Targeting treatment-resistant social anxiety with sitagliptin: Effects on social fear and comorbid depressive-like behavior in a preclinical model

Social anxiety disorder (SAD) is often complicated by comorbid depression and resistance to standard treatments, yet therapeutic strategies that effectively address both core and comorbid symptoms remain limited. We previously demonstrated that sitagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor commonly used in the treatment of type 2 diabetes mellitus, effectively reduces social fear in mice subjected to social fear conditioning (SFC), an ethologically valid model of SAD. In the present study, we extend these findings by evaluating the efficacy of sitagliptin in reducing social fear and preventing the development of comorbid depressive-like behavior in acid sphingomyelinase-deficient (ASM-/-) mice, a genetically defined model of antidepressant-resistant emotional behavior. Chronic oral administration of sitagliptin (100 mg/kg/day) significantly reduced social fear in both male and female ASM+/+ and ASM-/- mice following SFC. Notably, sitagliptin also prevented the emergence of depressive-like behavior in both genotypes, as well as the increase in anxiety-like behavior observed specifically in ASM-/- mice, two hallmark comorbidities in the SFC model. These findings indicate that sitagliptin exerts dual-action effects on both primary and comorbid behavioral symptoms of SAD, including in individuals resistant to conventional antidepressant treatment. Given its established clinical use and safety profile, sitagliptin may represent a promising candidate for repurposing as an early intervention in complex, treatment-resistant forms of SAD.