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Improved implicit self-esteem is associated with extended antidepressant effects following a novel synergistic intervention



In a previously published randomized controlled trial, automated self-association training (ASAT), a novel digital intervention, was found to extend the rapid antidepressant effect of a single infusion of ketamine for at least 30 days. In this secondary analysis, we aimed to understand the potential role of implicit self-esteem in the combined antidepressant effect of ketamine and ASAT training, by investigating the novel synergistic treatment’s effects on implicit self-associations and their relation to symptom improvement.


A total of 154 adults (ages 18–60) with treatment-resistant unipolar depression and lower-than-normative explicit self-esteem were randomized in a double-blind, parallel-arm design to receive one of three treatment allocations: an active/active treatment combination consisting of one infusion of ketamine (0.5 mg/kg) followed by four days of ASAT ( ~ 30–40 min/day), or one of two control arms that lacked either the active drug or the active behavioral component. The Implicit Association Test (IAT) was used to behaviorally assess the strength of association between self-related stimuli and negative concepts. Linear regression models were used to test the relationship between group assignment, IAT scores acquired immediately post-treatment, and both acute and extended clinical outcomes (% change in Montgomery-Asberg Depression Rating Scale scores, relative to pre-treatment baseline) in the trial.


The group assigned to ketamine + ASAT intervention, compared to the other groups, had a pattern of IAT scores indicating more positive self-associations immediately after treatment relative to the control arms (F(1, 131) = 3.979; p = 0.048). In regression models, IAT scores tracked with concurrent (acute post-treatment) % change in MADRS scores across all treatment arms (p = 0.001), and mediated more extended (Day 30) depression improvements specifically for the ketamine+ASAT arm (group * IAT interaction term: β = –0.201; p = 0.049).


Our findings suggest that changing implicit self-worth during a post-ketamine ‘plasticity window’ is one key mechanism whereby the novel ketamine+ASAT treatment combination exerts its antidepressant benefit, confirming the intended treatment target at the level of implicit cognition. Future studies should seek to further enhance the reliability of the biobehavioral intervention’s impact on implicit cognition, as this mechanism appears linked to the intervention’s enduring clinical benefits.

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Fig. 1: Study Design Features.
Fig. 2: Main effect of the intervention on IAT self-worth composite score.
Fig. 3: Scatterplots for relationships between IAT scores and depression improvement.

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Data availability

The datasets analyzed during the current study are available from the corresponding author on reasonable request.


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Supported by National Institute of Mental Health Biobehavioral Research Awards for Innovative New Scientists (BRAINS) R01 grant R01MH113857 (Dr. Price) and by the Clinical and Translational Sciences Institute at the University of Pittsburgh (UL1-TR-001857). We are deeply grateful to the study participants for their time and dedicated collaboration in this work.

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Authors and Affiliations



RBP, SJW, and MLW conceived and designed the study. CS, BP, AG, MD, NC, EB, KD, RHH, and RBP conducted the study and collected the data. HNE and RBP analyzed the data. HNE drafted the manuscript. All authors revised the manuscript for important intellectual content and approved the final version.

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Correspondence to Rebecca B. Price.

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Competing interests

RBP work has been funded by the NIH. RBP is the named inventor on a University of Pittsburgh-owned patent filing related to the combination intervention described in this letter. MLW has served as a statistical consultant for Health Rhythms, Noctem Health, and Sleep Number Bed. SJM is supported through the use of facilities and resources at the Michael E. Debakey VA Medical Center, Houston, Texas, and receives support from The Menninger Clinic. SJM has served as a consultant to Alkermes, Allergan, Almatica, Axsome Therapeutics, Biohaven, BioXcel Therapeutics, Clexio Biosciences, Eleusis, EMA Wellness, Engrail Therapeutics, Greenwich Biosciences, Intra-Cellular Therapies, Janssen, Levo Therapeutics, Neurocrine, Perception Neuroscience, Praxis Precision Medicines, Relmada Therapeutics, Sage Therapeutics, Seelos Therapeutics, and Signant Health. He has received research support from Biohaven Pharmaceuticals, Boehringer-Ingelheim, Merck, Sage Therapeutics, and VistaGen Therapeutics. All other authors report no financial conflicts of interest to disclose.

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Eken, H.N., Spotts, C., Panny, B. et al. Improved implicit self-esteem is associated with extended antidepressant effects following a novel synergistic intervention. Mol Psychiatry (2024).

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