Background: The objective of this study is to develop a new animal model based on signalingpathways to understand the pathophysiology, therapy of depression, and to investigate theantidepressant activity of Enicostemma littorale which is not yet established.Methods: Animal models of depression were raised by physical methods and administration ofmethyl isobutyl ketone (100 mg/kg b.w., i.p.,) and a protein tyrosine phosphatase inhibitor, sodiumorthovanadate (30 mg/kg b.w., i.p.,) to young Wistar rats. E. littorale aqueous extract (100 mg/kgb.w., oral) was administered. Forced swimming test (FST), biochemical, and histopathologicalparameters were performed with reference to fluoxetine (20 mg/kg b.w., oral) treatment.Results: High‑performance thin‑layer chromatography confirmed the presence of swertiamarin, a unique glycoside present in the Gentianaceae family. FST indicated high rates of immobility indepressed groups and low rates in plant extract‑administered group with reference to fluoxetine.Biochemical assays indicated significantly (P<0.05) increased levels of total protein, superoxidedismutase, triglycerides, and total serum cholesterol, whereas significant reduction (P<0.05)of glutathione peroxidase, catalase, and lipid peroxidation in plant extract‑administered groups incomparison to the depressed groups. Histopathological analysis indicated disorganized neuronalarchitecture during depression whereas rejuvenation of neuronal patterns was observed duringtreatment with plant extract and fluoxetine.Conclusions: This study shows that sodium orthovanadate induces depression in animals andalso establishes the antidepressant activity of E. littorale.