After coronary artery disease and stroke, venous thromboembolism (VTE), which comprises deep vein thrombosis (DVT) and pulmonary embolism (PE), is the third most common cardiovascular disease[1], VTE is considered to be a multifactorial disease, influenced by genetic, biological, and environmental factors[2, 3]. Even with improvements in knowledge of VTE and its risk factors, the condition continues to be a global public health concern[4, 5]. The one-year all-cause death rate for VTE is 22–24%[6, 7]. Modifiable risk factors that may be associated with VTE include immobility, trauma, surgery, hormone therapy, obesity, and hereditary sensitivity to embolism. It is predicted that in the upcoming years, the incidence of VTE would rise even more due to the prevalence of major risk factors for VTE[8–11], such as old age, obesity, and cancer, progressively increases in the population[12, 13]. Thus, in order to lessen the societal burden of VTE, modifiable risk factors must be identified and targeted as soon as possible.
The concern of VTE due to the use of antidepressant medications is currently becoming an urgent issue. Many studies have shown the potential link between the development of VTE and mental health factors such as stress, depression, anxiety, and low socioeconomic status[14–17]. It is hypothesized that these factors stimulate hypercoagulability via neuroendocrine and autonomic mechanisms[18]. A growing amount of research suggests that the development of VTE may be linked to the use of antidepressants. In the UK Million Women Study[19], several antidepressant classes have been linked to an increased risk of VTE, including selective 5-hydroxytryptamine reuptake inhibitors, which have been shown to impair platelet function [20, 21]. This could be due to serotonin is a mild platelet agonist that amplifies the effects of thrombin or ADP activation. When serotonin reuptake is inhibited, it cannot be replenished within the dense granules of platelets, which means it cannot improve platelet activation responses or help maintain procoagulant proteins (fibronectin, fibrinogen, vascular hemophilic factor, platelet reactive proteins, and α2-antifibrinolytic protein) on the platelet surface[22]. There have also been a lot of population-based observational studies have reported an association between antidepressant use and the risk of subsequent VTE, but with conflicting results. Some studies have shown evidence of a connection[19, 23], others have not found a significant relationship[24, 25]. As an observational study, confounder effects are hard to account for and can cause results to be misinterpreted. For example, in the Study of Antidepressant Use and Risk of Venous Thromboembolism, the relationship between antidepressant use and venous thromboembolic events was assessed in 782 patients with a diagnosis of VTE who were taking antidepressant medication and in 3,085 matched control subjects. Amitriptyline was found to increase the risk of thromboembolism (OR 1.7,95% CI 1.2–2.4) and to increase with increasing dose (> 25 mg/day), but there was no increased risk in users of other antidepressants or selective 5-hydroxytryptamine reuptake inhibitors[26]. Furthermore, it's not clear if reverse causation influences the understanding of the connection between antidepressant use and VTE. That is, symptoms of VTE may contribute to depression and antidepressant use in some people[27, 28]. Randomized controlled trials (RCTs) are the best way to determine causality, but for ethical and practical reasons, their implementation is difficult and time-consuming. In the lack of RCTs, Mendelian randomization (MR), a method often used in causal inference, can be applied to examine causal relationships between exposures and outcomes of interest. In MR, single nucleotide polymorphisms (SNPs) are used as unmixed instrumental variants (IVs) to proxy for the exposure phenotype. MR studies are also known as randomized trials in nature[29]. Since genetic variations are assigned randomly during fertilization, MR is designed to mimic RCTs in order to reduce the likelihood of confusion[30, 31]. In addition, genotypes are formed prior to the onset of the disease and are usually unaffected by the progression of the disease, and are therefore less susceptible to reverse causation.
We performed a two-sample MR investigation to investigate the independent roles of antidepressant use in the development of VTE using the genome-wide association studies (GWAS) genetic tool for antidepressant use. Furthermore, multivariable MR was used to determine the causal effects of antidepressant use after risk factors including smoking and BMI were taken into account.