In this episode, I’ll discuss whether selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) should be discontinued in the setting of active bleeding.
I am excited to announce that I have teamed up with the Wegman’s School of Pharmacy St. John Fisher College to offer ACPE Continuing Education credit for listeners of The Elective Rotation podcast!
Starting with the February 2017 episodes, I have bundled them into a 1 hour ACPE CE program. You can register by clicking here.
If enough participants register, I will publish additional CE programs based on other podcast episodes.
Shout out to “Pharmacy Jen” for suggesting this episode topic.
Serotonin is often thought of in the context of depression and as a neurotransmitter. However, serotonin and serotonin receptors are present throughout the body in myocardium, blood vessels, GI tract, platelets, smooth muscle, and elsewhere.
There are 7 different classes of serotonin receptors, 5-HT1 through 5-HT7. Many receptor classes have several subtypes.
Medications are classified as active against specific serotonin receptors based on relative ability to affect a receptor.
Remember the irritable bowel syndrome treatment tegaserod? Tegaserod is a serotonin 5-HT4 receptor agonist. While tegaserod had marginal effects on irritable bowel syndrome, it had significant effects on GI motility and the treatment of diabetic gastroparesis. It was being used off label frequently in diabetic patients for pro-motility effects. Unfortunately, the 5-HT4 receptor is also present in myocardium.
Tegaserod was soon found to have elevated risk of myocardial infarction and was withdrawn from the market. It is now available only under a special access program. This example serves as a powerful reminder that just because a medication is selective against one particular receptor subtype in one area of the body does not mean others are unaffected.
Serotonin also plays a vital role in the functioning of platelets. Inhibiting serotonin reuptake impairs platelet aggregation by decreasing the levels of platelet serotonin. For this reason, SSRIs and SNRIs have been investigated for the potential to increase bleeding.
Strength of the evidence suggesting SSRIs and SNRIs cause bleeding
No randomized controlled trials have found an increase risk of bleeding with SSRIs and SNRIs. Data is limited to case reports and observational studies that have suggested an association between SSRIs and SNRIs and increased bleeding risk. In particular, the association between upper GI bleeding and subarachnoid hemorrhage bleeding risk with SSRIs and SNRIs have been examined.
Upper GI bleeding
Several meta-analyses have found a link between SSRI use and increased risk of upper GI bleeding. A 2010 systematic review found the following result:
Epidemiologic studies show that SSRI use is associated with roughly doubled odds of upper gastrointestinal (GI) bleeding; bleeding at other sites has been less commonly described, as has a possibly increased risk of bleeding associated with surgical procedures. The risk of SSRI-associated GI bleeding is increased with the concurrent use of NSAIDs, anticoagulants, and antiplatelet agents and is decreased by concurrent proton pump inhibitors. The risk of bleeding is increased in patients with cirrhosis of the liver or liver failure…
While a “doubling” of the risk of bleed sounds significant, it is important to remember this is a relative measure of risk. When absolute measurements of risk are taken into account, one study found the number needed to harm was 411 and another found the number needed to harm was 3177. For this reason the risk of upper GI bleeding with SSRIs is generally considered not clinically significant. Risks associated with SNRIs use are not well studied for upper GI bleeding.
Subarachnoid hemorrhage
A 2012 meta-analysis found that:
SSRI exposure is associated with an increased risk of intracerebral and intracranial hemorrhage, yet given the rarity of this event, absolute risks are likely to be very low.
The number needed to harm in this study was approximately 10000. Risks associated with SNRIs use are not well studied for subarachnoid hemorrhage.
Drug interactions that may increase the risk of bleeding with SSRIs and SNRIs
NSAIDs
The number needed to harm decreases sharply when NSAIDs are combined with SSRIs. One meta-analysis showed a number needed to harm of 106. The median time from starting an SSRI to GI bleed onset was 25 weeks.
Anti-platelets
A 2011 meta-analysis found that adding an SSRI to aspirin or aspirin plus clopidogrel (but not clopidogrel alone) increased the risk of hospital admission for GI bleeding. The increased risk was most pronounced when an SSRI was added to dual antiplatelet therapy, with a number needed to harm of 75.
Anti-thrombotics
A 2014 analysis of the AnTicoagulation and Risk factors In Atrial fibrillation (ATRIA) cohort of 13,559 adults with atrial fibrillation found that hemorrhage rates were higher during periods of SSRI exposure compared with periods on no antidepressants. The authors of this analysis concluded:
…SSRI exposure was associated with higher major hemorrhage risk in patients taking warfarin, and this risk should be considered when selecting antidepressant treatments in those patients.
Conclusion
Based on available data, the likelihood that an SSRI or SNRI will cause bleeding in any given patient is low, but statistically significant. However, no data is available to evaluate the effects of continuing or holding SSRIs and SNRIs in the setting of active bleeding. One retrospective study found that SSRI or SNRI use prior to ICU admission is associated with increased hospital mortality.
Because of the known effects of SSRIs on platelet aggregation, and the association of SSRIs and SNRIs with bleeding, I believe it is prudent to temporarily hold SSRIs and SNRIs in patients who are actively bleeding. To minimize the chance of withdrawal symptoms, the SSRI or SNRI can be resumed after bleeding stops, as long as the SSRI or SNRI was not implicated as a cause of bleeding.
If you like this post, check out my book – A Pharmacist’s Guide to Inpatient Medical Emergencies: How to respond to code blue, rapid response calls, and other medical emergencies.
Given the urgency with which active bleeding needs to be dealt with and relatively long half of most SSRIs I don’t think witholding a dose or two is worthwhile.
It is an interesting area for study…check out this case (https://www.ncbi.nlm.nih.gov/pubmed/1482806) where 2 days after stopping fluoxetine (SSRI with longest half-life) platelet function normalized.
Thanks joe, Great post! Prior Antipsychotics use are becoming prevalent to patients admitted into the icu. There should be more discussions about their management in the critical setting.