Major Depressive Disorder (MDD) is an idiopathic neuropsychiatric disorder that is highly prevalent. The exact cause and mechanism of the illness are still unclear. To help investigate MDD, we proposed utilizing Drosophila Melanogaster as the model organism. In order to induce depressive like behavior, a chronic stress has to be used. When social isolation was used as a stressor, wild type fruit flies exhibited locomotor hyperactivity when compared with control. Similar behavior was observed when mice was given chronic unpredictable mild stress (CUMS). The locomotor hyperactivity was found to be dependent on physical interaction among the flies. It was also found that social isolation reduced the brain serotonin content in the flies, which is concurrent with the monoamine hypothesis. To confirm this possibility, we fed the flies with serotonin or monoamine based antidepressants and found these drugs could reverse the social isolation induced locomotor hyperactivity. Since neurogenesis is theorized to be the mechanism behind MDD, we tested this possibility by performing real time PCR on related genes, such as CREB. It turned out that socially isolated flies had lower CREB expression in the brain versus socially housed flies. Epigenetics were theorized as a possible mechanism that suppressed CREB expression. To test this, we fed several HDACi and DNMTi drugs to the flies. Certain epigenetic inhibitors were indeed capable of reversing the locomotor hyperactivity. These data suggest that Drosophila Melanogaster can be utilized in the research of MDD, and that epigenetics is causatively related to MDD. Further research into this model shows promise in the hope of procuring a treatment for MDD.