Effects of treatment with the atypical neuroleptic quetiapine on working memory function: a functional MRI follow-up investigation

  • E.M. Meisenzahl
  • J. Scheuerecker
  • M. Zipse
  • S. Ufer
  • M. Wiesmann
  • T. Frodl
  • N. Koutsouleris
  • T. Zetzsche
  • G. Schmitt
  • M. Riedel
  • I. Spellmann
  • S. Dehning
  • J. Linn
  • H. Brückmann
  • H.J. Möller
ORIGINAL PAPER

Abstract

Background

Working memory as a part of higher-order executive functions is defined by the parallel storage and processing of information. Recent functional fMRI studies have revealed a functional, interregional disintegration of a neuronal network connecting cortical, subcortical and cerebellar regions in schizophrenic patients (SZ). Cognitive impairment in working memory is a core psychopathological correlate of schizophrenic symptoms. Atypical neuroleptics such as quetiapine have shown good efficacy in treating positive and negative symptoms. The presented study evaluated the impact of a neuroleptic steady state treatment with quetiapine on the altered working memory activation patterns in schizophrenia.

Methods

Patients were examined by fMRI at baseline and after 12 weeks of steady state treatment with quetiapine. Matched healthy controls (HC) underwent baseline examination. In the scanner, stimuli were presented in a 2-back and 0-back condition of a working memory (wm) paradigm, whereby a degraded and a non-degraded version were used each time. Additionally, behavioural responses (reaction time to target stimuli and error ratio) were measured.

Results

At baseline, healthy controls revealed increased activity in the frontal lobe, especially in regions of the prefrontal cortex. Compared to HC, SZ showed hypoactivation in the right dorsolateral prefrontal cortex (DLPFC) and the ventrolateral prefrontal cortex (VLPFC) bilaterally for the 2-back condition. In the 2-back degraded condition there was a hypoactivation in both, the right DLPFC and the VLPFC. Additionally, patients showed bilaterally decreased activation in the basalganglia in the 2-back and in the right caudatus in the 2-back degraded condition compared to healthy controls. After treatment with quetiapine, patients activations patterns were increased. The pre–post comparison of the 2-back condition revealed a significant increase of activation in the left VLPFC at a significance level of 0.001 (uncorrected). The 2-back degraded condition led to a significant activation pattern in the lingual gyrus and the right precuneus. In both wm conditions, at baseline there were no differences in reaction time but only a worse performance in SZ. After treatment, behavioural measurement of responses, including reaction time and performance, showed slight improvements in SZ, although these did not reach statistical significance.

Conclusions

The neuronal networks underlying working memory are clearly altered in schizophrenia. After 12 weeks of treatment with quetiapine monotherapy, patients showed significant clinical improvement and revealed increased BOLD activity in the VLPFC during a working memory task, although there was no improvement of cognitive performance.

Keywords

working memory schizophrenia neuroleptic treatment quetiapine functional magnetic resonance imaging 

