Intranasal esketamine temporarily impairs cognitive performance and increases mental effort and sleepiness in healthy participants. At 40 minutes after dosing, performance on five cognitive tests (Detection, Identification, One-Card Learning, One Back, and Groton Maze Learning) was significantly worse compared with placebo. These effects resolved by 2 hours postdose, with no differences between esketamine and placebo at 2, 4, or 6 hours. Participants reported greater mental effort at 40 minutes and increased sleepiness at 40 minutes and 2 hours, which also returned to placebo levels later. Common mild adverse events included dizziness, nausea, attention disturbance, and fatigue.
A single 84 mg dose of intranasal esketamine did not impair next-morning driving performance in patients with mild-to-moderate major depressive disorder or persistent depressive disorder, and same-day driving was not impaired after twice-weekly administration over three weeks. Alcohol, used as a positive control, significantly worsened driving (increased weaving by 1.83 cm), while esketamine showed no such effect. Twenty-seven patients completed on-road driving tests on a public highway. The findings suggest that esketamine, at this dose, does not compromise driving ability the morning after or on the same day of repeated use.
Esketamine nasal spray is the first glutamate-modulating antidepressant approved as a monotherapy for adults with treatment-resistant depression. It acts rapidly by blocking NMDA receptors on inhibitory interneurons, which disinhibits glutamate release and alters synaptic plasticity. Administered at 56 mg or 84 mg, it reaches peak concentration in 20–40 minutes with about 50% bioavailability. This review covers its regulatory approval, mechanism of action, pharmacokinetics, and clinical trial data for efficacy and safety in treatment-resistant depression and major depressive disorder with acute suicidal ideation or behavior.