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Occupancy of dopamine D1, D2 and serotonin2A receptors in schizophrenic patients treated with flupentixol in comparison with risperidone and haloperidol

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Abstract

Rationale

Flupentixol (FLX) has been used as a neuroleptic for nearly 4 decades. In vitro data show comparable affinity to dopamine D2, D1 and 5-HT2A receptors and recently, FLX showed to be not inferior to risperidone in schizophrenic patients with predominant negative symptomatology, which was implicated with flupentixol’s interaction with 5-HT2A and/or D1 receptors.

Objectives

To assess in vivo receptor occupancy (RO) in patients clinically treated with FLX (n = 13, 5.7 ± 1.4 mg/day) in comparison with risperidone (RIS, n = 11, 3.6 ± 1.3 mg/day) and haloperidol (HAL, n = 11, 8.5 ± 5.5 mg/day).

Materials and methods

Each patient underwent two PET scans with 3-N-[11C]methylspiperone (target: frontal 5-HT2A), [11C]SCH23390 (striatal D1) or [11C]raclopride (striatal D2). RO was calculated as the percentage reduction of specific binding in comparison with healthy controls.

Results

D2-RO under FLX was between 50% and 70%, indicating an ED50 of about 0.7 ng/ml serum. 5-HT2A and D1-RO was 20 ± 10% and 20 ± 5% (mean, SEM). Under HAL, D1-RO was 14 ± 6% and under RIS not significantly different from zero.

Conclusions

We were able to demonstrate a moderate 5-HT2A and D1 occupancy under clinically relevant doses of flupentixol, albeit lower than expected from in vitro data and clearly below saturation. Therefore, if flupentixol’s efficacy on negative symptoms is based on its interaction with 5-HT2A and/or D1 receptors, it should be highly dependent on serum concentration and thus on dosage and metabolism. However, these data suggest that mechanisms other than D1 or 5-HT2A antagonism may contribute to flupentixol’s efficacy on negative symptoms.

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References

  • Abi-Dargham A, Gil R, Krystal J, Baldwin RM, Seibyl JP, Bowers M, van Dyck CH, Charney DS, Innis RB, Laruelle M (1998) Increased striatal dopamine transmission in schizophrenia: confirmation in a second cohort. Am J Psychiatry 155:761–767

    PubMed  CAS  Google Scholar 

  • Abi-Dargham A, Mawlawi O, Lombardo I, Gil R, Martinez D, Huang Y, Hwang DR, Keilp J, Kochan L, Van Heertum R, Gorman JM, Laruelle M (2002) Prefrontal dopamine D1 receptors and working memory in schizophrenia. J Neurosci 22(9):3708–3719

    PubMed  CAS  Google Scholar 

  • Andree B, Nyberg S, Ito H, Ginovart N, Brunner F, Jaquet F, Halldin C, Farde L (1998) Positron emission tomographic analysis of dose-dependent MDL 100,907 binding to 5-hydroxytryptamine-2A receptors in the human brain. J Clin Psychopharmacol 18(4):317–323

    Article  PubMed  CAS  Google Scholar 

  • Dannals RF, Ravert HT, Wilson AA, Wagner HN Jr (1986) An improved synthesis of (3-N-[11C]methyl)spiperone. Int J Rad Appl Instrum, A Appl Radiat Isot 37:433–434

    Article  CAS  Google Scholar 

  • Ehrin E, Gawell L, Högberg T, de Paulis S, Ström P (1987) Synthesis of [methoxy-3H]- and [methoxy-11C]-labelled raclopride. Specific dopamine-D2 receptor ligands. J Label Compd Radiopharm 24:931–940

    Article  CAS  Google Scholar 

  • Farde L, Nordstrom AL (1992) PET analysis indicates atypical central dopamine receptor occupancy in clozapine-treated patients. Br J Psychiatry Suppl (17):30–33