References

  1. 1.
    Andreasen NC (1989) The Scale for the Assessment of Negative Symptoms (SANS): conceptual and theoretical foundations. Br J Psychiatry 162(7):49–58Google Scholar
  2. 2.
    Arvanitis LA, Miller BG (1997) Multiple fixed doses of “Seroquel” (quetiapine) in patients with acute exacerbation of schizophrenia: a comparison with haloperidol and placebo. The Seroquel trial 13 study group. Biol Psychiatry 42(4):233–246PubMedCrossRefGoogle Scholar
  3. 3.
    Barch DM, Braver TS, Nystrom LE, Forman SD, Noll DC, Cohen JD (1997) Dissociating working memory from task difficulty in human prefrontal cortex. Neuropsychologia 35(10):1373–1380PubMedCrossRefGoogle Scholar
  4. 4.
    Barch DM, Carter CS, Braver TS, Sabb FW, MacDonald A 3rd, Noll DC, Cohen JD (2001) Selective deficits in prefrontal cortex function in medication-naive patients with schizophrenia. Arch Gen Psychiatry 58(3):280–288PubMedCrossRefGoogle Scholar
  5. 5.
    Bertolino A, Blasi G, Caforio G, Latorre V, De Candia M, Rubino V, Callicott JH, Mattay VS, Bellomo A, Scarabino T, Weinberger DR, Nardini M (2004) Functional lateralization of the sensorimotor cortex in patients with schizophrenia: effects of treatment with olanzapine. Biol Psychiatry 56(3):190–197PubMedCrossRefGoogle Scholar
  6. 6.
    Buchsbaum MS, Haier RJ, Potkin SG, Nuechterlein K, Bracha HS, Katz M, Lohr J, Wu J, Lottenberg S, Jerabek PA, Trenary M, Tafalla R, Reynolds C, Bunney WE Jr (1992) Frontostriatal disorder of cerebral metabolism in never-medicated schizophrenics. Arch Gen Psychiatry 49:935–942PubMedGoogle Scholar
  7. 7.
    Brett M, Penny WD, Kiebel SJ (2003) Introduction to random field theory. In: Frackowiak RSJ, Friston KJ, Frith C, Dolan R, Friston KJ, Price CJ, Zeki S, Ashburner J, Penny WD (eds) Human brain function, 2nd edn. Academic PressGoogle Scholar
  8. 8.
    Callicott JH, Mattay VS, Bertolino A, Finn K, Coppola R, Frank JA, Goldberg TE, Weinberger DR (1999) Physiological characteristics of capacity constraints in working memory as revealed by functional MRI. Cereb Cortex 9(1):20–26PubMedCrossRefGoogle Scholar
  9. 9.
    Callicott JH, Bertolino A, Mattay VS, Langheim FJ, Duyn J, Coppola R, Goldberg TE, Weinberger DR (2000) Physiological dysfunction of the dorsolateral prefrontal cortex in schizophrenia. Cereb Cortex 10(11):1078–1092PubMedCrossRefGoogle Scholar
  10. 10.
    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(12):2209–2215PubMedCrossRefGoogle Scholar
  11. 11.
    Chaudhury IB, Soni SD, Hellewell JSE, Deakin JWF (1997) Antisaccade, clinical and motor executive function in schizophrenia: effects of 5HT2 antagonist, cyproheptadine. Schizophre Res 112(24):212Google Scholar
  12. 12.
    Cuesta MJ, Peralta V, Zarzuela A (2001) Effects of olanzapine and other antipsychotics on cognitive function in chronic schizophrenia: a longitudinal study. Schizophr Res 48(1):17–28PubMedCrossRefGoogle Scholar
  13. 13.
    D’Esposito M, Postle BR, Rypma B (2000) Prefrontal cortical contributions to working memory: evidence from event-related fMRI studies. Exp Brain Res 133(1):3–11PubMedCrossRefGoogle Scholar
  14. 14.
    Erkwoh R, Sabri O, Schreckenberger M, Setani K, Aßfalg S, Sturz L, Fehler S, Pleßmann S (2002) Cerebral correlates of selective attention in schizophrenic patients with formal thought disorder: a controlled H215O-PET study. Psychiatry Res Neuroimaging 15(115):137–153CrossRefGoogle Scholar
  15. 15.
