Do NSAIDs Reduce the Effectiveness of Antidepressants? (American Jl Psy Oct 2012)


Both antidepressants and NSAIDs are widely used. Pain and depression are common human conditions. STAR*D study of antidepressant effectiveness suggested that NSAID-treated patients with major depression were less likely to achieve remission with citalopram than patients who were not treated with NSAIDs (Warner-Schmidt JL  et al 2011). NSAID use in the STAR*D cohort was not randomly assigned and hence the risk of confounding was substantial in that study. ( ie is it the NSAID or the condition that the NSAID is used to treat that reduces the response to antidepressants?)

Using data from electronic medical records system, patients with a diagnosis of major depression (ICD-9 codes)  were selected for inclusion in the study. From narrative records, researchers  identified individuals who either achieved remission with SSRI monotherapy or remained depressed despite two or more antidepressant treatments.Concomitant medications, including NSAIDs, cyclooxygenase (COX)-2 inhibitors, and salicylates, were extracted from the prescription list. Socio demographic ad comorbidity data were also collected.

The primary analysis compared antidepressant response between patients with chronic NSAID use and patients unexposed to NSAIDs. Of the 1,528 participants,   1,245 (81%) patients were exposed to NSAIDs or NSAID-like medications, and 283 (19%) were unexposed .

Findings: NSAID exposure was significantly associated with risk for treatment-resistant depression.This effect appeared to be confined to the NSAIDs-only group, since no significant association was observed in the COX-2 inhibitor and salicylate treatment groups. The association was less, but still significant for NSAID, when adjustment was made for Medical comorbidity.

Patients with chronic NSAID use continued to have increased risk for treatment-resistant depression relative to patients without NSAID use (odds ratio=1.47, 95% CI=1.03–1.76, p=0.02), but no increased risk was observed in patients with intermittent use.

This study thus confirmed a significant association between NSAID exposure and poorer antidepressant treatment outcome in major depressive disorder. The effect appeared specific to treatment with NSAIDs rather than with agents that have similar mechanisms of action. The study also  identified evidence of potential confounding effects using measures of medical comorbidity.

Authors raise a pertinent question. Should clinicians aim to avoid NSAID treatment in depressed patients receiving antidepressant treatment?

The study show that salicylates and COX-2 inhibitors might be preferable to NSAIDs when indicated for antidepressant- treated patients. Broader considerations of cost and safety needs to be considered.

Limitations: The study cannot fully exclude unmeasured confounding variables.Electronic medical record data are insufficient to identify specific comorbidities such as pain, which might be more closely associated with NSAID use.

Richard Shelton, in the accompanying editorial consider this effect as more likely to residual confounding.  Comorbidity is likely to be measured imperfectly. A trend for similar reduced response was seen for CBT as well, indicating that it is not limited or specific for antidepressants.

As  jury is out on this, caution  should prevail.

Summary of the article:

Antidepressant Response in Patients With Major Depression Exposed to NSAIDs:
A Pharmacovigilance Study. Am J Psychiatry 2012; 169:1065–1072

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