Effects of the 5-HT2A Agonist Psilocybin on Mismatch Negativity Generation and AX-Continuous Performance Task: Implications for the Neuropharmacology of Cognitive Deficits 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.

Study at a glance

Abstract

Previously the NMDA (N-methyl-D-aspartate) receptor (NMDAR) antagonist ketamine was shown to disrupt generation of the auditory event-related potential (ERP) mismatch negativity (MMN) and the performance of an 'AX'-type continuous performance test (AX-CPT)--measures of auditory and visual context-dependent information processing--in a similar manner as observed in schizophrenia. This placebo-controlled study investigated effects of the 5-HT(2A) receptor agonist psilocybin on the same measures in 18 healthy volunteers. Psilocybin administration induced significant performance deficits in the AX-CPT, but failed to reduce MMN generation significantly. These results indirectly support evidence that deficient MMN generation in schizophrenia may be a relatively distinct manifestation of deficient NMDAR functioning. In contrast, secondary pharmacological effects shared by NMDAR antagonists and the 5-HT(2A) agonist (ie disruption of glutamatergic neurotransmission) may be the mechanism underlying impairments in AX-CPT performance observed during both psilocybin and ketamine administration. Comparable deficits in schizophrenia may result from independent dysfunctions of 5-HT(2A) and NMDAR-related neurotransmission.