Effects of repeated intravenous esketamine administration on affective biases

Objectives: While neuropsychological effects of conventional antidepressants are well-documented, more research is needed for rapid-acting antidepressants. This study examines the effects of esketamine on emotion processing and cognitive functioning, both acutely and sub-chronically. Methods: Eighteen treatment-resistant depression (TRD) patients received repeated intravenous esketamine infusions. Mood state was reported daily, and the Facial Expression Recognition Task was administered 1h before and 4h after each infusion. Other assessments included the Digit Symbol Substitution Task. Results: 66.7% participants who received at least five infusions (n = 12) showed significant improvement. Emotion recognition improved for all emotions except sadness, where accuracy decreased, particularly for low-intensity expressions (p =.007, d = −1.09). Misclassifications of other emotions as sad also decreased (p =.035, d = −0.79), indicating a reduced response bias towards sadness. This shift in bias emerged after the first infusion and then consolidated over time. In parallel, participants showed significant reductions in feelings of sadness (p =.015, d = −0.89) and irritability (p =.001, d = −1.35). Symptomatic improvement negatively correlated with accuracy for and misclassifications of sadness, and cognitive functioning also improved (p =.001, d = 1.62). Conclusions: Improvement of TRD by esketamine may involve shifts in emotion processing and cognition, with the acute mood-lifting effects of esketamine being discernible from longer-lasting antidepressant response, which consolidates after repeated administration.