124. A comparative examination of the anti-inflammatory effects of SSRI and SNRI antidepressants on microglia

Abstract

Selective serotonin and serotonin norepinephrine reuptake inhibitors (SSRI; SNRI) are the frontline pharmacological treatment options for major depression. While these drugs have long been assumed to exert their antidepressant effects because of their ability to alter central monoamine levels, they have also been shown to exert anti-inflammatory effects. Recently it has become apparent that these drugs can also exert anti-inflammatory effects on microglia, the principal cells within the CNS that regulate and respond to inflammatory factors. From a pharmacological standpoint, much critical information remains unknown. In particular, the relative efficacy of these drugs in modulating microglial responses is yet to be determined. To address these issues, we evaluated the ability of different SSRIs (fluoxetine, sertraline, paroxetine, fluvoxamine and citalopram) and one SNRI (venlafaxine) to suppress microglial responses to an inflammatory stimulus. Specifically, we examined their ability to alter tumor necrosis factor-alpha (TNF-alpha) and nitric oxide (NO) production after stimulation with lipopolysaccharide. Our results indicated that the SSRIs potently inhibited microglial TNF-alpha and NO production. We then investigated whether these effects might involve either beta-adrenoceptor or cAMP signalling. Using the protein kinase A inhibitor Rp-CAMPs, we found evidence to suggest that cAMP signalling may be partially involved in regulating the anti-inflammatory response. Findings such as these could suggest that antidepressants may owe at least some of their therapeutic effectiveness to their anti-inflammatory properties.