Anti-Inflammatory Drugs Reduce Effectiveness of SSRI Antidepressants

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Scientists at the Fisher Center for Alzheimer's Disease Research at The Rockefeller University, led by Paul Greengard, Ph.D., and Jennifer Warner-Schmidt, Ph.D., have shown that anti-inflammatory drugs, which include ibuprofen, aspirin and naproxen, reduce the effectiveness of the most widely used class of antidepressant medications, the selective serotonin reuptake inhibitors, or SSRIs, taken for depression and obsessive-compulsive disorder and anxiety disorders.

This surprising discovery, published online this week in the Proceedings of the National Academy of Sciences, may explain why so many depressed patients taking SSRIs do not respond to antidepressant treatment and suggests that this lack of effectiveness may be preventable.

The study may be especially significant in the case of Alzheimer's disease.

Such patients commonly suffer from depression and unless this can be treated successfully, the course of the illness is likely to be more severe. Depression in the elderly is also a risk factor for developing Alzheimer's disease and researchers have suggested that treating depression in the elderly might reduce the risk of developing the disease.

In the recent study, investigators treated animal models with antidepressants in the presence or absence of anti-inflammatory drugs. They then examined how the models behaved in tasks that are sensitive to antidepressant treatment. The behavioral responses to antidepressants were inhibited by anti-inflammatory/analgesic treatments. They then confirmed these effects in a human population.

Depressed individuals who reported anti-inflammatory drug use were much less likely to have their symptoms relieved by an antidepressant than depressed patients who reported no anti-inflammatory drug use. The effect was rather dramatic since, in the absence of any anti-inflammatory or analgesic use, 54% of patients responded to the antidepressant, whereas, success rates dropped to approximately 40% for those who reported using anti-inflammatory agents.

"The mechanism underlying these effects is not yet clear. Nevertheless, our results may have profound implications for patients, given the very high treatment resistance rates for depressed individuals taking SSRIs," noted Dr. Warner-Schmidt. Dr. Greengard added, "Many elderly individuals suffering from Alzheimer's disease 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."

Published paper: http://www.pnas.org/content/early/2011/04/20/1104836108.abstract

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 April 25, 2011

Antiinflammatory drugs achieve their therapeutic actions at least in part by regulation of cytokine formation. A “cytokine hypothesis” of depression is supported by the observation that depressed individuals have elevated plasma levels of certain cytokines compared with healthy controls. Here we investigated a possible interaction between antidepressant agents and antiinflammatory agents on antidepressant-induced behaviors and on p11, a biochemical marker of depressive-like states and antidepressant responses. We found that widely used antiinflammatory drugs antagonize both biochemical and behavioral responses to selective serotonin reuptake inhibitors (SSRIs). In contrast to the levels detected in serum, we found that frontal cortical levels of certain cytokines (e.g., TNFα and IFNγ) were increased by serotonergic antidepressants and that these effects were inhibited by antiinflammatory agents. The antagonistic effect of antiinflammatory agents on antidepressant-induced behaviors was confirmed by analysis of a dataset from a large-scale real-world human study, “sequenced treatment alternatives to relieve depression” (STAR*D), underscoring the clinical significance of our findings. Our data indicate that clinicians should carefully balance the therapeutic benefits of antiinflammatory agents versus the potentially negative consequences of antagonizing the therapeutic efficacy of antidepressant agents in patients suffering from depression.