Cognitive Effects of Esketamine in Treatment-Resistant Depression: A Systematic Review.
Riccardo Guglielmo, Emma Laura Facchinetti, Daniele Cioci, Miriam Olivola, Beatriz Pereira da Silva, Alessandra Mazzocchi, Bernardo Dell'Osso, Mario Amore, Gianluca Serafini
Journal of Clinical Psychopharmacology March 24, 2026 DOI: 10.1097/jcp.0000000000002165 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Systematic review Longitudinal Peer reviewed |
|---|---|
| Population | Adults aged 18 to 80 with treatment-resistant depression |
| Intervention | intranasal or intravenous esketamine |
| Duration | Cognitive assessments performed at least 1 month after treatment initiation |
| Topics | Depression Esketamine |
| Keywords | Cognition Executive functions Memory |
| Key findings | Esketamine appears cognitively safe in adults with treatment-resistant depression and may improve attention and processing speed, with more variable benefits in memory and executive functioning over sustained treatment. |
Abstract
Treatment-resistant depression affects up to one third of patients with major depressive disorder and is frequently accompanied by persistent cognitive impairments that significantly hinder functional recovery. Emerging evidence suggests that sub-anesthetic esketamine does not appear to be associated with cognitive deterioration and may be associated with procognitive effects; however, no systematic review has specifically synthesized cognitive outcomes in this population. A systematic search was conducted. Eligible studies included adults aged 18 to 80 years receiving intranasal or intravenous esketamine, with cognitive assessments performed at least 1 month after treatment initiation. Six studies met the inclusion criteria. Cognitive outcomes were grouped into attention/processing speed, memory, and executive functions. Across studies, available evidence suggests that esketamine does not appear to be associated with cognitive deterioration in any assessed domain. Improvements in attention and processing speed were the most frequent and robust findings, observed in both RCT-derived datasets and naturalistic longitudinal studies. Memory remained stable in short-term designs but improved in studies with extended follow-up. Executive functions showed gains primarily among participants with baseline impairments and in long-term assessments. All remaining evaluations indicated cognitive stability. Current evidence, albeit limited, suggests that esketamine appears to be cognitively safe in adults with treatment-resistant depression and may confer selective improvements, particularly in attention and processing speed, with more variable benefits in memory and executive functioning over sustained treatment. These effects may support functional recovery and complement esketamine's antidepressant action. Further research using harmonized cognitive batteries, larger samples, and longer follow-up periods is needed to better characterize cognitive trajectories and their relevance for personalized treatment strategies.
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 |