A Novel, Brief, Fully Automated Intervention to Extend the Antidepressant Effect of a Single Ketamine Infusion: A Randomized Clinical Trial

This double-blind, placebo-controlled study (n=154) of ketamine (35mg/70kg) (or placebo) with (and without) positive self-regard training (automated self-association training) finds that the combination can extend the positive antidepressant (MADRS) effects of ketamine, whilst the effects of ketamine alone was not distinguishable from placebo 30 days later.

Abstract

“Objective: Intravenous ketamine, which displays rapid antidepressant properties, is posited to reverse depression by rapidly enhancing neuroplasticity. The authors tested whether an automated, computer-based approach could efficiently leverage enhanced neuroplasticity to extend the durability of rapid clinical response.

Methods: A total of 154 adults (ages 18–60) with treatment-resistant unipolar depression were randomized in a double-blind, parallel-arm design to receive an active/active treatment combination (ketamine plus active “automated self-association training” [ASAT]; N=53) or one of two control arms that lacked either the active drug component (saline plus active ASAT; N=51) or the active behavioral component (ketamine plus sham ASAT; N=50). One day after a single infusion of intravenous ketamine (0.5 mg/kg over 40 minutes) or inert placebo (saline), active ASAT—targeting self-worth through automated “evaluative conditioning” training delivered by computer—or sham ASAT (consisting of identical computer tasks that included no positive or self-referential stimuli) was given, delivered twice daily over 4 consecutive days (eight sessions, ≤20 minutes per session). The prespecified primary outcome measure throughout the main (30-day) study period was score on the Montgomery-Åsberg Depression Rating Scale (MADRS).

Results: Ketamine rapidly and significantly reduced depression scores at 24 hours postinfusion (group-by-time interaction: standardized beta [β]=−1.30, 95% CI=−1.89, −0.70; t=−4.29, df=150). In intent-to-treat linear mixed models, depression scores in the ketamine+ASAT group remained significantly and stably low over the 30-day study period relative to those of the saline+ASAT group (β=−0.61, 95% CI=−0.95, −0.28; t=−3.62, df=148). By contrast, depression scores following ketamine+sham treatment followed a significant, increasing linear trajectory from 24 hours to 30 days, approaching the levels observed in the saline+ASAT group (group-by-time interaction relative to the saline+ASAT group: β=0.015, 95% CI=0.003, 0.03; t=2.35, df=568).

Conclusions: After priming the brain with ketamine, training positive self-associations could provide an efficient, low-cost, portable, noninvasive, and highly dissemination-ready strategy for leveraging and extending ketamine’s rapid antidepressant effects.”

Authors: Rebecca B. Price, Crystal Spotts, Benjamin Panny, Angela Griffo, Michelle Degutis, Nicolas Cruz, Elizabeth Bell, Kevin Do-Nguyen, Meredith L. Wallace, Sanjay J. Mathew & Robert H. Howland