Risk of Bleeding Associated With Antidepressants: Impact of Causality Assessment and Competition Bias on Signal Detection

Abstract

Introduction: Until now, methods of pharmacovigilance as disproportionality analysis were not capable of proving the otherwise well-established increased bleeding risk related to antidepressants (ADs). As bleeding events with ADs often occur in combination with antithrombotics, they might not be considered causative of, but merely “linked” with, the bleeding event. Therefore, we hypothesized that the causality assessment of bleeding events in association with ADs and the competitive impact of antithrombotics are factors contributing to the non-findings of previous pharmacovigilance studies.Methods: We performed a case/non-case study based on data from VigiBaseTM and calculated reporting odds ratios (RORs) for 25 ADs. We used individual case safety reports (ICSRs) that were differently categorized in the database regarding their type of association between drug and event. Furthermore, we investigated the competitive impact of antithrombotics by comparing RORs with and without ICSRs related to antithrombotics.Results: Analysis of ICSRs that were categorized as causally associated resulted in the detection of only two signals (citalopram and escitalopram; upper gastrointestinal bleeding). Analysis of ICSRs irrespective of the type of association resulted in the detection of signals in 8 out of 25 ADs (regarding bleeding, in general, gastrointestinal bleeding and upper gastrointestinal bleeding). Consideration of ICSRs associated with antithrombotics as competitive substances did not have a major impact on signal detection in our analysis.Conclusion: Categorization of the type of association between drug and event affects the results of quantitative signal detection. Causality assessment seems to play a major role in signal detection, probably particularly concerning rare, unknown, or clinically insignificant adverse drug reactions. ADs appear to significantly increase the bleeding risk, even independent of antithrombotic comedication.

Harder, better, faster, stronger? Retrospective chart review of adverse events of interactions between adaptogens and antidepressant drugs

“…Possible mechanisms underlying those interactions include the addition of side effects. Studies showed that Eleutherococcus senticosus contains dihydroxybenzoic acid, which has antiplatelet activity (Yun-choi et al, 1987;Friedman et al, 2007) and may increase the risk of hemorrhage associated with the use of SSRIs and SNRIs (Zeiss et al, 2021). There is only one study reporting adverse bleeding-related events associated with the use of this adaptogen.…”

Treating Depression in Clinical Practice: New Insights on the Multidisciplinary Use of Tradozone

“…Once the GP has putatively diagnosed depression, the target outcome should be to obtain functional remission [60] [61], and to achieve complete psychosocial recovery of the patient [62]. According to the most recent scientific evidence, the cornerstone strategy for reaching clinical effectiveness is a personalized ("tailored") treatment based on a decision tree [63], which should primarily include the patient in the choice of medication(s), addressing potential therapeutic effects, likely time to respond, general tolerability, and possible adverse effects (e.g., weight gain, sexual adverse events, cardiovascular adverse events) [64]. Trazodone is often selected as a first choice antidepressant in primary care settings due to its multimodal action (anxiolytic, hypnotic, antidepressant) exerted at different dosages, as well as to its wide range of available formulations, its rapid efficacy, a low rate of adverse events, and less interaction with other drugs, all of which make trazodone extremely useful and malleable in high comorbid patients [71] [72] [73].…”

Treating depression in clinical practice: new insights on the multidisciplinary use of trazodone

“…Once the GP has supposedly diagnosed depression, the target outcome should be to obtain functional remission ( 59 , 60 ) and to achieve complete psychosocial recovery of the patient ( 61 ). According to the most recent scientific evidence, the cornerstone strategy for reaching clinical effectiveness is a personalized (“tailored”) treatment based on a decision tree ( 62 ) which should primarily include the patient in the choice of medication(s), addressing potential therapeutic effects, likely time to respond, general tolerability and possible adverse effects (e.g., weight gain, sexual adverse events, cardiovascular adverse events) ( 63 ).…”