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 inflammation (high sensitivity C reactive protein [hs-CRP] ≥ 3 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 more subjects with ≥ 50% sustained (at both week 8 and 12) decrease from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) scores than placebo 3) Demonstrate that sustained responders (≥ 50% MADRS score decrease from baseline at both week 8 and 12) to 4 g/day of EPA omega-3 have significantly greater increases in 18-HEPE levels than unsustained/nonresponders to EPA-enriched omega-3 as well as placebo-supplemented sustained responders.
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:~Do omega-3 fatty acids added to ineffective antidepressant treatment increase production of compounds that reduce inflammation?~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:~an omega-3 preparation~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.