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D1 receptor alleles predict PET metabolic correlates of clinical response to clozapine

Molecular Psychiatry volume 8, pages 109–113 (2003)Cite this article

Abstract

A goal of pharmacogenetics is to clarify associations between allelic variation and risk factors in psychiatric illness. We report changes in regional brain metabolism based on dopamine alleles. Treatment-resistant schizophrenic subjects were positron emission tomography scanned with 18F-fluorodeoxyglucose after 5 weeks each of placebo and clozapine treatment. Significant regional brain metabolic effects were found for the D1 receptor genotypes (P<0.05), adjusted for multiple comparisons. Metabolic decreases for the 2,2 genotype but not the 1,2 genotype were observed in all major sectors of the brain, with the exception of the ventral parts of the caudate and putamen. Frontal, temporal, parietal, and occipital neocortices showed decreased metabolism as did the cingulate juxta-allocortex and the parahippocampal allocortex. Decreases were also observed in the thalamus, amygdala, and cerebellum bilaterally. No significant metabolic differences by genotype were observed for D3, 5HT2A, and 5HT2C polymorphisms. In terms of clinical response, the DRD1 2,2 genotype significantly improved with clozapine treatment, demonstrating a 30% decrease in the Brief Psychiatric Rating Scale positive symptoms in contrast to a 7% worsening for the 1,2 genotype (P<0.05). In this preliminary study, brain metabolic and clinical response to clozapine are related to the D1 receptor genotype.

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Acknowledgements

This work was supported by NIH Grants MH-445962 (SGP) and the PET analysis by the General Clinical Research Center Public Health Service Grant M001RR00827-S1 from the National Center for Research Resources and the Medical Research Council of Canada Grant PG-1121 to JLK. The authors would like to make note of the special contribution of the late Dr Hyman B Niznik, whose group first cloned the DRD1 gene in 1991.

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Authors and Affiliations

  1. Department of Psychiatry and Human Behavior, University of California, Irvine, CA, USA

    S G Potkin, Y Jin, D Keator, J C Wu, G Alva, D T Carreon & W E Bunney Jr

  2. Clarke Division, Centre for Addiction and Mental Health, Neurogenetics Section, University of Toronto, Toronto, Canada

    V S Basile, M Masellis, F Badri & J L Kennedy

  3. Department of Anatomy and Neurobiology, University of California, Irvine, CA, USA

    J H Fallon

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  1. S G Potkin
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  2. V S Basile
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  3. Y Jin
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  4. M Masellis
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  6. D Keator
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  7. J C Wu
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  8. G Alva
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  10. W E Bunney Jr
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Correspondence to S G Potkin.

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Potkin, S., Basile, V., Jin, Y. et al. D1 receptor alleles predict PET metabolic correlates of clinical response to clozapine. Mol Psychiatry 8, 109–113 (2003). https://doi.org/10.1038/sj.mp.4001191

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