The AAPS Journal

, Volume 13, Issue 1, pp 121–130 | Cite as

Dopamine D2 Occupancy as a Biomarker for Antipsychotics: Quantifying the Relationship with Efficacy and Extrapyramidal Symptoms

  • Rik de Greef
  • Alan Maloney
  • Per Olsson-Gisleskog
  • Joep Schoemaker
  • John Panagides
Research Article


For currently available antipsychotic drugs, blockade of dopamine D2 receptors is a critical component for achieving antipsychotic efficacy, but it is also a driving factor in the development of extrapyramidal symptoms (EPS). To inform the clinical development of asenapine, generic mathematical models have been developed for predicting antipsychotic efficacy and EPS tolerability based on D2 receptor occupancy. Clinical data on pharmacokinetics, D2 receptor occupancy, efficacy, and EPS for several antipsychotics were collected from the public domain. Asenapine data were obtained from in-house trials. D2 receptor occupancy data were restricted to published positron emission tomography studies that included blood sampling for pharmacokinetics. Clinical efficacy data were restricted to group mean endpoint data from short-term placebo-controlled trials, whereas EPS evaluation also included some non-placebo-controlled trials. A generally applicable model connecting antipsychotic dose, pharmacokinetics, D2 receptor occupancy, Positive and Negative Syndrome Scale (PANSS) response, and effect on Simpson–Angus Scale (SAS) was then developed. The empirical models describing the D2–PANSS and D2–SAS relationships were used successfully to aid dose selection for asenapine phase II and III trials. A broader use can be envisaged as a dose selection tool for new antipsychotics with D2 antagonist properties in the treatment of schizophrenia.


asenapine dopamine D2 receptors mathematical models 



The authors thank Dr. Shitij Kapur for his insights and direction during the early development of the models. All authors contributed to the development and writing of the paper and are completely responsible for its scientific content. This study was funded by Merck (Whitehouse Station, NJ, USA). Editorial support was provided by Complete Healthcare Communications, Inc., and funded by Merck (Whitehouse Station, NJ, USA).

Conflicts of interest

Rik de Greef and Joep Schoemaker are employees of Merck Sharp & Dohme (Oss, the Netherlands). John Panagides was an employee of Schering-Plough (formerly Organon), now Merck, at the time the study was conducted. Drs. Maloney and Olsson-Gisleskog were employed by Pharsight, A Certara Company, at the time this research was conducted and have no other interests to report.

Supplementary material

12248_2010_9247_MOESM1_ESM.doc (140 kb)
Supplementary Table 1 (DOC 143 872 kb)


