Neurocognitive Effects of Ketamine and Association with Antidepressant Response in Individuals with Treatment-Resistant Depression: A Randomized Controlled Trial
This randomised, double-blind, active placebo-controlled study (n=62) investigated the neurocognitive and antidepressant effects of ketamine (35 mg/70kg) or midazolam (3.15mg/70kg) compared to the benzodiazepine anesthetic midazolam in patients with depression. Neurocognitive performance improved independently of treatment condition or change in depression severity due to learning, which indicates an absence of adverse effects of ketamine on neurocognitive functioning in contrast to electroconvulsive therapy which impacts memory.
Authors
- Sanjay Mathew
- James Murrough
- Dennis Charney
Published
Abstract
Introduction
The glutamate N-methyl-D-aspartate (NMDA) receptor antagonist ketamine displays rapid antidepressant effects in patients with treatment-resistant depression (TRD); however, the potential for adverse neurocognitive effects in this population has not received adequate study. The current study was designed to investigate the delayed neurocognitive impact of ketamine in TRD and examine baseline antidepressant response predictors in the context of a randomized controlled trial.
Methods
In the current study, 62 patients (mean age=46.2±12.2) with TRD free of concomitant antidepressant medication underwent neurocognitive assessments using components of the MATRICS Consensus Cognitive Battery (MCCB) before and after a single intravenous infusion of ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg). Participants were randomized to ketamine or midazolam in a 2:1 fashion under double-blind conditions and underwent depression symptom assessments at 24, 48, 72 h, and 7 days post treatment using the Montgomery-Asberg Depression Rating Scale (MADRS). Post-treatment neurocognitive assessment was conducted once at 7 days.
Results
Neurocognitive performance improved following the treatment regardless of treatment condition. There was no differential effect of treatment on neurocognitive performance and no association with antidepressant response. Slower processing speed at baseline uniquely predicted greater improvement in depression at 24 h following ketamine (t=2.3, p=0.027), while controlling for age, depression severity, and performance on other neurocognitive domains.
Discussion
In the current study, we found that ketamine was devoid of adverse neurocognitive effects at 7 days post treatment and that slower baseline processing speed was associated with greater antidepressant response. Future studies are required to further define the neurocognitive profile of ketamine in clinical samples and to identify clinically useful response moderators.
Research Summary of 'Neurocognitive Effects of Ketamine and Association with Antidepressant Response in Individuals with Treatment-Resistant Depression: A Randomized Controlled Trial'
Introduction
Ketamine is a high-affinity, noncompetitive NMDA glutamate receptor antagonist that has demonstrated rapid antidepressant effects in patients with treatment-resistant depression (TRD). Although single-dose ketamine (commonly 0.5 mg/kg over a slow 40-minute infusion) produces acute dissociative and cognitive effects that typically resolve within hours, there is limited data on its delayed or persistent neurocognitive impact in clinical mood-disorder populations. Prior work by the same group and others reported acute memory impairments following ketamine in healthy volunteers and in an open-label TRD sample, and an earlier observation that slower baseline processing speed was associated with greater antidepressant response at 24 hours. Murrough and colleagues designed the present two-site, double-blind, randomised controlled trial to extend those findings. The study aimed to (1) characterise the effect of a single sub-anesthetic ketamine infusion on neurocognitive performance measured 7 days post-treatment, and (2) examine whether baseline neurocognitive functioning predicts rapid antidepressant response to ketamine. The primary hypothesis was that ketamine would not worsen neurocognitive functioning at 7 days and that slower baseline processing speed would predict greater symptom improvement at 24 hours.
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Study Details
- Study Typeindividual
- Journal
- Compound
- Topics
- Authors
- APA Citation
Murrough, J. W., Burdick, K. E., Levitch, C. F., Perez, A. M., Brallier, J. W., Chang, L. C., Foulkes, A., Charney, D. S., Mathew, S. J., & Iosifescu, D. V. (2015). Neurocognitive Effects of Ketamine and Association with Antidepressant Response in Individuals with Treatment-Resistant Depression: A Randomized Controlled Trial. Neuropsychopharmacology, 40(5), 1084-1090. https://doi.org/10.1038/npp.2014.298
References (3)
Papers cited by this study that are also in Blossom
Murrough, J. W., Iosifescu, D. V., Chang, L. C. et al. · American Journal of Psychiatry (2013)
Murrough, J. W., Perez, A. M., Pillemer, S. et al. · Biological Psychiatry (2012)
Zarate, C. A., Brutsche, N. E., Ibrahim, L. et al. · Biological Psychiatry (2012)
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Mcintyre, R. S., Rosenblat, J. D., Nemeroff, C. B. et al. · American Journal of Psychiatry (2021)
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