Ketamine and Esketamine for Late-Life Depression: A Systematic Review of Efficacy, Safety, and Tolerability.
Ronesh Sukhdeo, Jocelyn K. Tamura, Christine E. Dri, Roger S McIntyre
American Journal of Geriatric Psychiatry August 1, 2025 DOI: 10.1016/j.jagp.2025.08.001 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Systematic review Open-label Peer reviewed |
|---|---|
| Sample size | 757 |
| Population | Adults aged 60 years and older with major depression |
| Interventions | Ketamine ketamine combined with ECT |
| Topics | Depression Esketamine Ketamine |
| Key findings | Across 13 prospective trials (757 adults aged 60+), antidepressant effects of ketamine were mixed: some studies showed symptomatic improvement, but not all reported positive outcomes. Adverse events were generally mild to moderate and rarely led to discontinuation, and cognitive outcomes were mostly stable or improved, with small long-term declines in reaction time. Ketamine used as an ECT anesthetic did not enhance antidepressant outcomes. The authors rate evidence certainty as very low to low. |
Abstract
Ketamine has emerged as a promising treatment for major depression, though its efficacy and safety remain incompletely characterized in older adults. This systematic review synthesizes current evidence for ketamine in geriatric depression. A search of PubMed, EMBASE, and PsycINFO was conducted. Prospective clinical trials were included, with age restriction to participants ≥60 years applied at full-text review to capture subgroup data. Thirteen studies met inclusion criteria, comprising 757 adults. Studies examined intranasal (n = 5), intravenous (n = 4), subcutaneous (n = 1), and oral (n = 1) ketamine formulations, as well as ketamine combined with ECT (n = 2). Antidepressant efficacy findings were mixed; with preliminary findings of symptomatic improvement in this difficult to treat disease state, although not all studies reported out positive outcomes.. Adverse events were generally mild to moderate and discontinuation due to side effects was rare. Cognitive outcomes were mostly stable or improved, though long-term studies noted small declines in reaction time. Ketamine as an ECT anesthetic did not enhance antidepressant outcomes. Evidence certainty was very low to low; findings were limited by small samples, open-label designs, and inconsistent age-stratified reporting.
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
Cited by 2
- KET-MCI: A Pilot Safety and Tolerability Study of Single Infusion Intravenous Ketamine for Older Adults with Depression and Mild Cognitive Impairment American Journal of Geriatric Psychiatry February 24, 2026
- Cognitive effects of ketamine and esketamine treatment for major depressive and bipolar disorder: a systematic review. Psychiatry Research September 14, 2026
Cites 17
- Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study American Journal of Psychiatry May 21, 2019
- 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
- Ketamine for rapid reduction of suicidal thoughts in major depression: a midazolam-controlled randomized clinical trial American Journal of Psychiatry December 5, 2017
- Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression The Journal of Clinical Psychiatry April 20, 2020
- The effect of intravenous, intranasal, and oral ketamine in mood disorders: A meta-analysis. Journal of Affective Disorders November 1, 2020
and 12 more in the library