Background: Major depressive disorder is a mental disorder characterized by at least two weeks of pervasive low mood, loss of interest in normally enjoyable activities, desvenlafaxine is one of the most commonly antidepressants, sodium butyrate is a HDACi, which has recently been shown to improve the prognosis in depressed patients. Purpose: 1) Assessment therapeutic benefits of sodium butyrate both alone or in combination with desvenlafaxine in a model of stress induced depression. This study included the parameters latency time to achieve immobilization after tail suspension, exploratory behavior on open field, Stereotypic behavior. 2) Assessment of possible side effects of tested drugs both alone or in-combination .The parameters used for this purpose were: histopathological study of heart as a measure of cardiovascular side effects of tested drugs. 3) Identifying the target gene for tested drug (gene expression of serotonin transporter was estimated). Materials & Methods: Rats were classified into: Group I: control normal group. Group II: (depression induced rats), Subgroup IIa (non –treated stress induced depressed rats), Subgroup IIb: (sodium butyrate treated group), Group II c: (Desvenlafaxine treated group), Group II d: Both sodium butyrate and desvenlafaxine was administrated. Results: Treated groups showed significant improvement in all parameters and improvement of the histopathology of the myocardium at the end of the 3rd week of drug administration. Conclusion: it was found that desvenlafaxine or sodium butyrate has anti-depressant effect, with decrease effect with combination.