Glutamatergic deficit and schizophrenia-like negative symptoms: new evidence from ketamine-induced mismatch negativity alterations in healthy male humans

Glutamatergic deficit and schizophrenia-like negative symptoms: new evidence from ketamine-induced mismatch negativity alterations in healthy male humans

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J Psychiatry Neurosci 2017;42(4):273-283

Stephanie Thiebes; Gregor Leicht, MD; Stjepan Curic, MD; Saskia Steinmann, MA; Nenad Polomac, MD; Christina Andreou, MD, PhD; Iris Eichler, MD; Lars Eichler, MD; Christian Zöllner, MD, PhD; Jürgen Gallinat, MD, PhD; Ileana Hanganu-Opatz, PhD; Christoph Mulert, MD, PhD

Abstract

Background: Targeting the N-methyl-d-aspartate receptor (NMDAR) is a major translational approach for treating negative symptoms of schizophrenia. Ketamine comprehensively produces schizophrenia-like symptoms, such as positive, cognitive and negative symptoms in healthy volunteers. The amplitude of the mismatch negativity (MMN) is known to be significantly reduced not only in patients with schizophrenia, but also in healthy controls receiving ketamine. Accordingly, it was the aim of the present study to investigate whether changes of MMN amplitudes during ketamine administration are associated with the emergence of schizophrenia-like negative symptoms in healthy volunteers.

Methods: We examined the impact of ketamine during an MMN paradigm with 64-channel electroencephalography (EEG) and assessed the psychopathological status using the Positive and Negative Syndrome Scale (PANSS) in healthy male volunteers using a single-blind, randomized, placebo-controlled crossover design. Low-resolution brain electromagnetic tomography was used for source localization.

Results: Twenty-four men were included in our analysis. Significant reductions of MMN amplitudes and an increase in all PANSS scores were identified under the ketamine condition. Smaller MMN amplitudes were specifically associated with more pronounced negative symptoms. Source analysis of MMN generators indicated a significantly reduced current source density (CSD) under the ketamine condition in the primary auditory cortex, the posterior cingulate and the middle frontal gyrus.

Limitations: The sample included only men within a tight age range of 20–32 years.

Conclusion: The MMN might represent a biomarker for negative symptoms in schizophrenia related to an insufficient NMDAR system and could be used to identify patients with schizophrenia with negative symptoms due to NMDAR dysfunction.


Submitted Sept. 21, 2016; Revised Jan. 13, 2017; Accepted Jan. 30, 2017; Early-released May 30, 2017

Acknowledgements: The authors thank Dr. Maja Maurer for providing the 5D-ASC questionnaire and thank the individuals who participated in this study. This research was performed within the collaborative research center grant SFB 936 C6 to C. Mulert and was supported by the German Research Foundation (DFG). J. Gallinat and I. Hanganu-Opatz were supported by DFG SFB 936 C7 and DFG SFB 936 B5, respectively. This work was prepared as part of S. Thiebes’ dissertation at the University of Hamburg.

Affiliations: From the Psychiatry Neuroimaging Branch, Department of Psychiatry and Psychotherapy, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (Thiebes, Leicht, Curic, Steinmann, Polomac, Andreou, Mulert); the Center for Gender Research and Early Detection, University of Basel Psychiatric Clinics, Basel, Switzerland (Andreou); the Department of Anesthesiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (Eichler, Zöllner); the Department of Psychiatry and Psychotherapy, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (Gallinat); and the Developmental Neurophysiology, Institute of Neuroanatomy, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (Hanganu-Opatz).

Competing interests: None declared.

Contributors: S. Thiebes, G. Leicht, S. Curic, C. Zöllner, J. Gallinat and C. Mulert designed the study. S. Thiebes, S. Curic, N. Polomac, I.  Eichler and L. Eichler acquired the data, which S. Thiebes, G. Leicht, S. Curic, S. Steinmann, C. Andreou, I. Hanganu-Opatz and C. Mulert analyzed. S. Thiebes wrote the article, which all authors reviewed and approved for publication.

DOI: 10.1503/jpn.160187

Correspondence to: C. Mulert, Martinistr. 52, D-20246 Hamburg, Germany; c.mulert@uke.uni-hamburg.de