Sertraline is one of the most widely prescribed antidepressants, worldwide detected in rivers, thus raising concern about its ecotoxicology. However, there is knowledge gap on its pharmacokinetics and pharmacody- namics in freshwater bivalves. Comparative biology can help to gain in understanding and improve our ability to assess ecotoxicological risks in a wide range of species. This study investigated the kinetic-based bio- concentration and depuration of sertraline by two freshwater bivalve species, Dreissena polymorpha (zebra mussel, ZM) and Dreissena rostriformis bugensis (quagga mussel, QM), and (2) its biological effects depending on the exposure duration and frequency. Several biomarkers related to known sertraline side effects in human were followed. Results document a higher body burden in QM than in ZM. The steady-stage was not reached after 5 days of exposure. Bivalves were unable to depurate sertraline in 5 days in clean water. Findings provide evidence that environmentally relevant concentration of sertraline can disturb the physiology of Dreissena species, but not in the same way. QM was found to be more sensitive to sertraline than ZM, experiencing oxidative stress and lipid disorder. Intermittent exposure also led to biochemical changes in the two species, requiring further study.