Glutamatergic Deficits in Schizophrenia - Biomarkers and Pharmacological Interventions within the Ketamine Model

Abstract

Background: The observation that N-methyl-D-aspartate glutamate receptor (NMDAR) antagonists such as ketamine transiently induce schizophrenia-like positive, negative and cognitive symptoms has led to a paradigm shift from dopaminergic to glutamatergic dysfunction in pharmacological models of schizophrenia. NMDAR hypofunction can explain many schizophrenia symptoms directly due to excitatory-to-inhibitory (E/I) imbalance, but also dopaminergic dysfunction itself. However, so far no new drug targeting the NMDAR has been successfully approved. In the search for possible biomarkers it is interesting that ketamine-induced psychopathological changes in healthy participants were accompanied by altered electro-(EEG), magnetoencephalographic (MEG) and functional magnetic resonance imaging (fMRI) signals.

Methods: We systematically searched PubMed/Medline and Web of Knowledge databases (January 2006 to July 2017) to identify EEG/MEG and fMRI studies of the ketamine model of schizophrenia with human subjects. The search strategy identified 209 citations of which 46 articles met specified eligibility criteria.

Results: In EEG/MEG studies, ketamine induced changes of event-related potentials, such as the P300 potential and the mismatch negativity, similar to alterations observed in schizophrenia patients. In fMRI studies, alterations of activation were observed in different brain regions, most prominently within the anterior cingulate cortex and limbic structures as well as task-relevant brain regions. These alterations were accompanied by changes in functional connectivity, indicating a balance shift of the underlying brain networks. Pharmacological treatments did alter ketamine-induced changes in EEG/MEG and fMRI studies to different extents.

Conclusion: This review highlights the potential applicability of the ketamine model for schizophrenia drug development by offering the possibility to assess the effect of pharmacological agents on schizophrenia- like symptoms and to find relevant neurophysiological and neuroimaging biomarkers.

Keywords: EEG; MEG; NMDA-receptor; fMRI; ketamine; schizophrenia..

Fig. (1)

PRISMA flowchart detailing selection of studies included in the systematic review.

Fig. (2)

Event-related brain potential grand average waveforms (left) and corresponding topographic maps (right) are shown for placebo (black), ketamine alone (red), nicotine alone (blue), and ketamine + nicotine (magenta) days. ERPs, overlaid for each test day, are shown to oddball targets at Pz (top row), to oddball novels at Cz (middle row), and to difference waveforms (deviants-standards) at Cz. The oddball target elicited a P3b, the oddball novel elicited a P3a, and the deviant elicited an MMN, with each peak denoted by an arrow on the ERP waveforms. Amplitude (in microvolts) is on the y-axis, and latency (in milliseconds) is on the x-axis. Stimulus onset is at 0 ms. Negativity is plotted down. Scalp topography maps are shown for each test day for each stimulus, at the peak latency for P3b (top), P3a (middle), and MMN (bottom). Hot colors indicate positive voltage; cool colors indicate negative voltage [21].