Abstract
D2 blockade has been implicated in having a central role in antipsychotic response. However, treatment refractoriness, in spite of complete D2 blockade, as well as the efficacy of clozapine (CLZ) in a portion of this patient population, indicates the involvement of other factors as well. Several lines of evidence suggest a role for D3. Furthermore, an earlier meta-analysis by Jönsson et al. (2003) (n=233) suggested a role for genetic variation in the D3 gene. Relevant to this study, Jönsson et al. found the Ser allele of the D3 serine-to-glycine substitution at amino acid position 9 (Ser9Gly) polymorphism to be associated with worse CLZ response compared with the Gly allele. In this study, we attempt to validate these findings by performing a meta-analysis in a much larger sample (n=758). Eight other variants were also tested in our own sample to explore the possible effect of other regions of the gene. We report a negative but consistent trend across individual studies in our meta-analysis for the DRD3 Ser allele and poor CLZ response. A possible minor role for this single-nucleotide polymorphism cannot be disregarded, as our sample size may have been insufficient. Other DRD3 variants and haplotypes of possible interest were also identified for replication in future studies.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 6 print issues and online access
$259.00 per year
only $43.17 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Malhotra AK, Murphy Jr GM, Kennedy JL . Pharmacogenetics of psychotropic drug response. Am J Psychiatry 2004; 161: 780–796.
Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005; 353: 1209–1223.
Mata I, Madoz V, Arranz MJ, Sham P, Murray RM . Olanzapine: concordant response in monozygotic twins with schizophrenia. Br J Psychiatry 2001; 178: 86.
Vojvoda D, Grimmell K, Sernyak M, Mazure CM . Monozygotic twins concordant for response to clozapine. Lancet 1996; 347: 61.
Kapur S, Mamo D . Half a century of antipsychotics and still a central role for dopamine D2 receptors. Prog Neuropsychopharmacol Biol Psychiatry 2003; 27: 1081–1090.
Hwang R, Shinkai T, De Luca V, Muller DJ, Ni X, Macciardi F et al. Association study of 12 polymorphisms spanning the dopamine D(2) receptor gene and clozapine treatment response in two treatment refractory/intolerant populations. Psychopharmacology (Berl) 2005; 181: 179–187.
Nordstrom AL, Farde L, Nyberg S, Karlsson P, Halldin C, Sedvall G . D1, D2, and 5-HT2 receptor occupancy in relation to clozapine serum concentration: a PET study of schizophrenic patients. Am J Psychiatry 1995; 152: 1444–1449.
Meltzer HY . The mechanism of action of novel antipsychotic drugs. Schizophr Bull 1991; 17: 263–287.
Sokoloff P, Diaz J, Le Foll B, Guillin O, Leriche L, Bezard E et al. The dopamine D3 receptor: a therapeutic target for the treatment of neuropsychiatric disorders. CNS Neurol Disord Drug Targets 2006; 5: 25–43.
Gurevich EV, Joyce JN . Distribution of dopamine D3 receptor expressing neurons in the human forebrain: comparison with D2 receptor expressing neurons. Neuropsychopharmacology 1999; 20: 60–80.
Gurevich EV, Bordelon Y, Shapiro RM, Arnold SE, Gur RE, Joyce JN . Mesolimbic dopamine D3 receptors and use of antipsychotics in patients with schizophrenia. A postmortem study. Arch Gen Psychiatry 1997; 54: 225–232.
Joyce JN, Gurevich EV . D3 receptors and the actions of neuroleptics in the ventral striatopallidal system of schizophrenics. Ann N Y Acad Sci 1999; 877: 595–613.
Amalric M, Koob GF . Functionally selective neurochemical afferents and efferents of the mesocorticolimbic and nigrostriatal dopamine system. Prog Brain Res 1993; 99: 209–226.
Csernansky JG, Murphy GM, Faustman WO . Limbic/mesolimbic connections and the pathogenesis of schizophrenia. Biol Psychiatry 1991; 30: 383–400.
