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
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.