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The most effective treatments for depression include pharmacotherapy and psychotherapy, but a pressing need remains for rapid, efficacious treatments. While the administration of ketamine can reduce depressive symptoms within two to 24 hours, these effects dissipate in a brief period following a single infusion. Rebecca Price, PhD (Associate Professor of Psychiatry and Psychology), and colleagues wanted to see whether ketamine’s benefits could be extended and combined with alternative treatment methods. In a 2022 randomized controlled trial, she demonstrated that automated self-association training (ASAT), a novel digital intervention, extends the rapid antidepressant effect of a single infusion of ketamine for at least 30 days. 

In a secondary analysis of the study recently published in Molecular Psychiatry,  Dr. Price and colleagues including H. Nur Eken, MD (PGY3 psychiatry resident); Meredith Wallace, PhD (Associate Professor of Psychiatry and Biostatistics); and Robert Howland, MD (Associate Professor of Psychiatry), from Pitt Psychiatry, sought to understand the potential role of implicit self-esteem in the combined antidepressant effect of ketamine and ASAT training. 

The investigators demonstrated that individuals receiving ketamine and ASAT treatment combination, compared to the two comparison groups (who received one of the two intervention components in the absence of the other) had better implicit self-esteem (i.e., weaker associations between self and negative concepts) immediately after the acute intervention. When exploring individual differences across participants, they found that when patients received ketamine and ASAT treatment, those specific patients who showed the most beneficial levels of implicit self-esteem immediately afterwards went on to prospectively sustain greater reductions in depression for up to 30 days. “We looked at scores from Implicit Association Tests and how they related to clinical outcomes in active treatment compared to other groups. This allowed us to confirm the mechanistic target of the combined ketamine and ASAT treatment—that it improved implicit self-associations during a ‘plasticity window’ induced by the ketamine infusion,” said Dr. Eken, first author of the study.

“Dr. Eken’s analyses have allowed us to reveal, for the first time, the neurocognitive mechanism at play during our novel synergistic treatment combination, which accounts for the extended clinical effect we observed among our patients. We can use this deepened understanding to further enhance the strength and impact of our treatment, and to expand the number of patients who might benefit,” said Dr. Price, the study’s senior and corresponding author.

Improved implicit self-esteem is associated with extended antidepressant effects following a novel synergistic intervention
Eken HN, Spotts C, Panny B, Griffo A, Degutis M, Cruz N, Bell E, Do-Nguyen K, Wallace ML, Mathew SJ, Howland RH, Price RB.
Molecular Psychiatry (2024). https://doi.org/10.1038/s41380-024-02564-y