Importance
Clinical research has shown that persistent negative beliefs maintain depression and that subanesthetic ketamine infusions induce rapid antidepressant responses.

Objective
To evaluate whether ketamine alters belief updating and how such cognitive effects are associated with the clinical effects of ketamine.

Design, Setting, and Participants
This study used an observational case-control protocol with a mixed-effects design that nested 2 groups by 2 testing time points. Observers were not blinded. Patients with treatment-resistant depression (TRD) and healthy volunteer participants aged 34 to 68 years were included. Patients with TRD were diagnosed with major depressive disorder or bipolar depression, had a Montgomery-Åsberg Depression Rating Scale score greater than 20, a Maudsley Staging Method score greater than 7, and failed to respond to at least 2 prior antidepressant trials. Exclusion criteria were any other psychiatric, neurological, or neurosurgical comorbidities, substance use or addictive disorders, and recreational ketamine consumption. Data were collected from January to February 2019 and from May to December 2019, and data were analyzed from January 2020 to July 2021.

Exposures
Patients with TRD were observed 24 hours before single ketamine infusion, 4 hours after the infusion, and 4 hours after the third infusion, which was 1 week after the first infusion. Healthy control participants were observed twice 1 week apart without ketamine exposure.

Main Outcomes and Measures
Montgomery-Åsberg Depression Rating Scale score and belief updating after belief updating when patients received good news and bad news measured by a cognitive belief-updating task and mathematically formalized by a computational reinforcement learning model.

Results
Of 56 included participants, 29 (52%) were male, and the mean (SEM) age was 52.3 (1.2) years. A total of 26 patients with TRD and 30 control participants were included. A significant group × testing time point × news valence interaction showed that patients with TRD updated their beliefs more after good than bad news following a single ketamine infusion (controlled for age and education: β = -0.91; 95% CI, -1.58 to -0.24; t216 = -2.67; P = .008) than controls. Computational modeling showed that this effect was associated with asymmetrical learning rates (LRs) after ketamine treatment (good news LRs after ketamine, 0.51 [SEM, 0.04]; bad news LRs after ketamine 0.36 [SEM, 0.03], t25 = 3.8; P < .001) and partially mediated early antidepressant responses (path a*b: β = -1.00 [SEM, 0.66]; t26 = -1.53; z = -1.98; P = .04).

Conclusions and Relevance
These findings provide novel insights into the cognitive mechanisms of the action of ketamine in patients with TRD, with promising perspectives for augmented psychotherapy for individuals with mood disorders.