What is the evidence for drug interactions between Selective Serotonin Reuptake Inhibitors (SSRIs) and Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)?

Drug Interactions Between SSRIs and NSAIDs: Increased Risk of Gastrointestinal Bleeding

Concurrent use of SSRIs and NSAIDs significantly increases the risk of gastrointestinal bleeding, with a 4.25-fold higher risk compared to using neither medication. 1

Evidence for SSRI-NSAID Interaction

Gastrointestinal Bleeding Risk

• SSRIs alone increase the risk of upper GI bleeding by approximately 1.66-1.68 times compared to no treatment 2
• NSAIDs alone are known to potentiate the risk of bleeding through antiplatelet effects and loss of GI protection
• The combination of SSRIs and NSAIDs creates a synergistic effect:
  • 2.14 times higher risk of GI bleeding compared to SSRI use alone 1
  • 1.49 times higher risk compared to NSAID use alone 1
  • 4.25 times higher risk compared to using neither medication 2

Mechanism of Interaction

The interaction occurs through multiple mechanisms:

1. SSRIs inhibit serotonin reuptake in platelets, impairing platelet aggregation
2. NSAIDs inhibit prostaglandin synthesis and have antiplatelet effects
3. Both medications can cause direct injury to the GI tract
4. The combination creates a synergistic effect on bleeding risk

Clinical Implications and Management

Risk Assessment

Patients at highest risk for this interaction include:

• Elderly patients (especially those over 80 years) 3
• Patients with history of peptic ulcer disease 4
• Patients on anticoagulants 4
• Patients with chronic alcohol use 4

Management Strategies

When prescribing these medications together:

1. Consider alternative medications:

   • For depression: Consider antidepressants with low or no serotonin reuptake inhibition (e.g., bupropion, mirtazapine) for patients at high bleeding risk 5
   • For pain: Consider acetaminophen (with caution not to exceed 4g daily) 4

2. If co-administration is necessary:

   • Add gastroprotection: Proton pump inhibitors should be used when SSRIs and NSAIDs are prescribed together 4
   • H2-receptor antagonists are inadequate for gastroprotection 4
   • Use the lowest effective doses for the shortest duration 4
   • Monitor for signs of GI bleeding (melena, hematemesis, unexplained anemia)

3. Special considerations:

   • In patients already on anticoagulants, this combination should be avoided if possible 4
   • Patients should be educated about the increased bleeding risk and warning signs 5

Conclusion

The evidence clearly demonstrates a significant and clinically important interaction between SSRIs and NSAIDs that increases the risk of GI bleeding. This risk is particularly pronounced in elderly patients and those with other risk factors for GI bleeding. Clinicians should carefully weigh the benefits against risks when considering co-prescribing these medications and implement appropriate risk mitigation strategies when co-administration is necessary.