, Volume 196, Issue 4, pp 673–684 | Cite as

Reward system activation in schizophrenic patients switched from typical neuroleptics to olanzapine

  • Florian Schlagenhauf
  • Georg Juckel
  • Michael Koslowski
  • Thorsten Kahnt
  • Brian Knutson
  • Theresa Dembler
  • Thorsten Kienast
  • Jürgen Gallinat
  • Jana Wrase
  • Andreas HeinzEmail author
Original Investigation



High blockade of dopamine D2 receptors in the ventral striatum including the nucleus accumbens may interfere with reward anticipation and cause secondary negative symptoms such as apathy or anhedonia. This may not be the case with newer neuroleptics such as olanzapine, which show less dopamine D2 receptor blockade and a faster off-rate from the receptor.


We used functional magnetic resonance imaging to assess the blood oxygenation level dependent response in the ventral striatum of schizophrenics medicated with typical neuroleptics (T1) and after switching them to olanzapine (T2) and of healthy control subjects at corresponding time points during reward anticipation.

Materials and methods

Ten schizophrenics, while medicated with typical neuroleptics (T1) and after having been switched to olanzapine (T2), and ten matched healthy volunteers participated in a monetary incentive delay task, in which visual cues predicted that a rapid response to a subsequent target stimulus would either result in monetary gain or have no consequence.


During reward anticipation, healthy volunteers showed significantly higher ventral striatal activation compared to schizophrenic patients treated with typical neuroleptics but not olanzapine, which was reflected in a significant interaction between group and session. In patients treated with typical neuroleptics, but not with olanzapine, decreased left ventral striatal activation was correlated with negative symptoms.


Failure to activate the ventral striatum during reward anticipation was pharmacologically state-dependent and observed only in patients treated with typical neuroleptics but not with olanzapine, which may indicate that this drug did not induce secondary negative symptoms via interference with reward anticipation.


Accumbens Basal ganglia Reward Schizophrenia Motivation Functional magnetic resonance imaging Antipsychotic agents 



This study was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft; HE 2597/4-2) and by investigator-initiated trails funded by Lilly Germany and by the Bernstein Center for Computational Neuroscience Berlin (BMBF grant 01GQ0411).

Financial Disclosures

Dr. Schlagenhauf, Mr. Koslowski, Mr. Kahnt, Mrs. Dembler, Dr. Knutson, Dr. Kienast and Dr. Wrase reported no biomedical financial interests or potential conflicts of interest. Dr. Juckel reports having received research funding from Lilly (IIT) and consultant fees from Janssen-Cilag, AstraZenics, Lilly, GSK and Bristol Myers Squibb. Dr. Gallinat disclosed research support from AstraZeneca and fees as consultant from Bristol Myers Squibb. Dr. Heinz has received research funding from the German Research Foundation and the Bernstein Center for Computational Neuroscience Berlin (German Federal Ministry of Education and Research), Eli Lilly & Company, Janssen-Cilag, and Bristol-Myers Squibb. Dr. Heinz has received Speaker Honoraria from Janssen-Cilag, Johnson & Johnson, Lilly, Pfizer, and Servier.

Supplementary material

213_2007_1016_MOESM1_ESM.doc (97 kb)
ESM Table 1 Activation during anticipation of monetary loss compared to the neutral condition in the healthy controls at two time points (T1 and T2) and in schizophrenic patients while treated with typical neuroleptics and after switching to olanzapine. Displayed are the corrected p values, the cluster size, the t values, uncorrected p values, and coordinates in MNI space of the peak voxels (DOC 97.0 kb).


