Abstract
BACKGROUND: Ketamine is increasingly used as a therapeutic option for treatment-resistant depression (TRD) due to its rapid antidepressant properties; however, the mechanisms underlying these effects remain elusive. Preclinical evidence suggests ketamine acts on neural pathways implicated in reward processing, but translational efforts have proven challenging due to a lack of paradigms allowing for analogous assessment of depressive phenotypes across species. METHODS: We investigated the effects of a single, subanesthetic dose of ketamine on reward responsiveness in individuals with TRD (0.5 mg/kg) and rats exposed to chronic stress (10 mg/kg) using functionally identical tasks. Humans completed the Probabilistic Reward Task (PRT) twice within 48 hours, either without intervention (healthy control [HC] participants, n = 36, 26 women) or 24 hours before and after ketamine administration (individuals with TRD, n = 24, 16 women). Rats (all male) completed a reverse-translated version of the PRT on 3 consecutive days (HC group, n = 10) or before and after chronic stress exposure as well as 2 hours and 24 hours after ketamine administration (experimental group, n = 10). RESULTS: Ketamine significantly increased response bias toward the more frequently rewarded stimulus in both species, resulting in levels comparable with HCs 24 hours postadministration. Exploratory analyses in humans suggested that this effect was strongest among individuals with more pronounced baseline anhedonia. Furthermore, in both species, ketamine had no effect on measures of discriminability, suggesting that ketamine selectively improved reward learning rather than overall task performance. CONCLUSIONS: Results highlight a shared behavioral mechanism through which ketamine alleviates anhedonic behaviors and offers important implications for the treatment of people with anhedonia in TRD and related psychopathologies.