Discussion
obesity, inflammation, Alzheimer’s disease, Parkinson’s disease, MDD, depression
OBESITY, CHRONIC INFLAMMATION, CARDIOVASCULAR DISEASE, INFLAMMATION, METABOLIC SYNDROME, DISEASES
EPA supplementation reduced clinical symptoms of depression, defined as achieving ≥ 50% reduction in IDS-C30 scores, in 64% of participants in the 4 g/d arm, relative to 40% in the placebo arm. At baseline, study participants who responded to treatment had plasma concentrations of EPA, DHA, DPA, AA and related lipid mediators similar to non-responders. However, after supplementation, there was a trend for greater increases in some of the lipid mediators derived from these fatty acids in responders versus non-responders, and differences were significant for 18-HEPE and 13-HDHA in the 4 g/d arm. To the best of our knowledge, this is the first clinical trial demonstrating a differential response to EPA supplementation in patients with MDD, with overall greater ability to synthesize EPA- and DHA-derived lipid mediators in responders than non-responders.Chronic low-grade inflammation is a characteristic feature of metabolic syndrome, obesity, and cardiovascular disease, and has recently emerged as a contributing factor to diseases of the central nervous system, including MDD, Parkinson’s disease and Alzheimer’s disease [Other mechanisms such as the activation of enzymatic pathways involved in SPM synthesis may account, at least in part, for the differences in response. Immune cells of subjects with obesity exhibit lower concentrations of 17-HDHA, a 15-LOX metabolite of DHA, but, when these cells were incubated with 17-HDHA, the production of SPMs was rescued [The results of our study are somewhat in contrast with those of a study conducted in 16 patients with MDD and supplemented with 1.6 g/d EPA and 0.8 g/d DHA for six weeks, where responders had higher mol% DHA, but not EPA mol%, in plasma phospholipids than non-responders [Efficacy of EPA supplementation was greater in the 4 g/d arm, consistent with findings from cardiovascular prevention studies [A strength of this study was the selection of patients with MDD and with chronic inflammation, who are the ideal target for activation of the resolution of inflammation. In addition, we were able to correlate changes in plasma SPMs with hs-CRP, a marker of systemic inflammation, and with clinical symptoms of depression. One limitation of our study was the sample size, with a small number of subjects in each group of responders and non-responders. Our analyses were exploratory. The parent study was limited by a high placebo response rate [Taken together, the results of our study indicate a dose-dependent reduction in depression symptoms following EPA supplementation. Among study participants receiving EPA, those who responded showed a greater ability to activate the synthesis of 18-HEPE. In addition, the increase in 18-HEPE following EPA supplementation in the 4 g/d arm was highly and negatively correlated with both systemic inflammation and symptoms of depression, highlighting the activation of the resolution of inflammation as a likely mechanism in the treatment of MDD.