by Nitin Pothen, MD; Prachi Patel, BSN, MD; and Aneela Jafri, MD 

All authors are with Ocean University Medical Center in Brick, New Jersey.

Funding: No funding was provided for this article.

Disclosures: The authors have no conflicts of interest relevant to the content of this article.

Innov Clin Neurosci. 2024;21(10–12):34–37.

Abstract

Introduction: The demographics of the United States (US) are evolving as time progresses. The geriatric population is growing, with many elderly people dealing with mental health issues. Major depressive episodes affect 1 to 5 percent of those aged 65 years or older, which emphasizes the importance of addressing mental health concerns in this populace. This article explores how antidepressant use can lead to bleeding problems in geriatric patients, as the prevalence of treatment-resistant depression in these patients is increasing, along with the identification of the potentially life-threatening bleeding risks associated with these medications.

Methods: We did a comprehensive literature search using PubMed, EBSCOhost, and Google Scholar to find the articles pertinent to our subject. Reference lists of relevant articles were also reviewed.

Conclusion: These findings highlight the heightened risk of severe bleeding events linked to use of selective serotonin reuptake inhibitors (SSRIs) in the elderly. This was most notable among octogenarians and those with a history of upper gastrointestinal (GI) bleeding. This risk is accentuated when SSRIs are combined with antiplatelet drugs and nonsteroidal anti-inflammatory drugs (NSAIDs), the highest risk being observed with use of a combination of aspirin, clopidogrel, and SSRIs. Our review concludes that while the relative risk is high, the absolute risk remains low. However, caution is advised when prescribing SSRIs to individuals aged 80 years or older. These findings emphasize the need for tailored medication management, vigilant monitoring, and a patient-centered approach in prescribing antidepressants to geriatric patients. Balancing mental healthcare with potential bleeding risks is paramount in the evolving landscape of geriatric mental health.

Keywords: SSRIs, geriatric population, antidepressants, bleeding risks, anticoagulants, NSAIDs, antiplatelets

The demographic picture of the United States (US) is transforming remarkably. In 2019, 54.1 million US adults were aged 65 years or older, representing 16 percent of the population.¹ Looking ahead, projections indicate a substantial increase in the elderly population, with the number of older adults expected to reach 80.8 million by 2040 and peaking at 94.7 million by 2060, accounting for nearly 25 percent of the US population.¹ This shift poses significant implications for healthcare, particularly in mental health, as about 20 percent of individuals aged 55 years or older face various mental health issues.² Common conditions in this age group include anxiety; mood disorders, such as depression and bipolar disorder; and severe cognitive impairment.² With 1 to 5 percent of individuals above the age of 65 years diagnosed with major depressive episodes,³ addressing mental health in the elderly is imperative, especially considering the alarming suicide rates among men aged 85 years or older, which is 55.7 per 100,000 population, compared to an age-adjusted rate of 14.1 deaths per 100,000 population in the US in 2021.⁴

Objectives

In the midst of this demographic evolution and the growing prevalence of mental health concerns among older individuals, this article delves into the crucial issue of the link between antidepressant use and the risk of bleeding in geriatric patients. This inquiry stems from the increasing prevalence of treatment-resistant depression in the elderly,³ rising polypharmacy rates,³ and the identification of uncommon but potentially serious bleeding risks associated with antidepressants. By exploring the role of serotonin in platelet activity, elucidating the connection between antidepressants and bleeding risk, and discussing associated risk factors, we aim to provide valuable insights for clinicians. We highlight the clinical significance of our findings and offer recommendations for clinicians to consider when providing care to older adults. Given the importance of serotonin in platelet activity, our primary focus lies on the use of antidepressants in the elderly, especially in combination with antiplatelet medications, coupled with the associated risks of bleeding. 

Methods

A comprehensive literature search was conducted using PubMed, EBSCOhost, and Google Scholar using the keywords “hemorrhage,” “antidepressants associated with bleeding,” “selective serotonin reuptake inhibitors,” “hemostasis,” “platelets,” “antiplatelet drugs,” “aspirin and hemorrhage,” “elderly,” “hemorrhagic stroke,” and other related terms. The reference lists of studies were also searched.

Results

The collective findings from distinct studies underscore the association between antidepressant use and an increased risk of bleeding complications in the geriatric population. The serotonergic mechanism of action appears to be a common thread, with the antidepressant class of selective serotonin reuptake inhibitors (SSRIs) exhibiting the highest risk of bleeding events. Multiple mechanisms are thought to contribute to the bleeding effect of SSRIs, some of which include blockade of intraplatelet calcium mobilization, inhibition of nitric oxide synthase, depletion of intracellular serotonin, reduced secretion of platelet factors in response to chemical stimuli leading to a loss of aggregation potential, and decreased expression of many membrane receptors involved in platelet activation.⁵ Conversely, antidepressants such as agomelatine, bupropion, reboxetine, and mirtazapine demonstrated a comparatively lower risk profile.⁶ We found that antidepressants with a low coefficient index had a higher affinity and hence a higher risk of bleeding. This was particularly noted among SSRIs.

