, Volume 197, Issue 2, pp 229–235 | Cite as

Dose-finding study of paliperidone ER based on striatal and extrastriatal dopamine D2 receptor occupancy in patients with schizophrenia

  • Ryosuke Arakawa
  • Hiroshi Ito
  • Akihiro Takano
  • Hidehiko Takahashi
  • Takuya Morimoto
  • Takeshi Sassa
  • Katsuya Ohta
  • Motoichiro Kato
  • Yoshiro Okubo
  • Tetsuya Suhara
Original Investigation



Paliperidone ER is a novel antipsychotic drug in an extended-release (ER) formulation. As with all antipsychotics, careful dose setting is necessary to avoid side effects.


In this study, we measured striatal and extrastriatal dopamine D2 receptor occupancy during paliperidone ER treatment in patients with schizophrenia using positron emission tomography (PET) to compare regional occupancy and to estimate the optimal dose.

Materials and methods

Thirteen male patients with schizophrenia participated in this 6-week multiple-dose study. Six of them took 3 mg of paliperidone ER per day, four took 9 mg, and three took 15 mg. Two to 6 weeks after first drug intake, two PET scans, one with [11C]raclopride and one with [11C]FLB 457, were performed in each patient on the same day. The relationship between the dose or plasma concentration of paliperidone and dopamine D2 receptor occupancy was calculated.


The dopamine D2 receptor occupancies in the striatum measured with [11C]raclopride and the temporal cortex measured with [11C]FLB 457 were 54.2–85.5% and 34.5–87.3%, respectively. ED50 values of the striatum and temporal cortex were 2.38 and 2.84 mg/day, respectively. There was no significant difference in dopamine D2 receptor occupancy between the striatum and the temporal cortex.


The data from this study suggest that paliperidone ER at 6–9 mg provides an estimated level of dopamine D2 receptor occupancy between 70–80% and that the magnitude of dopamine D2 receptor occupancy is similar between the striatum and temporal cortex.


Paliperidone ER Dopamine D2 receptor occupancy Striatum Extrastriatum Positron emission tomography Schizophrenia 



This study was supported by Janssen Pharmaceutical K.K. and the National Institute of Radiological Sciences. We extend our thanks to Dr. Shoko Nozaki, Dr. Amane Tateno, Dr. Tetsuya Ichimiya, Dr. Koichiro Watanabe, Dr. Kensuke Nomura, Dr. Takashi Nakayama, Mr. Katsuyuki Tanimoto, Mr. Takahiro Shiraishi, Mr. Akira Ando, and Ms. Yoshiko Fukushima for their help with this study.


