||Currently, the hazard posed by pharmaceutical residues is a major concern of ecotoxicology. Most of the antidepressants belong to a family named the Cationic Amphipathic Drugs known to have specific interactions with cell membranes. The present study assessed the impact of eight antidepressants belonging to selective serotonin reuptake inhibitors or serotonin norepinephrine reuptake inhibitors by the combination of multi-approaches (in vivo, in vitro, in silico) and gives some insights on the mode of action for these molecules. Antidepressants were from the most to the least toxic compound for Daphnia magna: Sertraline (EC50 = 1.15 mg L-1) > Clomipramine (2.74 mg L-1)> Amitriptyline (4.82 mg L-1)> Fluoxetine (5.91 mg L-1) > Paroxetine (6.24 mg L-1) > Mianserine (7.81 mg L-1) > Citalopram (30.14 mg L-1) and Venlafaxine (141.28 mg L-1). These acute toxicities were found correlated to Log K, coefficients (R = 0.93, p < 0.001) and to cytotoxicity assessed on abalone hemocytes through the neutral red uptake assay (R = 0.96, p < 0.001). If narcosis as mode of action is typically expected during acute ecotoxicity bioassays, we showed by molecular modeling that particular interactions can exist between antidepressants and phosphatidylcholine, a major component of cell membranes, leading to a more specific mode of action corresponding to a potential acidic hydrolysis of ester functions. (C) 2014 Elsevier Ltd. All rights reserved.