Skip to main content
SpringerLink
Log in

Serotonin2A receptor blockade and clinical effect in first-episode schizophrenia patients treated with quetiapine

  • original investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

We have previously reported decreased frontal cortical serotonin2A receptor binding in 30 antipsychotic naïve first-episode schizophrenic patients and a relationship between this binding and positive psychotic symptoms. Until now, no longitudinal studies of serotonin2A receptor in first-episode antipsychotic-naïve schizophrenia patients have reported on the relationship between serotonin2A receptor occupancy and treatment effect after sustained treatment with a specific atypical antipsychotic compound.

Objectives

Here, we measured serotonin2A receptor occupancy with [18F]altanserin PET in 15 first-episode antipsychotic-naïve schizophrenia patients before and after 6 months of quetiapine treatment. Moreover, we investigated possible relationships between clinical efficacy, oral dose, and plasma levels of quetiapine

Results

Significant nonlinear relationships were found between serotonin2A receptor occupancy, quetiapine dose, and plasma concentration. There was a modest effect on positive symptoms up until a serotonin2A receptor occupancy level of approximately 60%. A receptor occupancy level between 60% and 70% appeared to exert the optimal serotonin2A receptor related treatment effect on positive symptoms whereas no additional serotonin2A receptor associated treatment effect was obtained above a receptor occupancy of 70%.

Conclusions

Taken together, the data point to a therapeutic role of the serotonin2A receptor in the treatment of subgroups of patients with schizophrenia. Specifically, the study indicates a serotonin2A receptor associated therapeutic window on positive symptoms in responding patients in the range between 60% and 70% occupancy in antipsychotic-naïve first-episode schizophrenia. We speculate that non-responding patients need higher dopamine D2 receptor blockade. Future studies with concurrent measurement of interactions with the dopamine system are, however, warranted to clarify this.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Adams KH, Pinborg LH, Svarer C, Hasselbalch SG, Holm S, Haugbol S, Madsen K, Frokjaer V, Martiny L, Paulson OB, Knudsen GM (2004) A database of [(18)F]-altanserin binding to 5-HT(2A) receptors in normal volunteers: normative data and relationship to physiological and demographic variables. Neuroimage 21:1105–1113

    Article  PubMed  Google Scholar 

  • Arranz MJ, Munro J, Owen MJ, Spurlock G, Sham PC, Zhao J, Kirov G, Collier DA, Kerwin RW (1998) Evidence for association between polymorphisms in the promoter and coding regions of the 5-HT2A receptor gene and response to clozapine. Mol Psychiatry 3:61–66

    Article  CAS  PubMed  Google Scholar 

  • Berger GE, Proffitt TM, McConchie M, Kerr M, Markulev C, Yuen HP, O’Donnell C, Lubman D, Polari A, Wood S, Amminger PG, McGorry PD (2008) Dosing quetiapine in drug-naive first-episode psychosis: a controlled, double-blind, randomized, single-center study investigating efficacy, tolerability, and safety of 200 mg/day vs. 400 mg/day of quetiapine fumarate in 141 patients aged 15–25 years. J Clin Psychiatry 69:1702–1714

    Article  CAS  PubMed  Google Scholar 

  • Citrome L, Jaffe A, Levine J, Lindenmayer JP (2005) Dosing of quetiapine in schizophrenia: how clinical practice differs from registration studies. J Clin Psychiatry 66:1512–1516

    Article  PubMed  Google Scholar 

  • de Paulis T (2001) M-100907 (Aventis). Curr Opin Investig Drugs 2:123–132

    PubMed  Google Scholar 

  • Dean B (2003) The cortical serotonin2A receptor and the pathology of schizophrenia: a likely accomplice. J Neurochem 85:1–13

    Article  CAS  PubMed  Google Scholar 

  • Dean B, Crossland N, Boer S, Scarr E (2008) Evidence for altered post-receptor modulation of the serotonin 2a receptor in schizophrenia. Schizophr Res 104:185–197

    Article  PubMed  Google Scholar 

  • DeVane CL, Nemeroff CB (2001) Clinical pharmacokinetics of quetiapine: an atypical antipsychotic. Clin Pharmacokinet 40:509–522

