The present investigation studied the influence of the two hallucinogens N
-DMT and S
-ketamine on the generation of MMN and performance in an AX-CPT. Overall, the intensity of the hallucinogenic effects of both drugs was similar; however, phenomena that resemble positive symptoms of schizophrenia were more pronounced after DMT intake, and phenomena that resemble negative and catatonic symptoms of schizophrenia were clearly more pronounced after S
-ketamine intake (Gouzoulis-Mayfrank et al. 2005
). Taken together, these results are in line with the assumption that the two classes of drugs tend to model different aspects of psychoses. The NMDA antagonist state (S
-ketamine) may be an appropriate model for psychoses with prominent negative and possibly also catatonic features, while the 5-HT2A
agonist state (DMT) may be a better model for psychoses with prominent positive symptoms (Abi-Saab et al. 1998
; Gouzoulis-Mayfrank et al. 2005
Inspection of the descriptive data suggests a decrease in the generation of MMN under both substances. However, this effect was more pronounced after S-ketamine. The analyses of the grand average data showed that the MMN to the duration deviant was significantly reduced by S-ketamine. Moreover, there was a trend reduction for the frequency-deviant-induced MMN. According to the source analyses, S-ketamine reduced the duration-deviant MMN activity of the temporal (S1, S2, S3) and the frontal sources (S4). Regarding the frequency-deviant stimuli, the effect of S-ketamine was somewhat weaker: We found only a marginal MMN reduction at one temporal source (S3) and at the frontal source (S4). Nevertheless, the difference between frequency- and duration-deviant MMN did not reach statistical significance. The activity of the frontal source was only affected by S-ketamine and not by DMT. S-Ketamine had no effect on the N1 amplitude; therefore, the reduction in MMN by S-ketamine was not caused by a general weakening of ERP activity.
Our findings regarding the NMDA antagonist S
-ketamine are in line with the observation that MMN deficits in schizophrenia are more pronounced to duration deviants than to frequency-deviant stimuli (Michie et al. 2000
). A recent study also found a reduction in MMN to duration but not to frequency deviants in patients with schizophrenia and a short length of illness (Todd et al. 2008
). Remarkably, in the same study, patients with a longer length of illness showed a stronger reduction to frequency compared to duration deviants. The authors interpreted their findings as a result of a pronounced age-related decline in duration-deviant MMN in the healthy control group (Todd et al. 2008
). Baldeweg et al. (2002
) found a pronounced reduction in MMN at frontocentral electrodes in patients with schizophrenia in the presence of normal activity at mastoid electrodes and concluded that the frontal generators of MMN may be preferentially affected in schizophrenia. However, our descriptive data suggest that S
-ketamine affected the frontal and temporal sources of MMN generation. Since magnetoencephalography (MEG) predominantly detects the temporal sources of MMN generation (Rinne et al. 2000
; Rosburg et al. 2004
), the MEG findings of reduced MMN activity in schizophrenia (Kreitschmann-Andermahr et al. 1999
; Pekkonen et al. 2002
) also support the involvement of temporal sources in reduced MMN activity in patients with schizophrenia. The detection of frontal sources only in EEG and not in MEG recordings is in line with the assumption that these sources are either predominantly radial in orientation or located deeply in the brain (Rinne et al. 2000
; Waberski et al. 2001
). Nevertheless, even though several studies support a frontal lobe involvement in MMN generation (for a review, see Näätänen et al. 2007
), we cannot exclude that the frontal source is simply an artifact due to the inverse problem of source analyses.
The lack of influence on peak amplitude and latency of N1 and the predominant reduction in MMN activity after duration deviants in the NMDA antagonist model of psychosis are in line with observations in schizophrenic patients. It is noteworthy that recent studies reported an association between MMN deficits and poor functioning in schizophrenia (Light and Braff 2005a
). These reports are in line with the psychological findings in our study, which suggest that the NMDA antagonist state (S
-ketamine) is an appropriate model for psychoses with prominent negative symptoms (Gouzoulis-Mayfrank et al. 2005
). Furthermore, two studies that investigated first-episode patients failed to find alterations in MMN activity (Salisbury et al. 2002
; Umbricht et al. 2006
). These findings suggest that the MMN impairment may develop in the ongoing course of the schizophrenic disorder. Hence, in terms of our model, the S
-ketamine state may resemble not only the negative syndrome but also the more advanced stages of schizophrenia.
-ketamine, the 5HT2A
agonist DMT reduced the N1 peak amplitude. This finding is in line with the increase of the N1 amplitude after treatment with 5HT2A
antagonists (Juckel et al. 2003
). On the basis of the grand average data, DMT had no significant effect on MMN activity. However, regarding the sources of MMN, DMT diminished the MMN activity to frequency-deviant stimuli at the two right hemispheric sources (S1 and S3). Noteworthy, Umbricht et al. (2003a
) also found a significant reduction in the N1 amplitude and a stronger effect on MMN to frequency compared to duration deviants after administration of the 5HT2A
agonist hallucinogen psilocybin. However, we cannot exclude that the changes in MMN activity under DMT are confounded by the significant reduction in the N1 amplitude.
Both drugs led to higher missing and error rates, particularly for “BX” errors, in the AX-CPT. Javitt et al. (2000
) reported a similar AX-CPT response pattern in patients with schizophrenia (Javitt et al. 2000
). This is in line with an impairment in the use of contextual information, as indicated by a selective deficit in the ability of schizophrenia patients to inhibit responses to targets following presentation of incorrect no-go cues (Cohen et al. 1999
). Hence, in terms of the context-dependent visual information processing at an attention-dependent level, both models of psychosis seem to match previous findings with schizophrenia patients.
It must be acknowledged that our study has methodological limitations mainly due to the absence of a blinded placebo condition and the small sample sizes for completers, which limited the statistical power. These limitations and the rationale for our study design were discussed in detail in our previous publications (Gouzoulis-Mayfrank et al. 2005
). Taken together, although methodological caveats have to be taken into account, the data from the present study suggest that the NDMA antagonist and the 5HT2A
agonist models of psychosis share common features regarding both automatic and conscious attentional mechanisms. However, in terms of the automatic acoustic MMN generation, the NMDA antagonist model of psychosis appears to be more close to the findings in schizophrenia, whereas in terms of the visual context-dependent AX-CPT, both drugs lead to a performance deficit pattern, which comes close to previous findings in schizophrenic patients.