Early treatment with vildagliptin and linagliptin reduces social fear and prevents the onset of comorbid depression in a mouse model of social anxiety disorder

We have previously shown that sitagliptin, a widely used dipeptidyl peptidase-4 (DPP4) inhibitor for the treatment of type 2 diabetes mellitus, effectively reduces social fear in an animal model that closely mimics the main behavioral symptoms of social anxiety disorder (SAD). This social fear conditioning (SFC) model induces social fear without comorbidities in the short term, but over time, a depressive-like phenotype emerges, mimicking the comorbidity often observed in SAD patients. In this study, we investigated the effects of two DPP4 inhibitors, vildagliptin and linagliptin, both of which have distinct pharmacokinetic profiles compared to sitagliptin, on social fear and the prevention of comorbid depressive-like behavior. We show that administration of vildagliptin (50 mg/kg/day and 100 mg/kg/day) and linagliptin (5 mg/kg/day and 10 mg/kg/day) via the drinking water significantly reduced social fear in male CD1 mice subjected to SFC. Importantly, both gliptins also prevented the onset of comorbid depressive-like behavior in these mice. These results have important clinical connotations, as they suggest that early treatment with DPP4 inhibitors such as sitagliptin, vildagliptin and linagliptin could serve as promising therapeutic strategy for SAD, not only reducing the main symptoms of social anxiety but also the risk of developing comorbid mood disorders that often exacerbate the severity of symptoms and complicate treatment outcomes.