    Article  CAS  PubMed  Google Scholar 

  • Fabre LF Jr, Arvanitis L, Pultz J, Jones VM, Malick JB, Slotnick VB (1995) ICI 204, 636, a novel, atypical antipsychotic: early indication of safety and efficacy in patients with chronic and subchronic schizophrenia. Clin Ther 17:366–378

    Article  PubMed  Google Scholar 

  • Farde L, Nyberg S, Oxenstierna G, Nakashima Y, Halldin C, Ericsson B (1995) Positron emission tomography studies on D2 and 5-HT2 receptor binding in risperidone-treated schizophrenic patients. J Clin Psychopharmacol 15:19S–23S

    CAS  PubMed  Google Scholar 

  • Gefvert O, Bergstrom M, Langstrom B, Lundberg T, Lindstrom L, Yates R (1998) 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) 135:119–126

    Article  CAS  Google Scholar 

  • Gefvert O, Lundberg T, Wieselgren IM, Bergstrom M, Langstrom B, Wiesel F, Lindstrom L (2001) D(2) and 5HT(2A) receptor occupancy of different doses of quetiapine in schizophrenia: a PET study. Eur Neuropsychopharmacol 11:105–110

    Article  CAS  PubMed  Google Scholar 

  • Glenthoj BY, Hemmingsen R (1999) Transmitter dysfunction during the process of schizophrenia. Acta Psychiatr Scand Suppl 395:105–112

    Article  CAS  PubMed  Google Scholar 

  • Gray JA, Roth BL (2001) Paradoxical trafficking and regulation of 5-HT(2A) receptors by agonists and antagonists. Brain Res Bull 56:441–451

    Article  CAS  PubMed  Google Scholar 

  • Grubb F (1969) Procedures for detecting outlying observations in samples. Technometrics 469–479

  • Haugbol S, Pinborg LH, Arfan HM, Frokjaer VM, Madsen J, Dyrby TB, Svarer C, Knudsen GM (2007) Reproducibility of 5-HT2A receptor measurements and sample size estimations with [18F]altanserin PET using a bolus/infusion approach. Eur J Nucl Med Mol Imaging 34:910–915

    Article  PubMed  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  CAS  PubMed  Google Scholar 

  • Kapur S, Seeman P (2001) Does fast dissociation from the dopamine d(2) receptor explain the action of atypical antipsychotics? A new hypothesis. Am J Psychiatry 158:360–369

    Article  CAS  PubMed  Google Scholar 

  • Kapur S, Remington G, Jones C, Wilson A, DaSilva J, Houle S, Zipursky R (1996) High levels of dopamine D2 receptor occupancy with low-dose haloperidol treatment: a PET study. Am J Psychiatry 153:948–950

    CAS  PubMed  Google Scholar 

  • Kapur S, Zipursky R, Jones C, Shammi CS, Remington G, Seeman P (2000) 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 57:553–559

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Kerwin R (2007) When should clozapine be initiated in schizophrenia? Some arguments for and against earlier use of clozapine. CNS Drugs 21:267–278

    Article  CAS  PubMed  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  CAS  PubMed  Google Scholar 

  • Khazaal Y, Tapparel S, Chatton A, Rothen S, Preisig M, Zullino D (2007) Quetiapine dosage in bipolar disorder episodes and mixed states. Prog Neuropsychopharmacol Biol Psychiatry 31:727–730

    Article  CAS  PubMed  Google Scholar 

  • Kristiansen H, Elfving B, Plenge P, Pinborg LH, Gillings N, Knudsen GM (2005) Binding characteristics of the 5-HT2A receptor antagonists altanserin and MDL 100907. Synapse 58:249–257

    Article  CAS  PubMed  Google Scholar 

  • Lewis R, Kapur S, Jones C, DaSilva J, Brown GM, Wilson AA, Houle S, Zipursky RB (1999) Serotonin 5-HT2 receptors in schizophrenia: a PET study using [18F]setoperone in neuroleptic-naive patients and normal subjects. Am J Psychiatry 156:72–78

    CAS  PubMed  Google Scholar 

  • Mauri MC, Volonteri LS, Colasanti A, Fiorentini A, De Gaspari IF, Bareggi SR (2007) Clinical pharmacokinetics of atypical antipsychotics: a critical review of the relationship between plasma concentrations and clinical response. Clin Pharmacokinet 46:359–388

