Acute effects of ketamine and esketamine on cognition in healthy subjects: A meta-analysis

Introduction

Ketamine is a dissociative anaesthetic with emerging therapeutic applications in pain and depressive disorders, but it is also associated with psychiatric and cognitive adverse effects. Earlier experimental and non-placebo-controlled studies reported ketamine-related impairments in memory, learning and attention, and more recent placebo-controlled work has documented deficits in executive and sensorimotor functions. Ketamine acts primarily as an NMDA receptor antagonist; its two enantiomers, (S)-ketamine and (R)-ketamine, differ in NMDA binding affinity. Prior literature suggested that cognitive effects vary with dose and resultant plasma concentrations, and that sex and age might also modulate pharmacokinetics and cognitive vulnerability, but a quantitative synthesis across domains and moderating variables had not been conducted. Zhornitsky and colleagues set out to fill this gap by performing a multivariate meta-analysis of placebo-controlled experimental studies in healthy volunteers to quantify acute ketamine-induced cognitive changes across eleven predefined cognitive domains. The study also aimed to examine whether enantiomer type, route of administration, plasma level, infusion dose, sex composition and mean age of samples moderated cognitive effects, thereby informing the immediate cognitive risks associated with ketamine in controlled settings.