Researchers at the Rockefeller University in New York, have shown that nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the effectiveness of selective serotonin reuptake inhibitors, or SSRIs. Could this discovery, published online in the Proceedings of the National Academy of Sciences, explain cases of depressed patients with pain who do not respond as expected to antidepressant therapy when they also are taking over-the-counter analgesics?
This possible negative interaction was first explored by the researchers in animal experiments and then confirmed in humans. The investigators treated mice with antidepressants in the presence or absence of NSAIDs and found that behavioral responses typically sensitive to antidepressant effects were inhibited in the animals administered NSAIDs. Biochemical assays also found abnormalities associated with the combination of NSAIDs and antidepressants.
In a human population, depressed persons taking NSAIDs were much less likely to have their symptoms relieved by an SSRI than comparable depressed patients who reported no NSIAD use. The effect was of significance since, in the absence of NSAID use, 54% of patients responded well to the antidepressant, whereas success rates dropped to approximately 40% in those who reported concurrently using anti-inflammatory analgesics.
In a press release, one of the researchers, Paul Greengard, PhD, noted, “Many elderly individuals suffering from depression also have arthritic or related diseases and as a consequence are taking both antidepressant and anti-inflammatory medications. Our results suggest that physicians should carefully balance the advantages and disadvantages of continuing anti-inflammatory therapy in patients being treated with antidepressant medications.”
COMMENTARY: This research was supported by grants from the U.S. National Institutes of Health and The Fisher Center for Alzheimer's Research Foundation. Antidepressants tested in animals included: citalopram, fluoxetine, desipramine, imipramine, and buproprion. NSAID agents examined included ibuprofen, naproxen, and aspirin.
Human data came from a large-scale examination of major depressive disorders in adult outpatient settings — the NIH-supported study, “Sequenced Treatment Alternatives to Relieve Depression” (STAR*D, published in 2006). For this current, post hoc (retrospective) analysis, all subjects who had received the SSRI antidepressant citalopram for up to 12 weeks were extracted from the database and compared with more than 4,000 of those also taking NSAIDs, such as ibuprofen, naproxen, aspirin, and others.
Based on their animal experiments, the researchers propose a “cytokine hypothesis” as a possible explanation for their findings. Specifically, they suggest that levels of certain cytokines in the frontal cortex of the brain are increased by serotonergic antidepressants. However, since NSAIDs achieve their therapeutic actions in part by moderating cytokine formation, the beneficial effects of SSRIs may be inhibited by NSAIDs.
There were many limitations of this research and it raises some unanswered questions. For one thing, we have cautioned previously [here] about the questionable validity of studies extracting information from large, older databases that were not designed for the research at hand; that is, post hoc data-mining in which cause-effect relationships cannot be accurately determined. And, in this current investigation only a single SSRI was examined (citalopram), so we do not know if the results can be generalized in humans to the entire class of medications.
Still, the results may be of concern for patients with pain taking both SSRIs and NSAIDs, which may be common in certain treatment settings. As it is, there have been some warnings of increased GI bleeding in patients taking SSRIs alone and up to a 12-fold greater risk of this adverse event when they are combined with NSAIDs, or even low-dose aspirin to a lesser extent [article section here]. Now, there is an implication that the combination may diminish antidepressant effects as well.
Further questions might be raised about potential interactions of NSAIDs with other antidepressants, such as tricyclics, which also are used for their analgesic effects in treating migraines and neuropathic pain conditions [see UPDATES here and here]. Greengard noted that some research has suggested that NSAIDs may actually boost the potency of tricyclic (eg, amitriptyline) and noradrenergic (eg, reboxetine) antidepressants, but this may need further examination.
Clinical trials seem warranted to better define the possible interactions of antidepressants and NSAIDs in persons with pain. At the least, observational cohort studies might help to assess matched groups of persons with comorbid pain and depression who are prescribed antidepressants and concurrently taking or not taking NSAIDs.
REFERENCE: Warner-Schmidt JL, Vanover KE, Chen EY, Marshall JJ, Greengard P. Antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) are attenuated by antiinflammatory drugs in mice and humans. PNAS. 2011(Apr 25); online ahead of print [abstract here].