Can ketamine therapy overcome treatment-resistant depression in Alzheimer's disease and older adults? Preclinical and clinical evidence.

Ketamine and its derivatives, esketamine and arketamine, may provide rapid and robust antidepressant effects for older adults with treatment-resistant depression, including those with Alzheimer's disease. A systematic review of 19 human clinical studies and 8 preclinical studies found that these NMDA receptor antagonists can alleviate depressive symptoms in this population, potentially offering advantages over standard treatments like memantine due to a broader mechanism of action. However, neurodegenerative changes in older adults can affect receptor dynamics, and the evidence suggests these drugs are promising but require further investigation.

Study at a glance

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.