SSRI and SNRI Bleeding Risks

Primer

Bleeding risks (e.g. - GI bleeding and intracranial bleeding) are associated with selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) in individuals with risk factors.

Mechanism

The increased risk is thought to be due to the effect of SSRIs inhibiting serotonin uptake in platelets.

Gastrointestinal Bleeding

  • In addition to the effect of SSRIs inhibiting serotonin uptake in platelets, gastrointestinal bleeding risk is also thought to be a function of increased gastric acid secretion, as a direct action of SSRIs.[1]
  • The odds ratio for bleeding associated with SSRI use alone ranges from 1.7 to 2.36, with a number needed to harm (NNT) of 411.
    • By contrast, the odds ratio increases when both SSRIs and NSAIDs are used (OR = 6.33 and NNT = 106).[2]
  • The GI bleeding risk associated with SSRIs most commonly involves the upper GI tract.[3]
    • Other possible sites including intracranial bleeding, sites in those with liver disease, lower GI, and uterus.
    • Antidepressant use near the time of delivery is associated with an increased risk of postpartum hemorrhage.[4]
    • The absolute risk remains very low (with other studies also showing no correlation).[5][6][7]
  • The risk for bleeding is increased with concurrent use of NSAIDs, antiplatelet medications, and anticoagulants.
  • Conversely, the risk is lowered with the use of acid-suppressing medications including proton-pump inhibitors (PPIs).[8]

How Big Is the Risk?

Gastroprotection is not justified in patients who receive SSRIs alone. However, individuals taking non-steroidal anti-inflammatory drugs (NSAIDs) or aspirin, older adults, and those with a history of GI bleeds are at a higher risk. SSRIs should generally be avoided in patients with these risk factors, or only antidepressants with low affinity for the serotonin transporter should be considered.[9][10] If SSRIs are prescribed, the patient should be monitored closely and the addition of a protein pump inhibitor should be considered to mitigate against excessive SSRI-induced gastric acid secretion.

SSRIs vs. SNRIs

  • The bleeding risk is generally more significant with SSRI use, with SNRIs having conflicting evidence, but generally a lower risk.[11][12]

Serotonin Transporter Affinity

  • An association between the risk of bleeding and increasing affinity for the serotonin transporter (SERT) has been noted in several studies.[13]
  • Lower affinity medications are thought to be associated with a lower bleeding risk.

Serotonin Receptor Transporter Affinity

Adapted from: Paton, C., et al. (2005). SSRIs and gastrointestinal bleeding.
High affinity Clomipramine, fluoxetine, sertraline, and paroxetine
Intermediate affinity Citalopram, fluvoxamine, and venlafaxine
Low affinity Doxepin, mirtazapine, moclobemide, and nortriptyline[14]

Approach and Management

  • In individuals with bleeding risks, avoid an SSRI if possible, or choose medications with a lower serotonin transporter affinity.
  • If SSRIs or SNRIs are necessary, consider adding a proton pump inhibitor (PPI) to mitigate against GI bleeding.[15]
  • Monitor for signs and symptoms of bleeding (physical and lab results) in at-risk individuals.

Resources

References

1) Salam, O. M. A. (2004). Fluoxetine and sertraline stimulate gastric acid secretion via a vagal pathway in anaesthetised rats. Pharmacological research, 50(3), 309-316.
2) Loke, Y. K., Trivedi, A. N., & Singh, S. (2008). Meta‐analysis: gastrointestinal bleeding due to interaction between selective serotonin uptake inhibitors and non‐steroidal anti‐inflammatory drugs. Alimentary pharmacology & therapeutics, 27(1), 31-40.
3) Jiang, H. Y., Chen, H. Z., Hu, X. J., Yu, Z. H., Yang, W., Deng, M., ... & Ruan, B. (2015). Use of selective serotonin reuptake inhibitors and risk of upper gastrointestinal bleeding: a systematic review and meta-analysis. Clinical Gastroenterology and Hepatology, 13(1), 42-50.
4) Palmsten, K., Hernández-Díaz, S., Huybrechts, K. F., Williams, P. L., Michels, K. B., Achtyes, E. D., ... & Setoguchi, S. (2013). Use of antidepressants near delivery and risk of postpartum hemorrhage: cohort study of low income women in the United States. Bmj, 347.
5) Andrade, C., & Sharma, E. (2016). Serotonin reuptake inhibitors and risk of abnormal bleeding. Psychiatric Clinics, 39(3), 413-426.
6) Hackam, D. G., & Mrkobrada, M. (2012). Selective serotonin reuptake inhibitors and brain hemorrhage: a meta-analysis. Neurology, 79(18), 1862-1865.
7) Targownik, L. E., Bolton, J. M., Metge, C. J., Leung, S., & Sareen, J. (2009). Selective serotonin reuptake inhibitors are associated with a modest increase in the risk of upper gastrointestinal bleeding. Official journal of the American College of Gastroenterology| ACG, 104(6), 1475-1482.
8) Andrade, C., & Sharma, E. (2016). Serotonin reuptake inhibitors and risk of abnormal bleeding. Psychiatric Clinics, 39(3), 413-426.
9) Paton, C., & Ferrier, I. N. (2005). SSRIs and gastrointestinal bleeding. BMJ (Clinical research ed.), 331(7516), 529–530.
10) Taylor, D. M., Barnes, T. R., & Young, A. H. (2018). The Maudsley prescribing guidelines in psychiatry. John Wiley & Sons.
11) Cheng, Y. L., Hu, H. Y., Lin, X. H., Luo, J. C., Peng, Y. L., Hou, M. C., ... & Lee, F. Y. (2015). Use of SSRI, but not SNRI, increased upper and lower gastrointestinal bleeding: a nationwide population-based cohort study in Taiwan. Medicine, 94(46).
12) Mawardi, G., Markman, T. M., Muslem, R., Sobhanian, M., Converse, M., Meadows, H. B., ... & Houston, B. A. (2020). SSRI/SNRI therapy is associated with a higher risk of gastrointestinal bleeding in LVAD patients. Heart, Lung and Circulation, 29(8), 1241-1246.
13) Paton, C., & Ferrier, I. N. (2005). SSRIs and gastrointestinal bleeding. BMJ (Clinical research ed.), 331(7516), 529–530. https://doi.org/10.1136/bmj.331.7516.529
14) Paton, C., & Ferrier, I. N. (2005). SSRIs and gastrointestinal bleeding. BMJ (Clinical research ed.), 331(7516), 529–530. https://doi.org/10.1136/bmj.331.7516.529
15) Targownik, L. E., Bolton, J. M., Metge, C. J., Leung, S., & Sareen, J. (2009). Selective serotonin reuptake inhibitors are associated with a modest increase in the risk of upper gastrointestinal bleeding. Official journal of the American College of Gastroenterology| ACG, 104(6), 1475-1482.