    Article  CAS  PubMed  Google Scholar 

  • Meltzer HY, Mills R, Revell S, Williams H, Johnson A, Bahr D, Friedman JH (2010) Pimavanserin, a serotonin(2A) receptor inverse agonist, for the treatment of Parkinson’s disease psychosis. Neuropsychopharmacology 35:881–892

    Article  CAS  PubMed  Google Scholar 

  • Nichols DE (2004) Hallucinogens. Pharmacol Ther 101:131–181

    Article  CAS  PubMed  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  CAS  PubMed  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 66:2455–2464

    CAS  PubMed  Google Scholar 

  • Pierre JM, Wirshing DA, Wirshing WC, Rivard JM, Marks R, Mendenhall J, Sheppard K, Saunders DG (2005) High-dose quetiapine in treatment refractory schizophrenia. Schizophr Res 73:373–375

    Article  PubMed  Google Scholar 

  • Pinborg LH, Adams KH, Svarer C, Holm S, Hasselbalch SG, Haugbol S, Madsen J, Knudsen GM (2003) Quantification of 5-HT2A receptors in the human brain using [18F]altanserin-PET and the bolus/infusion approach. J Cereb Blood Flow Metab 23:985–996

    Article  CAS  PubMed  Google Scholar 

  • Pinborg LH, Adams KH, Yndgaard S, Hasselbalch SG, Holm S, Kristiansen H, Paulson OB, Knudsen GM (2004) [18F]altanserin binding to human 5HT2A receptors is unaltered after citalopram and pindolol challenge. J Cereb Blood Flow Metab 24:1037–1045

    Article  CAS  PubMed  Google Scholar 

  • Pinborg LH, Videbaek C, Ziebell M, Mackeprang T, Friberg L, Rasmussen H, Knudsen GM, Glenthoj BY (2007) [123I]epidepride binding to cerebellar dopamine D2/D3 receptors is displaceable: implications for the use of cerebellum as a reference region. Neuroimage 34:1450–1453

    Article  PubMed  Google Scholar 

  • Rasmussen H, Erritzoe D, Andersen R, Ebdrup BH, Aggernaes B, Oranje B, Kalbitzer J, Madsen J, Pinborg LH, Baare W, Svarer C, Lublin H, Knudsen GM, Glenthoj B (2010) Decreased frontal serotonin2A receptor binding in antipsychotic-naive patients with first-episode schizophrenia. Arch Gen Psychiatry 67:9–16

    Article  PubMed  Google Scholar 

  • Small JG, Hirsch SR, Arvanitis LA, Miller BG, Link CG (1997) Quetiapine in patients with schizophrenia. A high- and low-dose double-blind comparison with placebo. Seroquel study group. Arch Gen Psychiatry 54:549–557

    CAS  PubMed  Google Scholar 

  • Snigdha S, Horiguchi M, Huang M, Li Z, Shahid M, Neill JC, Meltzer HY (2010) Attenuation of phencyclidine-induced object recognition deficits by the combination of atypical antipsychotic drugs and pimavanserin (ACP 103), a 5-hydroxytryptamine(2A) receptor inverse agonist. J Pharmacol Exp Ther 332:622–631

    Article  CAS  PubMed  Google Scholar 

  • Sparshatt A, Jones S, Taylor D (2008) Quetiapine: dose–response relationship in schizophrenia. CNS Drugs 22:49–68

    Article  CAS  PubMed  Google Scholar 

  • Svarer C, Madsen K, Hasselbalch SG, Pinborg LH, Haugbol S, Frokjaer VG, Holm S, Paulson OB, Knudsen GM (2005) MR-based automatic delineation of volumes of interest in human brain PET images using probability maps. Neuroimage 24:969–979

    Article  PubMed  Google Scholar 

  • Tan PZ, Baldwin RM, Van Dyck CH, Al-Tikriti M, Roth B, Khan N, Charney DS, Innis RB (1999) Characterization of radioactive metabolites of 5-HT2A receptor PET ligand [18F]altanserin in human and rodent. Nucl Med Biol 26:601–608

    Article  CAS  PubMed  Google Scholar 

  • Tauscher-Wisniewski S, Kapur S, Tauscher J, Jones C, Daskalakis ZJ, Papatheodorou G, Epstein I, Christensen BK, Zipursky RB (2002) Quetiapine: an effective antipsychotic in first-episode schizophrenia despite only transiently high dopamine-2 receptor blockade. J Clin Psychiatry 63:992–997

