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Association study of 12 polymorphisms spanning the dopamine D2 receptor gene and clozapine treatment response in two treatment refractory/intolerant populations

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Abstract

Rationale

Dopamine D2 receptor blockade is the major basis for the antipsychotic action of typical antipsychotic drugs (AP) and a necessary but not sufficient basis for the antipsychotic action of atypical APs such as clozapine and other multireceptor antagonists which rely, in part, upon 5-HT2A antagonism. Genetic factors affecting the density and/or function of D2 receptors may therefore affect AP response.

Objectives

This exploratory study investigates the effect of 12 single nucleotide polymorphisms (SNPs) spanning the entire dopamine D2 gene on clozapine response in two distinct schizophrenic populations (Caucasian and African–American) refractory or intolerant to conventional APs.

Methods

This study included 183 Caucasian and 49 African–American DSM-III-R or DSM-IV schizophrenics. Genotyping was determined by 5′-exonuclease fluorescence assays. Within each population genotype, allele, allele +/−, and haplotype frequencies were compared between responders and non-responders by X 2 tests. Linkage disequilibrium analysis was also performed.

Results

In the Caucasian sample, no significant associations were found for individual SNP tests; however, two haplotypes were identified as having significant protective effects on treatment outcome. In the African–American sample, individual SNP tests identified the Taq1A, Taq1B, and rs1125394 markers as being predictive of clozapine response. Haplotype analyses identified four protective haplotypes containing these SNPs. In addition, no association between the −141C Ins/Del site and clozapine response was found in either population.

Conclusions

Interindividual variability in clozapine response among treatment refractory/intolerant patients is still not fully understood and likely involves multiple factors. This exploratory analysis suggests that the D2 receptor gene may be one such factor.

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Authors and Affiliations

  1. Neurogenetics Section, Center for Addiction and Mental Health, University of Toronto, 250 College Street, Toronto, Ontario, M5T 1R8, Canada

    Rudi Hwang, Vincenzo De Luca, Xingqun Ni, Fabio Macciardi & James L. Kennedy

  2. Department of Psychiatry, University of Occupational and Environmental Health, Yahatanishi-ku, Kitakyushu, 807-8555, Japan

    Takahiro Shinkai

  3. Brain Imaging Center, University of California, Irvine Hall, Room 166, Irvine, CA, 92697-3960, USA

    Steven Potkin

  4. University of North Carolina Medical School, 7025 Neurosciences Hospital, Chapel Hill, NC, 27599-7160, USA

    Jeffrey A. Lieberman

  5. Psychiatric Hospital, Vanderbilt University, 1601 23rd Avenue South, Suite 306, Nashville, TN, 37212, USA

    Herbert Y. Meltzer

  6. Departement of Psychiatry, Charité University Medicine Berlin, Campus Charité Mitte, Berlin, Germany

    Daniel J. Müller

Authors
  1. Rudi Hwang
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  2. Takahiro Shinkai
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  3. Vincenzo De Luca
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  4. Daniel J. Müller
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  5. Xingqun Ni
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  6. Fabio Macciardi
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  7. Steven Potkin
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  8. Jeffrey A. Lieberman
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  9. Herbert Y. Meltzer
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  10. James L. Kennedy
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Corresponding author

Correspondence to James L. Kennedy.

Additional information

Funding and Grants: (1) National Institutes of Health (NIH), (2) Canadian Institutes of Health Research (CIHR), (3) Ontario Mental Health Foundation (OMHF); (4) Ritter Foundation; (5) Warren Foundation; (6) Prentiss Foundation.

The scientific work conducted in the studies described in this manuscript complies with the current laws of the US and Canada and also have been performed in compliance with the ethical standards established in the 1964 Declaration of Helsinki.

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Hwang, R., Shinkai, T., De Luca, V. et al. Association study of 12 polymorphisms spanning the dopamine D2 receptor gene and clozapine treatment response in two treatment refractory/intolerant populations. Psychopharmacology 181, 179–187 (2005). https://doi.org/10.1007/s00213-005-2223-5

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  • DOI: https://doi.org/10.1007/s00213-005-2223-5

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