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

Abstract

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.

Conflict of interest statement

Conflict of interest

Drs. Morrison, Fedgchin, Singh, van der Ark, Wajs, Xi, Zannikos, and Drevets are employees of Janssen Research & Development and hold stock in the company. The study site received a research grant from Janssen Research & Development.

Figures

Fig. 1

Study design and participant flow

Fig. 2

Cognitive function measures mean plots (± SE) for a Detection, b Identification, c One-Card Learning d One Back, e Groton Maze Learning Test (ITT Analysis Set)

Fig. 2

Cognitive function measures mean plots (± SE) for a Detection, b Identification, c One-Card Learning d One Back, e Groton Maze Learning Test (ITT Analysis Set)

Fig. 3

Secondary cognitive function measures mean plots (± SE) for a Mental Effort Scale and b Karolinska Sleepiness Scale (ITT Analysis Set)

Fig. 4

Total scores over time [mean (SD)] for a Brief Psychiatric Rating Scale and b Clinician-Administered Dissociative States Scale (Safety Analysis Set)