Kelei Xiao, Yealin Woo, Christine E Dri, Gia Han Le, Sabrina Wong, Kayla M Teopiz, Yang Jing Zheng, Heidi Ka Ying Lo, Folkert H van Bruggen, Taeho Greg Rhee, Stavroula Bargiota, Bing Cao, Roger Ho, Angela T H Kwan, Roger S McIntyre
The findings suggest ketamine and esketamine treatment are associated with improvements across several domains of objective cognitive performance, predominantly in uncontrolled or within-group analyses. The extent to which these changes represent direct procognitive effects independent of antidepressant response, practice effects, or comparator differences remains uncertain.
BACKGROUND: Cognitive impairment is a core feature of major depressive disorder (MDD) and bipolar disorder (BD). Most conventional antidepressants do not have direct and clinically relevant procognitive effects. Ketamine and esketamine are effective in treating treatment-resistant depression (TRD). Herein, this systematic review aims to evaluate the effects of both pharmacotherapeutics on cognitive measures in adults with MDD, BD and TRD.
METHODS: OVID databases were searched from inception until February 8, 2026. Clinical studies examining the cognitive effects of ketamine and esketamine were included. A systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Risk of bias was assessed with the Risk Of Bias In Non-randomized Studies-of Interventions, Version 2 (ROBINS-I V2) and the NHLBI's Quality Assessment of Controlled Intervention Studies.
RESULTS: 22 studies were included, with a total sample size of 2,441 participants. In randomized controlled trials (RCTs), adults with MDD undergoing single-dose ketamine 0.5 mg/kg or esketamine 0.25 mg/kg showed inconsistent effects on cognition, with improvements in some domains as well as null findings and reports of impaired memory recall and processing speed. In open-label studies, maintenance ketamine 0.5 mg/kg in adults with MDD or BD was associated with improvements in memory, attention, language, processing speed, and verbal learning, though these were within-group changes not controlled against a comparator.
CONCLUSION: The findings suggest ketamine and esketamine treatment are associated with improvements across several domains of objective cognitive performance, predominantly in uncontrolled or within-group analyses. The extent to which these changes represent direct procognitive effects independent of antidepressant response, practice effects, or comparator differences remains uncertain.