  1. Agid O, Mamo D, Ginovart N, Vitcu I, Wilson AA, Zipursky RB, Kapur S (2007) Striatal vs extrastriatal dopamine D2 receptors in antipsychotic response—a double-blind PET study in schizophrenia. Neuropsychopharmacology 32:1209–1215PubMedCrossRefGoogle Scholar
  2. Bigliani V, Mulligan RS, Acton PD, Ohlsen RI, Pike VW, Ell PJ, Gacinovic S, Kerwin RW, Pilowsky LS (2000) Striatal and temporal cortical D2/D3 receptor occupancy by olanzapine and sertindole in vivo: a [123I]epidepride single photon emission tomography (SPET) study. Psychopharmacology (Berl) 150:132–140CrossRefGoogle Scholar
  3. Bressan RA, Erlandsson K, Jones HM, Mulligan R, Flanagan RJ, Ell PJ, Pilowsky LS (2003a) Is regionally selective D2/D3 dopamine occupancy sufficient for atypical antipsychotic effect? An in vivo quantitative [123I]epidepride SPET study of amisulpride-treated patients. Am J Psychiatry 160:1413–1420PubMedCrossRefGoogle Scholar
  4. Bressan RA, Erlandsson K, Jones HM, Mulligan RS, Ell PJ, Pilowsky LS (2003b) Optimizing limbic selective D2/D3 receptor occupancy by risperidone: a [123I]-epidepride SPET study. J Clin Psychopharmacol 23:5–14PubMedCrossRefGoogle Scholar
  5. Davidson M, Emsley R, Kramer M, Ford L, Pan G, Lim P, Eerdekens M (2007) Efficacy, safety and early response of paliperidone extended-release tablets (paliperidone ER): Results of a 6-week, randomized, placebo-controlled study. Schizophr Res 93:117–130PubMedCrossRefGoogle Scholar
  6. Delforge J, Bottlaender M, Loc’h C, Dolle F, Syrota A (2001) Parametric images of the extrastriatal D2 receptor density obtained using a high-affinity ligand (FLB 457) and a double-saturation method. J Cereb Blood Flow Metab 21:1493–1503PubMedCrossRefGoogle Scholar
  7. Erlandsson K, Bressan RA, Mulligan RS, Ell PJ, Cunningham VJ, Pilowsky LS (2003) Analysis of D2 dopamine receptor occupancy with quantitative SPET using the high-affinity ligand [123I]epidepride: resolving conflicting findings. Neuroimage 19:1205–1214PubMedCrossRefGoogle Scholar
  8. Farde L, Wiesel FA, Stone-Elander S, Halldin C, Nordstrom AL, Hall H, Sedvall G (1990) D2 dopamine receptors in neuroleptic-naive schizophrenic patients. A positron emission tomography study with [11C]raclopride. Arch Gen Psychiatry 47:213–219PubMedGoogle Scholar
  9. Farde L, Nordstrom AL, Wiesel FA, Pauli S, Halldin C, Sedvall G (1992) 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 49:538–544PubMedGoogle Scholar
  10. Gefvert O, Eriksson B, Persson P, Helldin L, Bjorner A, Mannaert E, Remmerie B, Eerdekens M, Nyberg S (2005) Pharmacokinetics and D2 receptor occupancy of long-acting injectable risperidone (Risperdal Consta) in patients with schizophrenia. Int J Neuropsychopharmacol 8:27–36PubMedCrossRefGoogle Scholar
  11. Grunder G, Landvogt C, Vernaleken I, Buchholz HG, Ondracek J, Siessmeier T, Hartter S, Schreckenberger M, Stoeter P, Hiemke C, Rosch F, Wong DF, Bartenstein P (2006) The striatal and extrastriatal D2/D3 receptor-binding profile of clozapine in patients with schizophrenia. Neuropsychopharmacology 31:1027–1035PubMedCrossRefGoogle Scholar
  12. Hall H, Farde L, Halldin C, Hurd YL, Pauli S, Sedvall G (1996) Autoradiographic localization of extrastriatal D2-dopamine receptors in the human brain using [125I]epidepride. Synapse 23:115–123PubMedCrossRefGoogle Scholar
  13. Innis RB, Cunningham VJ, Delforge J, Fujita M, Gjedde A, Gunn RN, Holden J, Houle S, Huang SC, Ichise M, Iida H, Ito H, Kimura Y, Koeppe RA, Knudsen GM, Knuuti J, Lammertsma AA, Laruelle M, Logan J, Maguire RP, Mintun MA, Morris ED, Parsey R, Price JC, Slifstein M, Sossi V, Suhara T, Votaw JR, Wong DF, Carson RE (2007) Consensus nomenclature for in vivo imaging of reversibly binding radioligands. J Cereb Blood Flow Metab 27:1533–1539PubMedCrossRefGoogle Scholar
  14. Ito H, Okubo Y, Halldin C, Farde L (1999) Mapping of central D2 dopamine receptors in man using [11C]raclopride: PET with anatomic standardization technique. Neuroimage 9:235–242PubMedCrossRefGoogle Scholar