Mogenson GJ, Yang CR, Yim CY . Influence of dopamine on limbic inputs to the nucleus accumbens. Ann N Y Acad Sci 1988; 537: 86–100.
Abi-Dargham A, Laruelle M . Mechanisms of action of second generation antipsychotic drugs in schizophrenia: insights from brain imaging studies. Eur Psychiatry 2005; 20: 15–27.
Damask SP, Bovenkerk KA, de la Pena G, Hoversten KM, Peters DB, Valentine AM et al. Differential effects of clozapine and haloperidol on dopamine receptor mRNA expression in rat striatum and cortex. Brain Res Mol Brain Res 1996; 41: 241–249.
Joyce JN, Lexow N, Bird E, Winokur A . Organization of dopamine D1 and D2 receptors in human striatum: receptor autoradiographic studies in Huntington's disease and schizophrenia. Synapse 1988; 2: 546–557.
Joyce JN, Goldsmith SG, Gurevich EV . Limbic circuits and monoamine receptors: dissecting the effects of antipsychotics from disease processes. J Psychiatr Res 1997; 31: 197–217.
Gyertyan I, Saghy K . Effects of dopamine D3 receptor antagonists on spontaneous and agonist-reduced motor activity in NMRI mice and Wistar rats: comparative study with nafadotride, U 99194A and SB 277011. Behav Pharmacol 2004; 15: 253–262.
Millan MJ, Dekeyne A, Rivet JM, Dubuffet T, Lavielle G, Brocco M . S33084, a novel, potent, selective, and competitive antagonist at dopamine D(3)-receptors: II. Functional and behavioral profile compared with GR218,231 and L741,626. J Pharmacol Exp Ther 2000; 293: 1063–1073.
Reavill C, Taylor SG, Wood MD, Ashmeade T, Austin NE, Avenell KY et al. Pharmacological actions of a novel, high-affinity, and selective human dopamine D(3) receptor antagonist, SB-277011-A. J Pharmacol Exp Ther 2000; 294: 1154–1165.
Park WK, Jeong D, Cho H, Lee SJ, Cha MY, Pae AN et al. KKHA-761, a potent D3 receptor antagonist with high 5-HT1A receptor affinity, exhibits antipsychotic properties in animal models of schizophrenia. Pharmacol Biochem Behav 2005; 82: 361–372.
Park WK, Jeong D, Yun CW, Lee S, Cho H, Kim GD et al. Pharmacological actions of a novel and selective dopamine D3 receptor antagonist, KCH-1110. Pharmacol Res 2003; 48: 615–622.
Swain SN, Beuk J, Heidbreder CA, Beninger RJ . Role of dopamine D3 receptors in the expression of conditioned fear in rats. Eur J Pharmacol 2008; 579: 167–176.
Zhang M, Ballard ME, Kohlhaas KL, Browman KE, Jongen-Relo AL, Unger LV et al. Effect of dopamine D3 antagonists on PPI in DBA/2J mice or PPI deficit induced by neonatal ventral hippocampal lesions in rats. Neuropsychopharmacology 2006; 31: 1382–1392.
Brocco M, Gobert A, Dekeyne A, Lavielle G, Millan M . S33138, a novel and preferential antagonist at dopamine D3 receptors: functional profile in rodent models of the control of negative-cognitive symptoms of schizophrenia. Int J Neuropsychopharmacol 2004; 7 S2: S265.
Rodriguez-Arias M, Felip CM, Broseta I, Minarro J . The dopamine D3 antagonist U-99194A maleate increases social behaviors of isolation-induced aggressive male mice. Psychopharmacology (Berl) 1999; 144: 90–94.
Glickstein SB, Desteno DA, Hof PR, Schmauss C . Mice lacking dopamine D2 and D3 receptors exhibit differential activation of prefrontal cortical neurons during tasks requiring attention. Cereb Cortex 2005; 15: 1016–1024.
Laszy J, Laszlovszky I, Gyertyan I . Dopamine D3 receptor antagonists improve the learning performance in memory-impaired rats. Psychopharmacology (Berl) 2005; 179: 567–575.
