A Novel, Brief, Fully Automated Intervention to Extend the Antidepressant Effect of a Single Ketamine Infusion: A Randomized Clinical Trial
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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.
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A randomized controlled trial of 154 participants with treatment-resistant depression found that acute ketamine (0.5 mg/kg) plus automated self-association training over four days significantly reduced depression scores over 30 days, whereas ketamine plus sham training showed increasing scores over 30 days.
“A large, randomized, controlled trial of 154 participants with TRD found that those who received an acute dose of ketamine (0.5 mg/kg) in conjunction with “automated selfassociation training” (ASAT) over four days had significantly reduced depression scores over a 30-day period; in contrast, the scores of those who received ketamine and a sham ASAT steadily increased over 30 days [56].”
From Ketamine in neuropsychiatric disorders: an update (2024) · cites this paper as [56]
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- Authors
- Price, R. B., Spotts, C., Panny, B., Griffo, A., Degutis, M., Cruz, N., Bell, E., Do-Nguyen, K., Wallace, M. L., Mathew, S. J., & Howland, R. H.
- Affiliations
- Michael E. DeBakey VA Medical Center (US)
- ORCID
- Venue
- American Journal of Psychiatry
- Published
- 2022-12-01
- Volume
- 179
- Issue
- 12
- Pages
- 959-968
- ISSN
- 0002-953X (ISSN-L)
- 1535-7228
- PMC
- PMC9722511
- OpenAlex
- W4296710292
- Cited by
- 85
- References
- 65
- Citations by year
- 2026: 20 · 2025: 19 · 2024: 17 · 2023: 25 · 2022: 4
- FWCI
- 9.72
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Commons-TMC (Texas Medical Center) (submittedVersion)
- Funders
- National Institutes of Health (UL1TR001857)
- National Institute of Mental Health (R01MH113857)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Health Sciences › Medicine › Psychiatry and Mental health › Electroconvulsive Therapy Studies
- Life Sciences › Neuroscience › Neurology › Transcranial Magnetic Stimulation Studies
- Keywords
- ketamine, treatment-resistant depression, major depressive disorder, evaluative conditioning, self-worth, neuroplasticity, computer-based intervention, rapid antidepressant response, antidepressant augmentation
- MeSH terms
- Adolescent, Adult, Antidepressive Agents, Double-Blind Method, Humans, Ketamine, Middle Aged, Treatment Outcome, Excitatory Amino Acid Antagonists, Young Adult, Depressive Disorder, Treatment-Resistant
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