Antiinflammatory drugs oppose antidepressant drug action

Life just got much more complicated for doctors prescribing both antidepressant and anti-inflamatory drugs to the same patient. Greengard and colleagues have found a specific molecular pathway linking cytokines and the actions of antidepressant drugs. Their findings confound established wisdom, because they imply that brain cytokines exert antidepressant actions and mediate the influences of the principal serotonin-specific reuptake inhibitor (SSRI) antidepressant drugs. Doctors now should weigh the benefits of antiinflammatory agents against their possible lessening of the effectiveness of antidepressant drugs.

Anti-inflammatory 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 anti-inflammatory agents on antidepressant-induced behaviors and on p11, a biochemical marker of depressive-like states and antidepressant responses. We found that widely used anti-inflammatory 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 anti-inflammatory agents. The antagonistic effect of anti-inflammatory 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 anti-inflammatory agents versus the potentially negative consequences of antagonizing the therapeutic efficacy of antidepressant agents in patients suffering from depression.