Esketamine is an S-enantiomer of ketamine approved by the EMA for treatment-resistant depression (TRD). As an NMDA receptor antagonist, its administration results in increase of glutamate release and AMPA receptor activation, supporting both rapid-onset and long-term antidepressant effects. Short-term tolerability seems acceptable but major concerns remain regarding long-term safety, specifically regarding potential neurocognitive toxicity.

To clarify the potential short and long-term cognitive beneficial-effects and side-effects of esketamine.

Research was made using the Medline database, through the Pubmed search engine, using the keywords: “esketamine”, “cognition”. Only randomized-controlled trials were considered.

One study focused on the effects of intranasal esketamine (INE) on cognitive functioning in 24 healthy individuals, who were evaluated pre- and postdose (40 min, 2h, 4h and 6h). The results showed a decline in cognitive performance at 40 min postdose, returning to comparable levels as placebo by 2h postdose. Another study, with a follow-up of 1 year, involving 802 TRD patients, accessed the long-term safety of INE. In patients aged <65 years-old, performance on all cognitive tests remained stable or slightly improved from baseline during long-term treatment. In patients ≥ 65 years-old, the mean performance on all tests improved or remained stable, while the simple and choice reaction time began slowing at week 20.

Esketamine has proven to be a promising new option for the treatment of TRD and available studies have shown promising results regarding patients’ cognitive function. Larger clinical trials are needed to further evaluate its short-term and long-term cognitive effects.

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