Get to know a gene: DRD2

What is DRD2?
The dopamine D2 receptor, encoded by the DRD2 gene, plays a critical role in response to antipsychotic medications. All antipsychotic medications bind to the D2 receptor, underscoring its importance in treating psychotic symptoms. Several polymorphisms have been identified in this gene, but the best studied has been a single nucleotide insertion/deletion known as the -141C indel polymorphism (-141C Ins/Del), which has been proposed to modulate antipsychotic efficacy and side effect burden.

What do the studies say about the DRD2 -141C Ins/Del polymorphism and antipsychotic efficacy?
We reviewed 18 publications that examined the effect of the DRD2 -141C Ins/Del polymorphism on antipsychotic efficacy. Five publications (n=377) demonstrated that the Ins allele showed a statistically significant association with greater response to antipsychotics.^1–5 However, sample sizes tended to be small, with 4 studies enrolling between 49-72 patients. The largest positive study (n=135) by Wu et al. evaluated chlorpromazine response over 8 weeks, and found that the insertion allele was more common in responders vs non-responders, but this finding did not survive correction for multiple testing.⁵ In contrast, 12 publications (n=1,736) showed no significant association between -141C Ins/Del genotype and antipsychotic response6–17, while one other study (n=83) showed that the Del allele was associated with greater response to antipsychotics¹⁸.

What do the studies say about the DRD2 -141C Ins/Del polymorphism and antipsychotic-induced adverse events?
We reviewed 15 publications that examined the effect of the DRD2 -141C Ins/Del polymorphism on antipsychotic-induced movement disorders. Fourteen (n=3,427) showed no significant association.^13,19–31 The lone positive study (n=126) showed an association with rigidity subscales, which did not survive correction for multiple testing.³² We also reviewed 5 publications (n=457) that examined the effect of the DRD2 -141C Ins/Del polymorphism on hyperprolactinemia, and all 5 showed no association.^33–37 Finally, of the 4 publications that examined the effect of the DRD2 -141C Ins/Del polymorphism on antipsychotic-induced weight gain, 1 (n=58) showed a significant association³⁸, while 3 studies (n=520) showed no association^31,39,40.

What is the clinical significance of the DRD2 -141C Ins/Del polymorphism?
While initial studies of the DRD2 -141C Ins/Del polymorphism were positive, subsequent studies have failed to replicate the initial findings. Extensive data regarding the effect of the DRD2 -141C Ins/Del polymorphism on antipsychotic response or antipsychotic-induced adverse events show no significant association. These data suggest a very modest, if any, impact of the DRD2 -141C Ins/Del polymorphism on either antipsychotic efficacy or adverse events. While DRD2 remains a very important target for pharmacogenomic research, this particular polymorphism in isolation does not appear to be clinically significant as a marker for antipsychotic response and is therefore not currently included on the GeneSight^® panels.

Methodology
The search was conducted within the PubMed database. Results were limited to English studies and focused on antipsychotic efficacy and tolerability, including antipsychotic-induced weight gain, movement disorders, and hyperprolactinemia. After redundant and irrelevant studies were eliminated, a total of 18 publications (n=2,196) entered the efficacy review, 15 publications (n=3,553) entered the antipsychotic-induced movement disorders review, 5 publications (n=457) entered the hyperprolactinemia review, and 4 publications (n=578) entered the weight gain review.

References
1. Suzuki, A. 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 11, 545–50 (2001).

2. Malhotra, A. K. et al. Allelic variation in the promoter region of the dopamine D2 receptor gene and clozapine response. Schizophr. Res. 36, 92–93 (1999).

3. Yasui-Furukori, N. et al. Comparing the influence of dopamine D₂ polymorphisms and plasma drug concentrations on the clinical response to risperidone. J. Clin. Psychopharmacol. 31, 633–7 (2011).

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

5. Wu, S. et al. Response to chlorpromazine treatment may be associated with polymorphisms of the DRD2 gene in Chinese schizophrenic patients. Neurosci. Lett. 376, 1–4 (2005).

