The present work involves the synthesis of three series of novel fluoxetine derivatives in order to evaluate their potential as antidepressants. The first series consists of 1-methyl-1-[3-phenyl-3(4-trifluoromethylphenoxy)propyl]-3-substituted ureas 2a-c and thioureas as their bioisosters 3a-m which were prepared by reacting fluoxetine 1a with different isocyanates and isothiocyanates respectively. The second series N-acyl/aroyl-Nmethyl-3-phenyl-3-(4-trifluoromethylphenoxy)-propylamines 4a-d were synthesized by refluxing 1a with acyl/aroyl chloride and trifluoroacetic anhydride. The third one, N-chloroacyl-fluoxetine 5a-c was obtained via the reaction of 1a with chloroacyl chloride. In addition to a propionitrile derivative 8 which was achieved by refluxing 1a with acrylonitrile. The twenty four final compounds were biologically screened throughout the work for their potential as serotonin reuptake inhibitors by measuring potentiation of 5HTP induced neurotoxity and some as norepinephrine reuptake inhibitor by measuring yohimbine-induced mortality in mice to calculate5-HTP/NE ratio as a parameter for selectivity to inhibit serotonin reuptake. Four compounds (3e, 3h, 3i, 5b) were found to be as potent as fluoxetine.