Acute cognitive effects of single-dose intravenous ketamine in major depressive and posttraumatic stress disorder

This open-label study (n=58) compared the effects of a single dose of ketamine (35-56.7mg/70kg) on the cognitive effects of those suffering from depression (MDD; n=14) or PTSD (n=15) and healthy control subjects (n=29). The study found acute declines in attention, executive function, and verbal memory. Only the effect on attention was larger in the patient groups. The baseline cognitive function of participants didn’t predict clinical outcomes.

Abstract

Intravenous (IV) subanesthetic doses of ketamine have been shown to reduce psychiatric distress in both major depressive (MDD) and posttraumatic stress disorder (PTSD). However, the effect of ketamine on cognitive function in these disorders is not well understood. To address this gap, we examined the effect of a single dose of IV ketamine on cognition in individuals with MDD and/or PTSD relative to healthy controls (HC). Psychiatric (n = 29; 15 PTSD, 14 MDD) and sex- age- and IQ matched HC (n = 29) groups were recruited from the community. A single subanesthetic dose of IV ketamine was administered. Mood and cognitive measures were collected prior to, 2 h and 1 day post-ketamine administration. MDD/PTSD individuals evidenced a large-magnitude improvement in severity of depressive symptoms at both 2-hours and 1 day post-ketamine administration (p’s < .001, Cohen d’s = 0.80-1.02). Controlling for baseline performance and years of education, IV ketamine induced declines in attention (ATTN), executive function (EF), and verbal memory (VM) 2 h post-administration, all of which had resolved by 1 day post-ketamine across groups. The magnitude of cognitive decline was significantly larger in MDD/PTSD relative to HC on attention only (p = .012, d = 0.56). Ketamine did not affect working memory (WM) performance. Cognitive function (baseline, change from baseline to post-ketamine) was not associated with antidepressant response to ketamine. Results suggest that while ketamine may have an acute deleterious effect on some cognitive domains in both MDD/PTSD and HC individuals, most notably attention, this reduction is transient and there is no evidence of ketamine-related cognitive dysfunction at 1 day post-administration.

Authors: Margaret T. Davis, Nicole DellaGiogia, Paul Maruff, Robert H. Pietrzak & Irina Esterlis

Summary

Intravenous (IV) subanesthetic doses of ketamine have been shown to reduce psychiatric distress in individuals with major depressive disorder and posttraumatic stress disorder, but the effect of ketamine on cognitive function in these disorders is not well understood.

Introduction

Ketamine is a dissociative anesthetic and NMDA receptor antagonist that reduces symptoms of both major depressive disorder and posttraumatic stress disorder. However, ketamine-induced cognitive dysfunction is an important adverse outcome associated with both acute and chronic IV ketamine use.

In experimental animal models and healthy human studies, high-dose ketamine has been shown to cause transient psychosis, and chronic abuse of ketamine is associated with decline across many domains of cognition. However, few studies have examined the relationship between IV ketamine and cognition in MDD or PTSD.

Although several studies have examined the effect of IV ketamine on cognition in individuals with MDD, results have been inconsistent with some studies reporting no effect on cognition, others reporting an improvement in cognition, and still others reporting a decline in cognition.

To understand the CNS risk for IV ketamine in MDD and PTSD, it is important to compare the acute and chronic cognitive effects of the drug.

We conducted an experiment to investigate the acute effects of therapeutic (subanesthetic) doses of IV ketamine on cognitive function in adults with MDD and PTSD. We found that the acute effects of IV ketamine were associated with acute improvement in mood symptoms and a decline in cognition.

Materials and Methods Participants

Participants were age 18 – 60 years old, English speaking, and had no recent regular history of psychiatric medication use. The psychiatric group had 14 participants with MDD and 15 participants with PTSD, and the healthy control group had 29 participants.

Ketamine administration

Ketamine IV was administered by a licensed nurse and attending physician. Half of the subjects received an initial bolus of 0.23 mg/kg over 1 min followed by constant infusion of 0.58 mg/kg per hour over 1 h, and the remaining half received constant IV infusion of 0.5 mg/kg over 40 min.

