Inhibition of serotonin reuptake by antidepressants and upper gastrointestinal bleeding in elderly patients: retrospective cohort study

Introduction

Serotonin potentiates platelet aggregation.1 Selective serotonin reuptake inhibitors decrease serotonin uptake from the blood by platelets. Because platelets do not synthesise serotonin, these inhibitors decrease the amount of serotonin in platelets.2 Case reports suggest that serotonin reuptake inhibitors are associated with a variety of bleeding events.3-10

The strongest evidence linking the use of selective serotonin reuptake inhibitors with bleeding comes from a case-control study.11 The authors identified 1651 incident cases of upper gastrointestinal bleeding or ulcer perforation from a high quality clinical database and randomly selected 10 000 controls matched by age, sex, and time. 12 13 Drug records were reviewed to determine if the participants had been exposed to selective serotonin reuptake inhibitors or other antidepressants. After potential confounders were controlled for, the odds of gastrointestinal bleeding for users of the inhibitors were three times that of the controls. Patients taking tricyclic antidepressants had no increased risk of upper gastrointestinal bleeding.

The study did, however, have potential limitations.14-17 Firstly, if the hypothesised pathophysiology of bleeding involved the inhibition of serotonin reuptake, the extent of this inhibition should correlate with the risk of bleeding and determine how these drugs were grouped.14 Yet the antidepressant groups comprised drugs with often disparate inhibition.14 Secondly, the association between the inhibitors and gastrointestinal bleeding could have been due to confounding. This is because patients with depression generally are sicker than those without.18-24 Patients who are sicker are more likely to experience gastrointestinal bleeding because such bleeding has been associated with factors that contribute to overall disease burden, including increased age, decreased physical activity, heart failure, diabetes, and annual number of hospital admissions.25-27 Thirdly, as only 131 bleeds were recorded in the antidepressant group, there were relatively wide confidence intervals for bleeding risks. Fourthly, serotonin plays a minor part in the haemostatic process. It is a comparatively weak agonist for platelet aggregation because its stimulation of platelet receptors induces change only in platelet shape and not the platelet secretory processes key to platelet activation.28 Finally, the study could not provide the absolute risk of serious bleeding associated with antidepressant use. Clinicians need this information when choosing antidepressants for patients.

To address these issues, we conducted a retrospective cohort study to determine the overall risk of serious upper gastrointestinal bleeding in elderly patients taking antidepressants. We also aimed to determine if this risk varied with the extent of inhibition of serotonin reuptake by antidepressants.

Patients and methods

Results

During the study period, 383 911 of 1 798 382 (21.3%) elderly patients were prescribed antidepressants. Of these, 317 824 (82.8%) started their drug during the study period and were included. They were observed for 132 812 person years, during which time there were 974 admissions to hospital for upper gastrointestinal bleeding. Table 2 describes the cohort. Patients entering the study in later years were much more likely to be prescribed antidepressants with greater inhibition of serotonin reuptake.

The overall risk of upper gastrointestinal bleeding was 7.3 per 1000 person years (table 1). The risk of upper gastrointestinal bleeding was significantly associated with each confounder. This was especially so with increasing age and previous upper gastrointestinal bleeding.

The risk of upper gastrointestinal bleeding increased slightly with inhibition of serotonin reuptake, rising from 6.6 bleeds per 1000 person years for antidepressants with the lowest inhibition to 7.9 bleeds per 1000 person years in the highest group (table 1). This trend did not reach significance.

However, significant increases in upper gastrointestinal bleeding with increasing inhibition were seen after controlling for variables strongly associated with upper gastrointestinal bleeding (table 1). When we controlled for age, the risk of bleeding increased by 10.7% for each higher inhibition group. For octogenarians, bleeding rates increased from 10.6 per 1000 person years in the lowest group to 14.7 per 1000 person years in the highest group. This corresponded with a number needed to harm of 244—that is, one extra upper gastrointestinal bleed would be expected when 244 patients were treated with an antidepressant from the high rather than the low serotonin reuptake inhibitors. When we controlled for previous upper gastrointestinal bleeding, bleeding risk increased by 9.8%. For patients with a history of active peptic ulcer disease, bleeding rates increased from 28.6 per 1000 person years in the lowest group to 40.3 per 1000 person years in the highest group. This corresponded with a number needed to harm of 85. Finally, we also found a period effect. When we controlled for the year of study entry, the relative risk of upper gastrointestinal bleeding increased significantly by 10.7% with increasing inhibition of serotonin reuptake.

Proportional hazards modelling gave similar results (see table A2). After all potential confounders were controlled for, increasing inhibition of serotonin reuptake was associated with a significantly increased risk of upper gastrointestinal bleeding (risk ratio 1.1, 1.02 to 1.19). The two analyses yielded similar results because six of the univariate relative risks lay within the 95% confidence intervals of corresponding estimates in the multivariate Cox model (table 2). In this analysis there is no period effect. Of all covariates in the final model (see table A2), only anticoagulation had a significant interaction with time. We kept the Cox model because this interaction was of borderline significance (P=0.03) and the point estimate was of questionable clinical significance (risk ratio 1.001).

Discussion

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 1). 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.