Attenuation of antidepressant and antisuicidal effects of ketamine by opioid receptor antagonism

Introduction

Suicide rates have risen in the United States over recent decades and suicide is now a leading cause of death in younger age groups, creating an urgent need for rapid-acting interventions to reduce suicidal thinking and behaviour. Ketamine, administered intravenously (racemic) or intranasally as esketamine, produces rapid reductions in suicidal ideation within hours that can last days to a week, and its clinical effects have commonly been attributed to antagonism of the N-methyl-D-aspartate receptor (NMDAR). However, emerging evidence implicates the endogenous opioid system in mood regulation and suicidality, and recent work by the study team found that ketamine’s antidepressant effect in humans depends on opioid receptor activation. Against this background, Williams and colleagues tested whether opioid receptor blockade with oral naltrexone attenuates ketamine’s antisuicidality effects. The investigation reported here is a post hoc secondary analysis of a previously completed randomised, double-blind, placebo-controlled crossover trial in which participants received oral naltrexone (50 mg) or placebo prior to a standard 0.5 mg/kg intravenous ketamine infusion. Suicidality was assessed with HDRS-17 item 3, MADRS item 10, and the Columbia Suicide Severity Rating Scale (CSSRS), and the primary contrast for this analysis focused on ketamine responders (defined as >50% reduction in HDRS-17 on postinfusion day 1).