Acute effects of ketamine and esketamine on cognition in healthy subjects: A meta-analysis

This meta-analysis assessed the effects of ketamine administration in healthy participants (n=1,041) on several cognitive domains. Deficits in verbal learning/memory were most prominent, whereas response inhibition was the least affected. Negative effects were dependent on infusion dose and plasma level but unaffected by enantiomer type, route of administration, sex or age.

Abstract

“Background: Impairment in cognition is frequently associated with acute ketamine administration. However, some questions remain unanswered as to which deficits are most prominent and what variables modulate these effects.

Methods: A literature search yielded 56 experimental studies of acute ketamine administration that assessed cognition in 1041 healthy volunteers. A multivariate meta-analysis was performed, and effect sizes were estimated for eleven cognitive domains: attention, executive function, response inhibition, social cognition, speed of processing, verbal / language, verbal learning, verbal memory, visual learning & memory, visuospatial abilities, and working memory.

Results: There were small-to-moderate impairments across all cognitive domains. Deficits in verbal learning/memory were most prominent, whereas response inhibition was the least affected. Meta-regression analysis revealed that the negative effects of ketamine on cognition are dependent on infusion dose and plasma level, but unaffected by enantiomer type, route of administration, sex or age. A publication bias was observed.

Discussion: Acute ketamine broadly impairs cognition across all domains among healthy individuals. Verbal learning and memory figures most prominently in cognitive impairment elicited by acute ketamine administration.

Authors: Simon Zhornitsky, Valerie Tourjman, Julie Pelletier, Roxane Assaf, Chiang-Shan R. Li & Stephane Potvin

Authors Highlights

• Acute ketamine affects multiple cognitive domains in healthy individuals.
• The most prominent ketamine-induced deficits are in verbal learning and memory.
• The negative effects of acute ketamine administration are dose-dependent.

Summary

Ketamine administration is associated with cognitive impairment.

A literature search yielded 56 studies of acute ketamine administration that assessed cognition in 1041 healthy volunteers. A meta-analysis was performed.

1. Introduction

Ketamine is a dissociative anesthetic drug that may be beneficial for the treatment of pain and depression, but it is associated with significant abuse potential, as well as psychiatric and cognitive side-effects.

Ketamine blocks glutamatergic N-methyl-D-aspartate (NMDA) receptors, which are abundant in nearly all brain areas and intimately involved in cognition functioning. Ketamine is administered intravenously, intramuscularly, or intranasally, and has a bioavailability of 100%, 93%, and 45%, respectively.

Ketamine-induced cognitive deficits are highly dependent on dose and resultant plasma levels. For instance, 0.5 mg/kg ketamine (100 – 250 ng/ml plasma target) produces cognitive deficits in neuropsychological tests of delayed memory, attention, verbal fluency, and executive function, but not in tests of immediate memory or psychomotor performance.

Sex and age may also play a role in ketamine’s effects on cognition. Males show a greater performance decrement on the Hopkins Verbal Learning Task and a greater subjective sense of memory impairment.

In the present meta-analysis, we examined placebo-controlled trials of acute effects of ketamine on cognition in non-clinical samples, and performed meta-regression analysis to investigate how variables such as enantiomer type, route of administration, plasma level, dose, sex, and age modulate the effects of ketamine.

2.1. Literature search and study selection

We searched PUBMED, Embase and Web of Science using the keywords “ketamine” and “cognit*” to find studies on the cognitive effects of ketamine.

A meta-analysis was performed to determine the effects of ketamine on cognitive performance in healthy volunteers. Studies were included if they met all of the criteria and were published before September 1st 2021.

2.2. Cognitive domains

The authors grouped neuropsychological tests into 11 cognitive domains and based their final decisions on test classification according to Lezak et al. (2012) and our meta-analyses of cognition in substance use disorders.

