What is the clinical evidence from this study?

Study design: Systematic Review. Population: Gastric ulcers. Intervention: Antidepressants (TCAs, SSRIs, and other classes) vs. Control (ulcerogenic agents alone). Primary outcome: Gastroprotective effect (reduction in ulcer size, severity, or ulcer index).

What question did this study set out to answer?

The aim is to summarize nonclinical evidence regarding the gastroprotective potential of antidepressants.

April 25, 2026Inflammopharmacology0 citationsOpen Access

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

CSCAROLINE STRINGARI HSHELOISA STRINGARI TSThiago Farias de Queiroz e Silva

Key Result

Antidepressants, particularly tricyclic antidepressants and selective serotonin reuptake inhibitors, demonstrated significant gastroprotective effects against acute gastric ulcers in nonclinical rodent models.

Key Points

The aim is to summarize nonclinical evidence regarding the gastroprotective potential of antidepressants.
Reviewed articles from PubMed, ScienceDirect, MedLine, and Lilacs, identifying 163 publications and selecting 27 for analysis.
Focused on experimental research utilizing acute gastric ulcer models, particularly ethanol- and indomethacin-induced ulcers.
Assessed various types of antidepressants, including tricyclics and selective serotonin reuptake inhibitors, for their effects on ulcer size and severity.
Tricyclic antidepressants like amitriptyline significantly reduced ulcer size and severity while inhibiting NOX2 and NOX4 enzyme expression in gastric mucosa.
Fluoxetine decreased ulcer size in stress and indomethacin models and increased antioxidant production, with noted sex differences in effectiveness.
Mirtazapine and duloxetine also demonstrated gastroprotective effects, reducing ulcer size in corresponding models and decreasing oxidative stress markers.

Study Design

Type

Systematic Review

Structured PICO

Do antidepressants reduce the severity of gastric ulcers in rodent models of acute gastric injury?

Population

28 articles comprising 50 independent experimental records using rodent models (3 using mice, 24 using rats) of acute gastric ulcers induced by agents such as ethanol, indomethacin, stress, reserpine, and pylorus ligation.

Intervention

Antidepressants as a class, including tricyclic antidepressants (e.g., amitriptyline, trimipramine, desipramine, doxepin), selective serotonin reuptake inhibitors (e.g., fluoxetine), mirtazapine, and duloxetine.

Comparator

Control animals receiving ulcerogenic agents (e.g., ethanol, indomethacin, stress) without antidepressant treatment.

Outcome

Effect of the antidepressant on the ulcerated area or on the gastric ulcer index.surrogate

Nonclinical evidence suggests that antidepressants possess significant gastroprotective properties against acute ulcerogenic agents, potentially mediated by antioxidant effects and central nervous system modulation.

Limitations

Significant heterogeneity in experimental methods, including variations in antidepressant dosages, delivery schedules, and outcome assessment techniques.
Moderate to unclear risk of bias among the included studies due to insufficient reporting of methodological details.
The impact on female animals was only assessed in one study, highlighting a need for further research on sex differences.

Abstract

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.

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