6. Shen, Y. C. et al. Effects of DRD2/ANKK1 gene variations and clinical factors on aripiprazole efficacy in schizophrenic patients. J. Psychiatr. Res. 43, 600–606 (2009).

7. Arranz, M. J. et al. Lack of association between a polymorphism in the promoter region of the dopamine-2 receptor gene and clozapine response. Pharmacogenetics 8, 481–484 (1998).

8. Hwang, R. et al. Dopamine D2 receptor gene variants and quantitative measures of positive and negative symptom response following clozapine treatment. Eur. Neuropsychopharmacol. 16, 248–259 (2006).

9. Ikeda, M. et al. Variants of dopamine and serotonin candidate genes as predictors of response to risperidone treatment in first-episode schizophrenia. Pharmacogenomics 9, 1437–43 (2008).

10. Xing, Q. et al. The relationship between the therapeutic response to risperidone and the dopamine D2 receptor polymorphism in Chinese schizophrenia patients. Int. J. Neuropsychopharmacol. 10, 631–7 (2007).

11. Vehof, J. et al. Clinical response to antipsychotic drug treatment: association study of polymorphisms in six candidate genes. Eur. Neuropsychopharmacol. 22, 625–31 (2012).

12. Alenius, M. et al. Gene polymorphism influencing treatment response in psychotic patients in a naturalistic setting. J. Psychiatr. Res. 42, 884–93 (2008).

13. Gunes, A., Scordo, M. G., Jaanson, P. & Dahl, M.-L. Serotonin and dopamine receptor gene polymorphisms and the risk of extrapyramidal side effects in perphenazine-treated schizophrenic patients. Psychopharmacology (Berl). 190, 479–84 (2007).

14. Zahari, Z., Teh, L. K., Ismail, R. & Razali, S. M. Influence of DRD2 polymorphisms on the clinical outcomes of patients with schizophrenia. Psychiatr. Genet. 21, 183–9 (2011).

15. Tybura, P. et al. Some dopaminergic genes polymorphisms are not associated with response to antipsychotic drugs in schizophrenic patients. Pharmacol. Reports 64, 528–535 (2012).

16. Miura, I. Influence of −141C Ins/Del Polymorphism in DRD2 Gene on Clinical Symptoms and Plasma Homovanillic Acid Levels in the Treatment of Schizophrenia With Aripiprazole. J. Clin. Psychopharmacol. 35, 333–334 (2015).

17. Bishop, J. R. et al. Pharmacogenetic associations of the type-3 metabotropic glutamate receptor (GRM3) gene with working memory and clinical symptom response to antipsychotics in first-episode schizophrenia. Psychopharmacology (Berl). 232, 145–154 (2015).

18. Lencer, R. Association of variants in DRD2 and GRM3 with motor and cognitive function in first-episode psychosis. Eur Arch Psychiatry Clin Neurosci 264, 345–355 (2014).

19. Dolžan, V. et al. Polymorphisms in dopamine receptor DRD1 and DRD2 genes and psychopathological and extrapyramidal symptoms in patients on long-term antipsychotic treatment. Am. J. Med. Genet. Part B Neuropsychiatr. Genet. 144, 809–815 (2007).

20. 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. 105, 774–778 (2001).

21. Kaiser, R., Tremblay, P.-B., Klufm ller, F., Roots, I. & Brockm ller, J. Relationship between adverse effects of antipsychotic treatment and dopamine D(2) receptor polymorphisms in patients with schizophrenia. Mol. Psychiatry 7, 695–705 (2002).

22. Lafuente, A. et al. Polymorphism of dopamine D2 receptor (TaqIA, TaqIB, and-141C Ins/Del) and dopamine degradation enzyme (COMT G158A, A-278G) genes and extrapyramidal symptoms in patients with schizophrenia and bipolar disorders. Psychiatry Res. 161, 131–141 (2008).

23. Liou, Y. J. et al. The human dopamine receptor D2 (DRD2) gene is associated with tardive dyskinesia in patients with schizophrenia. Schizophr. Res. 86, 323–325 (2006).