    Fahim C, Stip E, Mancini-Marie A, Gendron A, Mensour B, Beauregard M (2005) Differential hemodynamic brain activity in schizophrenia patients with blunted affect during quetiapine treatment. J Clin Psychopharmacol 25(4):367–371PubMedCrossRefGoogle Scholar
  16. 16.
    Good MF, Kiss I, Buiteman C, Woodley H, Ruui Q, Whitehorn D, Kopala L (2002) Improvement in cognitive functioning in patients with first-episode psychosis during treatment with quetiapine: an interim analysis. Br J Psychiatry 43:45–49CrossRefGoogle Scholar
  17. 17.
    Goldman-Rakic PS (1994) Working memory dysfunction in schizophrenia. J Neuropsychiatry Clin Neurosci 6(4):348–357PubMedGoogle Scholar
  18. 18.
    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 96(23):13432–13437PubMedCrossRefGoogle Scholar
  19. 19.
    Jones HM, Brammer MJ, O’Toole M, Taylor T, Ohlsen RI, Brown RG, Purvis R, Williams S, Pilowsky LS (2004) Cortical effects of quetiapine in first-episode schizophrenia: a preliminary functional magnetic resonance imaging study. Biol Psychiatry 56:938–942PubMedCrossRefGoogle Scholar
  20. 20.
    Kindermann SS, Brown GG, Zorrilla LE, Olsen RK, Jeste DV (2004) Spatial working memory among middle-aged and older patients with schizophrenia and volunteers using fMRI. Schizophr Res 68(2–3):203–216PubMedCrossRefGoogle Scholar
  21. 21.
    Manoach DS, Press DZ, Thangaraj V, Searl MM, Goff DC, Halpern E, Saper CB, Warach S (1999) Schizophrenic subjects activate dorsolateral prefrontal cortex during a working memory task, as measured by fMRI. Biol Psychiatry 45(9): 1128–1137PubMedCrossRefGoogle Scholar
  22. 22.
    Manoach DS, Gollub RL, Benson ES, Searl MM, Goff DC, Halpern E, Saper CB, Rauch SL (2000) Schizophrenic subjects show aberrant fMRI activation of dorsolateral prefrontal cortex and basal ganglia during working memory performance. Biol Psychiatry. 15, 48(2):99–109Google Scholar
  23. 23.
    Menon RS (2001) Imaging function in the working brain with fMRI. Curr Opin Neurobiol 11(5):630–636PubMedCrossRefGoogle Scholar
  24. 24.
    Möller HJ (1999a) Atypical neuroleptics: a new approach in the treatment of negative symptoms. Eur Arch Psychiatry Clin Neurosci 249(4):99–107CrossRefGoogle Scholar
  25. 25.
    Möller HJ (1999b) Can negative symptoms of schizophrenia be partially or totally controlled by antipsychotics? Eur Neuropsychopharmacol 9(5):135–136CrossRefGoogle Scholar
  26. 26.
    Möller HJ (2000) Results and methodological problems in the evaluation of newer atypical neuroleptics in the treatment of schizophrenic negative symptoms. Nervenarzt (71):345–353Google Scholar
  27. 27.
    Mortimer AM, Dye S (1997) Remediation of neuropsychological impairments with clozapine. Schizophr Res 24:187CrossRefGoogle Scholar
  28. 28.
    Perlstein WM, Dixit NK, Carter CS, Noll DC, Cohen JD (2003) Prefrontal cortex dysfunction mediates deficits in working memory and prepotent responding in schizophrenia. Biol Psychiatry 53(1):25–38PubMedCrossRefGoogle Scholar
  29. 29.
    Petrides M (2000) Dissociable roles of mid-dorsolateral prefrontal and anterior inferotemporal cortex in visual working memory. J Neurosci 20(19):7496–7503PubMedGoogle Scholar
  30. 30.
    Purdon SE (2000) Measuring neuropsychological change in schizophrenia with novel antipsychotic medications. J Psychiatry Neurosci 25(2):108–116PubMedGoogle Scholar
  31. 31.
