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Cytokines may be important in depression. These immunomodulators are produced by glial cells, regulate brain serotonin and noradrenergic systems, and activate the hypothalamic-pituitary-adrenal axis. Antidepressants increase levels of p11, a specific protein that regulates depression in rodent models and interacts with the serotonin receptor. To learn about possible interactions of antidepressants, cytokines, p11, and anti-inflammatory drugs (NSAIDs), researchers conducted experiments in mice and reanalyzed data from the large STAR*D study.
The selective serotonin reuptake inhibitors citalopram and fluoxetine increased p11 levels in mouse frontal cortex, but coadministered ibuprofen (IBU) or acetylsalicylic acid (ASA) blocked this increase. IBU lowered plasma citalopram levels. The tricyclic desipramine produced a small p11 increase, which was not affected by IBU or ASA. Antidepressant-related p11 increases were dependent on signaling by two cytokines (interferon-gamma and tumor necrosis factor-alpha). In a mouse model of depression, IBU, ASA, and acetaminophen prevented the behavioral response to SSRIs but not to antidepressants of other types.
Of STAR*D patients who took citalopram for 12 weeks, significantly fewer achieved remission if taking NSAIDs than if not taking NSAIDs (45% vs. 55%). Findings were similar in a comparison of other analgesic use with nonuse (37% vs. 54%).
Warner-Schmidt JL et al. Antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) are attenuated by antiinflammatory drugs in mice and humans. Proc Natl Acad Sci U S A 2011 Apr 25; [e-pub ahead of print]. (http://dx.doi.org/10.1073/pnas.1104836108)
Comment
This elegant translational study connects the observations in a rodent depression model with possible clinical response to antidepressants. SSRIs (but not noradrenergic antidepressants) increase cytokines, which increase p11, resulting in the antidepressant response. NSAIDs (and acetaminophen) inhibit the step-activating cytokines. Clinically, worse antidepressant response is associated with analgesic use. Further research is needed, including prospective studies of various antidepressant types and studies of other possible etiologies – e.g., putatively NSAID-lowered plasma levels of SSRIs or a greater likelihood that depression will be refractory to treatment in patients with pain. Meanwhile, clinicians should carefully evaluate their depressed patients' analgesic use; it may be one reason for poor response. For patients requiring analgesics, clinicians may wish to consider non-SSRIs.