We conducted a comprehensive meta-analysis of 42 observational studies, including 31 case-control studies and 11 cohort studies. The association between bleeding risk and SSRIs was found for the 31 case-control studies (1,255,073 patients), with a 41-percent increased risk of bleeding (odds ratio [OR]: 1.41 [95% confidence interval (CI): 1.25–1.60]), as well as for the 11 cohort studies , which included 187,956 patients (OR: 1.36 [95% CI: 1.12–1.64]; Figure 1). Gastrointestinal (GI) bleeding was identified as the primary contributor to this elevated risk, with a 55-percent higher incidence, whereas the increase in intracerebral hemorrhage risk was relatively lower at 16 percent. These findings emphasize the consistent and substantial link between SSRI use and an elevated risk of severe bleeding events. Although the risk of GI bleeding was higher, the absolute risk was found to be low.⁵

The increased risk of bleeding with SSRI use has been seen to be further exacerbated when SSRIs are used in combination with antiplatelet drugs and non-steroidal anti-inflammatory drugs (NSAIDs). In a study conducted by Labos et al,⁷ it was found that among 27,000 patients over 50 years of age with a history of acute myocardial infarction, the combination of SSRIs and antiplatelet drugs, particularly clopidogrel, resulted in varying levels of bleeding risks. The highest risk was associated with the combined regimen of aspirin, clopidogrel, and SSRI (hazard ratio [HR]: 2.35; Figure 2).⁷ Upon further review, we found additional systematic reviews and meta-analyses of studies on SSRI and NSAID combination therapy, which indicated a significant rise in the risk of upper GI bleeding. The integrated ORs for SSRIs only, NSAIDs only, and the combination were 1.73 (95% CI: 0.65–2.82) , 2.55 (95% CI: 1.51–3.59), and 4.02 (95% CI: 2.89-5.15), respectively. Use of the combination resulted in an OR 2.32-times higher than that seen with using either drug alone; this suggests that clinicians should avoid co-prescription, if possible. When a combination regimen must be prescribed, using the lowest effective doses for the shortest duration and close monitoring for upper GI bleeding symptoms is recommended.^8–10

Apart from antiplatelets and NSAIDs, Hauta-Aho et al¹¹ also noted a higher bleeding risk linked to the combined use of SSRIs with warfarin (OR: 2.6), whereas Targownik et al¹² reported a more modest increase in the risk of GI bleeding with SSRI use (OR: 1.43). Interestingly, however, both sertraline and citalopram were found to be the safest SSRIs, and fluvoxamine and fluoxetine were the riskiest options for patients on warfarin.^13–15 No association was found between SSRIs and low-molecular-weight heparin (LMWH) with reference to an increase in the risk of bleeding, which makes heparin a suitable choice.¹⁶

Finally, to further support the existence of a definite link between increased risk of bleeding with SSRI use among the geriatric population, we conducted thorough review of a retrospective study involving 317,824 elderly participants over 130,000 person-years. High doses of serotonin reuptake inhibitor antidepressants were linked to a significant 10.7- and 9.8-percent increased risk of upper GI bleeding, even after adjusting for age and prior bleeding history, respectively.Notably, the impact was more pronounced in octogenarians, those with chronic kidney disease, and those with prior upper GI bleeding, underscoring clinical significance in these groups.^6,17,18 In a study conducted in Taiwan, among adults aged 65 years or older, SSRI exposure was associated with a 2.66-times higher risk of stroke, independent of depression-related stroke risk. However, SSRIs remained generally safe for most older patients with preventive measures.¹⁹ In a regression analysis, SSRI antidepressants were found to be unrelated to an increased risk of traumatic intracranial hemorrhage.^6,20–22

Discussion and Conclusion

This article addresses the intricate relationship between antidepressant use and bleeding risk in geriatric patients. The findings emphasize that the risk of severe bleeding events is notably elevated with SSRI use, particularly in the elderly.

Our comprehensive literature review emphasized that elderly individuals, especially octogenarians and those with a history of upper GI bleeding, appear to be most susceptible. Combining SSRIs with other agents, such as antiplatelet drugs and NSAIDs, significantly escalates the risk of upper GI hemorrhage, with the highest risk observed in the combination of aspirin, clopidogrel, and SSRI. It is noteworthy that geriatric individuals might also use other blood thinners for atrial fibrillation and post-myocardial infarction stents. However, among the SSRIs, sertraline and citalopram appear to be safest in patients taking warfarin. In the context of stroke, SSRI exposure was associated with a 2.66-times higher risk of stroke, independent of depression-related stroke risk. Nonetheless, SSRIs remain generally safe for most older patients with precautionary measures. To mitigate this risk, clinicians are advised to avoid co-prescription, use the lowest effective doses, and minimize treatment duration.

Although the relative risk of bleeding is high, the absolute risk is low, as per the literature. Hence, SSRIs can be used with caution in high-risk patients. High-risk patients include those on antiplatelets and those with a diagnosis of high-risk medical conditions, such as cancer, post-myocardial infarction, and stroke. Overall, these findings underscore the need for tailored medication management, vigilant monitoring, and a patient-centered approach when prescribing antidepressants to geriatric patients. Balancing the imperative to address mental health concerns in the elderly with the potential risk of bleeding complications associated with antidepressant use is crucial in the evolving landscape of mental healthcare for older adults.

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