    Purdon SE, Malla A, Labelle A, Lit W (2001) Neuropsychological change in patients with schizophrenia after treatment with quetiapine or haloperidol. J Psychiatry Neurosci 26(2): 137–149PubMedGoogle Scholar
  32. 32.
    Riedel M, Müller N, Strassnig M, Spellmann I, Engel RR, Musil R, Dehning S, Douhet A, Schwarz MJ, Möller HJ (2005) Quetiapine has equivalent efficacy and superior tolerability to risperidone in the treatment of schizophrenia with predominantly negative symptoms. Eur Arch Psychiatry Clin Neurosci 255:432–437PubMedCrossRefGoogle Scholar
  33. 33.
    Robbins TW (1990) The case for frontostriatal dysfunction in schizophrenia. Schizophr Bull 16(3):391–402PubMedGoogle Scholar
  34. 34.
    Scheuerecker J, Ufer S, Frodl T, Koutsouleris N, Zipse M, Zetzsche T, Wiesmann M, Albrecht J, Schmitt G, Möller HJ, Meisenzahl EM (2006) Cerebral changes and cognitive dysfunctions in medication-free schizophrenia-an fMRI study. J Psychiatr Res (1st revision)Google Scholar
  35. 35.
    Schlosser R, Gesierich T, Kaufmann B, Vucurevic G, Hunsche S, Gawehn J, Stoeter P (2003) Altered effective connectivity during working memory performance in schizophrenia: a study with fMRI and structural equation modeling. Neuroimage 19(3):751–763PubMedCrossRefGoogle Scholar
  36. 36.
    Schmahmann JD, Sherman JC (1997) Cerebellar cognitive affective syndrome. Int rev Neurbiol 41:433–440CrossRefGoogle Scholar
  37. 37.
    Sharma T (2001) Quetiapine–efficacy in different domains. Eur Neuropsychopharmacol 11(4):385–390CrossRefGoogle Scholar
  38. 38.
    Stern CE, Owen AM, Tracey I, Look RB, Rosen BR, Petrides M (2000) Activity in ventrolateral and mid-dorsolateral prefrontal cortex during nonspatial visual working memory processing: evidence from functional magnetic resonance imaging. Neuroimage 11(5):392–399PubMedCrossRefGoogle Scholar
  39. 39.
    Stip E, Fahim C, Mancini-Marie A, Bentaleb LA, Mensour B, Mendrek A, Beauregard M (2005) Restoration of frontal activation during a treatment with quetiapine: a fMRI study of blunted affect in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 29(1):21–26PubMedCrossRefGoogle Scholar
  40. 40.
    Velligan DJ, Newcomer J, Pultz J, Csernansky J, Hoff AL, Mahurin R, Miller AL (2002) Does cognitive function improve with quetiapine in comparison to haloperidol? Schizophr Res (53):239–248CrossRefGoogle Scholar
  41. 41.
    Weickert TW, Goldberg TE, Marenco S, Bigelow LB, Egan MF, Weinberger DR (2003) Comparison of cognitive performances during a placebo period and an atypical antipsychotic treatment period in schizophrenia: critical examination of confounds. Neuropsychopharmacology 28(8):1491–1500PubMedCrossRefGoogle Scholar
  42. 42.
    Weinberger DR, Berman KF (1996) Prefrontal function in schizophrenia: confounds and controversies. Philos Trans R Soc Lond B Biol Sci 351(1346):1495–503PubMedGoogle Scholar

Copyright information

© Steinkopff Verlag Darmstadt 2006

Authors and Affiliations

  • E.M. Meisenzahl
    • 1
  • J. Scheuerecker
    • 1
  • M. Zipse
    • 1
  • S. Ufer
    • 1
  • M. Wiesmann
    • 2
  • T. Frodl
    • 1
  • N. Koutsouleris
    • 1
  • T. Zetzsche
    • 1
  • G. Schmitt
    • 1
  • M. Riedel
    • 1
  • I. Spellmann
    • 1
  • S. Dehning
    • 1
  • J. Linn
    • 2
  • H. Brückmann
    • 2
  • H.J. Möller
    • 1
  1. 1.Dept. of PsychiatryLudwig-Maximilians-University of MunichGermany
  2. 2.Dept. of NeuroradiologyLudwig-Maximilians-University of MunichGermany

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