Abstract At least one-third of patients who receive treatment for major depressive disorder (MDD) do not attain remission and meet criteria for treatment resistant depression (TRD). TRD carries an increased risk of suicide, medical comorbidity, and increased morbidity. There is a growing consensus that increased inflammatory activity contributes to the persistence of depressive symptoms in many of these patients, presenting the opportunity for a novel treatment approach to TRD. Studies suggest that a subset of patients with MDD may benefit from omega-3 fatty acids (n-3s), specifically individuals who manifest chronic inflammation as a component of their illness. One of the n-3s, eicosapentaenoic acid (EPA) is the precursor of a variety of bioactive lipid molecules, many with anti-inflammatory effects at concentrations 100 to 1000 times lower than EPA. A dosage of 4 g/day of EPA-enriched n-3, given over 12 weeks demonstrated a significantly greater antidepressant response than either 1 or 2 g/day. Furthermore, our work suggests that overweight/obese individuals with MDD and inflammation (hs-CRP levels ≥3 mg/L) may be highly responsive to this treatment. Preliminary data support involvement of resolution of inflammation, mediated by lipid molecules called specialized pro-resolving lipid mediators (SPMs). In keeping with the hypothesized inflammation-resolving mechanism of action of n-3s in MDD, our data demonstrated that a sustained response on the Inventory of Depressive Symptomatology, Clinician-Rated version (IDS-C30) scale was correlated with increased levels of the EPA-derived SPM precursor 18-hydroxyeicosapentaenoic acid (18-HEPE). We propose a 12-week, randomized placebo-controlled, double-masked, augmentation trial of 4 g/day EPA-enriched n-3 treatment in adults with MDD, inadequate response to antidepressants (TRD), BMI >25 and ≤ 40 kg/m2 and inflammation (hs-CRP ≥ 3 and ≤ 10 mg/L). We hypothesize that adding 4 g/day of EPA-enriched n-3 to overweight/obese MDD patients with inadequate response to ongoing antidepressant treatment and hs-CRP ≥ 3 and ≤ 10 mg/L will 1) significantly increase plasma 18-HEPE concentration since baseline, compared to treatment with placebo, and 2) result in 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. Exploratory Aims will evaluate whether EPA-enriched n-3 augmentation results in a significantly greater decrease in peripheral markers of inflammation than placebo and whether gene mediated variation is responsible for differences in n-3 and SPM levels and thus treatment response. This study will determine if plasma 18-HEPE is a mediator of treatment response. Further, this study will include additional evidence of safety and tolerab...