    PubMed  Google Scholar 

  • Farde L, Hall H, Ehrin E, Sedvall G (1986) Quantitative analysis of D2 dopamine receptor binding in the living human brain by PET. Science 231(4735):258–261

    Article  PubMed  ADS  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(7):538–544

    PubMed  CAS  Google Scholar 

  • Gattaz WF, Diehl A, Geuppert MS, Hubrich P, Schmitt A, Linde I, Maras A, Dittmann RW (2004) Olanzapine versus flupenthixol in the treatment of inpatients with schizophrenia: a randomized double-blind trial. Pharmacopsychiatry 37:279–285

    Article  PubMed  CAS  Google Scholar 

  • Glaser T, Soyka M (1998) Flupentixol—typisches oder atypisches Wirkspektrum? Steinkopff, Darmstadt

    Google Scholar 

  • Gründer G, Carlsson A, Wong DF (2003) Mechanism of new antipsychotic medications: occupancy is not just antagonism. Arch Gen Psychiatry 60(10):974–977

    Article  PubMed  Google Scholar 

  • Halldin C, Stone-Elander S, Farde L, Ehrin E, Fasth KJ, Långström B, Sedvall G (1986) Preparation of 11C-labelled SCH 23390 for the in vivo study of dopamine D-1 receptors using positron emission tomography. Int J Rad Appl Instrum, A Appl Radiat Isot 37:1039–1043

    Article  CAS  Google Scholar 

  • Huang N, Ase AR, Hebert C, van Gelder NM, Reader TA (1997) Effects of chronic neuroleptic treatments on dopamine D1 and D2 receptors: homogenate binding and autoradiographic studies. Neurochem Int 30(3):277–290

    Article  PubMed  CAS  Google Scholar 

  • Hyttel J, Larsen JJ, Christensen AV, Arnt J (1985) Receptor-binding profiles of neuroleptics. Psychopharmacology Suppl 2:9–18

    PubMed  CAS  Google Scholar 

  • Ichikawa J, Ishii H, Bonaccorso S, Fowler WL, O’Laughlin IA, Meltzer HY (2001) 5-HT2A and D2 receptor blockade increases cortical DA release via 5-HT1A receptor activation: a possible mechanism of atypical antipsychotic-induced cortical dopamine release. J Neurochem 76:1521–1531

    Article  PubMed  CAS  Google Scholar 

  • Kapur S, Seeman P (2001) Does fast dissociation from the dopamine D2 receptor explain the action of atypical antipsychotics?: a new hypothesis. Am J Psychiatry 158:360–369

    Article  PubMed  CAS  Google Scholar 

  • Kapur S, Zipursky RB, Remington G (1999) Clinical and theoretical implications of 5-HT2 and D2 receptor occupancy of clozapine, risperidone, and olanzapine in schizophrenia. Am J Psychiatry 156:286–293

    PubMed  CAS  Google Scholar 

  • Kapur S, Zipursky R, Jones C, Remington G, Houle S (2000a) 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 

  • Kapur S, Zipursky R, Jones C, Shammi CS, Remington G, Seeman P (2000b) A positron emission tomography study of quetiapine in schizophrenia: a preliminary finding of an antipsychotic effect with only transiently high dopamine D2 receptor occupancy. Arch Gen Psychiatry 57(6):553–559

    Article  PubMed  CAS  Google Scholar 

  • Karlsson P, Farde L, Halldin C, Sedvall G (2002) PET study of D(1) dopamine receptor binding in neuroleptic-naive patients with schizophrenia. Am J Psychiatry 159(5):761–767

    Article  PubMed  Google Scholar 

  • Kay SR, Fiszbein A, Opler LA (1987) The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 13(2):261–276

    PubMed  CAS  Google Scholar 

  • Kuehn KU, Meyer K, Maier W (2000) Flupentixol—ein partiell atypisches Neuroleptikum? Fortschr Neurol Psychiatr 68(Suppl 1):S38–S41

    Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Laruelle M (2000) Imaging synaptic neurotransmission with in vivo binding competition techniques: a critical review. J Cereb Blood Flow Metab 20:423–451

    Article  PubMed  CAS  Google Scholar 

  • Laruelle M, van Dyck C, Abi-Dargham A, Zea-Ponce Y, Zoghbi SS, Charney DS, Baldwin RM, Hoffer PB, Kung HF, Innis RB (1994) Compartmental modeling of iodine-123-iodobenzofuran binding to dopamine D2 receptors in healthy subjects. J Nucl Med 35:743–754

    PubMed  CAS  Google Scholar 

  • Lieberman JA, Mailman RB, Duncan G, Sikich L, Chakos M, Nichols DE, Kraus JE (1998) Serotonergic basis of antipsychotic drug effects in schizophrenia. Biol Psychiatry 44(11):1099–1117

    Article  PubMed  CAS  Google Scholar 

  • Logan J, Fowler JS, Volkow ND, Wang GJ, Ding YS, Alexoff DL (1996) Distribution volume ratios without blood sampling from graphical analysis of PET data. J Cereb Blood Flow Metab 16(5):834–840

    Article  PubMed  CAS  Google Scholar 

  • Lundberg T, Lindstrom L, Hartvig P, Reibring L, Agren H et al (1996) Serotonin-2 and dopamine-1 binding components of clozapine in frontal and striatum in the brain visualized by positron emission tomography. Psychiatry Res 67:1–10

    PubMed  CAS  Google Scholar 

  • Meltzer HY (1992) The importance of serotonin–dopamine interactions in the action of clozapine. Br J Psychiatry Suppl (17):22–29

    PubMed  ADS  Google Scholar 

  • Meltzer HY, Matsubara S, Lee JC (1989) Classification of typical and atypical antipsychotic drugs on the basis of dopamine D1, D2 and serotonin2 pKi values. J Pharmacol Exp Ther 251:238–246

    PubMed  CAS  Google Scholar 

  • Nordstroem 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 trial of schizophrenic patients. Biol Psychiatry 33:227–235

    Article  CAS  Google Scholar 

  • Nyberg S, Farde S, Eriksson L, Halldin C, Eriksson B (1993) 5-HT2 and D2 dopamine receptor occupancy in the living human brain. A PET study with risperidone. Psychopharmacology (Berl) 110:265–272

    Article  CAS  Google Scholar 

  • Nyberg S, Nordstrom AL, Halldin C, Farde L (1995) Position emission tomography studies on D2 dopamine receptor occupancy and plasma antipsychotic drug levels in man. Int Clin Psychopharmacol 10(Suppl 3):81–85

    Article  PubMed  Google Scholar 

  • Nyberg S, Nakashima Y, Nordstrom AL, Halldin C, Farde L (1996) Positron emission tomography of in-vivo binding characteristics of atypical antipsychotic drugs. Review of D2 and 5-HT2 receptor occupancy studies and clinical response. Br J Psychiatry Suppl (29):40–44

    PubMed  Google Scholar 

  • Nyberg S, Nilsson U, Okubo Y, Halldin C, Farde L (1998) Implications of brain imaging for the management of schizophrenia. Int Clin Psychopharmacol 13(Suppl 3):S15–S20

    Article  PubMed  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, Suhara T, Suzuki K, Kobayashi K, Inoue O, Terasaki O, Someya Y, Sassa T, Sudo Y, Matsushima E, Iyo M, Tateno Y, Toru M (2000) Serotonin 5-HT2 receptors in schizophrenic patients studied by positron emission tomography. Life Sci 66(25):2455–2464

