4.2 Pharmacological explanations for the association between
SSRIs and risk of UGIB
There are potential pharmacological explanations for the dose-response
relationship between fluoxetine use and UGIB risk. Fluoxetine was found
to stimulate gastric acid secretion in a dose-response fashion, and
larger amounts of gastric acid could cause formation of chronic
ulcer[28, 29]. Furthermore, fluoxetine decreased the incidence of
indomethacin (one kind of NSAID)-induced ulcers and ulcer bleeding in
rats[30, 31]. However, in our analysis, the dose-response
relationship between fluoxetine and UGIB remained significant after
controlling for NSAID use and other potential confounders. Despite the
fact that fluoxetine is not generally recommended for older patients due
to its long half-life and prolonged side effects[32], it was the
most frequently prescribed SSRI for both case and control groups in our
analysis and in other studies[33].
Our observation showed that paroxetine was associated with decreased
risk of UGIB, which was an unexpected result. Despite being known as the
most potent inhibitor of serotonin reuptake[34], previous
investigations did not find an association between paroxetine use and
UGIB risk[15, 25, 35]. However, a previous study has revealed that
the paroxetine effect on platelet function was modified by the serotonin
transporter gene (SLC6A4) promoter polymorphism (5-HTTLPR)[36].
After receiving paroxetine treatment, an increase in bleeding time was
observed in patients without L-alleles but not in those with L-alleles.
Patients without L-alleles experienced problems in platelet function
such as greater decreases in platelet serotonin levels[36]. In
contrast, a study conducted in Taiwan demonstrated no significant
differences between three 5-HTTLPR genotype groups[37]. More studies
are needed to clarify the role of genetic profile.
Our findings, which emphasized the association between UGIB risk and
recent use of fluoxetine, are consistent with those of a large systemic
review and meta-analysis, which found a 2.35-fold increased odds of UGIB
in patients using SSRIs for less than a month[38]. Meanwhile, no
association was observed between the time window of exposure and other
classes of SSRIs.