Ketamine and Esketamine for Treatment-Resistant Depression in Older Adults with Comorbid Cognitive Impairment or Dementia: A Systematic Review of Available Evidence

Introduction: Treatment-resistant depression (TRD) is common among older adults, and ketamine/esketamine have emerged as rapid-acting therapeutic options. However, pivotal randomized controlled trials have systematically excluded patients with dementia or significant cognitive impairment, leaving clinicians without clear evidence to guide treatment decisions in this vulnerable and increasingly relevant subgroup.

Methods: A focused literature search was conducted across PubMed-indexed sources up to July 2026 to identify studies reporting depressive and cognitive outcomes following ketamine or esketamine administration in older adults (≥60 years) with comorbid dementia or cognitive impairment. Case reports, case series, and clinical trials providing quantifiable outcomes were included; narrative reviews and preclinical studies without primary patient data were excluded.

Results: Five studies met inclusion criteria: four case reports and one open-label pilot trial. Patients ranged from 56 to 84 years old, with diagnoses spanning early-onset dementia to advanced Alzheimer's disease (Clinical Dementia Rating 3). Depressive symptoms improved substantially across cases (e.g., MADRS decreasing from 42 to 4 in one report), and cognitive performance remained stable or improved in most cases (MMSE increasing from 16 to 20 in one patient), although one case showed persistent vascular-related cognitive deficits despite mood improvement. The pilot trial supported preliminary safety and tolerability of intravenous ketamine in this population. Adverse effects were generally mild and transient (e.g., self-limited hypertension, brief motor slowing).

Conclusions: Preliminary, low-quality evidence suggests ketamine and esketamine may be feasible and generally well-tolerated in older adults with TRD and comorbid cognitive impairment, without clear evidence of cognitive worsening. Given the systematic exclusion of this population from pivotal trials, larger, controlled studies specifically designed for this subgroup are urgently needed.