The Possible Application of Ketamine in the Treatment of Depression in Alzheimer’s Disease

Depression affects 3.8% of the global population, with higher rates in older adults. Evidence links depression to Alzheimer's disease (AD), but conventional antidepressants, especially SSRIs, show conflicting efficacy in AD patients. A recent systematic review and meta-analysis of 25 randomized controlled trials found no high efficacy of fourteen antidepressant medications for AD symptoms. Ketamine, a nonselective NMDA receptor antagonist, has multiple effects including neuroprotection and antidepressant properties. Esketamine nasal spray was FDA-approved in 2019 for treatment-resistant depression. NMDA receptor antagonists may treat AD by counteracting pathological glutamate receptor stimulation. Recent findings suggest ketamine could provide neuroprotection and reduce neuropsychiatric symptoms in AD. This investigation evaluates ketamine's potential role and mechanism in AD management.

Study at a glance

Abstract

Depression is a leading cause of disability globally, with a prevalence of 3.8% among the whole population, 5% of the adult population, and 5.7% of the elderly population over 60 years of age. There is evidence that depression is linked to certain neurodegenerative diseases, one being Alzheimer’s disease (AD). The efficacy of conventional antidepressants to treat depression in AD is conflicting, especially regarding selective serotonin reuptake inhibitors (SSRIs). A recent systemic review and meta-analysis of 25 randomized controlled trials including fourteen antidepressant medications showed no high efficacy in treating AD patients’ symptoms. However, ketamine, a nonselective N-methyl-D-aspartate (NMDA) receptor antagonist, can mediate a wide range of pharmacological effects, including neuroprotection, anti-inflammatory and anticancer properties, multimodal analgesia, and treatment of depression, suicidal attempts, and status epilepticus. Esketamine, which is ketamine formulated as a nasal spray, was approved by the Federal Drug Administration (FDA) in March 2019 as an adjuvant drug to treat treatment-resistant depression. NMDA receptor antagonists treat AD through offsetting AD-related pathological stimulation of subtypes of glutamate receptors in the central nervous system. Recent clinical findings suggest that ketamine may provide neuroprotection and reduce neuropsychiatric symptoms associated with AD. In the present investigation, we evaluate the potential role of ketamine and its postulated mechanism in AD management.