Protective effects of antidepressants against ulcerogenic agents: insights from nonclinical studies

There is a marked overlap among the neuronal pathogenetic pathways involved in ulcer genesis and depression, and antidepressants can also exert a protective effect against gastric ulcers. To summarize and critically discuss non-clinical evidence about the gastroprotective potential of antidepressants. Articles related to the survey were searched on PubMed, ScienceDirect, MedLine, and Lilacs, identifying 163 publications from 1974 to 2024, after reviewing 27 articles were selected. All experimental research on the antiulcer potential of antidepressants has used acute gastric ulcer models, mainly ethanol- and indomethacin- induced ulcers. Tricyclic antidepressants, such as amitriptyline, are the most researched and have shown significant gastroprotective effects, reducing ulcer size and severity, and inhibiting NOX2 and NOX4 (enzymes from the NADPH oxidase family) expression in gastric mucosa. Selective serotonin reuptake inhibitors also exhibit gastroprotective effects. Fluoxetine decreased ulcer size in a stress and indomethacin model while increasing antioxidant production and decreasing inflammation in indomethacin-induced ulcers, but one study found that fluoxetine had a greater gastroprotective effect in male rodents than in females, highlighting the need for further research on sex differences. Mirtazapine and duloxetine have also shown gastroprotective benefits. Mirtazapine reduced ulcer size in an indomethacin model. In a stress and indomethacin model, duloxetine reduced ulcer size while also decreasing NOX1 and NOX4 expression. The mechanisms underlying the gastroprotective effects of antidepressants involve peripheral reduction of mucosal oxidative stress and central modulation of vagal stimulus and an increase in noradrenergic and serotonergic neurotransmission. Overall, the trials examined show that antidepressants are effective in preventing ulcers and may be useful in protecting against gastric ulcer development, especially in people with depression.