Dysregulation of brain synaptic proteins caused by chronic psychosocial stress has been linked with the development of major depression (MD). To gain insights into the pattern of synaptic proteome changes and different biological functions and pathways underlying MD and drug action, a comparative proteomic approach was employed in the hippocampus of rats exposed to chronic social isolation (CSIS, 6 weeks), an animal model of depression, with or without chronic antidepressant tianeptine (Tian) treatment (last 3 weeks of CSIS).