Combining these two common medications might kill you.

For the video version of this post, click here. With depression a major health problem, and broadening indications for antidepressants, these medications are seeing rapidly increasing use.  Non-steroidal anti-inflammatory drugs (NSAIDs), ranging from indomethacin, to ibuprofen, to the cox-2 inhibitors, are also very frequently used. Simple logic would tell us that there would be significant overlap in the Venn diagrams for these two classes, but it turns out that individuals with depression are more likely to experience chronic pain, and thus, more likely to take NSAIDs. The combination of these two classes may be problematic.

The problem is that the most commonly used class of antidepressants, the SSRIs, may increase bleeding risk by reducing serotonin uptake by platelets. And NSAIDs can mess with platelet function in multiple ways.  Now a study by Korean researchers, appearing in the BMJ suggests that the concomitant use of both of these agents can significantly increase the risk of intracranial hemorrhage.

This was a large, population-based study using the Korean national medical database. The researchers looked for everyone with an incident antidepressant prescription from 2009 to 2013.  Of these roughly 5 million individuals, just about half had received an NSAID prescription within the 30 days following the antidepressant. That proportion seems crazy to me, but apparently you can’t get NSAIDs over the counter in Korea, so the demand for prescriptions must be high.

Rather than comparing the NSAID group to the no NSAID group directly, the researchers matched NSAID users with non-NSAID users with similar qualities using propensity scores - this left roughly 2 million people in each group for analysis.

The results? Well, the intracerebral hemorrhage rate was about 60% higher in the group taking NSAIDs.  Now, the overall risk was low - you’d need to prevent around 250 people from taking NSAIDs to prevent one intracerebral hemorrhage, but there are a few issues with the study that make me question the results.

First - an issue of interpretation.  The authors state that caution should be used when combining NSAIDs with antidepressants.  But they don’t have data on people who take neither drug, nor do they have data on people taking NSAIDs alone. So the picture is incomplete.  Maybe NSAIDS increase the risk of intracerebral hemorrhage and antidepressants have nothing to do with it.

We also saw no difference based on the type of antidepressant prescribed. SSRIs, due to their mechanism of action, should increase bleeding risk more than tricyclics for example, but we don’t see that here.

Finally, the follow-up period was only 30 days, and the median length of follow-up was only 14 days. While a signal seen in such a short period of time may be compelling, it doesn’t help us advise our patients who are using antidepressants for a longer period of time.  This is a potential interaction worth following up on in more robust studies, but until we know more, I suggest we continue to do our best to relieve all types of pain.