldi E . Distribution of a novel mutation in the first exon of the human dopamine D4 receptor gene in psychotic patients Biol Psychiatry 1993; 34: 459–464

    Article  CAS  Google Scholar 

  17. Cichon S, Nöthen MM, Catalano M, Di Bella D, Maier W, Lichtermann D et al. Identification of two novel polymorphisms and a rare deletion variant in the human dopamine D4 receptor gene Psychiatr Genet 1995; 5: 97–103

    Article  CAS  Google Scholar 

  18. Daniels J, Williams J, Mant R, Asherson P, McGuffin P, Owen MJ . Repeat length variation in the dopamine D4 receptor gene shows no evidence of association with schizophrenia Am J Med Genet 1994; 54: 256–258

    Article  CAS  Google Scholar 

  19. Kohn Y, Ebstein RP, Heresco-Levy U, Shapira B, Nemanov L, Gritsenko I 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: 39–43

    Article  CAS  Google Scholar 

  20. Nanko S, Hattori M, Ikeda K, Sasaki T, Kazamatsuri H, Kuwatta S . Dopamine D4 receptor polymorphism and schizophrenia Lancet 1993; 341: 689–690

    Article  CAS  Google Scholar 

  21. Seeman P, Ulpian C, Chouinard G, Van Tol HHM, Dwosh H, Lieberman JA et al. Dopamine D4 receptor variant, D4Glycine 194, in Africans, but not in Caucasians: no association with schizophrenia Am J Med Genet 1994; 54: 384–390

    Article  CAS  Google Scholar 

  22. Shaikh S, Gill M, Owen M, Asheron P, McGuffin P, Nanko S et al. Failure to find linkage between a functional polymorphism in the dopamine D4 receptor gene and schizophrenia Am J Med Genet 1994; 54: 8–11

    Article  CAS  Google Scholar 

  23. Sommer SS, Lind TJ, Heston LL, Sobell JL . Dopamine D4 receptor variants in unrelated schizophrenic cases and controls Am J Med Genet 1993; 48: 90–93

    Article  CAS  Google Scholar 

  24. American Psychiatric Association . Diagnostic and Statistical Manual of Mental Disorders, 4th edn American Psychiatric Association: Washington DC 1994

    Google Scholar 

  25. Kay SR, Fiszbein A, Opler LA . The positive and negative syndrome scale (PANSS) for schizophrenia Schizophr Bull 1987; 13: 261–275

    Article  CAS  Google Scholar 

  26. Kotler M, Cohen H, Segman R, Gritsenko I, Nemanov L, Lerer B et al. Excess dopamine D4 receptor (D4DR) exon III seven repeat allele in opioid-dependent subjects Mol Psychiatry 1997; 2: 251–254

    Article  CAS  Google Scholar 

  27. Chang FM, Kidd JR, Livak KJ, Pakstis AJ, Kidd KK . The world wide distribution of allele frequencies at the human dopamine D4 receptor locus Hum Genet 1996; 98: 91–101

    Article  CAS  Google Scholar 

  28. Lysaker PH, Bell MD, Kaplan E, Greig TC, Bryson GJ . Personality and psychopathology in schizophrenia: the association between personality traits and symptoms Psychiatry 1999; 62: 36–48

    Article  CAS  Google Scholar 

  29. Shaikh S, Collier DA, Sham P, Pilowsky L, Sharma T, Lin LK et al. Analysis of clozapine response and polymorphisms of the dopamine D4 receptor gene (DRD4) in schizophrenic patients Am J Med Genet 1995; 60: 541–545

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Dr J Schmider for his contributions to the organisation and clinical monitoring of this study. We furthermore thank Dr D Filler, S Brockmeier, G Rott, S Strobel, M Lange, S Trautner, K Maronde and O Lüers for their contributions to the clinical section of this study. We express our appreciation to Professor Dr H Helmchen, Professor Dr R Uebelhack, Professor Dr B Nickel, and Priv Doz Dr A Mackert for supporting this study in their departments. This project was supported by BMBF grants 01EC9408 and 01ZZ9511.

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Authors and Affiliations

  1. Institute of Clinical Pharmacology, Charité University Medical Centre, Humboldt University of Berlin, Berlin, D-10098, Germany

    R Kaiser, M Könneker, I Roots & J Brockmöller

  2. Department of Biology, Chemistry, and Pharmacy, Free University of Berlin, Berlin, D-14195, Germany

    M Henneken

  3. Department of Neuropsychopharmacology, Benjamin Franklin University Medical Centre, Free University of Berlin, Berlin, D-14050, Germany

    M Dettling & B Müller-Oerlinghausen

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  1. R Kaiser
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Correspondence to J Brockmöller.

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Kaiser, R., Könneker, M., Henneken, M. et al. Dopamine D4 receptor 48-bp repeat polymorphism: no association with response to antipsychotic treatment, but association with catatonic schizophrenia. Mol Psychiatry 5, 418–424 (2000). https://doi.org/10.1038/sj.mp.4000729

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