How to manage bleeding risk with serotonin reuptake inhibitor antidepressants

Greater attention is being directed to the risk of bleeding with serotonin reuptake inhibitor (SRI) antidepressants. These agents are used for various indications, including depression, anxiety, premenstrual dysphoric disorder, pain disorders and to relieve vasomotor symptoms. SRI use has been associated with abnormal bleeding in the gastrointestinal (GI) tract, postpartum hemorrhage, intracranial hemorrhage, and other types of bleeding, such as female genital tract bleeding, epistaxis and hematoma.Mechanisms of bleeding SRIs are believed to cause bleeding by inhibition of the serotonin transporter on platelets, leading to a reduction in platelet aggregation. In addition, selective serotonin reuptake inhibitors (SSRIs) increase gastric acidity, which can increase the risk of ulcer formation and GI bleeds.Incidence of bleeding with SRIs A meta-analysis of observational studies examining bleeding risk with SSRIs in about 1.4 million patients found a 41% increase in any bleeding type, with a 55% increased risk of GI bleeds and a 16% increased risk of intracranial hemorrhage. Most published literature has focused on the risk of GI bleeds, making it difficult to determine the absolute risk of bleeding at other sites. Other meta-analyses have reported a 1.55–2.36-fold increased risk of GI bleeding among SRI users. Although significant GI bleeding is rare, it is essential to recognize that SRIs can increase GI bleeding risk, given that the baseline incidence of upper GI bleeds is 23 per 10,000 patients per year, with an associated mortality of 3%–14%. Overall, bleeding risk with SSRIs appears to be highest within the first 30 days of use, but more studies are needed to confirm this.Risk factors for bleeding SRIs with high serotonin transporter binding affinity (e.g., clomipramine, duloxetine, fluoxetine, paroxetine, sertraline, vilazodone, vortioxetine) are hypothesized to place patients at a higher bleeding risk than SRIs with intermediate (e.g., amitriptyline, citalopram, escitalopram, imipramine, venlafaxine) or low (e.g., bupropion, doxepin, mirtazapine, nortriptyline, phenelzine, tranylcypromine, trazodone) binding affinity.Concomitant medications such as antiplatelet agents (e.g., acetylsalicylic acid [ASA], clopidogrel), anticoagulants (e.g., warfarin) and nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of SRI bleeding. A meta-analysis found that concomitant SSRI and NSAID use was associated with an increased risk of GI bleeding (OR = 6.33), with a number needed to harm of 82 per year; this risk was higher than using either drug alone.Age and other medical conditions GI bleeding risk increases with age; in one study, 1.2%–1.9% of SSRI users older than 70 years developed a GI bleed. Comorbid conditions (e.g., peptic ulcer disease, diabetes, chronic liver disease, chronic renal failure, gastroesophageal reflux disease), smoking and alcohol consumption also increase the risk for SRI-related GI bleeding.Note that there is no evidence to support stopping or tapering SRIs before surgery. SRI treatment should continue in patients undergoing surgical procedures, as abrupt discontinuation may lead to serotonin withdrawal symptoms or negatively affect management of psychiatric symptoms.Drug-drug interactions are important considerations when determining the risk of bleeding with SRIs. CYP450-mediated drug interactions may pose a risk of bleeding when medications with additive bleeding risk are combined. Among the SRIs, the most notable CYP inhibitors are duloxetine (moderate CYP2D6 inhibitor), fluvoxamine (strong CYP1A2, 2C9, 2C19, moderate CYP3A4, and weak CYP2D6 inhibitor), fluoxetine (strong CYP2D6, 2C9, moderate CYP3A4, 2C19, and weak CYP1A2 inhibitor), and paroxetine (strong CYP2D6 and weak CYP1A2, 3A4, 2C9, 2C19 inhibitor). Citalopram, escitalopram, sertraline and venlafaxine are weak CYP2D6 inhibitors only.Strategies to mitigate SRI bleeding risk The review suggests the following strategies to reduce the risk of bleeding with SRIs:Consider an antidepressant with little to no effect on the serotonin transporter in patients with a high risk for bleeding (especially those on NSAIDs or of advanced age) or with a history of bleeding. For example, consider bupropion, which has a mechanism of action independent of serotonin.Avoid unnecessary NSAID use.Consider proton pump inhibitor (PPI) use to reduce the risk of SSRI-associated GI bleeds, especially when patients are also taking NSAIDs, particularly high-dose NSAIDs. However, use of PPIs for this purpose must also take into consideration their long-term adverse effects (e.g., fracture, hypomagnesemia, vitamin B12 deficiency, dementia, kidney damage, Clostridium difficile infection, pneumonia).Avoid discontinuation of SRI antidepressants based on bleeding risk alone, in patients with a valid indication for SRI use.If a patient develops a GI bleed, the risks and benefits must be weighed before discontinuing SRI antidepressant therapy. An acid-suppressing agent (e.g., PPI) may be added to reduce the risk of developing additional bleeds.Healthcare providers should consult a pharmacist about any questions related to SRI drug-drug interactions.Pharmacists should intervene in patients who are at high risk of bleeding (e.g., patient on an anticoagulant and an SRI).Patient educationEducate patients about the increased (but rare) risk of bleeding associated with SRIs, before starting SRI therapy.Educate patients about the signs and symptoms of abnormal bleeding and when to seek medical treatment.Caution patients on SRI antidepressants to check with their pharmacist before using over-the-counter medications, especially NSAIDs or ASA.ReferenceBixby AL, VandenBerg A, Bostwick JR. Clinical management of bleeding risk with antidepressants. Ann Pharmacother 2019;53:186-94.

How to manage bleeding risk with serotonin reuptake inhibitor antidepressants

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