Effects of NMDA-receptor blockade by ketamine on mentalizing and its neural correlates in humans: a randomized control trial

Abstract

Schizophrenia is associated with various deficits in social cognition that remain relatively unaltered by antipsychotic treatment. While faulty glutamate signaling has been associated with general cognitive deficits as well as negative symptoms of schizophrenia, no direct link between manipulation of glutamate signaling and deficits in mentalizing has been demonstrated thus far. Here, we experimentally investigated whether ketamine, an uncompetitive N-methyl-D-aspartate receptor antagonist known to induce psychotomimetic effects, influences mentalizing and its neural correlates. In a randomized, placebo-controlled between-subjects experiment, we intravenously administered ketamine or placebo to healthy participants performing a video-based social cognition task during functional magnetic resonance imaging. Psychotomimetic effects of ketamine were assessed using the Positive and Negative Syndrome Scale. Compared to placebo, ketamine led to significantly more psychotic symptoms and reduced mentalizing performance (more “no mentalizing” errors). Ketamine also influenced blood oxygen level dependent (BOLD) response during mentalizing compared to placebo. Specifically, ketamine increased BOLD in right posterior superior temporal sulcus (pSTS) and increased connectivity between pSTS and anterior precuneus. These increases may reflect a dysfunctional shift of attention induced by ketamine that leads to mentalizing deficits. Our findings show that a psychotomimetic dose of ketamine impairs mentalizing and influences its neural correlates, a result compatible with the notion that deficient glutamate signaling may contribute to deficits in mentalizing in schizophrenia. The results also support efforts to seek novel psychopharmacological treatments for psychosis and schizophrenia targeting glutamatergic transmission.

Identifying drug targets for schizophrenia through gene prioritization

“…We prioritized GRIN2A, which encodes a subunit of the N-methyl-D-aspartate receptor (NMDA-R, Figure 3B). In addition to GWAS, there is evidence that decreased NMDA-R function increases schizophrenia risk from GRIN2A ultra-rare variant burden tests 24 , GRIN2A mouse knockout models 45 , and pharmacological antagonism of the NMDA-R 46 . This raises the possibility that increasing NMDA-R activity may provide therapeutic benefit for schizophrenia patients.…”