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

Introduction

Neurocognitive impairments are a core feature of schizophrenia and include both higher-order deficits (attention, executive function, working memory) and more basic sensory memory impairments. Umbricht and colleagues describe mismatch negativity (MMN) as an auditory event-related potential (ERP) that indexes echoic sensory memory and context-sensitive preattentive processing, and note that MMN is reduced in most studies of schizophrenia. They contrast MMN with performance on an AX-type continuous performance task (AX-CPT), which taxes use of contextual information and is sensitive to prefrontal dysfunction; schizophrenic patients characteristically make excess BX errors, reflecting failure to use preceding cues to inhibit a prepotent response to a target stimulus. Against this background, previous pharmacological work has implicated NMDA receptor (NMDAR) dysfunction in both MMN and AX-CPT abnormalities: NMDAR antagonists such as ketamine reduce MMN and produce AX-CPT deficits in healthy volunteers that resemble schizophrenia. At the same time, evidence suggests that 5-HT2A receptor dysfunction may contribute to psychotic and cognitive phenomena, because 5-HT2A agonists (for example psilocybin) induce psychotomimetic effects and impair some cognitive functions. The present study therefore set out to test whether psilocybin (a 5-HT2A agonist) affects MMN generation, sensory ERPs and AX-CPT performance in healthy volunteers using the same procedures used previously with ketamine, with the aim of clarifying whether 5-HT2A-related neurotransmission contributes to the deficits observed in schizophrenia and whether shared downstream effects (for example on glutamate or dopamine systems) could account for overlapping cognitive impairments.