In a study published today, scientists at Rockefeller University proclaim that SSRI antidepressants (like Prozac and Celexa) may lose their efficacy when given with anti-inflammatory drugs like ibuprofen and aspirin. Considering the high prevalence of depression and the widespread use of both SSRIs and anti-inflammatory medications, this result is bound to receive much attention. As a matter of fact, it’s tantalizing to jump to the conclusion (as has been done in the Fox News and WSJ reports on this study) that the reason SSRIs may be so ineffective is because so many people with depression also use non-steroidal anti-inflammatory drugs (NSAIDs).
By my read of the data, it may be a bit too early to draw this conclusion. Nevertheless, the study, by Paul Greengard, Jennifer Warner-Schmidt, and their colleagues, and published online in the Proceedings of the National Academy of Sciences, does propose some interesting mechanisms by which anti-inflammatory agents may affect antidepressant action.
The majority of the work was performed in mice, for which there are valid “models” of depression that are routinely used in preclinical studies. In past work, Greengard’s group has shown that the expression of a small protein called p11 (which is associated with the localization and function of serotonin receptors) is correlated with “antidepressant-like” responses in mice, and probably in humans, too. In the present study, they demonstrate that the antidepressants Prozac and Celexa cause an increase in expression of p11 in the frontal cortex of mice, and, moreover, that p11 expression is mediated by the ability of these antidepressants to cause elevations in interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α). In other words, antidepressants enhance neural expression of these cytokines, which, in turn, increases p11 activity.
However, when mice are given NSAIDs or an analgesic (i.e., ibuprofen, naproxen, aspirin, or Tylenol), this prevents the increase in p11, as well as the increase in IFN-γ and TNF-α. NSAIDs also prevent the “antidepressant-like” behavioral responses elicited by Celexa (as well as other antidepressants like Wellbutrin, Parnate, and TCAs) in mouse models of depression.
The group went one step further and even created a p11 “knockout” mouse. These mice had no response to Celexa, nor did they have antidepressant-like responses to injections of IFN-γ or TNF-α. However, the p11 knockout mice did respond to desipramine, an antidepressant that works mainly on norepinephrine, thus emphasizing the significance of serotonin in the p11-mediated response.
What does this mean for humans? To answer this question, the group analyzed data from STAR*D, a huge multicenter antidepressant trial. In the first stage of STAR*D, all patients (total of approximately 1500 individuals) took Celexa for a 12-week period. The remission rate for patients who took an NSAID at any time during this 12-week period was only 45%, while those who took no NSAID remitted at a rate of 55%.
So does this mean that people taking antidepressants should avoid NSAIDs, and just deal with their pain? Probably not. (In fact, one might ask the opposite question: should people with chronic pain avoid SSRIs? Unfortunately, the study did not look at whether SSRIs inhibited the pain-relieving effects of NSAIDs.)
In my opinion, some of the mouse data need to be interpreted carefully. For instance, the mice received extremely high doses of NSAIDs (e.g., ibuprofen at 70 mg/kg/d, which corresponds to 4200 mg/d for a 60-kg man, or 21 Advil pills per day; similarly, the mice drinking aspirin received 210 mg/kg/d, or 12,600 mg = ~39 pills of regular-strength aspirin per day for a typical human). Also, in the behavioral studies the mice received NSAIDs for an entire week but received only a single injection of Celexa (20 mg/kg, or about 1200 mg, 60 pills) immediately before the behavioral experiments.
The human data, of course, are equally suspect. Patients in the STAR*D study were counted as “NSAID users” if they described using NSAIDs even once in the first 12 weeks of the study. It’s hard to see how the use of ibuprofen once or twice in a three-month period might interfere with someone’s daily Celexa. (Not to mention the fact that the “remission” data from STAR*D have come under some scrutiny themselves – see here and here). Moreover, as the authors point out, it’s quite likely that patients with more severe forms of depression also had concurrent pain syndromes and used NSAIDs more frequently. In other words, NSAID use might not attenuate SSRI activity, but may be a sign of depression that is more resistant to SSRIs.