24. Mihara, K. et al. No relationship between -141C Ins/Del polymorphism of dopamine D2 receptor and extrapyramidal adverse effects of selective dopamine D2 antagonists in schizophrenic patients: a preliminary study. Psychiatry Res. 33–38 (2001).

25. Segman, R. H. et al. Association of dopaminergic and serotonergic genes with tardive dyskinesia in patients with chronic schizophrenia. Pharmacogenomics J. 3, 277–83 (2003).

26. Zai, C. C. et al. Association study of tardive dyskinesia and twelve DRD2 polymorphisms in schizophrenia patients. Int. J. Neuropsychopharmacol. 10, 639–51 (2007).

27. de Leon, J., Susce, M. T., Pan, R.-M., Koch, W. H. & Wedlund, P. J. Polymorphic Variations in GSTM1, GSTT1, PgP, CYP2D6, CYP3A5, and Dopamine D2 and D3 Receptors and Their Association With Tardive Dyskinesia in Severe Mental Illness. J. Clin. Psychopharmacol. 25, 448–456 (2005).

28. Inada, T., Arinami, T. & Yagi, G. Association between a polymorphism in the promoter region of the dopamine D2 receptor gene and schizophrenia in Japanese subjects: replication and evaluation. The International Journal of … (1999). at <http://journals.cambridge.org/abstract_S1461145799001492>

29. Srivastava, V. et al. Genetic susceptibility to tardive dyskinesia among schizophrenia subjects: IV. Role of dopaminergic pathway gene polymorphisms. Pharmacogenet. Genomics 16, 111–7 (2006).

30. Wu, S. N. et al. Association of DRD2 polymorphisms and chlorpromazine-induced extrapyramidal syndrome in Chinese schizophrenic patients. Acta Pharmacol. Sin. 27, 966–970 (2006).

31. Tybura, P. et al. Pharmacogenetics of adverse events in schizophrenia treatment: Comparison study of ziprasidone, olanzapine and perazine. Psychiatry Res. 219, 261–267 (2014).

32. Al Hadithy, A. F. et al. Pharmacogenetics of Parkinsonism, rigidity, rest tremor, and bradykinesia in African-Caribbean inpatients: Differences in association with dopamine and serotonin receptors. Am. J. Med. Genet. Part B Neuropsychiatr. Genet. 147, 890–897 (2008).

33. Aklillu, E. et al. CYP2D6 and DRD2 genes differentially impact pharmacodynamic sensitivity and time course of prolactin response to perphenazine. Pharmacogenet. Genomics 17, 989–993 (2007).

34. Anderson, G. M. et al. Effects of Short- and Long-Term Risperidone Treatment on Prolactin Levels in Children with Autism. Biol. Psychiatry 61, 545–550 (2007).

35. Calarge, C. A. et al. Variants of the dopamine D2 receptor and risperidone-induced hyperprolactinemia in children and adolescents. Pharmacogenet Genomics 19, 373–382 (2009).

36. Nagai, G. et al. Prolactin concentrations during aripiprazole treatment in relation to sex, plasma drugs concentrations and genetic polymorphisms of dopamine D2 receptor and cytochrome P450 2D6 in Japanese patients with schizophrenia. Psychiatry Clin. Neurosci. 66, 518–24 (2012).

37. Yasui-Furukori, N. et al. Association between dopamine-related polymorphisms and plasma concentrations of prolactin during risperidone treatment in schizophrenic patients. Prog. Neuro-Psychopharmacology Biol. Psychiatry 32, 1491–1495 (2008).

38. Lencz, T. et al. DRD2 promoter region variation predicts antipsychotic-induced weight gain in first episode schizophrenia. Pharmacogenet Genomics 20, 569–572 (2010).

39. Lane, H.-Y. et al. Risperidone-related weight gain: genetic and nongenetic predictors. J. Clin. Psychopharmacol. 26, 128–134 (2006).

40. Müller, D. J. et al. Systematic analysis of dopamine receptor genes (DRD1-DRD5) in antipsychotic-induced weight gain. Pharmacogenomics J. 12, 156–64 (2012).