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Functional magnetic resonance imaging was used during emotion recognition to identify changes in functional brain activation in 21 first-episode, treatment-naive major depressive disorder patients before and after antidepressant treatment. Following escitalopram oxalate treatment, patients exhibited decreased activation in bilateral precentral gyrus, bilateral middle frontal gyrus, left middle temporal gyrus, bilateral postcentral gyrus, left cingulate and right parahippocampal gyrus, and increased activation in right superior frontal gyrus, bilateral superior parietal lobule and left occipital gyrus during sad facial expression recognition. After antidepressant treatment, patients also exhibited decreased activation in the bilateral middle frontal gyrus, bilateral cingulate and right parahippocampal gyrus, and increased activation in the right inferior frontal gyrus, left fusiform gyrus and right precuneus during happy facial expression recognition. Our experimental findings indicate that the limbic-cortical network might be a key target region for antidepressant treatment in major depressive disorder.