Major depressive disorder (MDD) is one of the most popular diseases affecting an enormous population of worldwide. MDD is considered a complex mental disorder with unknown clear etiology. It becomes the most common neuropsychiatric disorder. MDD affects a person's life efficiency. Many data support that the excess administration of glucocorticoids may lead lot of behavioral, biochemical, functional and morphological characteristics of depression. The disturbance in glucose metabolism involves depression pathogenesis. The concentration of glucose and glycogen in the frontal cortex and hippocampus increases during depression. The marked increase in the concentration of carbohydrates and glucose transporters is evidence of animal exposure to stress. Mammalian targets of rapamycin (mTOR) signaling pathways are involved in the pathogenesis of depression. This signaling is impaired in the frontal cortex and hippocampus of an animal with MDD. It was demonstrated that mTOR is activated by its phosphorylation at serine 2448 and promoting two downstream molecules. It was reported that the mTOR system is involved in antidepressant mechanisms. This review discusses the role of brain glucose and mTOR pathways involved in controlling major depressive disorder in addition to the different therapeutic approaches for the treatment of depression.