Audinot V, Newman-Tancredi A, Gobert A, Rivet JM, Brocco M, Lejeune F et al. A comparative in vitro and in vivo pharmacological characterization of the novel dopamine D3 receptor antagonists (+)-S 14297, nafadotride, GR 103,691 and U 99194. J Pharmacol Exp Ther 1998; 287: 187–197.
Gyertyan I, Saghy K . The selective dopamine D3 receptor antagonists, SB 277011-A and S 33084 block haloperidol-induced catalepsy in rats. Eur J Pharmacol 2007; 572: 171–174.
Guo N, Klitenick MA, Tham CS, Fibiger HC . Receptor mechanisms mediating clozapine-induced c-fos expression in the forebrain. Neuroscience 1995; 65: 747–756.
Robertson GS, Fibiger HC . Neuroleptics increase c-fos expression in the forebrain: contrasting effects of haloperidol and clozapine. Neuroscience 1992; 46: 315–328.
Robertson GS, Lee CJ, Sridhar K, Nakabeppu Y, Cheng M, Wang YM et al. Clozapine-, but not haloperidol-, induced increases in deltaFosB-like immunoreactivity are completely blocked in the striatum of mice lacking D3 dopamine receptors. Eur J Neurosci 2004; 20: 3189–3194.
Southam E, Lloyd A, Jennings CA, Cluderay JE, Cilia J, Gartlon JE et al. Effect of the selective dopamine D3 receptor antagonist SB-277011-A on regional c-Fos-like expression in rat forebrain. Brain Res 2007; 1149: 50–57.
Ashby Jr CR, Minabe Y, Stemp G, Hagan JJ, Middlemiss DN . Acute and chronic administration of the selective D(3) receptor antagonist SB-277011-A alters activity of midbrain dopamine neurons in rats: an in vivo electrophysiological study. J Pharmacol Exp Ther 2000; 294: 1166–1174.
Chiodo LA, Bunney BS . Typical and atypical neuroleptics: differential effects of chronic administration on the activity of A9 and A10 midbrain dopaminergic neurons. J Neurosci 1983; 3: 1607–1619.
Macdonald GJ, Branch CL, Hadley MS, Johnson CN, Nash DJ, Smith AB et al. Design and synthesis of trans-3-(2-(4-((3-(3-(5-methyl-1,2,4-oxadiazolyl))- phenyl)carboxamido)cyclohexyl)ethyl)-7-methylsulfonyl-2,3,4,5-tetrahydro-1 H-3-benzazepine (SB-414796): a potent and selective dopamine D3 receptor antagonist. J Med Chem 2003; 46: 4952–4964.
Jeanneteau F, Funalot B, Jankovic J, Deng H, Lagarde JP, Lucotte G et al. A functional variant of the dopamine D3 receptor is associated with risk and age-at-onset of essential tremor. Proc Natl Acad Sci USA 2006; 103: 10753–10758.
Lundstrom K, Turpin MP . Proposed schizophrenia-related gene polymorphism: expression of the Ser9Gly mutant human dopamine D3 receptor with the Semliki Forest virus system. Biochem Biophys Res Commun 1996; 225: 1068–1072.
Hellstrand M, Danielsen EA, Steen VM, Ekman A, Eriksson E, Nilsson CL . The ser9gly SNP in the dopamine D3 receptor causes a shift from cAMP related to PGE2 related signal transduction mechanisms in transfected CHO cells. J Med Genet 2004; 41: 867–871.
Dubertret C, Gorwood P, Ades J, Feingold J, Schwartz JC, Sokoloff P . Meta-analysis of DRD3 gene and schizophrenia: ethnic heterogeneity and significant association in Caucasians. Am J Med Genet 1998; 81: 318–322.
Jönsson EG, Flyckt L, Burgert E, Crocq MA, Forslund K, Mattila-Evenden M et al. Dopamine D3 receptor gene Ser9Gly variant and schizophrenia: association study and meta-analysis. Psychiatr Genet 2003; 13: 1–12.
