Specialized Pro-resolving Lipid Mediators and Treatment Resistant Depression

The goal of this clinical trial is to determine the impact of omega-3 fatty acids on the production of anti-inflammatory effects and clinical improvement in people with depression who have not responded well to standard antidepressant treatment. The main questions it seeks to answer are: 1. Do omega-3 fatty acids added to ineffective antidepressant treatment increase production of compounds that reduce inflammation? 2. Is the increase in these anti-inflammatory compounds associated with a stronger antidepressant effect? Participants taking antidepressants that have not worked completely will be assigned at random for a 12-week period to one of the following: 1. an omega-3 preparation 2. an inactive placebo During the course of the study, blood tests will be obtained for compounds associated with inflammation, and questionnaires to measure clinical improvement in depressive symptoms will be administered.

This R33 application builds directly on a previous collaborative R01 (NCT00517036) and UG3 (NCT02553915) grants. The investigators will carry out a 12-week, randomized placebo-controlled, double-masked, augmentation trial of 4 g/day eicosapentaenoic acid (EPA)-enriched omega-3 treatment in adults with major depressive disorder (MDD), an inadequate response to antidepressants (treatment-resistant depression \[TRD\]), body mass index (BMI) \>25 kg/m2 and ≤ 40 kg/m2, and inflammation (high sensitivity C reactive protein \[hs-CRP\] ≥ 3 mg/L and ≤ 10 mg/L). It is hypothesized that 4 g/day of EPA-enriched omega-3 will: 1) Significantly increase plasma 18-hydroxy eicosapentaeoic acid \[18-HEPE\] concentrations compared to placebo (primary biological endpoint); 2) produce significantly greater increases in plasma 18-HEPE concentration since baseline for sustained MADRS responders (those with at least 50% reduction since baseline in MADRS scores at both treatment week 8 and week 12) than for (a) unsustained/non-responders to EPA-enriched n-3 as well as (b) placebo-supplemented sustained responders (secondary biological endpoint).