Neural correlates of S-ketamine induced psychosis during overt continuous verbal fluency

The glutamatergic N-methyl-d-aspartate (NMDA) receptor has been implicated in the pathophysiology of schizophrenia. Administered to healthy volunteers, a subanesthetic dose of the non-competitive NMDA receptor antagonist ketamine leads to psychopathological symptoms similar to those observed in schizophrenia. In patients with schizophrenia, ketamine exacerbates the core symptoms of illness, supporting the hypothesis of a glutamatergic dysfunction.In a counterbalanced, placebo-controlled, double-blind study design, healthy subjects were administered a continuous subanesthetic S-ketamine infusion while differences in BOLD responses measured with fMRI were detected. During the scanning period, subjects performed continuous overt verbal fluency tasks (phonological, lexical and semantic). Ketamine-induced psychopathological symptoms were assessed with the Positive and Negative Syndrome Scale (PANSS).Ketamine elicited psychosis like psychopathology. Post-hoc t-tests revealed significant differences between placebo and ketamine for the amounts of words generated during lexical and semantic verbal fluency, while the phonological domain remained unaffected. Ketamine led to enhanced cortical activations in supramarginal and frontal brain regions for phonological and lexical verbal fluency, but not for semantic verbal fluency.Ketamine induces activation changes in healthy subjects similar to those observed in patients with schizophrenia, particularly in frontal and temporal brain regions. Our results provide further support for the hypothesis of an NMDA receptor dysfunction in the pathophysiology of schizophrenia.

Research Highlights►Subanesthetic administration of S-ketamine resulted in activation differences in frontal as well as in supramarginal regions. ►Similarities to patients with schizophrenia were found on the level of psychopathological abnormalities, on the levels of task performance, and reduced as well as increased brain activations in frontal cortical areas. ►Combined, the results of previous ketamine studies in humans as well as in rodents, the disinhibition of glutamatergic activity is of significant interest due to the potential relevance to psychosis and concomitant cognitive impairments found in patients with schizophrenia. ►Results provide further support for the hypothesis of an NMDA receptor dysfunction being involved in the pathophysiology of schizophrenia.