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

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.

Ketamine increases fronto-posterior functional connectivity during meta-perceptual confidence ratings.

Recent advances in the neuropsychopharmacology of metacognition indicate a constituent role of glutamate for the integrity of metamnestic processes. However, the extent to which previous results can be generalized across functional domains to characterize the relationship between glutamate and metacognition remains unclear. Here, in a randomized, double-blind, placebo-controlled, preregistered fMRI study, we tested the effects of a psychotomimetic dose (target plasma concentration 100 ng/mL) of the N-methyl-D-aspartate (NMDA) glutamate receptor antagonist ketamine on metacognition in a perceptual decision-making framework. We collected trial-by-trial metacognitive reports as participants performed a two-alternative forced-choice perceptual task during functional magnetic resonance imaging (fMRI). Results indicated ketamine-induced deterioration in metacognitive performance, whereas no significant effects were observed for perceptual performance, response times and - unexpectedly - metacognitive bias. Whilst there were no detectable ketamine effects on mean BOLD activation, exploratory psychophysiological interaction (PPI) analysis revealed alterations in functional connectivity during metacognitive confidence ratings under ketamine. Specifically, there was increased task-specific connectivity for ketamine compared to placebo between right anterior dorsolateral prefrontal cortex and left middle temporal, supramarginal and precentral gyrus, as well as between right insula/inferior frontal gyrus and left lingual gyrus, possibly indicating re-representations of object-level features supplied for metacognitive evaluations. Overall, these findings contribute towards the emerging picture of the substructures underlying metacognitive operations at the neurotransmitter level and may shed light on a neural pattern characteristic of pharmacologically challenged metacognition.

Effects of ketamine on brain function during metacognition of episodic memory.

Only little research has been conducted on the pharmacological underpinnings of metacognition. Here, we tested the modulatory effects of a single intravenous dose (100 ng/ml) of the N-methyl-D-aspartate-glutamate-receptor antagonist ketamine, a compound known to induce altered states of consciousness, on metacognition and its neural correlates. Fifty-three young, healthy adults completed two study phases of an episodic memory task involving both encoding and retrieval in a double-blind, placebo-controlled fMRI study. Trial-by-trial confidence ratings were collected during retrieval. Effects on the subjective state of consciousness were assessed using the 5D-ASC questionnaire. Confirming that the drug elicited a psychedelic state, there were effects of ketamine on all 5D-ASC scales. Acute ketamine administration during retrieval had deleterious effects on metacognitive sensitivity (meta-d') and led to larger metacognitive bias, with retrieval performance (d') and reaction times remaining unaffected. However, there was no ketamine effect on metacognitive efficiency (meta-d'/d'). Measures of the BOLD signal revealed that ketamine compared to placebo elicited higher activation of posterior cortical brain areas, including superior and inferior parietal lobe, calcarine gyrus, and lingual gyrus, albeit not specific to metacognitive confidence ratings. Ketamine administered during encoding did not significantly affect performance or brain activation. Overall, our findings suggest that ketamine impacts metacognition, leading to significantly larger metacognitive bias and deterioration of metacognitive sensitivity as well as unspecific activation increases in posterior hot zone areas of the neural correlates of consciousness.

Multimodal prevention of first psychotic episode through N-acetyl-l-cysteine and integrated preventive psychological intervention in individuals clinically at high risk for psychosis: Protocol of a randomized, placebo-controlled, parallel-group trial.

AIM: Meta-analyses indicate positive effects of both antipsychotic and cognitive-behavioural interventions in subjects clinically at high risk (CHR) for psychosis in terms of a delay or prevention of psychotic disorders. However, these effects have been limited regarding social functioning and the relative efficacy of both types of interventions remains unclear. Furthermore, neuroprotective substances seem to be a promising alternative agent in psychosis-prevention as they are associated with few and weak side-effects. METHODS: In this multi-centre randomized controlled trial (RCT), we investigate the effects of two interventions on transition to psychosis and social functioning: (a) an integrated preventive psychological intervention (IPPI) including stress-/symptom-management and social-cognitive remediation; (b) N-acetyl-l-cysteine (NAC) as a pharmacological intervention with glutamatergic, neuroprotective and anti-inflammatory capabilities. RESULTS: This is a double-blind, placebo-controlled RCT with regard to NAC and a single-blind RCT with regard to IPPI using a 2 × 2-factorial design to investigate the individual and combined preventive effects of both interventions. To this aim, a total of 200 CHR subjects will be randomized stratified by site to one of four conditions: (a) IPPI and NAC; (b) IPPI and Placebo; (c) NAC and psychological stress management; (d) Placebo and psychological stress management. Interventions are delivered over 26 weeks with a follow-up period of 12 months. CONCLUSION: This paper reports on the rationale and protocol of an indicated prevention trial to detect the most effective and tolerable interventions with regard to transition to psychosis as well as improvements in social functioning, and to evaluate the synergistic effects of these interventions.