Mood assessments

The Structured Clinical Interview for DSM (IV)61, Hamilton Depression Rating Scale62, Beck Depression Inventory, 2nd edition63 (BDI-II), and Montgomery – sberg Depression Rating Scale64 (MADRS) were used to assess participants’ mood at screening, before ketamine administration, 2 h post-ketamine administration, and 1 day post-ketamine administration.

Cognitive assessments

Cognitive function was measured using the Cogstate battery, which includes the Detection (DET) test of psychomotor function and the Identification (IDN) test of visual attention. The One Back (ONB) test of working memory, the One Card Learning (OCL) test of visual learning, the Groton Maze Learning Test (GMLT) of executive function, and the International Shopping List Test (ISLT) of learning and memory were used to measure cognitive functions.

A test was administered to determine if ketamine could be readministered at short retest intervals without practice effects.

Data processing

The main performance measures for each cognitive outcome measure were standardized using the mean and standard deviation of age stratified normative data. Then, the four age-standardized outcome measures were organized into the main cognitive domain they measured and submitted to statistical analyses.

Data analysis

Data analyses were conducted in four steps: chi-squared tests, ANOVAs, exploratory analyses, and a repeated-measures ANOVA. The BDI-II was used to evaluate the effect of ketamine on mood.

We conducted five analysis of covariance (ANCOVA) models to examine the relationship between baseline cognition and ketamine responder status. We found that the response to ketamine was significantly different between HC, MDD, and PTSD groups.

Sample characteristics

Table 1 shows demographic and clinical characteristics of the sample. The MDD/PTSD group had moderate depression based on self-report and clinician-administered measures, and had significantly greater depressive symptoms at all timepoints than the HC group.

Effect of ketamine on mood symptoms

MDD/PTSD participants improved by 11.6 points (52.5%) on the BDI-II at 2 h post-ketamine administration, and by 8 points (36.4%) at 1 day post-ketamine, on average, compared to HC, and by 9.3 points (42.2%) at 1 day post-ketamine administration, on average.

Cognition pre- and post-ketamine

Ketamine administration induced a decline in performance on ATTN, VM, and EF in the HC group, and a greater decline in ATTN only in the MDD/PTSD group. The observed decline resolved 1 day post-ketamine.

Exploratory analyses: Cognition and treatment response

A study was conducted to examine the relationship between baseline cognitive functioning, diagnostic status, and treatment responder status post-ketamine administration. No significant differences were observed between individuals with PTSD and MDD on ATTN or VM, but individuals with MDD performed significantly worse on EF and WM.

Discussion

In individuals with MDD and PTSD, ketamine improved depressive symptoms at both 2 h and 1 day post-ketamine administration. However, ketamine had an acute and substantial decline in higher cognitive functions such as attention and working memory, which resolved completely following clearance of ketamine.

Ketamine administration in MDD/PTSD induces an acute reduction in attention and psychomotor speed that is clinically meaningful and domain specific. Ketamine has been shown to impair driving safety in previous studies.

These findings add to the growing literature on the relationship between subanesthetic ketamine and cognitive functioning. Participants with MDD and PTSD showed comparable effects of ketamine on cognition, and a majority of participants qualified as responders to ketamine. Despite some research suggesting that cognitive deficits mediate the relationship between depression and functional impairment, one IV administration of subanesthetic doses of ketamine did not substantively affect cognitive functioning.

This study was limited by the lack of a randomized, controlled design and absence of a placebo condition. It also had a small sample size and was only evaluated short-term over two timepoints, so conclusions concerning the likely effect of ketamine on cognition in the long term cannot be drawn. The cognitive battery used in this study was extensive, but not comprehensive. There was some procedural variability, but no effects of dosing on clinical or cognitive variables, and the population recruited was not wholly representative of the psychiatric population in general.

Researchers and clinicians should examine the relationship between ketamine and cognition in large, representative samples, and consider the impact of research design and methodology on their ability to answer questions concerning ketamine’s effect on cognition.

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