A little-known fact in the field of cardiology is that the depression rate among patients after a heart attack is quite high. Rates of major depressive disorder have varied between 15% and 25% in cardiac patients and depression has been shown to be a significant predictor of mortality. So, on the one hand, treating depression in cardiac patients should be an obvious proposition.
But on the other hand, anti-depressants are not benign medications. They have had a long and complicated history. One of my first articles for Maclean’s was about Study 329, a now infamous study about anti-depressant use in teens. Although the initial study was negative, researchers re-analyzing the original data years later claimed the original results had been manipulated to obscure a possible link between SSRI use and suicidal thoughts in teens. What’s more, a 2008 report in the New England Journal of Medicine found that many of the studies showing SSRIs to be ineffective were never published.
To understand how SSRIs became so popular we have to review how medications like Prozac, Paxil and Zoloft got to market. Before SSRIs, older antidepressants like tricyclics were available but they had multiple side effects and toxicities that limited their use. Doctors were eager for a safer alternative because it had long been known that cardiac patients with depression did worse than those without. The link between these two diseases was thought to be serotonin. Lack of serotonin in the brain can cause depression, but it is also involved in platelet aggregation and clot formation. Therefore, a medication that could boost serotonin levels in the brain and prevent platelets from clogging the arteries would be most welcome. This is exactly what SSRIs do.
Unfortunately, as happens so often in science, a beautiful theory was slain by an ugly fact. The SADHART clinical trial with sertraline (Zoloft) found that while it did improve depression symptoms it had no effect on cardiac outcomes. The ENRICHD trial later showed similar results. While the new class of medications had few side effects for the heart, they didn’t improve survival or reduce heart attacks.
There are however side effects to SSRI use. My first major research project involved analyzing data about SSRIs and their interaction with common blood thinners. Since SSRIs can stop platelets from forming clots, I wondered if they interact with medications like aspirin, Plavix, or coumadin (this was before newer medications largely replaced the use of coumadin for cardiac patients). It turned out that SSRIs did increase the risk of bleeding when combined with these medications.
Then there are studies like this one that proclaim that anti-depressants increase the risk of death and generate news reports warning that antidepressants increase the risk of early death. The study was a meta-analysis of 17 trials. Its final conclusion proposed that anti-depressants increased mortality by 33% and cardiac events by 14%. It also drew some other rather surprising conclusions. While anti-depressants increased mortality in the general population, there was no effect in cardiac patients. There also appeared to be no difference between SSRI antidepressants and the older type of tricyclic antidepressants.
Thus, this meta-analysis is hard to reconcile with the existing facts. First off, the SADHART and ENRICHD trials were not part of the 17 studies in the review. The failure to include some of these larger studies does introduce some doubt about the analysis. It is also somewhat hard to imagine how a medication could cause heart attacks in most people but not in people who already have heart disease.
There are other problems that deserve mention. Double counting may have played a role here as well. The problem is statistically subtle but, simply put, it results when reviewers include data from the same study (usually from different subgroups) multiple times in the same analysis. Thus, they make it seem as if more people are included in the analysis then there were in the original studies. Also, some of the studies included in the data-analysis were observational studies rather than randomized trials. So, it’s always possible that older patients at higher cardiovascular risk were more likely to get SSRIs rather than TCA anti-depressants because of the possible side effects, which would, therefore, make SSRIs look worse than they actually are.
Weighing out the harms and benefits of SSRIs can be complicated. Analyses suggest they have little benefit in people with mild and moderate depression but do seem to help people with severe symptoms. While SSRIs can have serious side effects their toxicity potential does seem to be less than their predecessors. You can make a good argument that SSRIs were, and still are, overprescribed to many people who may not need them. But for those who do need them, the benefits may outweigh the risks.
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