4.1 Comparison with previous studies
Previous studies have shown that SSRI use is associated with increased risk of UGIB among older people and that the risks varies based on the SSRI categories[10]. In a British study consisting of people initiating SSRIs treatments after the age of 65 years, citalopram was the only SSRI that showed a statistically significant association with increased incidence of UGIB[25]. Another study in Canada, which focused on older people treated with antidepressants, revealed that the risk of UGIB increased in patients with high inhibition of serotonin reuptake compared with those with low inhibition of serotonin reuptake[10]. Our observations further showed a dose-response relationship between SSRI use and risk of UGIB in older people, and the risk was primarily associated with fluoxetine, one of the inhibitor with high affinity to serotonin transporter[10].
Previous studies examining the dose-related risk of UGIB were largely conducted in younger population and showed inconsistent findings[11, 26]. A population-based case-crossover study did not show a dose-response relationship across SSRI doses of <0.5 DDD/day, 0.5–1.0 DDD/day, and ≥1.0 DDD/day[26]. However, the case-crossover study evaluated the effect of short-term rather than long-term exposures. A retrospective cohort study found that compared with non-use of SSRIs, the hazard ratio of developing UGIB was 2.39 for doses 28–140 DDDs and 141–280 DDDs, but it decreased to 1.71 for doses above 280 DDDs[11]. Our analysis focused on older people treated with SSRIs and showed that the risk of UGIB increased as the cumulative exposures of SSRIs increased, specifically fluoxetine. A possible explanation was that aging could modify the pharmacokinetics and pharmacodynamics of drugs, and drug interactions that resulted from polypharmacy were of significant relevance to antidepressant safety[27]. Furthermore, SSRIs could interfere with the pharmacological effects by competing for the binding sites of plasma proteins with other drugs or inhibiting drug transporters, which increased the absorption of drugs from the gastrointestinal tract and decreased the elimination from the body[27].