  1. Abi-Dargham A, Rodenhiser J, Printz D, Zea-Ponce Y, Gil R, Kegeles LS, Weiss R, Cooper TB, Mann JJ, Van Heertum RL, Gorman JM, Laruelle M (2000) Increased baseline occupancy of D2 receptors by dopamine in schizophrenia. Proc Natl Acad Sci USA 97:8104–8109PubMedCrossRefGoogle Scholar
  2. Abler B, Erk S, Walter H (2007) Human reward system activation is modulated by a single dose of olanzapine in healthy subjects in an event-related, double-blind, placebo-controlled fMRI study. Psychopharmacology (Berl) 191:823–833CrossRefGoogle Scholar
  3. Akhondzadeh S (2001) The 5-HT hypothesis of schizophrenia. IDrugs 4:295–300PubMedGoogle Scholar
  4. Andreasen NC (1990) Positive and negative symptoms: historical and conceptual aspects. Mod Probl Pharmacopsychiatry 24:1–42PubMedGoogle Scholar
  5. Beninger RJ (2006) Dopamine and incentive learning: a framework for considering antipsychotic medication effects. Neurotox Res 10:199–209PubMedCrossRefGoogle Scholar
  6. Bertolino A, Caforio G, Blasi G, De CM, Latorre V, Petruzzella V, Altamura M, Nappi G, Papa S, Callicott JH, Mattay VS, Bellomo A, Scarabino T, Weinberger DR, Nardini M (2004) Interaction of COMT (Val(108/158)Met) genotype and olanzapine treatment on prefrontal cortical function in patients with schizophrenia. Am J Psychiatry 161:1798–1805PubMedCrossRefGoogle Scholar
  7. Breiter HC, Aharon I, Kahneman D, Dale A, Shizgal P (2001) Functional imaging of neural responses to expectancy and experience of monetary gains and losses. Neuron 30:619–639PubMedCrossRefGoogle Scholar
  8. Callicott JH, Mattay VS, Verchinski BA, Marenco S, Egan MF, Weinberger DR (2003) Complexity of prefrontal cortical dysfunction in schizophrenia: more than up or down. Am J Psychiatry 160:2209–2215PubMedCrossRefGoogle Scholar
  9. Cohen MS (1997) Parametric analysis of fMRI data using linear systems methods. Neuroimage 6:93–103PubMedCrossRefGoogle Scholar
  10. Corlett PR, Murray GK, Honey GD, Aitken MR, Shanks DR, Robbins TW, Bullmore ET, Dickinson A, Fletcher PC (2007) Disrupted prediction-error signal in psychosis: evidence for an associative account of delusions. Brain 130:2387–2400PubMedCrossRefGoogle Scholar
  11. Crespo-Facorro B, Paradiso S, Andreasen NC, O’Leary DS, Watkins GL, Ponto LL, Hichwa RD (2001) Neural mechanisms of anhedonia in schizophrenia: a PET study of response to unpleasant and pleasant odors. JAMA 286:427–435PubMedCrossRefGoogle Scholar
  12. de Haan L, Lavalaye J, van BM, van NL, Booij J, van AT, Linszen D (2004) Subjective experience and dopamine D2 receptor occupancy in patients treated with antipsychotics: clinical implications. Can J Psychiatry 49:290–296PubMedGoogle Scholar
  13. 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
  14. First M, Spitzer R, Gibbon M, Williams J (1997) Structured clinical interview for DSM-IV personality disorders, (SCID-II). American Psychiatric, Washington, DCGoogle Scholar
  15. First MB, Spitzer RL, Gibbon M, Williams J (2001) Structured clinical interview for DSM-IV-TR Axis I disorders, research version, patient edition with psychotic screen (SCID-I/P W/ PSY SCREEN). New York State Psychiatric Institute, New YorkGoogle Scholar
  16. Fox PT, Lancaster JL (2002) Opinion: mapping context and content: the BrainMap model. Nat Rev Neurosci 3:319–321PubMedCrossRefGoogle Scholar
  17. Friston KJ, Holmes AP, Worsley KJ, Poline JB, Frith CD, Frackowiak RSJ (1995) Statistical parametric maps in functional imaging: a general linear approach. Hum Brain Mapp 2:189–210CrossRefGoogle Scholar