2.3. Quantitative data synthesis

We performed multivariate analyses with R using the metafor package and estimated the combined effect size using a multivariate model with a random intercept nested in studies. The direction of the effect size was considered positive if cognitive performance during ketamine administration was worse relative to placebo.

We performed meta-regression analyses to estimate the effects of continuous variables, sex ratio, ketamine dosage, route of administration and type of ketamine on cognitive effects.

3.1. Study selection

We included 123 studies on ketamine-induced psychotic-like symptoms and excluded 67 studies for the following reasons: irrelevant tasks, overlapping results, lack of placebo, incomplete data, case reports/series and wrong population. 56 studies were retained in the meta-analysis, including 1175 participants.

3.2. Combined outcomes across cognitive domains

The primary analysis of 244 studies showed that ketamine produced impairments of cognitive function of moderate magnitude. A possible publication bias was observed, with small studies having the largest standardized effect size estimates.

3.3. Outcomes of specific cognitive domains

Ketamine had moderate to large detrimental effects on cognition, including verbal learning, attention, executive functions, social cognition, verbal memory, visual learning / memory and working memory.

3.4. Sub-analyses of ketamine plasma level, dose, enantiomer, route of administration, age, and sex

Meta-regression analyses revealed a significant association between plasma ketamine levels and cognitive deficits, but not between age or ex ratio of study samples.

4. Discussion

Ketamine negatively impacts cognitive function in nearly all domains, with the exception of response inhibition and visuospatial ability. Plasma level and infusion dose significantly influence these effects.

The current study shows that acute ketamine administration is associated with cognitive impairment in multiple domains, and that these impairments are consistent with those documented among chronic ketamine abusers in cross-sectional studies.

Ketamine impaired verbal learning, verbal memory, and visual learning / memory in rats. These findings support the idea that ketamine interferes with the formation of episodic memory via frontotemporal mechanisms.

Ketamine reduced emotional processing and social cognition in healthy volunteers, as measured by emotion recognition tasks. This finding supports its use in experimental models of negative symptoms of schizophrenia.

Ketamine produced moderate impairment in executive function, working memory, attention, and speed of processing, which was subserved by frontoparietal cortex and fronto-striatal-cerebellar networks. Ketamine also decreased accuracy on a spatial working task and frontal cortical activation during the encoding and early maintenance phase of task trials.

Ketamine administration was associated with diminished left inferior frontal cortical activation to lexical verbal fluency and compensatory responses in non-task-relevant regions in functional neuroimaging studies.

Ketamine-induced cognitive deficits are dose-dependent and are associated with lower plasma ketamine levels and higher infusion doses. No association was found for ketamine-induced cognitive deficits and age or sex ratio of the study samples.

Ketamine is commonly administered in a IV dose of 0.5 mg/kg, producing a maximum concentration of 168-219 ng/ ml. A few randomized controlled trials have produced mixed results in patients with treatment-resistant depression.

A study found no difference in cognition between responders to ketamine and placebo at 24 h or 7 days post-infusion. Open-label, uncontrolled trials have suggested that ketamine may improve cognition in depression, but the results of our meta-analysis are inconsistent with these findings. This could be because the acute cognitive impairments produced by ketamine do not necessarily persist after the acute effect of the substance.

The limitations of this study include a publication bias, a lack of studies on route of administration, a lack of studies on response inhibition, social cognition, visual learning/memory, and visuospatial abilities, and a heterogeneous result.

This meta-analysis shows that acute ketamine administration impairs nearly all cognitive domains, with the most prominent deficits being in verbal learning and social cognition. Ketamine may be an alternative to electroconvulsive therapy for certain patients with treatment-resistant depression. Ketamine use may impair cognitive functioning in some populations and under some conditions. Further studies are needed to determine the effects of ketamine use on cognitive functioning.

CRediT authorship contribution statement

Simon Zhornitsky, Valerie Tourjman, Julie Pelletier, Roxane Assaf, Chiang-Shan R. Li and Stephane Potvin contributed to this work.