Evaluating the antidepressant effects of tirzepatide on unpredictable chronic mild stress-induced depression in Swiss Albino mice

A BSTRACT Objectives: Depression, diabetes, and obesity often coexist, forming a complex “metabolic-mood syndrome” characterized by inflammation, impaired neuroplasticity, and neuroendocrine dysregulation. Conventional antidepressants show limited efficacy in such cases and may worsen metabolic profiles. Tirzepatide, a dual glucagon-like peptide-1/glucose-dependent insulinotropic polypeptide receptor agonist approved for diabetes and obesity, may offer neuropsychiatric benefits. The objective of this study was to evaluate its antidepressant-like effects in an unpredictable chronic mild stress (UCMS)-induced depression model of Swiss Albino mice. Materials and Methods: Forty male Swiss Albino mice were randomly divided into five groups ( n = 8): normal control, disease control (DC) (UCMS + saline), positive control (UCMS + fluoxetine 10 mg/kg), and two test groups (UCMS + tirzepatide at 50 μg/kg and 120 μg/kg). UCMS was induced over 28 days. Behavioral assessments were conducted using forced swim test (FST) and tail suspension test (TST). After that, “hippocampal brain-derived neurotrophic factor (BDNF)” and “whole brain interleukin (IL-6) and serotonin” levels were analyzed using the enzyme-linked immunosorbent assay method. Results: Duration of immobility was significantly reduced in both FST and TST, in the high-dose group compared to the DC group. Hippocampal BDNF levels were significantly elevated in the high-dose group, suggesting enhanced neuroplasticity. While IL-6 and serotonin levels showed no statistically significant changes, the directional trends point toward possible anti-inflammatory effect and serotonergic modulation. Conclusion: This study provides preclinical evidence for the antidepressant-like effects of tirzepatide, likely mediated through neurotrophic and anti-inflammatory pathways. Tirzepatide holds promise as a novel therapeutic option for managing depression in patients with comorbid metabolic conditions.