  18. Glick ID, Lemmens P, Vester-Blokland E (2001) Treatment of the symptoms of schizophrenia: a combined analysis of double-blind studies comparing risperidone with haloperidol and other antipsychotic agents. Int Clin Psychopharmacol 16:265–274PubMedCrossRefGoogle Scholar
  19. Heaton R (1981) A manual for the Wisconsin Card Sorting Test. Psychological Assessment Resources, Odessa, FloridaGoogle Scholar
  20. Heinz A (2002) Dopaminergic dysfunction in alcoholism and schizophrenia—psychopathological and behavioral correlates. Eur Psychiatry 17:9–16PubMedCrossRefGoogle Scholar
  21. Heinz A, Knable MB, Coppola R, Gorey JG, Jones DW, Lee KS, Weinberger DR (1998) Psychomotor slowing, negative symptoms and dopamine receptor availability—an IBZM SPECT study in neuroleptic-treated and drug-free schizophrenic patients. Schizophr Res 31:19–26PubMedCrossRefGoogle Scholar
  22. Honey GD, Bullmore ET, Soni W, Varatheesan M, Williams SC, Sharma T (1999) Differences in frontal cortical activation by a working memory task after substitution of risperidone for typical antipsychotic drugs in patients with schizophrenia. Proc Natl Acad Sci USA 96:13432–13437PubMedCrossRefGoogle Scholar
  23. Jensen J, Willeit M, Zipursky RB, Savina I, Smith AJ, Menon M, Crawley AP, Kapur S (2007) The formation of abnormal associations in schizophrenia: neural and behavioral evidence. Neuropsychopharmacology 28:294–302Google Scholar
  24. Juckel G, Schlagenhauf F, Koslowski M, Filonov D, Wustenberg T, Villringer A, Knutson B, Kienast T, Gallinat J, Wrase J, Heinz A (2006a) Dysfunction of ventral striatal reward prediction in schizophrenic patients treated with typical, not atypical, neuroleptics. Psychopharmacology (Berl) 187:222–228CrossRefGoogle Scholar
  25. Juckel G, Schlagenhauf F, Koslowski M, Wustenberg T, Villringer A, Knutson B, Wrase J, Heinz A (2006b) Dysfunction of ventral striatal reward prediction in schizophrenia. Neuroimage 29:409–416PubMedCrossRefGoogle Scholar
  26. Kapur S (2003) Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophrenia. Am J Psychiatry 160:13–23PubMedCrossRefGoogle Scholar
  27. 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 158:360–369PubMedCrossRefGoogle Scholar
  28. Kapur S, Barsoum SC, Seeman P (2000) Dopamine D(2) receptor blockade by haloperidol. (3)H-raclopride reveals much higher occupancy than EEDQ. Neuropsychopharmacology 23:595–598PubMedCrossRefGoogle Scholar
  29. Kay SR, Fiszbein A, Opler LA (1987) The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 13:261–276PubMedGoogle Scholar
  30. Knutson B, Adams CM, Fong GW, Hommer D (2001) Anticipation of increasing monetary reward selectively recruits nucleus accumbens. J Neurosci 21:RC159PubMedGoogle Scholar
  31. Knutson B, Bjork JM, Fong GW, Hommer D, Mattay VS, Weinberger DR (2004) Amphetamine modulates human incentive processing. Neuron 43:261–269PubMedCrossRefGoogle Scholar
  32. Kumakura Y, Cumming P, Vernaleken I, Buchholz HG, Siessmeier T, Heinz A, Kienast T, Bartenstein P, Grunder G (2007) Elevated [18F]fluorodopamine turnover in brain of patients with schizophrenia: an [18F]fluorodopa/positron emission tomography study. J Neurosci 27:8080–8087PubMedCrossRefGoogle Scholar
  33. Lahti AC, Weiler MA, Medoff DR, Tamminga CA, Holcomb HH (2005) Functional effects of single dose first- and second-generation antipsychotic administration in subjects with schizophrenia. Psychiatry Res 139:19–30PubMedCrossRefGoogle Scholar
  34. Meisenzahl EM, Schmitt GJ, Scheuerecker J, Moller HJ (2007) The role of dopamine for the pathophysiology of schizophrenia. Int Rev Psychiatry 19:337–345PubMedCrossRefGoogle Scholar
  35. Meltzer HY, Li Z, Kaneda Y, Ichikawa J (2003) Serotonin receptors: their key role in drugs to treat schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 27:1159–1172PubMedCrossRefGoogle Scholar
