Editors' ChoiceSchizophrenia

Connecting the dots on ketamine and schizophrenia

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Science Translational Medicine  24 Aug 2016:
Vol. 8, Issue 353, pp. 353ec134
DOI: 10.1126/scitranslmed.aah5498

Many theories have been proposed to account for the neurobiological mechanisms of schizophrenia, with new theories driven by developments in human brain imaging and post-mortem work along with new animal models. One prominent view posits that there is an excess of excitatory neurotransmission in schizophrenia, which is mediated by glutamate and its receptor, the N-methyl-D-aspartate (NMDA) type glutamate receptor. It is thought that excessive glutamatergic transmission may alter the balance between excitatory and inhibitory processes regulating brain activity and network connectivity. Although simplistic, this model has nonetheless allowed for empirical testing, which researchers have done by infusing intravenously the club drug and NMDA antagonist ketamine into schizophrenia patients or healthy individuals. In schizophrenia patients, ketamine provokes psychotic symptoms at doses that have minimal effects on healthy individuals, resulting in alterations in the connectivity of brain networks broadly implicated in cognition.

In a new study, Kraguljac et al. add to this body of work by imaging ketamine-induced changes in both brain network connectivity (with resting-state functional magnetic resonance imaging) and metabolite concentrations (with magnetic resonance spectroscopy) in healthy individuals infused intravenously with ketamine. They found that ketamine reduced hippocampal connectivity and increased hippocampal glutamate levels and that the degree of hypoconnectivity was related to the degree of glutamate increase. Thus, these findings strengthen the link between glutamatergic neurotransmission, glutamate levels, and brain connectivity in a manner that supports a unified mechanistic model for schizophrenia. Despite this advance, several caveats are important to consider, including the lack of a placebo arm in this trial (blinding is difficult with ketamine due to its psychotropic effects), that intravenous ketamine affected the entire brain rather than discrete circuits, and that spectroscopy signals measured crude metabolite concentrations irrespective of their cellular location or function. Nonetheless, these findings show how work integrating diverse imaging modalities can shed light on the complex mechanisms underpinning diseases such as schizophrenia.

N. V. Kraguljac et al., Ketamine modulates hippocampal neurochemistry and functional connectivity: A combined magnetic resonance spectroscopy and resting-state fMRI study in healthy volunteers. Mol. Psychiatry 10.1038/mp.2016.122 (2016). [Abstract]

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