Williams J, Spurlock G, Holmans P, Mant R, Murphy K, Jones L et al. A meta-analysis and transmission disequilibrium study of association between the dopamine D3 receptor gene and schizophrenia. Mol Psychiatry 1998; 3: 141–149.
Jönsson EG, Kaiser R, Brockmoller J, Nimgaonkar VL, Crocq MA . Meta-analysis of the dopamine D3 receptor gene (DRD3) Ser9Gly variant and schizophrenia. Psychiatr Genet 2004; 14: 9–12.
Ma G, He Z, Fang W, Tang W, Huang K, Li Z et al. The Ser9Gly polymorphism of the dopamine D3 receptor gene and risk of schizophrenia: an association study and a large meta-analysis. Schizophr Res 2008; 101: 26–35.
Utsunomiya K, Shinkai T, De Luca V, Hwang R, Sakata S, Fukunaka Y et al. Genetic association between the dopamine D3 gene polymorphism (Ser9Gly) and schizophrenia in Japanese populations: evidence from a case–control study and meta-analysis. Neurosci Lett 2008; 444: 161–165.
APA. Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) 4th edn. American Psychiatric Association: Washington, DC, 1994.
Kane J, Honigfeld G, Singer J, Meltzer H . Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry 1988; 45: 789–796.
Lahiri DK, Nurnberger Jr JI . A rapid non-enzymatic method for the preparation of HMW DNA from blood for RFLP studies. Nucleic Acids Res 1991; 19: 5444.
International HapMap Consortium. The International Hapmap Project. Nature 2003; 426: 789–796.
SPSS (2007). Statistical Package for the Social Sciences for Windows, release 15.0.1.1. SPSS Inc.: Chicago.
Barrett JC, Fry B, Maller J, Daly MJ . Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21: 263–265.
Dudbridge F . Pedigree disequilibrium tests for multilocus haplotypes. Genet Epidemiol 2003; 25: 115–121.
Bland JM, Altman DG . Statistics notes. The odds ratio. BMJ 2000; 320: 1468.
Shaikh S, Collier DA, Sham PC, Ball D, Aitchison K, Vallada H et al. Allelic association between a Ser-9-Gly polymorphism in the dopamine D3 receptor gene and schizophrenia. Hum Genet 1996; 97: 714–719.
Gaitonde EJ, Morris A, Sivagnanasundaram S, McKenna PJ, Hunt DM, Mollon JD . Assessment of association of D3 dopamine receptor MscI polymorphism with schizophrenia: analysis of symptom ratings, family history, age at onset, and movement disorders. Am J Med Genet 1996; 67: 455–458.
Malhotra AK, Goldman D, Buchanan RW, Rooney W, Clifton A, Kosmidis MH et al. The dopamine D3 receptor (DRD3) Ser9Gly polymorphism and schizophrenia: a haplotype relative risk study and association with clozapine response. Mol Psychiatry 1998; 3: 72–75.
Scharfetter J, Chaudhry HR, Hornik K, Fuchs K, Sieghart W, Kasper S et al. Dopamine D3 receptor gene polymorphism and response to clozapine in schizophrenic Pakistani patients. Eur Neuropsychopharmacol 1999; 10: 17–20.
Arranz MJ, Munro J, Birkett J, Bolonna A, Mancama D, Sodhi M et al. Pharmacogenetic prediction of clozapine response. Lancet 2000; 355: 1615–1616.
Barlas IO, Cetin M, Erdal ME, Semiz UB, Basoglu C, Ay ME et al. Lack of association between DRD3 gene polymorphism and response to clozapine in Turkish schizoprenia patients. Am J Med Genet B Neuropsychiatr Genet 2009; 150B: 56–60.
StataCorp (2003). Stata Statistical Software, release 8. StataCorp LP: College Station, TX.
Ioannidis JP, Ntzani EE, Trikalinos TA, Contopoulos-Ioannidis DG . Replication validity of genetic association studies. Nat Genet 2001; 29: 306–309.
Lohmueller KE, Pearce CL, Pike M, Lander ES, Hirschhorn JN . Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat Genet 2003; 33: 177–182.
