About 34 million adult Americans take selective serotonin reuptake inhibitors (SSRIs) for depression, anxiety, and other mental health conditions These include fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), citalopram (Celexa), escitalopram, (Cipralex), and fluvoxamine, (Luvox). A similar number of Americans take nonsteroidal anti-inflammatory drugs (NSAIDs) to control pain, inflammation, and fever. These drugs include ibuprofen (Advil, Motrin), naproxen (Aleve), and diclofenac (Voltaren). Individually, both classes of drugs, SSRIs, and NSAIDs, can cause peptic ulceration and bleeding. When SSRIs and NSAIDs are taken together, this risk of GI is much greater than the sum of taking one or the other alone.
All antidepressant SSRIs share the same mechanism of action: they inhibit the cellular uptake of serotonin in the pre-synaptic nerve ending, which increases serotonin in the synapse and activates receptors in the post-synaptic nerve ending. (Fig. 1). Serotonin activation in the post-synaptic synapse improves mood and is the central mechanism of action for the antidepressant effect of SSRIs
Figure 1.
However, serotonin has other important effects outside of the CNS. In the blood, serotonin induces platelets to aggregate, an essential process in blood clotting, and in the stomach, sertonin inhibits gastric acid secretion. Importantly, SSRIs, due to their mechanism of action in blocking serotonin reuptake, increase gastric acid secretion and decrease platelet aggregation/blood clotting. As a result, SSRI use is associated with an increased incidence of gastric bleeding and ulcers.
Nonsteroidal anti-inflammation Drugs (NSAIDs) are used to relieve pain and inflammation and lower fever associated with various health conditions. All NSAIDs work by inhibiting the cyclooxygenase enzymes that convert arachidonic acid into pro-inflammatory mediators. There are two cyclooxygenases targeted (COX 1 and COX 2). Nonselective NSAIDs inhibit both enzymes and include aspirin, ibuprofen (Advil, Motrin), naproxen (Aleve), and diclofenac (Voltaren). Unlike SSRIs, these drugs are available both by prescription and over-the-counter (OTC) without a prescription. Selective COX 2 inhibitors (COXibs)
such as celecoxib (Celebrex) are only available by prescription. The mechanism of action of nonselective and selective COX inhibitors is shown in Figure 2.
Figure 2.
As seen in Figure 2., prostaglandins have positive and negative effects. Negatively, they cause inflammation. Positive effects include protecting the stomach, aiding in hemostasis (blood clotting), and helping regulate renal function. Nonselective NSAIDS inhibit both the positive and negative effects of prostaglandins. To some extent the selective NSAIDS also do this, and the FDA makes no distinction in issuing its most serious, Black Box, warning on package inserts for both selective and nonselective inhibitors. That warning states: NSAIDs, cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal (GI) events.
The FDA also recognizes the increased risk of combining SSRIs with NSAIDS. SSRI labels state SSRIs May increase the risk of bleeding. Use with NSAIDs, aspirin, warfarin, or other drugs that affect coagulation may potentiate the risk of gastrointestinal or other bleeding.
Because NSAIDs are available OTC, and the term NSAID is not ubiquitous, many people do not know or tell their physicians or pharmacists they are taking NSAIDs. Thus, the health system cannot alert all patients to the danger of combining NSAIDs with SSRIs. That danger is significant. One meta-analysis concluded that the risk of upper gastrointestinal bleeds is synergistic rather than additive. The risk factor for bleeds in this study in the group taking both drugs was 500% higher than the predicted value of just adding individual risks. If you are on SSRIs and are experiencing stomach issues, alert your physician and provide a complete list of all prescription and OTC drugs you are taking.
Sources:
https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/j.1365-2036.2007.03541.x Assessed and Endorsed by the MedReport Medical Review Board