  36. Menon M, Jensen J, Vitcu I, Graff-Guerrero A, Crawley A, Smith MA, Kapur S (2007) Temporal difference modeling of the blood-oxygen level dependent response during aversive conditioning in humans: effects of dopaminergic modulation. Biol Psychiatry 62:765–772PubMedCrossRefGoogle Scholar
  37. Muller JL, Klein HE (2000) Neuroleptic therapy influences basal ganglia activation: a functional magnetic resonance imaging study comparing controls to haloperidol- and olanzapine-treated inpatients. Psychiatry Clin Neurosci 54:653–658PubMedCrossRefGoogle Scholar
  38. Muller JL, Deuticke C, Putzhammer A, Roder CH, Hajak G, Winkler J (2003) Schizophrenia and Parkinson’s disease lead to equal motor-related changes in cortical and subcortical brain activation: an fMRI fingertapping study. Psychiatry Clin Neurosci 57:562–568PubMedCrossRefGoogle Scholar
  39. Murray GK, Corlett PR, Clark L, Pessiglione M, Blackwell AD, Honey G, Jones PB, Bullmore ET, Robbins TW, Fletcher PC (2007) Substantia nigra/ventral tegmental reward prediction error disruption in psychosis. Mol Psychiatry Aug 7 (in press) DOI  10.1038/
  40. Nielsen FA, Hansen LK (2002) Automatic anatomical labeling of Talairach coordinates and generation of volumes of interest via the BrainMap database. Neuroimage 16(2)Google Scholar
  41. Oldfield RC (1971) The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 9:97–113PubMedCrossRefGoogle Scholar
  42. Paquet F, Soucy JP, Stip E, Levesque M, Elie A, Bedard MA (2004) Comparison between olanzapine and haloperidol on procedural learning and the relationship with striatal D2 receptor occupancy in schizophrenia. J Neuropsychiatry Clin Neurosci 16:47–56PubMedGoogle Scholar
  43. Pessiglione M, Seymour B, Flandin G, Dolan RJ, Frith CD (2006) Dopamine-dependent prediction errors underpin reward-seeking behaviour in humans. Nature 442:1042–1045PubMedCrossRefGoogle Scholar
  44. Sawa A, Snyder SH (2003) Schizophrenia: neural mechanisms for novel therapies. Mol Med 9:3–9PubMedGoogle Scholar
  45. Schmidt K, Metzler P (1992) Wortschatztest (WST). Beltz test, WeinheimGoogle Scholar
  46. Schultz W (1998) Predictive reward signal of dopamine neurons. J Neurophysiol 80:1–27PubMedGoogle Scholar
  47. Schultz W, Tremblay L, Hollerman JR (1998) Reward prediction in primate basal ganglia and frontal cortex. Neuropharmacology 37:421–429PubMedCrossRefGoogle Scholar
  48. Siessmeier T, Kienast T, Wrase J, Larsen JL, Braus DF, Smolka MN, Buchholz HG, Schreckenberger M, Rosch F, Cumming P, Mann K, Bartenstein P, Heinz A (2006) Net influx of plasma 6-[18F]fluoro-l-DOPA (FDOPA) to the ventral striatum correlates with prefrontal processing of affective stimuli. Eur J Neurosci 24:305–313PubMedCrossRefGoogle Scholar
  49. Wrase J, Kahnt T, Schlagenhauf F, Beck A, Cohen MX, Knutson B, Heinz A (2007) Different neural systems adjust motor behavior in response to reward and punishment. Neuroimage 36:1253–1262PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Florian Schlagenhauf
    • 1
  • Georg Juckel
    • 1
    • 2
  • Michael Koslowski
    • 1
  • Thorsten Kahnt
    • 1
  • Brian Knutson
    • 3
  • Theresa Dembler
    • 1
  • Thorsten Kienast
    • 1
  • Jürgen Gallinat
    • 1
  • Jana Wrase
    • 1
  • Andreas Heinz
    • 1
    Email author
  1. 1.Department of Psychiatry and PsychotherapyCharité University Medical Center, Campus Charité Mitte (CCM)BerlinGermany
  2. 2.Department of PsychiatryRuhr-University BochumBochumGermany
  3. 3.Department of PsychologyStanford UniversityStanfordUSA

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