In healthy volunteers, the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine significantly reduced the amplitude of mismatch negativity (MMN) brain responses to pitch and duration changes by 27% and 21%, respectively. Ketamine also impaired performance on a continuous performance test, decreasing hit rates and increasing specific context-dependent errors (BX errors), indicating a failure to form and use transient memory traces. These findings suggest that NMDARs are critically involved in generating MMN and that NMDAR dysfunction may underlie deficits in transient memory at different levels of information processing in schizophrenia.
The NMDA receptor antagonist ketamine disrupts auditory mismatch negativity (MMN) and performance on an AX-type continuous performance test (AX-CPT), similar to deficits seen in schizophrenia. This placebo-controlled study tested the 5-HT(2A) receptor agonist psilocybin on the same measures in 18 healthy volunteers. Psilocybin caused significant performance deficits on the AX-CPT but did not significantly reduce MMN generation. These results suggest that deficient MMN generation in schizophrenia may specifically reflect NMDA receptor dysfunction, while impairments in AX-CPT performance during both psilocybin and ketamine administration may stem from shared disruption of glutamatergic neurotransmission. Comparable deficits in schizophrenia may arise from independent dysfunctions of 5-HT(2A) and NMDA receptor-related neurotransmission.