To compare the efficacy and safety of newer antidepressants like Escitalopram and Desvenlafaxine versus conventional antidepressant like Imipramine in patients with Depressive episode. An open label, prospective, comparative study was conducted in the psychiatry outpatient department (OPD), Victoria hospital, from Nov 2011- May 2013. 90 newly diagnosed patients of depressive episode according to ICD-10 criteria were divided into three groups of 30 each receiving Imipramine (Group A), Escitalopram (Group B) and Desvenlafaxine (Group C) and followed up for 12 weeks. Efficacy measurement was reduction in MADRS, CGI-S and CGI-I scores. Safety assessment was by number, severity and dropouts due to adverse drug reactions and laboratory investigations. Data was analyzed using ANOVA and Chi square test. Response rate was 63% in Group B, 53% in Group A and 50% in Group C, but this difference was not statistically significant. Initial response was seen as early as 2 weeks in 63% in group B and 43% in group C but none in group A and showed statistical significance. No statistically significant difference was seen in CGI-S and CGI-I scores at the end of 12 weeks. 43 ADRs were noted in group A most of which were moderate in severity, 27 ADRs and 37 ADRs were noted in group B and C respectively, most of which were mild. 9 patients in group A and 4 patients each in group B and C dropped out before the completion of the study. Commonest reason for drop out in groups A and B were ADRs whereas in group C was lack of response. No statistically significant difference was noted in efficacy between the three drugs however, escitalopram and desvenlafaxine had faster onset of action and were better tolerated than imipramine.