Grant Abstract: Specialized pro-resolving lipid mediators and treatment resistant depression

Grant Number: 5R33AT012329-02
PI Name: Rapaport
Project Title: Specialized pro-resolving lipid mediators and treatment resistant depression

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 kg/m2 and inflammation (hs-CRP ≥3 mg/L). We hypothesize that 4 g/day of EPA-enriched n-3 will, 1) Significantly increase plasma 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, and 3) Demonstrate that sustained responders (≥ 50% MADRS score decrease from baseline at both week 8 and 12) have significantly greater increases in 18-HEPE levels than unsustained/non-responders as well as 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 1) inform whether 4 g/day EPA-enriched n-3 substantially improves functional/symptom outcomes, 2) include additional evidence of safety and tolerability, and 3) evaluate the strength of the association between target engagement and change in symptoms/function. PUBLIC HEALTH RELEVANCE: At least one-third of patients who receive treatment for major depressive disorder do not attain remission and there is a growing agreement that increased inflammatory activity contributes to the persistence of depressive symptoms in many of these patients, presenting the opportunity for novel treatment approaches. Omega-3 fatty acids reduce signs of inflammation and may have benefit for treatment of depression, especially in combination with other antidepressant drugs. This study will test whether omega-3 fatty acids added to ineffective antidepressant treatment increase compounds that resolve inflammation and whether the increase in these compounds is associated with improved antidepressant response.

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