Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial

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 anesthetic 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 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.

Trial registration: ClinicalTrials.gov NCT00768430.

FIGURE 1

Change in Depression Severity Over Time in Patients With Treatment-Resistant Major Depression Given a Single Infusion of Ketamine or Midazolama ^a Modified intention-to-treat group. MADRS scores range from 0 to 60, with higher scores indicating a greater severity of symptoms. ^b Reduction in MADRS score 24 hours after infusion was the primary outcome measure and was significantly greater for the ketamine group than for the midazolam group (p≤0.002).

FIGURE 2

Response Rates Over Time in Patients With Treatment-Resistant Major Depression Given a Single Infusion of Ketamine or Midazolama ^a Modified intention-to-treat group. Response at each time point was defined as a decrease from baseline of at least 50% in score on the Montgomery-Åsberg Depression Rating Scale.

FIGURE 3

Time to Relapse for Responders at Day 7 Among Patients With Treatment-Resistant Major Depression Given a Single Infusion of Ketamine or Midazolama ^a Response was defined as a decrease from baseline of at least 50% in score on the Montgomery-Åsberg Depression Rating Scale (MADRS). Relapse was defined as a MADRS score of 20 or higher maintained for two consecutive visits and meeting criteria for a major depressive episode for 1 week.