Effect of intranasal esketamine on cognitive functioning in healthy participants: a randomized, double-blind, placebo-controlled study

Psychopharmacology (Berl). 2018 Apr;235(4):1107-1119. doi: 10.1007/s00213-018-4828-5. Epub 2018 Feb 1.


Background: The effect of intranasal esketamine on cognitive functioning in healthy participants is assessed in this study.

Methods: Twenty-four participants (19-49 years) were randomized to one of two treatment sequences in which either esketamine 84 mg or placebo was intranasally administered in a double-blind, two-period crossover design. Primary measures included five tests of Cogstate® computerized test battery assessed at 1 h predose and 40 min, 2, 4, and 6 h postdose. Secondary measures included the Mental Effort Scale, Karolinska Sleepiness Scale (KSS), and safety.

Results: Esketamine was associated with significant cognitive performance impairment at 40 min postdose for all five Cogstate® tests (Detection p = 0.0011, Identification p = 0.0006, One-Card Learning p = 0.0040, One Back p = 0.0017, and Groton Maze Learning Test p < 0.0001) versus placebo. In contrast, performance on these tests did not differ significantly between esketamine and placebo at 2, 4, or 6 h postdose. Secondary outcomes indicated a significant, transient increase from baseline under esketamine versus placebo at 40 min postdose on the Mental Effort Scale and at 40 min and 2 h postdose on KSS (p < 0.0001 for both); however, no significant difference was observed on these outcomes between esketamine and placebo at later timepoints. The most commonly reported adverse events were dizziness (67%), nausea (37.5%), disturbance in attention (29.2%), and fatigue (29.2%); the majority were considered mild in severity.

Conclusions: Esketamine was associated with cognitive performance decline, and greater effort was required to complete the test battery versus placebo at 40 min postdose, which returned to placebo-comparable levels by 2 h postdose.

Trial registration: ClinicalTrials.gov identifier: NCT02094378.

Keywords: Cognitive functioning; Cogstate® computerized test battery; Intranasal esketamine; Treatment-resistant depression.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Intranasal
  • Adult
  • Cognition / drug effects*
  • Cognition / physiology
  • Cognitive Dysfunction / chemically induced
  • Cross-Over Studies
  • Dizziness / chemically induced
  • Double-Blind Method
  • Excitatory Amino Acid Antagonists / administration & dosage*
  • Excitatory Amino Acid Antagonists / chemistry
  • Fatigue / chemically induced
  • Female
  • Follow-Up Studies
  • Healthy Volunteers
  • Humans
  • Ketamine / administration & dosage*
  • Ketamine / adverse effects
  • Ketamine / analogs & derivatives*
  • Male
  • Maze Learning / drug effects
  • Maze Learning / physiology
  • Middle Aged
  • Psychomotor Performance / drug effects*
  • Psychomotor Performance / physiology
  • Treatment Outcome
  • Young Adult


  • Excitatory Amino Acid Antagonists
  • Ketamine

Associated data

  • ClinicalTrials.gov/NCT02094378