| Summary: | Abstract Background The identification of biomarkers that predict susceptibility to major depressive disorder and treatment response to antidepressants is a major challenge. Vortioxetine is a novel multimodal antidepressant that possesses pro-cognitive properties and differentiates from other conventional antidepressants on various cognitive and plasticity measures. The aim of the present study was to identify biological systems rather than single biomarkers that may underlie vortioxetine’s treatment effects. Results We show that the biological systems regulated by vortioxetine are overlapping between mouse and rat in response to distinct treatment regimens and in different brain regions. Furthermore, analysis of complexes of physically-interacting proteins reveal that biomarkers involved in transcriptional regulation, neurodevelopment, neuroplasticity, and endocytosis are modulated by vortioxetine. A subsequent qPCR study examining the expression of targets in the protein–protein interactome space in response to chronic vortioxetine treatment over a range of doses provides further biological validation that vortioxetine engages neuroplasticity networks. Thus, the same biology is regulated in different species and sexes, different brain regions, and in response to distinct routes of administration and regimens. Conclusions A recurring theme, based on the present study as well as previous findings, is that networks related to synaptic plasticity, synaptic transmission, signal transduction, and neurodevelopment are modulated in response to vortioxetine treatment. Regulation of these signaling pathways by vortioxetine may underlie vortioxetine’s cognitive-enhancing properties.
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