Cognitive Effects of Esketamine in Treatment-Resistant Depression: A Systematic Review.

Treatment-resistant depression affects up to one third of patients with major depressive disorder and is frequently accompanied by persistent cognitive impairments that significantly hinder functional recovery. Emerging evidence suggests that sub-anesthetic esketamine does not appear to be associated with cognitive deterioration and may be associated with procognitive effects; however, no systematic review has specifically synthesized cognitive outcomes in this population. A systematic search was conducted. Eligible studies included adults aged 18 to 80 years receiving intranasal or intravenous esketamine, with cognitive assessments performed at least 1 month after treatment initiation. Six studies met the inclusion criteria. Cognitive outcomes were grouped into attention/processing speed, memory, and executive functions. Across studies, available evidence suggests that esketamine does not appear to be associated with cognitive deterioration in any assessed domain. Improvements in attention and processing speed were the most frequent and robust findings, observed in both RCT-derived datasets and naturalistic longitudinal studies. Memory remained stable in short-term designs but improved in studies with extended follow-up. Executive functions showed gains primarily among participants with baseline impairments and in long-term assessments. All remaining evaluations indicated cognitive stability. Current evidence, albeit limited, suggests that esketamine appears to be cognitively safe in adults with treatment-resistant depression and may confer selective improvements, particularly in attention and processing speed, with more variable benefits in memory and executive functioning over sustained treatment. These effects may support functional recovery and complement esketamine's antidepressant action. Further research using harmonized cognitive batteries, larger samples, and longer follow-up periods is needed to better characterize cognitive trajectories and their relevance for personalized treatment strategies.