Newton-Cheh C, Hirschhorn JN . Genetic association studies of complex traits: design and analysis issues. Mutat Res 2005; 573: 54–69.
Bowers Jr MB, Study RE . Cerebrospinal fluid cyclic AMP and acid monoamine metabolites following probenecid: studies in psychiatric patients. Psychopharmacology (Berl) 1979; 62: 17–22.
Hatta Y, Hatta S, Saito T . Effects of ceruletide on the dopamine receptor-adenylate cyclase system in striatum and frontal cortex of rats chronically treated with haloperidol. Psychopharmacology (Berl) 1993; 110: 383–389.
Biederman J, Rimon R, Ebstein R, Zohar J, Belmaker R . Neuroleptics reduce spinal fluid cyclic AMP in schizophrenic patient. Neuropsychobiology 1976; 2: 324–327.
Millan MJ, Mannoury la Cour C, Novi F, Maggio R, Audinot V, Newman-Tancredi A et al. S33138 [N-[4-[2-[(3aS,9bR)-8-cyano-1,3a,4,9b-tetrahydro[1]-benzopyrano[3,4-c]pyrr ol-2(3H)-yl)-ethyl]phenylacetamide], a preferential dopamine D3 versus D2 receptor antagonist and potential antipsychotic agent: I. Receptor-binding profile and functional actions at G-protein-coupled receptors. J Pharmacol Exp Ther 2008; 324: 587–599.
Nishi A, Snyder GL, Greengard P . Bidirectional regulation of DARPP-32 phosphorylation by dopamine. J Neurosci 1997; 17: 8147–8155.
Muller N, Strassnig M, Schwarz MJ, Ulmschneider M, Riedel M . COX-2 inhibitors as adjunctive therapy in schizophrenia. Expert Opin Investig Drugs 2004; 13: 1033–1044.
Kaiya H, Uematsu M, Ofuji M, Nishida A, Takeuchi K, Nozaki M et al. Elevated plasma prostaglandin E2 levels in schizophrenia. J Neural Transm 1989; 77: 39–46.
Muller N, Riedel M, Scheppach C, Brandstatter B, Sokullu S, Krampe K et al. Beneficial antipsychotic effects of celecoxib add-on therapy compared to risperidone alone in schizophrenia. Am J Psychiatry 2002; 159: 1029–1034.
Sugino H, Futamura T, Mitsumoto Y, Maeda K, Marunaka Y . Atypical antipsychotics suppress production of proinflammatory cytokines and up-regulate interleukin-10 in lipopolysaccharide-treated mice. Prog Neuropsychopharmacol Biol Psychiatry 2009; 33: 303–307.
Monteleone P, Fabrazzo M, Tortorella A, Maj M . Plasma levels of interleukin-6 and tumor necrosis factor alpha in chronic schizophrenia: effects of clozapine treatment. Psychiatry Res 1997; 71: 11–17.
Nilsson CL, Hellstrand M, Ekman A, Eriksson E . Both dopamine and the putative dopamine D3 receptor antagonist PNU-99194A induce a biphasic inhibition of phorbol ester-stimulated arachidonic acid release from CHO cells transfected with the dopamine D3 receptor. Life Sci 1999; 64: 939–951.
Kyosseva SV . The role of the extracellular signal-regulated kinase pathway in cerebellar abnormalities in schizophrenia. Cerebellum 2004; 3: 94–99.
Browning JL, Patel T, Brandt PC, Young KA, Holcomb LA, Hicks PB . Clozapine and the mitogen-activated protein kinase signal transduction pathway: implications for antipsychotic actions. Biol Psychiatry 2005; 57: 617–623.
Lu XH, Dwyer DS . Second-generation antipsychotic drugs, olanzapine, quetiapine, and clozapine enhance neurite outgrowth in PC12 cells via PI3K/AKT, ERK, and pertussis toxin-sensitive pathways. J Mol Neurosci 2005; 27: 43–64.
Beom S, Cheong D, Torres G, Caron MG, Kim KM . Comparative studies of molecular mechanisms of dopamine D2 and D3 receptors for the activation of extracellular signal-regulated kinase. J Biol Chem 2004; 279: 28304–28314.
