Abstract
RATIONALE: At least six different types of antidepressant treatments have been shown to either increase the neuroprotective kynurenine pathway (KP) metabolite, kynurenic acid (KynA), or decrease the neurotoxic KP metabolite, quinolinic acid (QA). Nonsteroidal anti-inflammatory drugs (NSAIDs) including ibuprofen have shown some efficacy in the treatment of depression but their effects on the KP have not been studied in humans. OBJECTIVES: To evaluate the effect of ibuprofen on circulating KP metabolites. METHODS: In a randomized, placebo-controlled, crossover study, 20 healthy adults (10 women) received a single oral dose of 200-mg ibuprofen, 600-mg ibuprofen, or placebo in a counterbalanced order (NCT02507219). Serum samples were drawn in the mid-afternoon, 5 h after ibuprofen/placebo administration. KP metabolites were measured blind to visit by tandem mass spectrometry. Data were analyzed with linear mixed effect models. The primary outcome was KynA/QA and the secondary outcome was KynA. RESULTS: After Bonferroni correction, there was a significant effect of treatment on KynA/QA. The effect was driven by an increase in KynA concentration after the 600-mg dose but not the 200-mg dose relative to placebo (Cohen's d = 1.71). In contrast, both the 200-mg (d = 1.03) and 600-mg (d = 2.05) doses of ibuprofen decreased tryptophan concentrations relative to placebo. CONCLUSIONS: Given its KynA-elevating effects, ibuprofen could have neuroprotective effects in the context of depression as well as other neuroinflammatory disorders that are characterized by a reduction in KynA.