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].