Bouvier M . Oligomerization of G-protein-coupled transmitter receptors. Nat Rev Neurosci 2001; 2: 274–286.
Nimchinsky EA, Hof PR, Janssen WG, Morrison JH, Schmauss C . Expression of dopamine D3 receptor dimers and tetramers in brain and in transfected cells. J Biol Chem 1997; 272: 29229–29237.
Lee SP, Xie Z, Varghese G, Nguyen T, O’Dowd BF, George SR . Oligomerization of dopamine and serotonin receptors. Neuropsychopharmacology 2000; 23 (4 Suppl): S32–S40.
Liu N, Zhang K, Zhao H . Haplotype-association analysis. Adv Genet 2008; 60: 335–405.
Ishiguro H, Okuyama Y, Toru M, Arinami T . Mutation and association analysis of the 5′ region of the dopamine D3 receptor gene in schizophrenia patients: identification of the Ala38Thr polymorphism and suggested association between DRD3 haplotypes and schizophrenia. Mol Psychiatry 2000; 5: 433–438.
Sivagnanasundaram S, Morris AG, Gaitonde EJ, McKenna PJ, Mollon JD, Hunt DM . A cluster of single nucleotide polymorphisms in the 5′-leader of the human dopamine D3 receptor gene (DRD3) and its relationship to schizophrenia. Neurosci Lett 2000; 279: 13–16.
Talkowski ME, Mansour H, Chowdari KV, Wood J, Butler A, Varma PG et al. Novel, replicated associations between dopamine D3 receptor gene polymorphisms and schizophrenia in two independent samples. Biol Psychiatry 2006; 60: 570–577.
Joyce JN, Millan MJ . Dopamine D3 receptor antagonists as therapeutic agents. Drug Discov Today 2005; 10: 917–925.
Naheed M, Green B . Focus on clozapine. Curr Med Res Opin 2001; 17: 223–229.
Nyholt DR . A simple correction for multiple testing for single-nucleotide polymorphisms in linkage disequilibrium with each other. Am J Hum Genet 2004; 74: 765–769.
Gauderman WJ . Sample size requirements for matched case–control studies of gene–environment interaction. Stat Med 2002; 21: 35–50.
Lahti AC, Weiler M, Carlsson A, Tamminga CA . Effects of the D3 and autoreceptor-preferring dopamine antagonist (+)-UH232 in schizophrenia. J Neural Transm 1998; 105: 719–734.
Lecrubier Y . A partial D3 receptor agonist in schizophrenia. Eur Neuropsychopharmacol 2003; 13 (S4): S167–S168.
Acknowledgements
RH was supported by the Canadian Institute of the Health Research (CIHR) Molecular Medicine Training Program, JLK was supported by the CIHR and GlaxoSmithKline, and AM was supported by the Instituto de Salud Carlos III, Centro de Investigacion en Red de Salud Mental, CIBERSAM.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
JLK has been a consultant for GlaxoSmithKline, Johnson and Johnson and for TheraGenetics. JLK and RH are co-authors on a patent application for genetic prediction of antipsychotic response.
Rights and permissions
About this article
Cite this article
Hwang, R., Zai, C., Tiwari, A. et al. Effect of dopamine D3 receptor gene polymorphisms and clozapine treatment response: exploratory analysis of nine polymorphisms and meta-analysis of the Ser9Gly variant. Pharmacogenomics J 10, 200–218 (2010). https://doi.org/10.1038/tpj.2009.65
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/tpj.2009.65
Keywords
This article is cited by
-
Pharmakogenetik in der Psychiatrie: eine Standortbestimmung
Der Nervenarzt (2018)
-
Genetics and Antipsychotic Response in Schizophrenia: an Update
Current Behavioral Neuroscience Reports (2017)
-
Association studies of genomic variants with treatment response to risperidone, clozapine, quetiapine and chlorpromazine in the Chinese Han population
The Pharmacogenomics Journal (2016)
-
Personalized medicine in psychiatry: problems and promises
BMC Medicine (2013)