Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Research Article
  • Published:

Association in Japanese patients between neuroleptic malignant syndrome and functional polymorphisms of the dopamine D2 receptor gene

Molecular Psychiatry volume 9, pages 293–298 (2004)Cite this article

Abstract

A genetic predisposition to the development of neuroleptic malignant syndrome (NMS) has been suggested by clinical studies. Although the molecular basis of NMS is unclear, a dopaminergic blockade mechanism has been considered the main cause. We therefore investigated the association between NMS and three functional polymorphisms of the dopamine D2 receptor (DRD2) gene: TaqI A, −141C Ins/Del, and Ser311Cys. Subjects included 32 Japanese patients, previously diagnosed with NMS, and 132 schizophrenic patients treated with neuroleptics without occurrence of NMS. Polymerase chain reaction and restriction fragment length polymorphism analyses were performed to determine each genotype. We found significant differences in genotypic and allelic frequencies of the –141C Ins/Del polymorphism between patients with and without NMS. The −141C Del allele was significantly more frequent in the NMS group (23.4 vs 11.7%, P=0.026). Similarly, the proportion of −141C Del allele carriers was significantly higher in the NMS group (40.6 vs 20.5%, P=0.022). No significant differences between the two groups were seen for allelic and genotypic frequencies of the TaqI A and Ser311Cys polymorphisms. This result suggests that the −141C Ins/Del polymorphism is likely to predispose toward the development of NMS, probably together with other unidentified factors.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Deuschl G, Oepen G, Hermle L . Neuroleptic malignant syndrome: observations on altered consciousness. Pharmacopsychiatry 1987; 20: 168–170.

    Article  CAS  Google Scholar 

  2. Otani K, Horiuchi M, Kondo T, Kaneko S, Fukushima Y . Is the predisposition to neuroleptic malignant syndrome genetically transmitted? Br J Psychiatry 1991; 158: 850–853.

    Article  CAS  Google Scholar 

  3. Cravchik A, Sibley DR, Gejman PV . Functional analysis of the human D2 dopamine receptor missense variants. J Biol Chem 1996; 271: 26013–26017.

    Article  CAS  Google Scholar 

  4. Arinami T, Gao M, Hamaguchi H, Toru M . A functional polymorphism in the promoter region of the dopamine D2 receptor gene is associated with schizophrenia. Hum Mol Genet 1997; 6: 577–582.

    Article  CAS  Google Scholar 

  5. Jönsson EG, Nöthen MM, Grünhage F, Farde L, Nakashima Y, Propping P et al. Polymorphisms in the dopamine D2 receptor gene and their relationships to striatal dopamine receptor density of healthy volunteers. Mol Psychiatry 1999; 4: 290–296.

    Article  Google Scholar 

  6. Pohjalainen T, Rinne JO, Någren K, Lehikoinen P, Anttila K, Syvälahti EKG et al. The A1 allele of the human D2 dopamine receptor gene predicts low D2 receptor availability in healthy volunteers. Mol Psychiatry 1998; 3: 256–260.

    Article  CAS  Google Scholar 

  7. Schäfer M, Rujescu D, Giegling I, Guntermann A, Erfurth A, Bondy B et al. Association of short-term response to haloperidol treatment with a polymorphism in the dopamine D2 receptor gene. Am J Psychiatry 2001; 158: 802–804.

    Article  Google Scholar 

  8. Suzuki A, kondo T, Mihara K, Yasui-Furukori N, Ishida M, Furukori H et al. The −141C Ins/Del polymorphism in the dopamine D2 receptor gene promoter region is associated with anxiolytic and antidepressive effects during treatment with dopamine antagonists in schizophrenic patients. Pharmacogenetics 2001; 11: 545–550.

    Article  CAS  Google Scholar 

  9. Mihara K, Kondo T, Suzuki A, Yasui N, Nagashima U, Ono S et al. Prolactin response to nemonapride, a selective antagonist for D2 like dopamine receptors, in schizophrenic patients in relation to Taq1 A polymorphism of DRD2 gene. Psychopharmacology 2000; 149: 246–250.

    Article  CAS  Google Scholar 

  10. Suzuki A, Kondo T, Otani K, Mihara K, Yasui-Furukori N, Sano A et al. Association of the TaqI A polymorphism of the dopamine D2 receptor gene with predisposition to neuroleptic malignant syndrome. Am J Psychiatry 2001; 158: 1714–1716.

    Article  CAS  Google Scholar 

  11. Kishida I, Kawanishi C, Furuno T, Matsumura T, Hasegawa H, Sugiyama N et al. Lack of association in Japanese patients between neuroleptic malignant syndrome and the Taq I A polymorphism of the dopamine D2 receptor gene. Psychiatric Genet 2003; 13: 55–57.

    Article  Google Scholar 

  12. Pope GH, Keck PE, McElroy SL . Frequency and presentation of neuroleptic malignant syndrome in a large psychiatric hospital. Am J Psychiatry 1986; 143: 1227–1233.

