Investigating the cytotoxicity and genotoxicity of Vortioxetine with in vivo and in silico methods

Vortioxetine is a multimodal antidepressant with reported benefits on cognitive functioning, social functioning, and fatigue, however its potential genotoxic risks have not been adequately studied. Therefore, this study aims to investigate the cytotoxicity and genotoxicity of vortioxetine in vivo and in silico. Genotoxic effects were assessed using Chromosome aberration (CA) and micronucleus (MN) assays in cultured human peripheral blood lymphocyte. Cytotoxicity was evaluated through Mitotic index (MI), and DNA interaction was analysed by UV titration and agarose gel electrophoresis. In silico analyses were performed with Attraction Cavities and AutoDock Vina methods. Experimental results demonstrate that vortioxetine binds to Calf Thymus DNA (CT-DNA) through intercalative interactions and cleaves pBR322 DNA in the presence of hydrogen peroxide. DNA binding studies indicated that groove binding is the effective interaction between vortioxetine and CT-DNA (Kb: 6.25 × 10⁵ M^{- 1}). It was also supported by molecular docking results, where binding affinities of vortioxetine and escitalopram were - 7.29 and - 7.69 kcal/mol for Attracting Cavities and - 6.01 and - 6.57 kcal/mol for AutoDock Vina. When comparing vortioxetine to escitalopram, both drugs were found to be potentially genotoxic. These findings suggest a potential genotoxic risk with prolonged use and provide valuable insight for clinicians in evaluating long-term safety.