Long-term effects of ketamine on cognitive function in patients with treatment-resistant depression (TRD): a narrative review

Background: Major depressive disorder is a leading cause of disability worldwide, affecting nearly 300 million people. A substantial proportion of patients develop treatment-resistant depression (TRD), characterized by inadequate response to at least two antidepressant therapies. Ketamine has emerged as a promising therapeutic option due to its rapid antidepressant effects mediated through modulation of glutamatergic neurotransmission. However, concerns remain regarding the potential long-term cognitive effects associated with repeated therapeutic exposure.

Objective: To review the long-term cognitive effects of therapeutic ketamine or esketamine use in adults with treatment-resistant depression.

Methods: A systematic search was conducted in PubMed/MEDLINE, SciELO, LILACS (BVS), and the Brazilian Registry of Clinical Trials (ReBEC). Controlled descriptors and free-text terms related to treatment-resistant depression, ketamine or esketamine, and cognitive outcomes were used. Studies published in English or Portuguese between January 2000 and March 2025 were included if they evaluated adults with treatment-resistant depression treated with intravenous ketamine or intranasal esketamine in a therapeutic setting with objective or subjective cognitive assessment. Studies involving recreational or anesthetic use and pediatric populations were excluded. Data were analyzed descriptively with emphasis on studies with follow-up ≥6 months.

Results: Most studies evaluating ketamine for treatment-resistant depression focus on short- and medium-term outcomes. Long-term follow-up studies (>6 months) remain scarce, particularly in Brazil, limiting the understanding of potential cumulative cognitive effects. Cognitive changes after ketamine exposure are usually acute and transient, often associated with dissociative effects, including temporary impairments in attention, short-term memory, and processing speed that typically resolve after the acute effects subside. This profile suggests that adverse cognitive effects in current therapeutic regimens are largely reversible. Some studies have reported improvements in cognitive domains such as processing speed and executive function during repeated ketamine infusions, possibly related to reduction of depressive symptoms rather than a direct neurocognitive effect. A Brazilian longitudinal study with 6-month follow-up found no sustained cognitive impairment associated with intranasal esketamine. However, small sample sizes, short follow-up periods, and methodological heterogeneity limit firm conclusions.

Conclusion: Ketamine is a promising option for treatment-resistant depression and current evidence does not indicate persistent cognitive impairment with therapeutic use. However, most studies have short follow-up and heterogeneous methods, highlighting the need for larger longitudinal studies with objective cognitive assessments.