Effects of Selective Serotonin Reuptake Inhibitors on Platelet Function: Mechanisms, Clinical Outcomes and Implications for Use in Elderly Patients

Abstract

Among the antidepressants, the selective serotonin reuptake inhibitors (SSRIs) are often preferred to other classes of antidepressants in the treatment of depression in the elderly because of their better safety profile. Most of the known effects of SSRIs, either beneficial or adverse, are linked to their inhibitory action on the serotonin reuptake transporter (5-HTT). This reuptake mechanism is present not only in neurons but also in other cells such as platelets. Serotoninergic mechanisms seem to play an important role in haemostasis, and their importance in this regard has long been underestimated. Abnormal activation may lead to a pro-thrombotic state, as may occur in patients with major depressive disorder, whilst downregulation, as occurs in patients treated with SSRIs, may have two clinical consequences, both of particular interest in the elderly. On the one hand, there may be an increased risk of bleeding; on the other hand, a reduction in thrombotic risk may be possible. Polymorphism in the promoter region of the gene that transcribes the 5-HTT has been shown to have a relevant impact on its function and, in turn, on the beneficial and adverse effects of SSRIs. Bleeding has been a concern since the introduction of SSRIs, with multiple case reports published and communicated to the pharmacovigilance systems. The first epidemiological study was published in 1999 and since then, 34 epidemiological studies from different areas, most of them including elderly patients in their study populations, have been published with a variety of results. Broadly, the epidemiological evidence supports a moderately increased risk of bleeding associated with the use of SSRIs, which may be critically dependent on patient susceptibility and the presence of risk factors. The impairment of primary haemostasis induced by SSRIs may result, as a beneficial counterpart, in a reduction in the thrombotic risk. A small number of clinical trials and an increasing number of epidemiological studies that include elderly patients have been conducted to clarify whether SSRIs reduce the risk of primary and secondary ischaemic disorders. However, the results have been inconclusive with some studies suggesting a preventive effect and others no effect or even an increased risk. Behind such contradictory results may be the role of depression itself as a cardiovascular risk factor and, therefore, a major confounding factor. How to disentangle its effect from that of the antidepressants is the methodological challenge to be overcome in future studies. In this complex scenario, the elderly seem to be at a crossroads, because they are the group in which both the risks and the benefits can be the greatest. Studies performed to date have provided us with some clues that can help orient clinicians in taking the most appropriate course of action. For instance, as the gastrointestinal bleeding risk appears to increase with age, prudent advice in patients with a previous history of upper-gastrointestinal bleeding or peptic ulcer, and in those who take NSAIDs, oral anticoagulants, antiplatelet drugs or corticosteroids, would be to suggest addition of an acid-suppressing agent to the drug regimen in those elderly patients in whom SSRIs are indicated.