PMID- 28556775 OWN - NLM STAT- MEDLINE DCOM- 20180309 LR - 20191113 IS - 1488-2434 (Electronic) IS - 1180-4882 (Print) IS - 1180-4882 (Linking) VI - 42 IP - 4 DP - 2017 Jun TI - Glutamatergic deficit and schizophrenia-like negative symptoms: new evidence from ketamine-induced mismatch negativity alterations in healthy male humans. PG - 273-283 AB - 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. FAU - Thiebes, Stephanie AU - Thiebes S AD - 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, Zollner); 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). FAU - Leicht, Gregor AU - Leicht G AD - 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, Zollner); 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). FAU - Curic, Stjepan AU - Curic S AD - 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, Zollner); 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). FAU - Steinmann, Saskia AU - Steinmann S AD - 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, Zollner); 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). FAU - Polomac, Nenad AU - Polomac N AD - 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, Zollner); 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). FAU - Andreou, Christina AU - Andreou C AD - 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, Zollner); 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). FAU - Eichler, Iris AU - Eichler I AD - 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, Zollner); 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). FAU - Eichler, Lars AU - Eichler L AD - 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, Zollner); 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). FAU - Zollner, Christian AU - Zollner C AD - 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, Zollner); 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). FAU - Gallinat, Jurgen AU - Gallinat J AD - 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, Zollner); 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). FAU - Hanganu-Opatz, Ileana AU - Hanganu-Opatz I AD - 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, Zollner); 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). FAU - Mulert, Christoph AU - Mulert C AD - 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, Zollner); 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). LA - eng PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't PL - Canada TA - J Psychiatry Neurosci JT - Journal of psychiatry & neuroscience : JPN JID - 9107859 RN - 0 (Excitatory Amino Acid Antagonists) RN - 0 (Receptors, N-Methyl-D-Aspartate) RN - 3KX376GY7L (Glutamic Acid) RN - 690G0D6V8H (Ketamine) SB - IM MH - Adult MH - Brain/drug effects/*physiology MH - Evoked Potentials, Auditory/*drug effects MH - Excitatory Amino Acid Antagonists/*pharmacology MH - Glutamic Acid/*metabolism MH - Healthy Volunteers/*psychology MH - Humans MH - Ketamine/*pharmacology MH - Male MH - Receptors, N-Methyl-D-Aspartate/metabolism MH - Schizophrenia/*chemically induced/diagnosis MH - Single-Blind Method MH - Young Adult PMC - PMC5487274 COIS- Competing interests: None declared. EDAT- 2017/05/31 06:00 MHDA- 2018/03/10 06:00 PMCR- 2017/07/01 CRDT- 2017/05/31 06:00 PHST- 2017/05/31 06:00 [pubmed] PHST- 2018/03/10 06:00 [medline] PHST- 2017/05/31 06:00 [entrez] PHST- 2017/07/01 00:00 [pmc-release] AID - 10.1503/jpn.160187 [pii] AID - 42-4-273 [pii] AID - 10.1503/jpn.160187 [doi] PST - ppublish SO - J Psychiatry Neurosci. 2017 Jun;42(4):273-283. doi: 10.1503/jpn.160187.