By the year 2020, depression will be the second leading cause of death. So it should be treated carefully. Classically, Tricyclic antidepressants and Monoamine oxidase Inhibitors were used to treat depression. But recently, clinically effective antidepressants with rapid onset of action and less side effects are developed. Here, selective serotonin reuptake inhibitors like fluoxetine, escitalopram are used in combination with ondansetron.Ondansetron may directly block 5HT3 receptors which modulate neuronal release of other neurotransmitters like Nor-epinephrine which is the possible mechanism of action. And also SSRI's are having gastrointestinal side effects which can be inhibited by ondansetron & also show additive antidepressant effect. In present study, an attempt was made to find out which is the best combination for antidepressant treatment between different doses of ondansetron and SSRI's.