Psychopharmacology (2008) 199:77–88 DOI 10.1007/s00213-008-1129-4 ORIGINAL INVESTIGATION Mismatch negativity generation in the human 5HT2A agonist and NMDA antagonist model of psychosis Karsten Heekeren & Jörg Daumann & Anna Neukirch & Carsten Stock & Wolfram Kawohl & Christine Norra & Till D. Waberski & Euphrosyne Gouzoulis-Mayfrank Received: 22 July 2007 / Accepted: 27 February 2008 / Published online: 18 May 2008 # The Author(s) 2008 Abstract 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 intra- individual crossover design. K. Heekeren : J. Daumann : A. Neukirch : E. Gouzoulis-Mayfrank (*) Department of Psychiatry and Psychotherapy, University of Cologne, Kerpener Strasse 62, 50924 Cologne, Germany e-mail: e.gouzoulis@uni-koeln.de C. Stock Department of Psychiatry and Psychotherapy, University of Technology Aachen (RWTH), Pauwelsstrasse 30, 52074 Aachen, Germany K. Heekeren : W. Kawohl Psychiatric University Hospital, Lenggstrasse 31, 8032 Zurich, Switzerland C. Norra Max-Planck-lnstitute for Experimental Medicine, Göttingen, Germany T. D. Waberski Department of Neurology, University of Technology Aachen (RWTH), Pauwelsstrasse 30, 52074 Aachen, Germany 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 electroen- cephalographic 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. Keywords Mismatch negativity . Model psychosis . Dimethyltryptamine . S-Ketamine Introduction Disturbances of both automatic and controlled mechanisms of information processing and attention are core symptoms of schizophrenia, and recordings of event-related potentials are commonly used to investigate them. Apart from the well-documented deficits of P300 (Pfefferbaum et al. 1989; Winterer et al. 2003), which reflect conscious attention to expected salient stimuli, several studies demonstrated impairments of the mismatch negativity (MMN), which is