Is there an increased risk of intracranial hemorrhage (ICH) or cerebral hemorrhage when combining Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) and Selective Serotonin Reuptake Inhibitors (SSRIs)?

From the Guidelines

There is an increased risk of bleeding, including intracranial hemorrhage (ICH) or cerebral hemorrhage, when combining Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) and Selective Serotonin Reuptake Inhibitors (SSRIs).

Key Points

• NSAID use is associated with an increased risk of bleeding 1, thus regular long-term use should be avoided when possible in patients with ICH.
• The concurrent use of SSRIs with a nonsteroidal anti-inflammatory drug (NSAID) increases the risk for upper gastrointestinal (UGI) bleeding in adults 1.
• While the evidence does not directly address the risk of ICH with combined NSAID and SSRI use, the increased risk of bleeding associated with both medications suggests that caution should be exercised when prescribing them together.
• The risk-benefit profiles for an individual patient must be weighed when considering the use of these medications, particularly in patients with a history of ICH or other bleeding disorders.
• Regular monitoring and careful consideration of the potential risks and benefits are necessary when combining NSAIDs and SSRIs in clinical practice.

From the Research

Risk of Intracranial Hemorrhage with NSAIDs and SSRIs

• The risk of intracranial hemorrhage (ICH) or cerebral hemorrhage when combining Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) and Selective Serotonin Reuptake Inhibitors (SSRIs) has been investigated in several studies 2, 3, 4, 5, 6.
• A meta-analysis published in 2012 found that SSRI exposure was associated with an increased risk of intracranial hemorrhage (RR 1.51,95% CI 1.26-1.81) and intracerebral hemorrhage (RR 1.42,95% CI 1.23-1.65) 2.
• Another study published in 2019 found that SSRI use was associated with a significantly increased risk of ICrH (RR 1.26,95%CI 1.11-1.42), although the association was partly accounted for by biases and methodological limitations in the available observational data 3.
• A case-control study published in 2020 found that current use of SSRIs was associated with a higher SDH risk (aOR 1.32 [1.25-1.38]), and that combined use of antidepressants with either antithrombotics or NSAIDs yielded similar ORs to those observed for single use of antithrombotics or NSAIDs 4.
• However, a study published in 2007 found no increased risk associated with SSRI use for intracerebral hemorrhage (odds ratio=1.1,95% CI: 0.7 to 1.8; P=0.63) or subarachnoid hemorrhage (odds ratio=0.6,95% CI: 0.4 to 1.0; P=0.054) 5.
• A nationwide population-based cohort study published in 2016 found that use of SNRIs was not associated with an increased risk of either ischemic stroke or intracranial hemorrhage as compared to use of SSRIs in adult patients with depression or anxiety 6.

Key Findings

• SSRI exposure is associated with an increased risk of intracranial hemorrhage and intracerebral hemorrhage 2, 3.
• Combined use of antidepressants with either antithrombotics or NSAIDs may yield similar ORs to those observed for single use of antithrombotics or NSAIDs 4.
• The risk of intracranial hemorrhage associated with SSRI use may be small in absolute terms, given the low incidence rate of ICH 2, 4.
• The association between SSRI use and ICH risk may be partly accounted for by biases and methodological limitations in the available observational data 3.