We found a trend towards an increased risk of upper gastrointestinal bleeding for patients taking antidepressants with greater inhibition of serotonin reuptake. This association was significant when we controlled for age or previous upper gastrointestinal bleeding. We believe that the increased bleeding rates are clinically important for octogenarians or patients with previous upper gastrointestinal bleeding and should be considered when selecting antidepressants. For most patients, however, such precautions are probably unnecessary.
Our conclusions are similar to those of de Ajabo et al,11
despite some notable differences between our studies. Firstly, increased overall illness is associated with both depression18–24
and gastrointestinal bleeding.25–27,36
The large size of our study allowed us to remove potential confounding from this association by restricting the analysis to patients taking antidepressants. Secondly, our study contained a different collection of drugs because it included venlaflaxine, nefazodone, and bupropion but not dothiepin, citalopram, lofepramine, and mianserin. Additionally, as has been suggested,14
we categorised antidepressants on the basis of their inhibition of serotonin reuptake rather than their structure. Finally, our study took place in a different healthcare system with an older patient population. Our findings corroborate those of de Ajabo et al in a distinct patient population using a different study design. We believe that this strengthens the association between inhibition of serotonin reuptake by antidepressants and gastrointestinal bleeding.
Octogenarians and patients with previous upper gastrointestinal bleeding are at especially high risk from antidepressants with high inhibition of serotonin reuptake.25
It is possible that increased bioavailability of selective serotonin reuptake inhibitors in elderly patients results in a stronger antiplatelet effect at the same dose, thereby increasing the risk of gastrointestinal bleeding. These findings might also be a function of particular vulnerability to gastrointestinal bleeding in elderly patients26
and those with previous upper gastrointestinal bleeding, thereby allowing the antiplatelet effect of the antidepressant to become apparent. These factors would explain why the association between bleeding risk and inhibition of serotonin reuptake was seen only after these strong confounders were controlled for.
Two factors could explain why upper gastrointestinal bleeding was associated with inhibition of serotonin reuptake after the year of study entry was controlled for (table ). Firstly, the number of octogenarians who were prescribed antidepressants with high inhibition increased from 892 in 1992 to 11
179 in 1997. Secondly, the use of upper endoscopy in elderly patients increased noticeably during the study. Whereas rates for upper endoscopy for patients aged between 65 and 70 years in Ontario decreased from 28.3 per 1000 population in 1992 to 23.7 per 1000 in 1998, rates for octogenarians increased from 23.7 to 30.4 per 1000 during the same period. Therefore major changes during the study in the bleeding risk of patients taking selective serotonin reuptake inhibitors and the use of an important technology to diagnose upper gastrointestinal bleeds may explain the cohort effect in our base analysis. No cohort effect was, however, found in our multivariate proportional hazards model (see table A2).
We believe that our study is valid and provides new information that is useful to clinicians. It is population based and includes a large number of participants. This increased the precision of point estimates for bleeding rates and allowed us to limit the analysis to patients taking antidepressants. It also allowed us to measure absolute differences in bleeding risks, which are essential for determining clinical relevance. The validity of our methods to calculate bleeding rates is supported by our rates being similar to those in two other cohort studies.26,37
Although drug exposure was measured by prescription only, this method agrees well with self reported use of drugs.38
Our study outcome of admission to hospital with upper gastrointestinal bleeding was explicitly determined by using diagnostic codes that are highly indicative of such bleeding.
Our results potentially have two minor limitations. Firstly, although we controlled for important confounders, we did not control for all of the factors that de Ajabo et al considered, such as smoking or “antecedents of upper gastrointestinal disorders.” Because the independent risks of bleeding associated with these factors were not provided,11
we are unsure of the importance of their control when studying upper gastrointestinal bleeding. Secondly, we considered only upper gastrointestinal bleeds that resulted in admission to hospital. We may therefore have missed those patients whose bleed resulted in death before admission to hospital or that did not require admission. This problem is common to many studies with admission to hospital for gastrointestinal bleeding as an outcome.11,26,27,32,36,37,39
Despite this potential misclassification bias,40
we found a significant association between the inhibition of serotonin reuptake and gastrointestinal bleeding when important confounders were controlled for.
Depressed patients have a higher risk of gastrointestinal bleeding when taking antidepressants with higher inhibition of serotonin reuptake. For high risk patients, such as octogenarians and those with previous gastrointestinal bleeding, we believe that the differences are clinically important and should be considered when antidepressants are selected. Further study is required to determine if serotonin blockade increases the risk of gastrointestinal bleeding as well as the risk of other clinical bleeds in other patient populations. In contrast, it needs to be determined whether the antiplatelet effects of antidepressants are beneficial for patients at high risk of thromboembolic disorders.