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, 108 (22), 9262-7

Antidepressant Effects of Selective Serotonin Reuptake Inhibitors (SSRIs) Are Attenuated by Antiinflammatory Drugs in Mice and Humans

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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 et al. Proc Natl Acad Sci U S A.

Erratum in

  • Proc Natl Acad Sci U S A. 2011 Jul 5;108(27):11297

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.

Trial registration: ClinicalTrials.gov NCT00021528.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Schematic representation of the model tested in the current study. Here we suggest that antidepressants, specifically SSRI antidepressants, increase brain levels of certain cytokines, which in turn increase levels of p11, the effect of which produces behavioral antidepressant responses. Each step in this pathway can be antagonized by NSAID coadministration.
Fig. 2.
Fig. 2.
Effect of antidepressants and NSAIDs on cytokine levels and p11 in the mouse frontal cortex. (A) Mouse frontal cortex samples from animals treated with vehicle (VEH), citalopram (CIT), ibuprofen (IBU), or both IBU and CIT were analyzed for levels of cytokines. Group 1 cytokines were increased by citalopram, the effect of which was abolished by ibuprofen cotreatment. Group 2 cytokines were increased by citalopram, the effect of which was not affected by ibuprofen. (B) Western blot analysis of p11 protein or actin loading control in the frontal cortex of mice receiving a chronic selective serotonin reuptake inhibitor (citalopram or fluoxetine) or a tricyclic antidepressant (desipramine), alone or in combination with ibuprofen or acetylsalicylic acid. Representative blots (Upper); quantification of five to six mice per group (Lower). All data are presented as means ± SEM. Statistically significant effects of antidepressants (#P < 0.05) or NSAIDs (*P < 0.05) are noted.
Fig. 3.
Fig. 3.
IFNγ and TNFα are necessary and sufficient for antidepressant-induced increases in p11 levels. (A) Western blot analysis of p11 protein or actin loading control in the frontal cortex of WT, IFNGR1 KO, or TNFR1 KO mice treated for 3 wk with citalopram. Representative blots (Upper); quantification of 8–10 mice per group (Lower). All data are presented as means ± SEM. Statistically significant effects of antidepressants (##P < 0.01) or genotype (*P < 0.05) are noted. (B) Western blot analysis of p11 or actin loading control reveals that acute i.p. injection of IFNγ (10 μg/kg bodyweight) or TNFα (10 μg/kg bodyweight) significantly increases p11 protein in mouse cortex compared with vehicle injected controls. Representative blots (Upper); quantification of 5–6 mice per group (Lower). All data are presented as means ± SEM. (*P < 0.05).
Fig. 4.
Fig. 4.
Effects of antidepressants and NSAIDs on behavioral responses. NSAIDs and other analgesics attenuate the behavioral response to SSRIs. IBU (5–7 d) diminished the behavioral response to the selective serotonin reuptake inhibitors citalopram (CIT) and fluoxetine (FLX), was less effective in altering behavioral responses to the tricyclic antidepressants imipramine (IMI) and desipramine (DMI), and did not affect responses to other classes of antidepressants, including the monoamine oxidase inhibitor tranylcipromine (TCP) and the atypical antidepressant bupropion (BUP) in two tests of antidepressant activity, the tail suspension test (A) and forced swim test (B). Mice receiving 5–7 d of nonsteroidal antiinflammatory drugs ibuprofen (IBU), naproxen (NPX), acetylsalicylic acid (ASA), or the analgesic acetaminophen (ACE) showed diminished response to citalopram (CIT) in the tail suspension test (C) and forced swim test (D). There was no response to chronic citalopram treatment when ibuprofen was coadministered before testing in the tail suspension test (E) or the novelty suppressed feeding test (F). All data are presented as means ± SEM. Statistically significant effects of antidepressants (#P < 0.05) or NSAIDs/analgesics (*P < 0.05, **P < 0.01) are noted. n = 8–16 per group.
Fig. 5.
Fig. 5.
Effects of cytokines and p11 on behavioral responses. (A) CAMK2α conditional p11 KO mice show reduced immobility in response to desipramine, but do not respond to citalopram in the tail suspension test. (B) Immobility is significantly reduced by acute injection of IFNγ or TNFα in wild-type mice, but not in CAMK2α-conditional p11 KO mice (n = 13–24 per group). All data are presented as means ± SEM. *P < 0.05, **P < 0.01. (C and D) Behavioral analysis of WT, IFNGR1 KO, or TNFR1 KO mice treated for 14 d with citalopram in the tail suspension test (C) or the novelty suppressed feeding test (D). All data are presented as means ± SEM. Statistically significant effects of citalopram (#P < 0.05) or genotype (*P < 0.05) are noted.

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