No abstract

The present study suggests that the NMDA antagonist model of psychosis is not overall superior to the serotonin 5-HT2A agonist model. Rather, the two classes of drugs tend to model different aspects or types of schizophrenia. The NMDA antagonist state may be an appropriate model for psychoses with prominent negative and possibly also catatonic features, while the 5-HT2A agonist state may be a better model for psychoses of the paranoid type.

This prognostic study evaluates whether psychosis transition can be predicted in patients with clinical high-risk syndromes or recent-onset depression by multimodal machine learning that optimally integrates clinical and neurocognitive data, structural magnetic resonance imaging, and polygenic risk scores for schizophrenia.

The task-positive network (TPN) is anticorrelated with activity in the default mode network (DMN), and possibly reflects competition between the processing of external and internal information, while the salience network (SN) is pivotal in regulating TPN and DMN activity. Because abnormal functional connectivity in these networks has been related to schizophrenia, we tested whether alterations are also evident in subjects at risk for psychosis. Resting-state functional magnetic resonance imaging was tested in 28 subjects with basic symptoms reporting subjective cognitive-perceptive symptoms; 19 with attenuated or brief, limited psychotic symptoms; and 29 matched healthy controls. We characterized spatial differences in connectivity patterns, as well as internetwork connectivity. Right anterior insula (rAI) was selected as seed region for identifying the SN; medioprefrontal cortex (MPFC) for the DMN and TPN. The 3 groups differed in connectivity patterns between the MPFC and right dorsolateral prefrontal cortex (rDLPFC), and between the rAI and posterior cingulate cortex (PCC). In particular, the typically observed antagonistic relationship in MPFC-rDLPFC, rAI-PCC, and internetwork connectivity of DMN-TPN was absent in both at-risk groups. Notably, those connectivity patterns were associated with symptoms related to reality distortions, whereas enhanced connectivity strengths of MPFC-rDLPFC and TPN-DMN were related to poor performance in cognitive functions. We propose that the loss of a TPN-DMN anticorrelation, accompanied by an aberrant spatial extent in the DMN, TPN, and SN in the psychosis risk state, reflects the confusion of internally and externally focused states and disturbance of cognition, as seen in psychotic disorders.

RationaleMany studies have reported deficits of mismatch negativity (MMN) in schizophrenic patients. Pharmacological challenges with hallucinogens in healthy humans are used as models for psychotic states. Previous studies reported a significant reduction of MMN after ketamine (N-methyl-d-aspartate acid [NMDA] antagonist model) but not after psilocybin (5HT2A agonist model).ObjectivesThe aim of the present study was to directly compare the two models of psychosis using an intraindividual crossover design.Materials and methodsFifteen healthy subjects participated in a randomized, double-blind, crossover study with a low and a high dose of the 5HT2A agonist dimethyltryptamine (DMT) and the NMDA antagonist S-ketamine. During electroencephalographic recording, the subjects were performing the AX-version of a continuous performance test (AX-CPT). A source analysis of MMN was performed on the basis of a four-source model of MMN generation.ResultsNine subjects completed both experimental days with the two doses of both drugs. Overall, we found blunted MMN and performance deficits in the AX-CPT after both drugs. However, the reduction in MMN activity was overall more pronounced after S-ketamine intake, and only S-ketamine had a significant impact on the frontal source of MMN.ConclusionsThe NDMA antagonist model and the 5HT2A agonist model of psychosis display distinct neurocognitive profiles. These findings are in line with the view of the two classes of hallucinogens modeling different aspects of psychosis.