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Mismatch negativity generation in the human 5HT2A agonist and NMDA antagonist model of psychosis
Karsten Heekeren1, Jörg Daumann, Anna Neukirch
1Department of Psychiatry and Psychotherapy, University of Cologne, Kerpener Strasse 62, 50924, Cologne, Germany.
Rationale:
Many 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).
Objectives:
The aim of the present study was to directly compare the two models of psychosis using an intraindividual crossover design.
Materials And Methods:
Fifteen 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.
Results:
Nine 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.
Conclusions:
The 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.
Insights
Both S-ketamine (NMDA antagonist) and dimethyltryptamine (5HT2A agonist) impaired mismatch negativity (MMN) and performance. S-ketamine showed a more pronounced MMN reduction, particularly affecting frontal brain activity.
Area of Science:
- Neuroscience
- Psychopharmacology
- Cognitive Science
Background:
- Schizophrenia is associated with deficits in mismatch negativity (MMN).
- Pharmacological agents like ketamine (NMDA antagonist) and psilocybin (5HT2A agonist) are used to model psychosis in healthy individuals.
- Previous research indicated MMN reduction with ketamine but not psilocybin.
Purpose of the Study:
- To directly compare the effects of NMDA antagonist (S-ketamine) and 5HT2A agonist (dimethyltryptamine) on MMN and cognitive performance.
- To investigate distinct neurocognitive profiles of these two models of psychosis using an intraindividual crossover design.
Main Methods:
- A randomized, double-blind, crossover study involving 15 healthy subjects.
- Administration of low and high doses of S-ketamine and dimethyltryptamine (DMT).
- Electroencephalographic (EEG) recording during the AX-continuous performance test (AX-CPT) with source analysis of MMN.
Main Results:
- Nine subjects completed the study.
- Both S-ketamine and DMT blunted MMN and impaired AX-CPT performance.
- S-ketamine caused a more significant reduction in overall MMN activity and specifically impacted the frontal MMN source.
Conclusions:
- NMDA antagonist and 5HT2A agonist models of psychosis exhibit distinct neurocognitive effects.
- These findings support the hypothesis that different classes of hallucinogens model different facets of psychosis.
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