Skip to main content
SpringerLink
Log in

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

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

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.

Objectives

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.

Results

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.

Conclusions

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • 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 32:1209–1215

    Article  PubMed  CAS  Google Scholar 

  • 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) 150:132–140

    Article  CAS  Google Scholar 

  • 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 160:1413–1420

    Article  PubMed  Google Scholar 

  • 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 23:5–14

    Article  PubMed  CAS  Google Scholar 

  • 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 93:117–130

    Article  PubMed  Google Scholar 

  • 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 21:1493–1503

    Article  PubMed  CAS  Google Scholar 

  • 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 19:1205–1214

    Article  PubMed  Google Scholar 

  • 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 47:213–219

    PubMed  CAS  Google Scholar 

  • 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 49:538–544

    PubMed  CAS  Google Scholar 

  • 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 8:27–36

    Article  PubMed  CAS  Google Scholar 

  • 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 31:1027–1035

    Article  PubMed  Google Scholar 

  • 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 23:115–123

    Article  PubMed  CAS  Google Scholar 

  • 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 27:1533–1539

    Article  PubMed  CAS  Google Scholar 

  • 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 9:235–242

    Article  PubMed  CAS  Google Scholar 

  • 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 13:531–539

    Article  PubMed  CAS  Google Scholar 

  • 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 90:147–161

    Article  PubMed  CAS  Google Scholar 

  • 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 157:514–520

    Article  PubMed  CAS  Google Scholar 

  • 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 30:2283–2289

    Article  PubMed  CAS  Google Scholar 

  • 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 31:1991–2001

    Article  PubMed  CAS  Google Scholar 

  • 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 27:6–14

    Article  PubMed  CAS  Google Scholar 

  • Lammertsma AA, Hume SP (1996) Simplified reference tissue model for PET receptor studies. Neuroimage 4:153–158

    Article  PubMed  CAS  Google Scholar 

  • 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 247:661–670

    PubMed  CAS  Google Scholar 

  • 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):5–12

    PubMed  Google Scholar 

  • Lidow MS, Williams GV, Goldman-Rakic PS (1998) The cerebral cortex: a case for a common site of action of antipsychotics. Trends Pharmacol Sci 19:136–140

    Article  PubMed  CAS  Google Scholar 

  • 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 353:1209–1223

    Article  PubMed  CAS  Google Scholar 

  • 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 33:227–235

    Article  PubMed  CAS  Google Scholar 

  • 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 152:173–178

    PubMed  CAS  Google Scholar 

  • 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 156:869–875

    PubMed  CAS  Google Scholar 

  • 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 10:666–674

    Article  PubMed  CAS  Google Scholar 

  • 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 14:936–945

    Article  PubMed  CAS  Google Scholar 

  • Olsson H, Halldin C, Farde L (2004) Differentiation of extrastriatal dopamine D2 receptor density and affinity in the human brain using PET. Neuroimage 22:794–803

    Article  PubMed  Google Scholar 

  • Pilowsky LS, Mulligan RS, Acton PD, Ell PJ, Costa DC, Kerwin RW (1997) Limbic selectivity of clozapine. Lancet 350:490–491

    Article  PubMed  CAS  Google Scholar 

  • 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 163:396–401

    Article  PubMed  Google Scholar 

  • 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 177:408–415

    Article  PubMed  CAS  Google Scholar 

  • 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 2:73–82

    Article  CAS  Google Scholar 

  • 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 59:25–30

    Article  PubMed  CAS  Google Scholar 

  • 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 7:19–26

    Article  PubMed  CAS  Google Scholar 

  • 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 30:75–81

    Article  PubMed  CAS  Google Scholar 

  • 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 9:539–545

    Article  PubMed  CAS  Google Scholar 

  • 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 158:926–930

    PubMed  CAS  Google Scholar 

  • 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 6:361–370

    Article  PubMed  CAS  Google Scholar 

  • 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 179:503–508

    Article  PubMed  CAS  Google Scholar 

  • 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) 154:112–114

    Article  CAS  Google Scholar 

Download references

Acknowledgment

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.

Author information

Authors and Affiliations

  1. Department of Molecular Neuroimaging, Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1, Anagawa, Inage-ku, Chiba, 263-8555, Japan

    Ryosuke Arakawa, Hiroshi Ito, Akihiro Takano, Hidehiko Takahashi, Takuya Morimoto & Tetsuya Suhara

  2. Department of Neuropsychiatry, Nippon Medical School, Tokyo, Japan

    Ryosuke Arakawa & Yoshiro Okubo

  3. Asai Hospital, Chiba, Japan

    Takeshi Sassa

  4. Onda-daini Hospital, Chiba, Japan

    Katsuya Ohta

  5. Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan

    Motoichiro Kato

Authors
  1. Ryosuke Arakawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hiroshi Ito
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Akihiro Takano
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hidehiko Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Takuya Morimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Takeshi Sassa
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Katsuya Ohta
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Motoichiro Kato
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yoshiro Okubo
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Tetsuya Suhara
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tetsuya Suhara.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Arakawa, R., Ito, H., Takano, A. et al. Dose-finding study of paliperidone ER based on striatal and extrastriatal dopamine D2 receptor occupancy in patients with schizophrenia. Psychopharmacology 197, 229–235 (2008). https://doi.org/10.1007/s00213-007-1029-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-007-1029-z

Keywords

Search

Navigation