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

• Published in: Journal of psychiatry & neuroscience Vol. 42; no. 4; pp. 273 - 283
• Main Authors: Thiebes, Stephanie, Leicht, Gregor, Curic, Stjepan, Steinmann, Saskia, Polomac, Nenad, Andreou, Christina, Eichler, Iris, Eichler, Lars, Zöllner, Christian, Gallinat, Jürgen, Hanganu-Opatz, Ileana, Mulert, Christoph
• Format: Journal Article
• Language: English
• Published: Canada Joule Inc 01-07-2017; CMA Impact, Inc
• Subjects: Adult; Antidepressants; Brain - drug effects; Brain - physiology; Cognitive ability; Cortex (auditory); Dopamine; Dosage and administration; Drug therapy; EEG; Emotional behavior; Evoked Potentials, Auditory - drug effects; Excitatory Amino Acid Antagonists - pharmacology; Frontal gyrus; Glutamate; Glutamatergic transmission; Glutamic Acid - metabolism; Glutamic acid receptors; Health aspects; Healthy Volunteers - psychology; Humans; Ketamine; Ketamine - pharmacology; Localization; Male; Men; Mental disorders; Mismatch negativity; N-Methyl-D-aspartic acid receptors; Psychiatry; Psychosis; Receptors, N-Methyl-D-Aspartate - metabolism; Research Paper; Schizophrenia; Schizophrenia - chemically induced; Schizophrenia - diagnosis; Single-Blind Method; Statistical analysis; Young Adult
• ISSN: 1180-4882; 1488-2434
• DOI: 10.1503/jpn.160187

Targeting the
-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.
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.
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.
The sample included only men within a tight age range of 20-32 years.
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.