  1. 1.
    Lieberman JA. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia: efficacy, safety and cost outcomes of CATIE and other trials. J Clin Psychiatry. 2007;68:e04.PubMedCrossRefGoogle Scholar
  2. 2.
    Kapur S, Zipursky RB, Remington G. Clinical and theoretical implications of 5-HT2 and D2 receptor occupancy of clozapine, risperidone, and olanzapine in schizophrenia. Am J Psychiatry. 1999;156:286–93.PubMedGoogle Scholar
  3. 3.
    Farde L, Nordstrom AL, Wiesel FA, Pauli S, Halldin C, Sedvall G. Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine. Relation to extrapyramidal side effects. Arch Gen Psychiatry. 1992;49:538–44.PubMedGoogle Scholar
  4. 4.
    Pani L, Pira L, Marchese G. Antipsychotic efficacy: relationship to optimal D(2)-receptor occupancy. Eur Psychiatry. 2007;22:267–75.PubMedCrossRefGoogle Scholar
  5. 5.
    Kapur S, Remington G, Jones C, Wilson A, DaSilva J, Houle S, et al. High levels of dopamine D2 receptor occupancy with low-dose haloperidol treatment: a PET study. Am J Psychiatry. 1996;153:948–50.PubMedGoogle Scholar
  6. 6.
    Nordstrom AL, Farde L, Wiesel FA, Forslund K, Pauli S, Halldin C, et al. Central D2-dopamine receptor occupancy in relation to antipsychotic drug effects: a double-blind PET study of schizophrenic patients. Biol Psychiatry. 1993;33:227–35.PubMedCrossRefGoogle Scholar
  7. 7.
    Horacek J, Bubenikova-Valesova V, Kopecek M, Palenicek T, Dockery C, Mohr P, et al. Mechanism of action of atypical antipsychotic drugs and the neurobiology of schizophrenia. CNS Drugs. 2006;20:389–409.PubMedCrossRefGoogle Scholar
  8. 8.
    Saphris® (asenapine sublingual tablets). Full prescribing information, Schering Corporation, a subsidiary of Merck & Co., Inc, Whitehouse Station, NJ; 2010.Google Scholar
  9. 9.
  10. 10.
    Shahid M, Walker GB, Zorn SH, Wong EH. Asenapine: a novel psychopharmacologic agent with a unique human receptor signature. J Psychopharmacol. 2009;23:65–73.PubMedCrossRefGoogle Scholar
  11. 11.
    Andree B, Halldin C, Vrijmoed-de Vries M, Farde L. Central 5-HT2A and D2 dopamine receptor occupancy after sublingual administration of ORG 5222 in healthy men. Psychopharmacology Berl. 1997;131:339–45.PubMedCrossRefGoogle Scholar
  12. 12.
    Data on file. Summit, NJ: Merck; 2010.Google Scholar
  13. 13.
    Geodon® (ziprasidone). Full prescribing information, Pfizer Inc., New York, NY; 2009.Google Scholar
  14. 14.
    Cheng YF, Paalzow LK, Bondesson U, Ekblom B, Eriksson K, Eriksson SO, et al. Pharmacokinetics of haloperidol in psychotic patients. Psychopharmacology Berl. 1987;91:410–4.PubMedCrossRefGoogle Scholar
  15. 15.
    Heyden S. Risperidone expert report (Serial No. R64 766). April 1992.Google Scholar
  16. 16.
    Kay SR, Fiszbein A, Opler LA. The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophr Bull. 1987;13:261–76.PubMedGoogle Scholar
  17. 17.
    Simpson GM, Angus JW. A rating scale for extrapyramidal side effects. Acta Psychiatr Scand Suppl. 1970;212:11–9.PubMedCrossRefGoogle Scholar
  18. 18.
    Risperdal® (risperidone). Full prescribing information. Janssen, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc., Titusville, NJ; 2009.Google Scholar
  19. 19.
    Zyprexa. Eli Lilly and Company, Indianapolis, IN; 2010.Google Scholar
  20. 20.
    Friberg LE, de Greef R, Kerbusch T, Karlsson MO. Modeling and simulation of the time course of asenapine exposure response and dropout patterns in acute schizophrenia. Clin Pharmacol Ther. 2009;86:84–91.PubMedCrossRefGoogle Scholar
  21. 21.
    Kapur S, Zipursky R, Jones C, Remington G, Houle S. Relationship between dopamine D(2) occupancy, clinical response, and side effects: a double-blind PET study of first-episode schizophrenia. Am J Psychiatry. 2000;157:514–20.PubMedCrossRefGoogle Scholar
  22. 22.
    Kane JM, Cohen M, Zhao J, Alphs L, Panagides J. Efficacy and safety of asenapine in a placebo- and haloperidol-controlled trial in patients with acute exacerbation of schizophrenia. J Clin Psychopharmacol. 2010;30:106–15.PubMedCrossRefGoogle Scholar
