Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial
This rigorous randomised controlled trial (n=73) found that ketamine has rapid (24 hours) anti-depressant effects (MARDS) for those with treatment-resistant depression (TRD). Compared to the placebo group (midazolam), ketamine led to greater improvements in MADRS scores by 7.95 points and the response rate was greater in the ketamine group.
Authors
- Sanjay Mathew
- James Murrough
- Dennis Charney
Published
Abstract
Objective
Ketamine, a glutamate N-methyl-D-aspartate (NMDA) receptor antagonist, has shown rapid antidepressant effects, but small study groups and inadequate control conditions in prior studies have precluded a definitive conclusion. The authors evaluated the rapid antidepressant efficacy of ketamine in a large group of patients with treatment-resistant major depression.
Method
This was a two-site, parallel-arm, randomized controlled trial of a single infusion of ketamine compared to an active placebo control condition, the anaesthetic midazolam. Patients with treatment-resistant major depression experiencing a major depressive episode were randomly assigned under double-blind conditions to receive a single intravenous infusion of ketamine or midazolam in a 2:1 ratio (N=73). The primary outcome was a change in depression severity 24 hours after drug administration, as assessed by the Montgomery-Åsberg Depression Rating Scale (MADRS).
Results
The ketamine group had greater improvement in the MADRS score than the midazolam group 24 hours after treatment. After adjustment for baseline scores and site, the MADRS score was lower in the ketamine group than in the midazolam group by 7.95 points (95% confidence interval [CI], 3.20 to 12.71). The likelihood of response at 24 hours was greater with ketamine than with midazolam (odds ratio, 2.18; 95% CI, 1.21 to 4.14), with response rates of 64% and 28%, respectively.
Conclusions
Ketamine demonstrated rapid antidepressant effects in an optimized study design, further supporting NMDA receptor modulation as a novel mechanism for accelerated improvement in severe and chronic forms of depression. More information on response durability and safety is required before implementation in clinical practice.
Research Summary of 'Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial'
Introduction
Major depressive disorder is a leading cause of disability worldwide and a substantial subgroup of patients fail to achieve clinically meaningful improvement despite multiple antidepressant trials and augmentation strategies. Treatment-resistant major depression is typically defined as inadequate response to at least two adequate antidepressant treatments and is associated with poor outcomes and a slow therapeutic onset for conventional agents, which generally act on monoamine systems and require 4–12 weeks to produce benefit. Converging evidence implicates glutamatergic dysfunction in depression, and small case series and crossover studies had suggested that the NMDA receptor antagonist ketamine can produce rapid antidepressant effects within hours of a single subanesthetic intravenous infusion; however, prior work was limited by small samples, inert placebos, and potential unblinding due to ketamine's psychoactive effects. Murrough and colleagues designed a two-site, parallel-arm, double-blind randomized controlled trial to test whether a single low-dose ketamine infusion produces a rapid antidepressant effect in patients with treatment-resistant major depression. To strengthen blinding and control for nonspecific anaesthetic effects they used midazolam as an active placebo comparator, selected 24 hours postinfusion as the primary endpoint to capture rapid effects while minimising contamination by acute psychoactive symptoms, and powered the study to detect clinically meaningful differences in clinician-rated depression severity.
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Study Details
- Study Typeindividual
- Journal
- Compound
- Topics
- Authors
- APA Citation
Murrough, J. W., Iosifescu, D. V., Chang, L. C., Al Jurdi, R. K., Green, C. E., Perez, A. M., Iqbal, S., Pillemer, S., Foulkes, A., Shah, A., Charney, D. S., & Mathew, S. J. (2013). Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial. American Journal of Psychiatry, 170(10), 1134-1142. https://doi.org/10.1176/appi.ajp.2013.13030392
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