A randomized, double-blind, active placebo-controlled study of efficacy, safety, and durability of repeated vs single subanesthetic ketamine for treatment-resistant depression

Abstract

The strategy of repeated ketamine in open-label and saline-control studies of treatment-resistant depression suggested greater antidepressant response beyond a single ketamine. However, consensus guideline stated the lack of evidence to support frequent ketamine administration. We compared the efficacy and safety of single vs. six repeated ketamine using midazolam as active placebo. Subjects received either six ketamine or five midazolam followed by a single ketamine during 12 days followed by up to 6-month post-treatment period. The primary end point was the change from baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) score at 24 h after the last infusion. Fifty-four subjects completed all six infusions. For the primary outcome measure, there was no significant difference in change of MADRS scores between six ketamine group and single ketamine group at 24 h post-last infusion. Repeated ketamine showed greater antidepressant efficacy compared to midazolam after five infusions before receiving single ketamine infusion. Remission and response favored the six ketamine after infusion 4 and 5, respectively, compared to midazolam before receiving single ketamine infusion. For those who responded, the median time-to-relapse was nominally but not statistically different (2 and 6 weeks for the single and six ketamine group, respectively). Repeated infusions were relatively well-tolerated. Repeated ketamine showed greater antidepressant efficacy to midazolam after five infusions but fell short of significance when compared to add-on single ketamine to midazolam at the end of 2 weeks. Increasing knowledge on the mechanism of ketamine should drive future studies on the optimal balance of dosing ketamine for maximum antidepressant efficacy with minimum exposure.

Retracing our steps to understand ketamine in depression: A focused review of hypothesized mechanisms of action

“…34 Interestingly, all of these reports [31][32][33][34] describe attenuation of both acute and sustained effects of ketamine in MDD. While a recent study 35 did not replicate these findings, BZD doses were not reported. Since this may be a dosedependent effect, it is challenging to interpret the significance of this.…”

“…BZDs have been reported [31][32][33][34] to attenuate the effect of ketamine in MDD. While not all studies have reported evidence of this interaction, 35 given the persistence of this effect in the setting of heterogeneous data and proposed mechanism of ketamine in MDD, it seems likely that BZDs pose a pharmacodynamic interaction in a dose-dependent manner. Limited data exists around ketamine and concomitant AEDs in MDD.…”

Ketamine as an adjunctive therapy for major depression - a randomised controlled pragmatic pilot trial (Karma-Dep Trial)

“…No participants met response criteria within four hours of the first infusion session in either group. There have been very few trials that have examined serial ketamine infusions in depressed patients and results have been inconsistent in terms of its potential to prolong its antidepressant effects [22][23][24] . As this is a pilot trial with a small number of participants, we were unable to establish differences in depression scores at the follow-up time points.…”

“…Results showed that ketamine was not superior over placebo in reducing depression scores. A very recent clinical trial (n=54) compared a single ketamine infusion (preceded by five midazolam (active placebo) infusions) to six repeated ketamine infusions in medicated participants with diagnosed treatment resistant depression 24 . Ketamine had a greater antidepressant effect over midazolam.…”

Ketamine—50 years in use: from anesthesia to rapid antidepressant effects and neurobiological mechanisms

“…Because the antidepressant effects of ketamine are relatively transient, repeated doses are often required to maintain them. However, repeated doses may not produce markedly enhanced antidepressant effects than a single ketamine treatment [ 99 ].…”