Neurocognitive aspects of ketamine and esketamine on subjects with treatment-resistant depression: A comparative, randomized and double-blind study

Introduction

Major Depressive Disorder (MDD) is highly prevalent and often accompanied by cognitive impairments in domains such as executive functioning, attention, memory, verbal fluency and visual learning. A substantial proportion of patients—commonly termed treatment-resistant depression (TRD)—do not respond to standard monoaminergic antidepressants, and both ketamine (racemic mixture) and its S-enantiomer esketamine have emerged as rapid-acting treatments that can produce response or remission within 24–72 hours. Despite clinical efficacy at subanesthetic doses, concerns remain about their cognitive effects because higher, anaesthetic or recreational doses of ketamine produce cognitive deficits; the literature on cognitive outcomes at antidepressant doses is mixed, with studies reporting no impairment and some reporting improvements in specific domains such as visual memory, processing speed and verbal learning. Araújo-De-Freitas and colleagues set out to fill a gap in the literature by directly comparing the cognitive effects of intravenous ketamine and esketamine in patients with TRD. The study reports neuropsychological outcomes collected before and after a single infusion of either drug, testing whether cognitive trajectories differ between the two treatments and whether, when pooled, these drugs affect cognition across a one-week follow-up period. The cognitive evaluation was a secondary outcome of a larger randomised, double-blind, active-controlled, bicentric non-inferiority trial of antidepressant efficacy.