The Impact of Intravenous Ketamine on Attentional Bias: Probing Mechanisms of Rapid-Acting Antidepressant Effects in Two Clinical Studies

Abstract

Background: Ketamine is known for its rapid antidepressant effect, but its impact on affective information processing (including attentional bias [AB], a putative cognitive mechanism of depression) remains largely unexplored. We leveraged a novel measurement of AB and sought to 1) establish adequate test-retest reliability and validity among participants with depression prior to ketamine treatment and 2) harness a single dose of ketamine to assess mechanistic shifts in AB and their relationship to antidepressant efficacy.

Methods: A novel dual probe video task was used to index AB toward sad film clips. In study 1, treatment-seeking adults with moderate-to-severe depression (N = 40) completed the task at baseline, 1-week retest, and 1-month retest; a subset of participants (n = 15) also performed the task at 24 hours postketamine infusion (0.5 mg/kg over 40 minutes). In study 2, participants (N = 43) completed the task pre- and 24 hours postketamine.

Results: Indices from the novel AB task were stable prior to ketamine, demonstrating good 1-week and 1-month test-retest reliability. Participants in both studies exhibited a robust reduction in AB from pre- to 24 hours postketamine infusion. In study 1, cross-sectional correlations were observed between AB and clinician-rated depressive symptoms at each pretreatment assessment. In study 2, changes in AB were correlated with improved symptoms from pre- to postinfusion.

Conclusions: Results provide evidence for the validity of a novel, psychometrically robust measure of AB among individuals with depression. Findings indicate that ketamine reliably and rapidly reduces AB, offering insight into a replicable, potential cognitive mechanism involved in its antidepressant action.

Keywords: Attentional bias; Depression; Intravenous ketamine; Psychedelics; Rapid-acting antidepressants; Replication and reproducibility.

Figure 1.. Cross-Sectional Correlations Between Attentional Bias and MADRS Scores during Study 1 Test-Retest Phase

Figure 2.. Change in Attentional Bias Score, as a Function of Interval

Note. AB = Attentional Bias. In this graph, interval is defined as either no-intervention or pre-post ketamine infusion 1-week interval. For visualization purposes, participants’ change score is plotted against the zero point, which would indicate no change in attentional bias. Error bars represent the 95% confidence intervals around mean change in attentional bias for each group at each timepoint.

Figure 3.. Correlations Between Percent Change in Attentional Bias and MADRS Scores following Ketamine Infusion in Study 1 and 2