  23. 23.
    Meltzer HY, Li Z, Kaneda Y, Ichikawa J. Serotonin receptors: their key role in drugs to treat schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2003;27:1159–72.PubMedCrossRefGoogle Scholar
  24. 24.
    Reynolds GP, Yao Z, Zhang X, Sun J, Zhang Z. Pharmacogenetics of treatment in first-episode schizophrenia: D3 and 5-HT2C receptor polymorphisms separately associate with positive and negative symptom response. Eur Neuropsychopharmacol. 2005;15:143–51.PubMedCrossRefGoogle Scholar
  25. 25.
    Lieberman JA, Mailman RB, Duncan G, Sikich L, Chakos M, Nichols DE, et al. Serotonergic basis of antipsychotic drug effects in schizophrenia. Biol Psychiatry. 1998;44:1099–117.PubMedCrossRefGoogle Scholar
  26. 26.
    Lane HY, Lee CC, Liu YC, Chang WH. Pharmacogenetic studies of response to risperidone and other newer atypical antipsychotics. Pharmacogenomics. 2005;6:139–49.PubMedCrossRefGoogle Scholar
  27. 27.
    Farde L, Nyberg S, Oxenstierna G, Nakashima Y, Halldin C, Ericsson B. Positron emission tomography studies on D2 and 5-HT2 receptor binding in risperidone-treated schizophrenic patients. J Clin Psychopharmacol. 1995;15:19S–23S.PubMedGoogle Scholar
  28. 28.
    Gefvert O, Bergstrom M, Langstrom B, Lundberg T, Lindstrom L, Yates R. Time course of central nervous dopamine-D2 and 5-HT2 receptor blockade and plasma drug concentrations after discontinuation of quetiapine (Seroquel) in patients with schizophrenia. Psychopharmacology Berl. 1998;135:119–26.PubMedCrossRefGoogle Scholar
  29. 29.
    Gefvert O, Lundberg T, Wieselgren IM, Bergstrom M, Langstrom B, Wiesel F, et al. D(2) and 5HT(2A) receptor occupancy of different doses of quetiapine in schizophrenia: a PET study. Eur Neuropsychopharmacol. 2001;11:105–10.PubMedCrossRefGoogle Scholar
  30. 30.
    Seeman P, Tallerico T. Antipsychotic drugs which elicit little or no parkinsonism bind more loosely than dopamine to brain D2 receptors, yet occupy high levels of these receptors. Mol Psychiatry. 1998;3:123–34.PubMedCrossRefGoogle Scholar
  31. 31.
    Kapur S, Seeman P. Antipsychotic agents differ in how fast they come off the dopamine D2 receptors. Implications for atypical antipsychotic action. J Psychiatry Neurosci. 2000;25:161–6.PubMedGoogle Scholar
  32. 32.
    Potkin SG, Cohen M, Panagides J. Efficacy and tolerability of asenapine in acute schizophrenia: a placebo- and risperidone-controlled trial. J Clin Psychiatry. 2007;68:1492–500.PubMedCrossRefGoogle Scholar
  33. 33.
    Nordstrom AL, Farde L, Halldin C. Time course of D2-dopamine receptor occupancy examined by PET after single oral doses of haloperidol. Psychopharmacology Berl. 1992;106:433–8.PubMedCrossRefGoogle Scholar
  34. 34.
    Nyberg S, Farde L, Halldin C. A PET study of 5-HT2 and D2 dopamine receptor occupancy induced by olanzapine in healthy subjects. Neuropsychopharmacology. 1997;16:1–7.PubMedCrossRefGoogle Scholar
  35. 35.
    Remington G, Kapur S, Zipursky R. The relationship between risperidone plasma levels and dopamine D2 occupancy: a positron emission tomographic study. J Clin Psychopharmacol. 1998;18:82–3.PubMedCrossRefGoogle Scholar
  36. 36.
    Nyberg S, Farde L, Eriksson L, Halldin C, Eriksson B. 5-HT2 and D2 dopamine receptor occupancy in the living human brain. A PET study with risperidone. Psychopharmacology Berl. 1993;110:265–72.PubMedCrossRefGoogle Scholar
  37. 37.
    Nyberg S, Eriksson B, Oxenstierna G, Halldin C, Farde L. Suggested minimal effective dose of risperidone based on PET-measured D2 and 5-HT2A receptor occupancy in schizophrenic patients. Am J Psychiatry. 1999;156:869–75.PubMedGoogle Scholar
  38. 38.
    Bench CJ, Lammertsma AA, Dolan RJ, Grasby PM, Warrington SJ, Gunn K, et al. Dose dependent occupancy of central dopamine D2 receptors by the novel neuroleptic CP-88, 059–01: a study using positron emission tomography and 11C-raclopride. Psychopharmacology Berl. 1993;112:308–14.PubMedCrossRefGoogle Scholar
