Protective effect of concurrent bupropion and citicoline treatment on lipopolysaccharide-induced depression- and anxiety-like behavior in mice: The role of neuroinflammation.

Depression and anxiety cause substantial functional disabilities, and current treatments often have limited efficacy and notable adverse effects. Developing adjunctive therapies may help address these shortcomings. With established neuroprotective and antidepressant properties, citicoline may improve outcomes and minimize adverse effects. To assess citicoline as an adjuvant to bupropion in a lipopolysaccharide-induced model of depression and anxiety. Six-week-old male Naval Medical Research Institute mice were assigned to control or experimental groups receiving lipopolysaccharide alone or followed by daily bupropion (60 or 100 mg/kg), citicoline (25 or 75 mg/kg), or their combination. On Day 14, behavioral evaluations were performed in 8-week-old mice using the elevated plus maze, open field test, and forced swimming test, and hippocampal tumor necrosis factor-alpha, interleukin-1beta, malondialdehyde, and nitric oxide levels were assessed. Coadministration of low-dose bupropion (60 mg/kg) with an otherwise ineffective dose of citicoline (25 mg/kg) significantly improved anxiety- and depression-like behaviors in the elevated plus maze and forced swimming test and reduced hippocampal tumor necrosis factor-alpha, interleukin-1beta, malondialdehyde, and nitric oxide metabolites. These effects were consistently greater than those of bupropion (60 mg/kg) alone and were comparable or even superior to those achieved with the higher bupropion dose (100 mg/kg). Citicoline appears to positively potentiate bupropion's efficacy against depression- and anxiety-like behaviors in preclinical models of these human disorders, at least in part through attenuation of neuroinflammatory and oxidative processes. These findings suggest a promising experimental strategy that may help guide future clinical studies, particularly for unresponsive individuals. (PsycInfo Database Record (c) 2026 APA, all rights reserved).