    Article  Google Scholar 

  13. Grandy DK, Litt M, Allen L, Bunzow JR, Marchionni M, Makam H et al. The human dopamine D2 receptor gene is located on chromosome 11 at q22–q23 and identifies a TaqI RFLP. Am J Hum Genet 1989; 45: 778–785.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Hori H, Ohmori O, Shinkai T, Kojima H, Nakamura J . Association between three functional polymorphisms of dopamine D2 receptor gene and tardive dyskinesia in schizophrenia. Am J Med Genet 2001; 105: 774–778.

    Article  CAS  Google Scholar 

  15. Arinami T, Itokawa M, Enguchi H, Tagaya H, Yano S, Shimizu H, Hamaguchi H et al. Association of dopamine D2 receptor molecular variant with schizophrenia. Lancet 1994; 343: 703–704.

    Article  CAS  Google Scholar 

  16. Inagaki A, Inada T, Fujii Y, Yagi G . Dose equivalence orally administered neuroleptics. In: Dose Equivalence of Psychotropic Drugs. Seiwa Shoten: Tokyo, 1999; 11–60, (in Japanese).

    Google Scholar 

  17. American Psychiatry Association. Practice guideline for the treatment of patients with schizophrenia. III. Treatment principles and alternatives. Am J Psychiatry 1997; 154: 7–34.

  18. Schneider S, Roessli D, Excoffier L . ARLEQUIN: a Software for Population Genetic Data Analysis. University of Geneva: Geneva, 2000.

    Google Scholar 

  19. Nishijima K, Ishiguro T . Neuroleptic malignant syndrome: a study of CSF monoamine metabolism. Biol Psychiatry 1990; 27: 280–288.

    Article  Google Scholar 

  20. Jauss M, Krack P, Franz M, Klett R, Bauer R, Gallhofer B et al. Imaging of dopamine receptors with [123I]iodobenzamide single-photon emission-computed tomography in neuroleptic malignant syndrome. Movement Disord 1996; 11: 726–728.

    Article  CAS  Google Scholar 

  21. Ishiguro H, Arinami T, Saito T, Akazawa S, Enomoto M, Mitushio H et al. Association study between the –141C Ins/Del and TaqI A polymorphisms of the dopamine D2 receptor gene and alcoholism. Alc Clin Exp Res 1998; 22: 845–848.

    CAS  Google Scholar 

  22. Katsuragi S, Kiyota A, Tsutsumi T, Isogawa K, Nagayama H, Arinami T et al. Lack of association between a polymorphism in the promoter region of the dopamine D2 receptor and personality traits. Psychiatry Res 2001; 105: 123–127.

    Article  CAS  Google Scholar 

  23. Ohara K, Nagai M, Tani K, Nakamura Y, Ino A, Ohara K . Functional polymorphism of –141C Ins/Del in the dopamine D2 receptor gene promoter and schizophrenia. Psychiatry Res 1998; 81: 117–123.

    Article  CAS  Google Scholar 

  24. Pohjalainen T, Någren K, Syvälahti EKG, Hietala J . The dopamine D2 receptor 5′-flanking variant, −141C Ins/Del, is not associated with reduced dopamine D2 receptor density in vivo. Pharmacogenetics 1999; 9: 505–509.

    CAS  PubMed  Google Scholar 

  25. Mihara K, Kondo T, Suzuki A, Yasui-Furukori N, Ono S, Sano A et al. Relationship between functional dopamine D2 and D3 receptors gene polymorphisms and neuroleptic malignant syndrome. Am J Med Genet 2003; 117B: 57–60.

    Article  Google Scholar 

  26. Kawanishi C, Hanihara T, Shimoda Y, Suzuki K, Sugiyama N, Onishi H et al. Lack of association between neuroleptic malignant syndrome and polymorphisms in the 5HT1A and 5HT2A receptor genes. Am J Psychiatry 1998; 155: 1275–1277.

    Article  CAS  Google Scholar 

  27. Kawanishi C, Furuno T, Onishi H, Sugiyama N, Suzuki K, Matsumura T et al. Lack of association in Japanese patients between neuroleptic malignant syndrome and debrisoquine 4-hydroxylase genotype with low enzyme activity. Psychiatric Genet 2000; 10: 145–147.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Dr Shinsuke Washizuka for his helpful advice.

Author information

Authors and Affiliations

  1. Department of Psychiatry, Yokohama City University School of Medicine, Yokohama, Japan

    I Kishida, C Kawanishi, T Furuno, D Kato & K Kosaka

  2. Department of Internal Medicine II, Yokohama City University School of Medicine, Yokohama, Japan

    T Ishigami

Authors
  1. I Kishida
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C Kawanishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. T Furuno
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. D Kato
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. T Ishigami
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. K Kosaka
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to I Kishida.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kishida, I., Kawanishi, C., Furuno, T. et al. Association in Japanese patients between neuroleptic malignant syndrome and functional polymorphisms of the dopamine D2 receptor gene. Mol Psychiatry 9, 293–298 (2004). https://doi.org/10.1038/sj.mp.4001422

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.mp.4001422

Keywords

This article is cited by

Search

Advanced search

Quick links