Increased orbitofrontal cortex activation associated with “pro-obsessive” antipsychotic treatment in patients with schizophrenia

Increased orbitofrontal cortex activation associated with “pro-obsessive” antipsychotic treatment in patients with schizophrenia

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J Psychiatry Neurosci 2015;40(2):89-99

Frederike Schirmbeck, PhD*; Daniela Mier, PhD*; Christine Esslinger, MD; Franziska Rausch, MPsych; Susanne Englisch, MD; Sarah Eifler, MPsych; Andreas Meyer-Lindenberg, MD; Peter Kirsch, PhD; Mathias Zink, MD


Background: Patients with schizophrenia have an approximately 10-fold higher risk for obsessive–compulsive symptoms (OCS) than the general population. A large subgroup seems to experience OCS as a consequence of second-generation antipsychotic agents (SGA), such as clozapine. So far little is known about underlying neural mechanisms.

Methods: To investigate the role of SGA treatment on neural processing related to OCS in patients with schizophrenia, we stratified patients according to their monotherapy into 2 groups (group I: clozapine or olanzapine; group II: amisulpride or aripiprazole). We used an fMRI approach, applying a go/no-go task assessing inhibitory control and an n-back task measuring working memory.

Results: We enrolled 21 patients in group I and 19 patients in group II. Groups did not differ regarding age, sex, education or severity of psychotic symptoms. Frequency and severity of OCS were significantly higher in group I and were associated with pronounced deficits in specific cognitive abilities. Whereas brain activation patterns did not differ during working memory, group I showed significantly increased activation in the orbitofrontal cortex (OFC) during response inhibition. Alterations in OFC activation were associated with the severity of obsessions and mediated the association between SGA treatment and co-occurring OCS on a trend level.

Limitations: The main limitation of this study is its cross-sectional design.

Conclusion: To our knowledge, this is the first imaging study conducted to elucidate SGA effects on neural systems related to OCS. We propose that alterations in brain functioning reflect a pathogenic mechanism in the development of SGA-induced OCS in patients with schizophrenia. Longitudinal studies and randomized interventions are needed to prove the suggested causal interrelations.

*These authors contributed equally to this work.

Submitted Jan. 20, 2014; Revised May 12, June 20, 2014; Accepted July 15, 2014; Early-released Sept. 30, 2014.

Funding and competing interests: F. Schirmbeck was supported by a PhD fellowship of the Evangelisches Studienwerk and by a fellowship within the Postdoc-Programme of the German Academic Exchange Service (DAAD). D. Mier and C. Esslinger were funded by the Olympia-Morata Program. S. Eifler was supported by a research grant of the Landesgraduiertenförderung of the Heidelberg University. S. Englisch has received travel expenses and consultant fees from AstraZeneca, Bristol-Myers Squibb GmbH & CoKGaA, Eli- Lilly, Janssen Cilag, Otsuka Pharma, Pfizer Pharma and Servier. A. Meyer-Lindenberg received consultant fees and travel expenses from AstraZeneca, Hoffmann-La Roche and Lundbeck Foundation and speaker´s fees from Pfizer Pharma, Lilly Deutschland, Glaxo SmithKline, Janssen Cilag, Bristol-Myers Squibb, Lundbeck, Servier and AstraZeneca. M. Zink received unrestricted scientific grants of the European Research Advisory Board (ERAB), German Research Foundation (DFG), Pfizer Pharma GmbH, Servier and Bristol Myers Squibb Pharmaceuticals; further speaker and travel grants were provided from Astra Zeneca, Lilly, Pfizer Pharma GmbH, Bristol Myers Squibb Pharmaceuticals, Otsuka, Servier, Lundbeck and Janssen Cilag. M. Zink, A. Meyer-Lindenber and P. Kirsch were funded by the Deutsche Forschungsgesellschaft (DFG,, projects ZI1253/3-1, ZI1253/3-2, KI 576/14-2, ME 1591/6-2). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Acknowledgements: We are grateful to all participants and to Dagmar Gass for assisting in data acquisition.

Affiliations: From the Departments of Psychiatry and Psychotherapy (Schirmbeck, Esslinger, Rausch, Englisch, Eifler, Meyer-Lindenberg, Zink) and Clinical Psychology (Mier, Kirsch), Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany; and the Department of Psychiatry, Academic Medical Centre, Amsterdam, the Netherlands (Schirmbeck).

Contributors: F. Schirmbeck, C. Esslinger, A. Meyer-Lindenberg, P. Kirsch and M. Zink designed the study. F. Schirmbeck, D. Mier, C. Esslinger, F. Rausch, S. Englisch and S. Eifler acquired the data, which F. Schirmbeck, D. Mier, C. Esslinger, P. Kirsch and M. Zink analyzed. F. Schirmbec, D. Mier and M. Zink wrote the article, which all authors reviewed and approved for publication.

DOI: 10.1503/jpn.140021

Correspondence to: F. Schirmbeck, Academic Medical Centre, Meibergdreef 5, 1105 AZ Amsterdam, The Netherlands;