In Vitro Investigation of the Toxicity Mechanisms of Antidepressant Drugs on Adipose Tissue in 3T3‐L1 Cells

Major depressive disorder (MDD) is a common and disabling psychiatric illness often treated with antidepressants such as amitriptyline and citalopram. While effective for symptom relief, these drugs are linked to metabolic effects like weight changes, whose mechanisms remain unclear. This study examined the direct actions of clinically relevant concentrations of amitriptyline (1 ng/mL) and citalopram (2 ng/mL) on differentiated 3T3-L1 adipocytes, independent of systemic influences. Cells were exposed for short-term (24 h) and long-term (192 h) periods, and markers of adipogenesis, oxidative stress, adipokine secretion, and inflammation were evaluated. Short-term exposure to both agents reduced adipogenic markers [peroxisome proliferator activated receptors alpha and gamma (PPARα, PPARγ), fatty acid-binding protein 4 (FABP4), and aromatase] and decreased leptin and adiponectin secretion. After prolonged exposure, partial recovery occurred, with citalopram showing greater restoration of PPARγ and FABP4, whereas amitriptyline induced sustained stress signaling, reflected by increased C/EBPβ. Oxidative parameters showed transient changes, with stronger lipid peroxidation under amitriptyline. Inflammatory cytokines showed mild, non-significant elevations, mainly in amitriptyline-treated cells. Overall, both antidepressants directly modulated adipocyte function, altering adipogenic signaling, oxidative balance, and adipokine release. The distinct recovery profiles suggest that citalopram may pose a lower metabolic burden than amitriptyline. By clarifying adipocyte-specific pathways involved in antidepressant-associated weight alterations, this study underscores the need to consider tissue-level effects when assessing the metabolic safety of psychiatric drugs. Further studies in human adipocytes are warranted to refine antidepressant selection and reduce metabolic complications in long-term therapy.