Dopamine D2 Receptor Genetic Variation and Antipsychotic Drug Response: A Meta-Analysis

Jianping Zhang, MD, PhD; Todd Lencz, PhD; and Anil Malhotra, MD
Zucker Hillside Hospital and North Shore-Long Island Jewish Health System, Glen Oaks, New York

This poster presentation did not receive funding.

Background: Several lines of evidence suggest that antipsychotic drug efficacy is mediated by dopamine D2 receptor (DRD2) blockade. Therefore, it seems plausible that variation in the DRD2 gene is associated with clinical antipsychotic response. We examined the relationship between DRD2 gene polymorphisms and antipsychotic response via a meta-analysis.

Methods: Medline search (31 Dec 2008) yielded 16 prospective studies examining DRD2 variation and antipsychotic response. Treatment duration with a number of antipsychotic agents ranged from three to 16 weeks, except three studies of >6 months. Clinical response to antipsychotic treatment was defined as a 50% reduction of either Brief Psychiatric Rating Scale (BPRS) or Positive and Negative Syndrome Scale (PANSS) total score. Odds ratio (OR) was the primary effect size measure and was computed for each polymorphism in each study. Sufficient data were available for two DRD2 polymorphisms, Taq1A and -141C Ins/Del.

Results: Eleven studies assessed the Taq1A polymorphism and antipsychotic response; nine (n=1027) reported sufficient data to compute OR. There was no significant difference in response rate in A1 carrier versus A2/A2 genotype or A2 carrier versus A1/A1, but heterogeneity among studies was marginally significant, p=0.06 and 0.08, respectively. Exclusion of the two studies with longer durations resulted in marginally significant mean ORs. OR for A1 carrier vs A2/A2 = 1.41 (95%CI 0.95~2.09), p=0.09; A2 carrier versus A1/A1 =0.63 (95%CI .38~1.03), p=0.06, suggesting that the A1 allele was associated with better clinical response. Eight studies reported results on the -141C Ins/Del polymorphism; seven (n=935) reported sufficient data to compute OR. There was no difference in response rate between Del carrier versus Ins/Ins genotype, but again study heterogeneity was significant, p=0.05. Exclusion of the two studies with longer durations resulted in a significant mean OR of 0.62 (95%CI 0.39~0.99), p=0.04, indicating poorer response in patients with the Del allele. The three studies comprised of patients with first-episode schizophrenia demonstrated poorer clinical response in Del carriers, OR=0.53, p=0.05. No significant publication bias was detected.

Conclusions: DRD2 genetic variation is modestly associated with clinical response to antipsychotic treatment. Studies of first episode schizophrenia may be particularly sensitive to genetic effects by avoiding confounds related to variation in prior medication exposure.

References
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Kapur S, Mamo D. Half a century of antipsychotics and still a central role for dopamine D2 receptors. Prog Neuropsychopharmacol Biol Psychiatry. 2003;27(7):1081–1090.

Lencz T, Robinson DG, Xu K, et al. DRD2 promoter region variation as a predictor of sustained response to antipsychotic medication in first-episode schizophrenia patients. Am J Psychiatry. 2006;163(3):529–531.

Arranz MJ, de Leon J. Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research. Mol Psychiatry. 2007;12(8):707–747.

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