  15. Ito H, Sudo Y, Suhara T, Okubo Y, Halldin C, Farde L (2001) Error analysis for quantification of [11C]FLB 457 binding to extrastriatal D2 dopamine receptors in the human brain. Neuroimage 13:531–539PubMedCrossRefGoogle Scholar
  16. Kane J, Canas F, Kramer M, Ford L, Gassmann-Mayer C, Lim P, Eerdekens M (2007) Treatment of schizophrenia with paliperidone extended-release tablets: a 6-week placebo-controlled trial. Schizophr Res 90:147–161PubMedCrossRefGoogle Scholar
  17. Kapur S, Zipursky R, Jones C, Remington G, Houle S (2000) Relationship between dopamine D2 occupancy, clinical response, and side effects: a double-blind PET study of first-episode schizophrenia. Am J Psychiatry 157:514–520PubMedCrossRefGoogle Scholar
  18. Kessler RM, Ansari MS, Riccardi P, Li R, Jayathilake K, Dawant B, Meltzer HY (2005) Occupancy of striatal and extrastriatal dopamine D2/D3 receptors by olanzapine and haloperidol. Neuropsychopharmacology 30:2283–2289PubMedCrossRefGoogle Scholar
  19. Kessler RM, Ansari MS, Riccardi P, Li R, Jayathilake K, Dawant B, Meltzer HY (2006) Occupancy of striatal and extrastriatal dopamine D2 receptors by clozapine and quetiapine. Neuropsychopharmacology 31:1991–2001PubMedCrossRefGoogle Scholar
  20. Kramer M, Simpson G, Maciulis V, Kushner S, Vijapurkar U, Lim P, Eerdekens M (2007) Paliperidone extended-release tablets for prevention of symptom recurrence in patients with schizophrenia: a randomized, double-blind, placebo-controlled study. J Clin Psychopharmacol 27:6–14PubMedCrossRefGoogle Scholar
  21. Lammertsma AA, Hume SP (1996) Simplified reference tissue model for PET receptor studies. Neuroimage 4:153–158PubMedCrossRefGoogle Scholar
  22. Leysen JE, Gommeren W, Eens A, de Chaffoy de Courcelles D, Stoof JC, Janssen PA (1988) Biochemical profile of risperidone, a new antipsychotic. J Pharmacol Exp Ther 247:661–670PubMedGoogle Scholar
  23. Leysen JE, Janssen PM, Megens AA, Schotte A (1994) Risperidone: a novel antipsychotic with balanced serotonin–dopamine antagonism, receptor occupancy profile, and pharmacologic activity. J Clin Psychiatry 55(Suppl):5–12PubMedGoogle Scholar
  24. Lidow MS, Williams GV, Goldman-Rakic PS (1998) The cerebral cortex: a case for a common site of action of antipsychotics. Trends Pharmacol Sci 19:136–140PubMedCrossRefGoogle Scholar
  25. Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Keefe RS, Davis SM, Davis CE, Lebowitz BD, Severe J, Hsiao JK (2005) Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 353:1209–1223PubMedCrossRefGoogle Scholar
  26. Nordstrom AL, Farde L, Wiesel FA, Forslund K, Pauli S, Halldin C, Uppfeldt G (1993) Central D2-dopamine receptor occupancy in relation to antipsychotic drug effects: a double-blind PET study of schizophrenic patients. Biol Psychiatry 33:227–235PubMedCrossRefGoogle Scholar
  27. Nyberg S, Farde L, Halldin C, Dahl ML, Bertilsson L (1995) D2 dopamine receptor occupancy during low-dose treatment with haloperidol decanoate. Am J Psychiatry 152:173–178PubMedGoogle Scholar
  28. Nyberg S, Eriksson B, Oxenstierna G, Halldin C, Farde L (1999) Suggested minimal effective dose of risperidone based on PET-measured D2 and 5-HT2A receptor occupancy in schizophrenic patients. Am J Psychiatry 156:869–875PubMedGoogle Scholar
  29. Okubo Y, Olsson H, Ito H, Lofti M, Suhara T, Halldin C, Farde L (1999) PET mapping of extrastriatal D2-like dopamine receptors in the human brain using an anatomic standardization technique and [11C]FLB 457. Neuroimage 10:666–674PubMedCrossRefGoogle Scholar
  30. Olsson H, Farde L (2001) Potentials and pitfalls using high affinity radioligands in PET and SPET determinations on regional drug induced D2 receptor occupancy—a simulation study based on experimental data. Neuroimage 14:936–945PubMedCrossRefGoogle Scholar
  31. Olsson H, Halldin C, Farde L (2004) Differentiation of extrastriatal dopamine D2 receptor density and affinity in the human brain using PET. Neuroimage 22:794–803PubMedCrossRefGoogle Scholar
