Specialized Pro-resolving Lipid Mediators and Treatment Resistant Depression

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
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.

Official Title
-----------------
Specialized Pro-resolving Lipid Mediators and Treatment Resistant Depression

Conditions
-----------------
Treatment Resistant Depression, Inflammation, Overweight

Intervention / Treatment
-----------------
* Drug: Omega 3
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age: 18 and above Patients with MDD who have not responded to at least 2 and no more than 5 antidepressant trials during the current episode and have been on a current stable antidepressant regiment for at least 4 weeks. The diagnosis of MDD will be confirmed using the MINI and the historical failure to respond to antidepressant therapy will be documented using the Antidepressant Treatment Response Questionnaire (ATRQ), with failure to respond defined as less than 50% improvement by subject history. hs-CRP ≥ 3 mg/L and ≤ 10 mg/L BMI >25 kg/m2 17-item Hamilton Depression Rating Scale (HAM-D) score ≥15, and <25% decrease in score between screen and baseline Able to clearly understand English Exclusion Criteria: Diagnostic Exclusions: Meeting lifetime DSM-5 criteria for: a neurocognitive disorder, psychotic disorder, bipolar disorder, or anorexia nervosa in the 3 months prior to the screening; any substance use disorder (except for nicotine or caffeine use disorder); obsessive compulsive disorder or bulimia nervosa. Patients who, in the investigator's judgment, pose a current, serious suicidal or homicidal risk Presence of a serious or unstable medical illness, including insulin-dependent diabetes mellitus or bleeding disorder which, in the investigator's opinion, could compromise response to treatment, participant safety, or interpretation of study results Currently breastfeeding or pregnant women Currently participating in another clinical trial Treatment and Concomitant Medication Exclusions: Failure to respond during the course of the current major depressive episode to >5 adequate antidepressant trials Current use of antipsychotic medications or lithium Having received ketamine therapy within 90 days of the screening visit Patients who have initiated psychotherapy ≤ 90 days prior to screening.Having received electroconvulsive therapy during the current depressive episode or within 6 months of the screening visit Concomitant use of any psychotropic agents within 2 weeks of the baseline visit, except for the ongoing antidepressant, prescription hypnotics, diphenhydramine, or a stable daily dose of a benzodiazepine. Concomitant medications that might confound the biomarker findings within 1 week of the baseline visit and during the trial, including: regular (i.e. more than three times per week) ingestion of non-steroidal anti-inflammatory drugs (NSAIDs) or cyclooxygenase (COX)-2 inhibitors; any use of oral steroids, immunosuppressants, interferon, chemotherapy, or anticoagulants. Omega-3 Exclusions: A history of severe sensitivity to soy products, fish products, or PUFA supplements Patients who had taken supplements enriched with n-3 fatty acids within 60 days of the screening visit or who, at baseline, were consuming a diet containing > 3 g/day of n-3 fatty acids, or who consume > 2 meals of fatty fish per week. Having taken a supplement of ≥1 g/day of n-3 fatty acids for ≥6 weeks during the current major depressive episode Patients who have had either a poor response or intolerable side effects from n-3s in the past. Patients with the following conditions: Crohn's disease, Irritable Bowel Syndrome-diarrhea type, history of gastric bypass surgery, history of cholecystectomy, recent/current history of bulimia with purging, use of prokinetic medications that affect GI transit time, and small intestinal bacterial overgrowth (SIBO)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Double blind randomized placebo controlled clinical trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Omega-3<br>Omega-3 fatty acid (ProEPA Xtra) capsules containing 4 g/day of eicosapentaenoic acid (EPA), administered for 12 weeks. | Drug: Omega 3<br>* Omega-3 fatty acid enriched for eicosapentaenoic acid (EPA)<br>* Other names: EPA;|
| Placebo Comparator: Placebo<br>Placebo capsules containing soybean oil (about 54% omega-6 and 6% omega-3, but no EPA or docosahexaenoic acid (DHA)), and matched to the ProEPA Xtra capsules in terms of appearance, odor, and taste. | Other: Placebo<br>* Placebo consisting of soybean oil (about 54% omega-6 and 6% omega-3, but no EPA or docosahexaenoic acid (DHA)).<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 18-HEPE (18-hydroxy eicosapentaeoic acid) | Evaluate plasma 18-HEPE (18-hydroxy eicosapentaeoic acid) concentrations in 4 g/day EPA-enriched n-3 treatment vs placebo. | 12 weeks | 
| 18-HEPE (18-hydroxy eicosapentaeoic acid) in Responders | Evaluate 18-HEPE (18-hydroxy eicosapentaeoic acid) levels in sustained responders (≥ 50% Montgomery-Asberg Depression Rating Scale [MADRS] score decrease from baseline at both week 8 and 12) to 4 g/day EPA-enriched n-3 treatment versus a) unsustained/non-responders to 4 g/day EPA-enriched n-3 treatment and b) placebo-supplemented sustained responders. The Montgomery-Asberg Depression Rating Scale [MADRS] measures depressive symptom severity. It contains 10 items, each one graded from 0-6 for a total score range of 0-60, with higher scores indicating greater depressive severity. | 12 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
omega-3, fatty acid, major depressive disorder