A large observational study published in the British Medical Journal (2015; 351:h3517) examined the risk of intracranial hemorrhage in patients treated with antidepressants alone compared with those treated with a combination of antidepressants and non-steroidal anti-inflammatory drugs (NSAIDs).
The study included over four million individuals in South Korea who began antidepressant therapy between 2009 and 2013. Patients with prior antidepressant use in the preceding year or a recent history of cerebrovascular disease were excluded. Approximately half of the participants were also prescribed an NSAID, such as ibuprofen or naproxen.
The primary outcome measured was the first hospital admission for intracranial hemorrhage within 30 days of initiating NSAID therapy. Researchers found that patients taking both antidepressants and NSAIDs had a significantly higher risk of intracranial bleeding compared with those taking antidepressants alone.
Overall, the combination therapy was associated with a 60% increased risk of intracranial hemorrhage. This increased risk was observed across different classes of antidepressants, including selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants.
The risk appeared to be especially elevated in men. Men taking both medications had approximately a 2.6-fold higher risk of intracranial hemorrhage compared with men taking antidepressants alone, whereas women experienced a more modest increase in risk (approximately 1.2-fold).
The analysis focused only on bleeding events occurring within 30 days of NSAID initiation, so long-term risk could not be assessed. In addition, only prescription NSAIDs were included; over-the-counter use was not evaluated.
Both antidepressants and NSAIDs are known to affect platelet function, and each independently carries a modest bleeding risk. When used together, these effects may be additive, increasing the likelihood of bleeding complications.
An editorial accompanying the study noted that approximately 65% of individuals with major depression also experience chronic pain, making concurrent use of antidepressants and NSAIDs common. These findings highlight the importance of carefully weighing risks and benefits and considering non-pharmacologic or integrative strategies for managing pain and mood when appropriate.