In the end, however, I find the study to be quite provocative. Certainly the correlation of antidepressant effect with expression of the p11 protein and with TNF-α and IFN-γ activity suggests a novel mechanism of antidepressant action—as well as new markers for antidepressant activity. Moreover, the potential roles of NSAIDs in reducing antidepressant effects (or, in some cases, enhancing these effects), need to be explored.
But it raises even more unanswered questions. For one, how do we reconcile the fact that antidepressant effects are associated with increased TNF-α and IFN-γ activity in the brain, while increases in these cytokines in the periphery are thought to cause depression? Also, how can we explain the fact that other analgesic compounds, such as tramadol and buprenorphine, might actually have an antidepressant effect? Finally, what does this mean for our treatment of pain symptoms in depression? Should we avoid SSRIs and use other types of antidepressants instead? Do NSAIDs inhibit the effects of SNRIs like Cymbalta, which has recently been FDA-approved for the treatment of chronic musculoskeletal pain (and whose users are most certainly also taking medications like NSAIDs)?
It’s great that the interface between mental illness and physical syndromes is receiving some well-deserved attention. It’s also exciting to see that the neuroscience and pharmacology of depression and pain may overlap in critical ways that influence how we will treat these disorders in the future. Perhaps it may also explain our failures up to now. With future work in this area, studies like these will help us develop more appropriate antidepressant strategies for the “real world.”
[Finally, a “hat tip,” of sorts, to Fox News, which first alerted me to this article. Unfortunately, the story, written by Dr. Manny Alvarez, was fairly low on substance but high on the “wow” factor. It drew some broad conclusions and—my biggest pet peeve—did not refer the reader to any site or source to get more detailed information. Alas, such is the case with much public science and medicine reporting: Alarm first, ask questions later.]
Thought Broadcast 
Carroll’s dictum: The model is not the disease.
Nice work laying this story out. I for one am intensely skeptical.
I have to wonder what this means for those with chronic intractable pain for whom antidepressant meds help their pain (and they do not have concommitant mental illness). I would make the assumption that many use anti inflammatories as part of their med regimen since most of the pain is body pain. Might this be a reason for lack of benefit from one or the other, or the use of both together?
Carol Jay Levy
author A PAINED LIFE, a chronic pain journey
http://womeninpainawareness.ning.com/
http://apainedlife.blogspot.com/
Musing from the lay person side of things: I wonder if there is a cytochrome P450 interaction (previously unknown) going on in which the NSAIDs are “inducers” and SSRIs “substrates” of the same enzyme?
On another drug-drug interaction: my son is on a cocktail of meds, and every new OTC drug he thinks of taking is first run past the pharmacist — my son was advised against taking NSAIDs with ADs (fluoxetine) because of an increased risk (although a small one) of bleeding. And that was when he had flu-like symptoms, a temporary condition, and was only planning to take the NSAIDs for a week or so. I was surprised to read that people with chronic pain and depression would take ADs and NSAIDs on a long-term basis. Isn’t this really dangerous?
I’m very skeptical of this.
The human data are uninterpretable. People who take NSAIDs presumably have a reason to take them, maybe they have comorbid medical conditions, maybe they have somatic complaints due to their depression, maybe they’re just older and taking aspirin for the good of their heart. You could control for some of this, but not all of it.
The mouse stuff’s also weird. The high doses are not that surprising, mouse metabolism is much faster than ours so all drugs need to be given in relatively higher doses. however the fact that the SSRI was only given acutely is weird, typically in these rodent studies you find that acute antidepressants don’t do anything and chronic ones do (which is said to support the validity of the model.)…
I haven’t read it yet though, I’m just going on your description of it.
Neuroskeptic,
Thanks for pointing out the concerns re: murine metabolism. Hadn’t considered that. But that just begs the question, if human & mouse metabolic rates differ by orders of magnitude, how can we draw any conclusion about anything else in this study, much less the implications for a complex behavioral phenotype like human depression?
Not saying further research shouldn’t be done, but let’s try not to jump to conclusions.
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