  39. 39.
    Bench CJ, Lammertsma AA, Grasby PM, Dolan RJ, Warrington SJ, Boyce M, et al. The time course of binding to striatal dopamine D2 receptors by the neuroleptic ziprasidone (CP-88, 059–01) determined by positron emission tomography. Psychopharmacology Berl. 1996;124:141–7.PubMedCrossRefGoogle Scholar
  40. 40.
    Beasley Jr CM, Tollefson G, Tran P, Satterlee W, Sanger T, Hamilton S. Olanzapine versus placebo and haloperidol: acute phase results of the North American double-blind olanzapine trial. Neuropsychopharmacology. 1996;14:111–23.PubMedCrossRefGoogle Scholar
  41. 41.
    Beasley Jr CM, Sanger T, Satterlee W, Tollefson G, Tran P, Hamilton S. Olanzapine versus placebo: results of a double-blind, fixed-dose olanzapine trial. Psychopharmacology Berl. 1996;124:159–67.PubMedCrossRefGoogle Scholar
  42. 42.
    Beasley Jr CM, Hamilton SH, Crawford AM, Dellva MA, Tollefson GD, Tran PV, et al. Olanzapine versus haloperidol: acute phase results of the international double-blind olanzapine trial. Eur Neuropsychopharmacol. 1997;7:125–37.PubMedCrossRefGoogle Scholar
  43. 43.
    Marder SR, Meibach RC. Risperidone in the treatment of schizophrenia. Am J Psychiatry. 1994;151:825–35.PubMedGoogle Scholar
  44. 44.
    Borison R, et al. Risperidone versus haloperidol versus placebo in the treatment of schizophrenia. Clinical Research Report No. RIS-USA-9001, N83170. Piscataway, NJ: Janssen; 1991.Google Scholar
  45. 45.
    Peuskens J. Risperidone in the treatment of patients with chronic schizophrenia: a multi-national, multi-centre, double-blind, parallel-group study versus haloperidol. Risperidone Study Group. Br J Psychiatry. 1995;166:712–26.PubMedCrossRefGoogle Scholar
  46. 46.
    Clinical Report: RIS-USA-72. 1997. NDA 20588/S002.Google Scholar
  47. 47.
    Daniel DG, Zimbroff DL, Potkin SG, Reeves KR, Harrigan EP, Lakshminarayanan M. Ziprasidone 80 mg/day and 160 mg/day in the acute exacerbation of schizophrenia and schizoaffective disorder: a 6-week placebo-controlled trial. Ziprasidone Study Group. Neuropsychopharmacology. 1999;20:491–505.PubMedCrossRefGoogle Scholar
  48. 48.
    Keck Jr P, Buffenstein A, Ferguson J, Feighner J, Jaffe W, Harrigan EP, et al. Ziprasidone 40 and 120 mg/day in the acute exacerbation of schizophrenia and schizoaffective disorder: a 4-week placebo-controlled trial. Psychopharmacology Berl. 1998;140:173–84.PubMedCrossRefGoogle Scholar
  49. 49.
    Goff DC, Posever T, Herz L, Simmons J, Kletti N, Lapierre K, et al. An exploratory haloperidol-controlled dose-finding study of ziprasidone in hospitalized patients with schizophrenia or schizoaffective disorder. J Clin Psychopharmacol. 1998;18:296–304.PubMedCrossRefGoogle Scholar
  50. 50.
    Clinical Report: Study 104. 1998. NDA 20825.Google Scholar
  51. 51.
    Clinical Report: Study 115. 1998. NDA 20825.Google Scholar
  52. 52.
    Arvanitis LA, Miller BG. Multiple fixed doses of “Seroquel” (quetiapine) in patients with acute exacerbation of schizophrenia: a comparison with haloperidol and placebo. The Seroquel Trial 13 Study Group. Biol Psychiatry. 1997;42:233–46.PubMedCrossRefGoogle Scholar
  53. 53.
    Zimbroff DL, Kane JM, Tamminga CA, Daniel DG, Mack RJ, Wozniak PJ, et al. Controlled, dose–response study of sertindole and haloperidol in the treatment of schizophrenia. Sertindole Study Group. Am J Psychiatry. 1997;154:782–91.PubMedGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2010

Authors and Affiliations

  • Rik de Greef
    • 1
  • Alan Maloney
    • 2
    • 3
  • Per Olsson-Gisleskog
    • 2
    • 3
  • Joep Schoemaker
    • 1
  • John Panagides
    • 4
  1. 1.Merck Research Laboratories, Merck Sharp & DohmeOssthe Netherlands
  2. 2.Pharsight, A Certara CompanyMountain ViewUSA
  3. 3.Exprimo ConsultingMechelenBelgium
  4. 4.MerckSummitUSA

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