Can ketamine therapy overcome treatment-resistant depression in Alzheimer's disease and older adults? Preclinical and clinical evidence.
Altamura Mario, Leccisotti Ivana, Moretti Maria Claudia, Bellomo Antonello, Panza Francesco, Cassano Tommaso, Lozupone Madia
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie July 1, 2025 DOI: 10.1016/j.biopha.2025.118199 (opens in new tab)
The journal has published a correction to this paper. Read the correction (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Systematic review Peer reviewed |
|---|---|
| Population | Older adults with treatment-resistant depression, including those with Alzheimer's disease |
| Interventions | Ketamine Esketamine Arketamine |
| Topics | Depression Esketamine Ketamine |
| Keywords | Alzheimer’s disease Elderly population Late-life depression Nmda receptor antagonists Ketamine therapy Geriatric depression Alzheimer's disease Mental health interventions |
| Citations | 5 |
| Key findings | Ketamine and its derivatives show rapid and robust antidepressant effects in older adults with treatment-resistant depression and Alzheimer's disease. |
Abstract
Treatment-resistant depression (TRD) presents substantial clinical challenges, particularly in patients with Alzheimer's disease (AD) and older adults experiencing late-life depression. Traditional monoaminergic therapies often fail in this population due to neurodegenerative changes that impact receptor dynamics and neurotransmitter systems. Emerging evidence suggests that N-methyl-D-aspartate (NMDA) receptor antagonists, such as ketamine, esketamine, and arketamine, may offer new avenues for treatment. This review examines the potential of ketamine and its derivatives in treating TRD in older adults and individuals with AD, focusing on their mechanisms of action, clinical efficacy, and limitations in the context of neurodegenerative pathology. Following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, we conducted a systematic search of PubMed, Google Scholar, and Web of Science databases up until January 2025, with no year restrictions. Nineteen human clinical studies and eight preclinical studies met the inclusion criteria. Evidence suggests that ketamine may offer advantages over standard treatments for AD, potentially due to its broader mechanism of action compared to the NMDA antagonist memantine, as observed in animal models of AD. Clinical findings have demonstrated the rapid and robust antidepressant effects of ketamine and esketamine, alleviating depressive symptoms in both AD patients and older adults with TRD, indicating their potential as effective therapeutic options for these complex conditions.
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 |