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Research Article

Antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) are attenuated by antiinflammatory drugs in mice and humans

Jennifer L. Warner-Schmidt, Kimberly E. Vanover, Emily Y. Chen, John J. Marshall, and Paul Greengard
PNAS first published April 25, 2011; https://doi.org/10.1073/pnas.1104836108
Jennifer L. Warner-Schmidt
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  • For correspondence: jschmidt@rockefeller.edu greengard@rockefeller.edu
Kimberly E. Vanover
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Emily Y. Chen
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John J. Marshall
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Paul Greengard
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  • For correspondence: jschmidt@rockefeller.edu greengard@rockefeller.edu
  1. Contributed by Paul Greengard, March 28, 2011 (sent for review March 10, 2011)

This article has a Correction. Please see:

  • Correction for Warner-Schmidt et al., Antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) are attenuated by antiinflammatory drugs in mice and humans - June 15, 2011

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  • Serotonin, cytokines, p11, and depression
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Abstract

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.

  • citalopram
  • fluoxetine
  • S100A10

Footnotes

  • ↵1To whom correspondence may be addressed. E-mail: jschmidt{at}rockefeller.edu or greengard{at}rockefeller.edu.
  • Author contributions: J.L.W.-S., K.E.V., and P.G. designed research; J.L.W.-S., K.E.V., E.Y.C., and J.J.M. performed research; J.L.W.-S., K.E.V., E.Y.C., and J.J.M. analyzed data; and J.L.W.-S., K.E.V., and P.G. wrote the paper.

  • The authors declare no conflict of interest.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1104836108/-/DCSupplemental.

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Antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) are attenuated by antiinflammatory drugs in mice and humans
Jennifer L. Warner-Schmidt, Kimberly E. Vanover, Emily Y. Chen, John J. Marshall, Paul Greengard
Proceedings of the National Academy of Sciences Apr 2011, 201104836; DOI: 10.1073/pnas.1104836108

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Antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) are attenuated by antiinflammatory drugs in mice and humans
Jennifer L. Warner-Schmidt, Kimberly E. Vanover, Emily Y. Chen, John J. Marshall, Paul Greengard
Proceedings of the National Academy of Sciences Apr 2011, 201104836; DOI: 10.1073/pnas.1104836108
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