  32. Pilowsky LS, Mulligan RS, Acton PD, Ell PJ, Costa DC, Kerwin RW (1997) Limbic selectivity of clozapine. Lancet 350:490–491PubMedCrossRefGoogle Scholar
  33. Remington G, Mamo D, Labelle A, Reiss J, Shammi C, Mannaert E, Mann S, Kapur S (2006) A PET study evaluating dopamine D2 receptor occupancy for long-acting injectable risperidone. Am J Psychiatry 163:396–401PubMedCrossRefGoogle Scholar
  34. Stephenson CM, Bigliani V, Jones HM, Mulligan RS, Acton PD, Visvikis D, Ell PJ, Kerwin RW, Pilowsky LS (2000) Striatal and extra-striatal D2/D3 dopamine receptor occupancy by quetiapine in vivo. [123I]-epidepride single photon emission tomography(SPET) study. Br J Psychiatry 177:408–415PubMedCrossRefGoogle Scholar
  35. Suhara T, Sudo Y, Okauchi T, Maeda J, Kawabe K, Suzuki K, Okubo Y, Nakashima Y, Ito H, Tanada S, Halldin C, Farde L (1999) Extrastriatal dopamine D2 receptor density and affinity in the human brain measured by 3D PET. Int J Neuropsychopharmcol 2:73–82CrossRefGoogle Scholar
  36. Suhara T, Okubo Y, Yasuno F, Sudo Y, Inoue M, Ichimiya T, Nakashima Y, Nakayama K, Tanada S, Suzuki K, Halldin C, Farde L (2002) Decreased dopamine D2 receptor binding in the anterior cingulate cortex in schizophrenia. Arch Gen Psychiatry 59:25–30PubMedCrossRefGoogle Scholar
  37. Takano A, Suhara T, Ikoma Y, Yasuno F, Maeda J, Ichimiya T, Sudo Y, Inoue M, Okubo Y (2004) Estimation of the time-course of dopamine D2 receptor occupancy in living human brain from plasma pharmacokinetics of antipsychotics. Int J Neuropsychopharmacol 7:19–26PubMedCrossRefGoogle Scholar
  38. Takano A, Suhara T, Kusumi I, Takahashi Y, Asai Y, Yasuno F, Ichimiya T, Inoue M, Sudo Y, Koyama T (2006a) Time course of dopamine D2 receptor occupancy by clozapine with medium and high plasma concentrations. Prog Neuropsychopharmacol Biol Psychiatry 30:75–81PubMedCrossRefGoogle Scholar
  39. Takano A, Suhara T, Yasuno F, Suzuki K, Takahashi H, Morimoto T, Lee YJ, Kusuhara H, Sugiyama Y, Okubo Y (2006b) The antipsychotic sultopride is overdosed—a PET study of drug-induced receptor occupancy in comparison with sulpiride. Int J Neuropsychopharmacol 9:539–545PubMedCrossRefGoogle Scholar
  40. Talvik M, Nordstrom AL, Nyberg S, Olsson H, Halldin C, Farde L (2001) No support for regional selectivity in clozapine-treated patients: a PET study with [11C]raclopride and [11C]FLB 457. Am J Psychiatry 158:926–930PubMedGoogle Scholar
  41. Talvik M, Nordstrom AL, Olsson H, Halldin C, Farde L (2003) Decreased thalamic D2/D3 receptor binding in drug-naive patients with schizophrenia: a PET study with [11C]FLB 457. Int J Neuropsychopharmacol 6:361–370PubMedCrossRefGoogle Scholar
  42. Xiberas X, Martinot JL, Mallet L, Artiges E, Loc HC, Maziere B, Paillere-Martinot ML (2001) Extrastriatal and striatal D2 dopamine receptor blockade with haloperidol or new antipsychotic drugs in patients with schizophrenia. Br J Psychiatry 179:503–508PubMedCrossRefGoogle Scholar
  43. Yasuno F, Suhara T, Okubo Y, Sudo Y, Inoue M, Ichimiya T, Tanada S (2001) Dose relationship of limbic-cortical D2-dopamine receptor occupancy with risperidone. Psychopharmacology (Berl) 154:112–114CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Ryosuke Arakawa
    • 1
    • 2
  • Hiroshi Ito
    • 1
  • Akihiro Takano
    • 1
  • Hidehiko Takahashi
    • 1
  • Takuya Morimoto
    • 1
  • Takeshi Sassa
    • 3
  • Katsuya Ohta
    • 4
  • Motoichiro Kato
    • 5
  • Yoshiro Okubo
    • 2
  • Tetsuya Suhara
    • 1
  1. 1.Department of Molecular Neuroimaging, Molecular Imaging CenterNational Institute of Radiological SciencesChibaJapan
  2. 2.Department of NeuropsychiatryNippon Medical SchoolTokyoJapan
  3. 3.Asai HospitalChibaJapan
  4. 4.Onda-daini HospitalChibaJapan
  5. 5.Department of NeuropsychiatryKeio University School of MedicineTokyoJapan

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