    Article  PubMed  CAS  Google Scholar 

  • Philipp M, Lesch OM, Walter H, Patras L, Kurtz G, Schmauß M, Seemann U, Roth G, Stöhr K, Dose M, Hetzel G, Ruhrmann S, Beneke M, Rappard F, Glaser T (2002) Wirksamkeit von Flupentixol vs Risperidon auf die Negativsymptomatik schizophrener Patienten. Psychopharmakotherapie 9:67–74

    Google Scholar 

  • Philipp M, Lesch OM, Schmauss M, Dose M, Glaser T (2003) Comparative effectiveness of flupenthixol and risperidone on negative symptoms of schizophrenia. Psychiatr Prax 30(Suppl 2):S94–S96

    Article  PubMed  Google Scholar 

  • Reimold M, Mueller-Schauenburg W, Becker GA, Reischl G, Dohmen BM, Bares R (2004) Non-invasive assessment of distribution volume ratios and binding potential: tissue heterogeneity and interindividually averaged time–activity curves. Eur J Nucl Med Mol Imaging 31(4):564–577

    Article  PubMed  CAS  Google Scholar 

  • Schröder J, Silvestri S, Bubeck B, Karr M, Demisch S, Scherrer S, Geider FJ, Sauer H (1998) D2 dopamine receptor up-regulation, treatment response, neurological soft signs, and extrapyramidal side effects in schizophrenia: a follow-up study with 123I-iodobenzamide single photon emission computed tomography in the drug-naive state and after neuroleptic treatment. Biol Psychiatry 43(9):660–665

    Article  PubMed  Google Scholar 

  • Seeman P (2002) Atypical antipsychotics: mechanism of action. Can J Psychiatry 47:27–38

    PubMed  Google Scholar 

  • Tauscher J, Hussain T, Agid O, Verhoeff NP, Wilson AA, Houle S, Remington G, Zipursky RB, Kapur S (2004) Equivalent occupancy of dopamine D1 and D2 receptors with clozapine: differentiation from other atypical antipsychotics. Am J Psychiatry 161(9):1620–1625

    Article  PubMed  Google Scholar 

  • Weiner DM, Burstein ES, Nash N, Croston GE, Currier EA, Vanover KE, Harvey SC, Donohue E, Hansen HC, Andersson CM, Spalding TA, Gibson DF, Krebs-Thomson K, Powell SB, Geyer MA, Hacksell U, Brann MR (2001) 5-hydroxytryptamine2A receptor inverse agonists as antipsychotics. J Pharmacol Exp Ther 299(1):268–276

    PubMed  CAS  Google Scholar 

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Acknowledgement

Flupentixol is marketed in Germany by Bayer Vital GmbH, Leverkusen, Germany. Bayer Vital GmbH is the sponsor of this study. T. Glaser and M. Beneke are employed by Bayer Vital GmbH.

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Authors and Affiliations

  1. Department of Nuclear Medicine/PET Center, University of Tuebingen, Tuebingen, Germany

    M. Reimold & R. Bares

  2. Department of Psychiatry and Psychotherapy, University of Tuebingen, Tuebingen, Germany

    S. Noda, J.-E. Schaefer, M. Bartels & H. Wormstall

  3. Radiopharmacy, University of Tuebingen, Tuebingen, Germany

    C. Solbach & H.-J. Machulla

  4. Bayer Vital GmbH, Leverkusen, Germany

    M. Beneke & T. Glaser

  5. PET Center, Roentgenweg 15, 72076, Tuebingen, Germany

    M. Reimold

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  1. M. Reimold
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  2. C. Solbach
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  3. S. Noda
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  9. T. Glaser
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Correspondence to M. Reimold.

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Reimold, M., Solbach, C., Noda, S. et al. Occupancy of dopamine D1, D2 and serotonin2A receptors in schizophrenic patients treated with flupentixol in comparison with risperidone and haloperidol. Psychopharmacology 190, 241–249 (2007). https://doi.org/10.1007/s00213-006-0611-0

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  • DOI: https://doi.org/10.1007/s00213-006-0611-0

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