Do you know what other medications your depressed patients are taking? You should. If they’re taking non-steroidal anti-inflammatory drugs (NSAIDs), they may be less likely to respond to SSRIs. That was the surprising conclusion of a paper published last year (Warner-Schmidt JL et al, Proc Natl Acad Sci USA 2011;108:9262–9267), and a newly released report reaches a similar conclusion.
Using the electronic medical record of a large HMO, investigators identified 1,528 depressed patients who either achieved remission or who remained treatment-resistant after two or more antidepressant trials. Of these, 1,245 (81%) received at least one prescription of an NSAID or NSAID-like medication during their treatment period. Consistent with the earlier report, depressed patients who received NSAIDs were more likely to be treatment-resistant (odds ratio 1.55, with 95% confidence interval 1.21-2.00).
The investigators attempted to factor out other medical problems. After doing so, the odds ratio remained elevated but was not statistically significant (OR=1.17, 95% CI 0.83-1.64). But then the investigators looked more specifically at the type of NSAIDs used. They found that cyclooxygenase-2 (COX-2) inhibitors—drugs like celecoxib (Celebrex)—and salicylates (aspirin) were not associated with treatment resistance, whereas “pure” NSAIDs were. Thus, NSAIDs alone (drugs like ibuprofen and naproxen) correlate with treatment resistance, while other NSAID-like drugs do not. This result remained significant even when adjusting for medical comorbidities.
The investigators also performed their analysis on the 1,546 subjects in STAR‡D (a large, multicenter antidepressant trial in which all subjects received citalopram in phase I) and found a strikingly similar response: NSAIDs were more highly associated with treatment resistance (OR=1.23, 95%CI 1.06-1.44). The risk of treatment resistance was particularly high when COX-2 inhibitors and salicylates were removed, and remained high after controlling for medical problems (OR=1.26, 95%CI 1.02-1.55).
This study is subject to the same limitations of other “pharmacovigilance” studies (lack of randomization, many unmeasured confounding variables like level of pain or medication adherence). It also gives no indication of a dose-response effect and doesn’t consider pain relievers purchased over-the-counter. It also reports risk in the form of an odds ratio, rather than a risk ratio, which may overestimate the actual effect. Nonetheless, its main conclusion is worth considering: patients taking NSAIDs may respond more poorly to antidepressants (Gallagher PJ et al, Am J Psychiatry 2012;169(10):1065–1072).
TCPR’s Take: Should you ask your patients to stop NSAIDs when you prescribe an SSRI? Probably not—and that would be impractical anyway. But the take-home message seems to be that inflammation and medical illness are linked to depression in ways we are just beginning to understand. Authors of the earlier paper, for instance, hypothesized that the expression of a certain intracellular protein (called p11) underlies antidepressant response and is enhanced by certain cytokines, while other research holds that inflammation and elevated cytokines are responsible for depression (see TCPR, October 2012). Clearly more research is needed to tease out these relationships.