Cognitive effects of ketamine and esketamine treatment for major depressive and bipolar disorder: a systematic review.
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
Psychiatry Research September 14, 2026 DOI: 10.1016/j.psychres.2026.117456 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Systematic review Randomized Open-label Peer reviewed |
|---|---|
| Sample size | 2,441 |
| Population | Adults with major depressive disorder, bipolar disorder, or treatment-resistant depression |
| Interventions | Ketamine Esketamine |
| Dose | ketamine 0.5 mg/kg, esketamine 0.25 mg/kg |
| Topics | Depression Esketamine Ketamine |
| Keywords | Bipolar disorder Cognition |
| Key findings | In randomized controlled trials, single-dose ketamine 0.5 mg/kg or esketamine 0.25 mg/kg showed inconsistent cognitive effects in adults with major depressive disorder, with some domain improvements, null findings, and reports of impaired memory recall and processing speed. Open-label maintenance ketamine was associated with within-group improvements in memory, attention, language, processing speed, and verbal learning, but the authors note it remains uncertain whether these reflect direct procognitive effects independent of antidepressant response, practice effects, or comparator differences. |
Abstract
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. 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. 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. 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.
In the evidence
This study is part of the evidence base for a synthesis in the library. Here is how each one recorded it.
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Single-dose ketamine or esketamine showed inconsistent cognitive effects in randomized trials, with some domain improvements, null findings, and reports of impaired memory recall and processing speed.
Synthesized
Comparable studies
Other systematic reviews and meta-analyses on esketamine for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Comparative efficacy of racemic ketamine and esketamine for depression: a systematic review and meta-analysis Adults with unipolar or bipolar major depression | 2020 | Systematic review and meta-analysis | n = 1,877 |
| The acute antisuicidal effects of single-dose intravenous ketamine and intranasal esketamine in individuals with major depression and bipolar disorders: A systematic review and meta-analysis. Participants in randomized controlled trials of ketamine for suicidal ideation | 2020 | Systematic review and meta-analysis | n = 197 |
| Efficacy of Esketamine Augmentation in Major Depressive Disorder Patients with major depressive disorder who are treatment-resistant or acutely suicidal | 2020 | Systematic review and meta-analysis | n = 774 |
| Esketamine Treatment for Depression in Adults: A PRISMA Systematic Review and Meta-Analysis. Patients with treatment-resistant major depressive disorder | 2025 | Systematic review and meta-analysis | |
| EFFICACY AND SAFETY OF RACEMIC KETAMINE AND ESKETAMINE FOR DEPRESSION: A SYSTEMATIC REVIEW AND META-ANALYSIS Adults with unipolar or bipolar major depression | 2022 | Systematic review and meta-analysis | n = 2,903 |
Citations in the library
Cites 25
- Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation American Journal of Psychiatry March 17, 2021
- The Effects of Ketamine on Cognition in Treatment-Resistant Depression: A Systematic Review and Priority Avenues for Future Research. Neuroscience & Biobehavioral Reviews November 23, 2020
- Brain Changes Associated With Long-Term Ketamine Abuse, A Systematic Review Frontiers in Neuroanatomy March 18, 2022
- Neurocognitive effects of six ketamine infusions and the association with antidepressant response in patients with unipolar and bipolar depression Journal of Psychopharmacology September 27, 2018
- Glutamatergic Modulators for Major Depression from Theory to Clinical Use. CNS Drugs November 1, 2024
and 20 more in the library