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

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

Methods: 154 adults (age 18–60) with unipolar, treatment-resistant depression were randomized in a double-blind, parallel arm design to receive an active/active treatment combination [ketamine+active Automated Self-Association Training (ASAT);n=53], or one of two control arms that lacked either the active drug (saline+active ASAT;n=51) or the active behavioral (ketamine+sham ASAT;n=50) components. One day after a single infusion of intravenous ketamine (0.5mg/kg over 40minutes) 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 nor self-referential stimuli) was given, delivered twice daily over 4 consecutive days (eight ~20min sessions; 2.5hours total). The Montgomery-Asberg Depression Rating Scale (MADRS) was the pre-specified primary outcome throughout the main (30-day) study period.

Results: Ketamine rapidly reduced depression scores at 24-hours post-infusion (group*time:β*=−1.30[95% CI: −1.89 to −0.70];t150=−4.29;p<.0001). In intent-to-treat, linear mixed models, ket+ASAT depression scores remained stably low over the 30-day acute phase, relative to saline+ASAT (β*=−0.61[95% CI:−0.95 to −0.28];t148=−3.62;p=.0004). By contrast, depression scores following ket+Sham followed an increasing linear trajectory from 24-hours to 30-days, approaching saline+ASAT levels (group*time relative to saline+ASAT:β*=0.015[95% CI:0.003 to 0.03];t568=2.35;p=.019).

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

Trial Registration: Clinicaltrials.gov NCT03237286, “Intravenous Ketamine Plus Neurocognitive Training for Depression” (https://clinicaltrials.gov/ct2/show/NCT03237286)