Major depression is a disease characterized by an inability of neuronal systems to show appropriate adaptive plasticity especially under challenging conditions, such as stress. Conversely, pharmacological intervention may normalize such defects through the modulation of factors that might act in concert for the functional recovery of depressed patients, like the neuropeptide VGF, which has previously shown to possess antidepressant like activity. We analyzed VGF mRNA levels in the brain of rodents exposed to stress or treated with antidepressant drugs. In addition, we assessed VGF expression in leukocytes obtained from 25 drug-free depressed patients before and during antidepressant treatment. We found a persistent reduction of VGF expression after exposure to prenatal stress and an upregulation of its levels following chronic treatment with different antidepressant drugs. Moreover, VGF mRNA levels were significantly reduced in drug-free depressed patients, as compared with controls, and were modulated in response to effective antidepressant treatment. Our data provide further support to the role of VGF in mood disorders and suggest that VGF could be a more specific biomarker for treatment responsiveness.