    CAS  PubMed  Google Scholar 

  • Trichard C, Paillere-Martinot ML, Attar-Levy D, Blin J, Feline A, Martinot JL (1998) No serotonin 5-HT2A receptor density abnormality in the cortex of schizophrenic patients studied with PET. Schizophr Res 31:13–17

    Article  CAS  PubMed  Google Scholar 

  • Verhoeff NP, Meyer JH, Kecojevic A, Hussey D, Lewis R, Tauscher J, Zipursky RB, Kapur S (2000) A voxel-by-voxel analysis of [18F]setoperone PET data shows no substantial serotonin 5-HT(2A) receptor changes in schizophrenia. Psychiatry Res 99:123–135

    Article  CAS  PubMed  Google Scholar 

  • Willendrup P, Pinborg LH, Hasselbalch SG, Adams KH, Stahr K, Knudsen GM, Svarer C (2008) Assessment of the precision in co-registration of structural MR-images and PET-images with localized binding. Int Congress Series, ISBN: 0444515674, 275–280

  • Wing JK, Babor T, Brugha T, Burke J, Cooper JE, Giel R, Jablenski A, Regier D, Sartorius N (1990) SCAN. Schedules for clinical assessment in neuropsychiatry. Arch Gen Psychiatry 47:589–593

    CAS  PubMed  Google Scholar 

  • Woods RP, Cherry SR, Mazziotta JC (1992) Rapid automated algorithm for aligning and reslicing PET images. J Comput Assist Tomogr 16:620–633

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The study was sponsored by Danish Medical Research Council, Copenhagen Hospital Cooperation Research Council, Copenhagen University Hospital, Bispebjerg, The University of Copenhagen, Faculty of Health Sciences, The Copenhagen Counsel Research Foundation, The Gangsted Foundation, The Lundbeck Foundation and a nonrestricted grant from AstraZeneca. We would like to thank Dr Jacob Madsen and the PET & Cyclotron Unit, Copenhagen University Hospital Rigshospitalet, Denmark for technical support.

Disclosure/conflicts of interest

The authors have nothing to disclose and report no conflicts of interest.

Author information

Authors and Affiliations

  1. Center for Neuropsychiatric Schizophrenia Research, Faculty of Health Sciences, Psychiatric Center Glostrup, Copenhagen University Hospital Glostrup, Copenhagen, DK-2600, Denmark

    Hans Rasmussen, Bjorn H. Ebdrup, Bodil Aggernaes, Bob Oranje, Henrik Lublin & Birte Glenthoj

  2. Center for Clinical Intervention and Neuropsychiatric Schizophrenia Research, Faculty of Health Sciences, Psychiatric Center Glostrup, Copenhagen University Hospital Glostrup, Copenhagen, DK-2600, Denmark

    Hans Rasmussen, Bjorn H. Ebdrup, Bodil Aggernaes, Bob Oranje, Henrik Lublin & Birte Glenthoj

  3. Neurobiology Research Unit and Center for Integrated Molecular Brain Imaging, Faculty of Health Sciences, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark

    Hans Rasmussen, David Erritzoe, Jan Kalbitzer, Lars H. Pinborg, Claus Svarer & Gitte M. Knudsen

  4. Danish Centre for Magnetic Resonance Imaging, University Hospital Hvidovre, Copenhagen, Denmark

    Bjorn H. Ebdrup & William F. C. Baaré

  5. Center for Integrated Molecular Brain Imaging, Faculty of Health Sciences, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark

    William F. C. Baaré

Authors
  1. Hans Rasmussen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bjorn H. Ebdrup
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David Erritzoe
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bodil Aggernaes
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bob Oranje
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jan Kalbitzer
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lars H. Pinborg
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. William F. C. Baaré
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Claus Svarer
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Henrik Lublin
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Gitte M. Knudsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Birte Glenthoj
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hans Rasmussen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rasmussen, H., Ebdrup, B.H., Erritzoe, D. et al. Serotonin2A receptor blockade and clinical effect in first-episode schizophrenia patients treated with quetiapine. Psychopharmacology 213, 583–592 (2011). https://doi.org/10.1007/s00213-010-1941-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-010-1941-5

Keywords

Search

Navigation