Omega-3 Fatty Acids for Major Depressive Disorder With High Inflammation: A Personalized Approach

NCT02553915 | Completed Phase 2 Results DMC

• 1 other identifier: R01AT008857-01
• Study Type: interventional
• Target: 61
• Locations: 1 country
• Sites: 2

Brief Summary

This project aims to evaluate whether a dose-response relationship exists between dose of polyunsaturated fatty acids (PUFA), delivered as eicosapentaenoic acid (EPA), and change in markers of inflammation, and whether these effects differ from placebo. A key secondary aim is to evaluate the antidepressant effectiveness of EPA in overweight adult outpatients with current major depressive disorder (MDD). To address these aims, the project will use a four-arm, randomized, parallel-group, placebo-controlled design comparing placebo versus three doses of EPA (1 gm/day, 2 gm/day, or 4 gm/day) administered over 12 weeks. The study is to be conducted at two sites: Emory University School of Medicine, and Massachusetts General Hospital. Eligible participants will be between the ages of 18-80 who have current MDD, are overweight, and who demonstrate peripheral inflammation, defined as an high sensitivity C-reactive protein (hs-CRP) level ≥ 3 mg/L. The primary outcome will be change in plasma interleukin-6 (IL-6) levels and/or mitogen-stimulated peripheral blood mononuclear cells (PBMC) Tumor Necrosis Factor-alpha (TNF-α) expression levels in EPA- versus placebo-treated participants. The results of this investigation are intended to be used to design and power a larger definitive test of the efficacy and biological effects of EPA in patients with major depressive disorder.

Conditions

Major Depressive Disorder; Overweight; Inflammation

Keywords

Omega-3; EPA; Depression; Overweight; Inflammation; Eicosapentaenoic acid

Outcome Measures

Primary Outcomes (3)

• Percent Change in Plasma Concentration of Inflammatory Biomarkers IL-6 (pg/mL) and PBMC TNF-α (pg/mL)

  To evaluate whether a dose-response relationship exists between dose of EPA and decrease either in plasma interleukin-6 (IL-6) levels (pg/mL) or in mitogen-stimulated peripheral blood mononuclear cell (PBMC) Tumor Necrosis Factor-α (TNF-α) expression and secretion (pg/mL), when compared with placebo. Levels of inflammatory biomarkers were assessed at baseline (week 0) and at week 12 for comparison. Percent changes were calculated as relative to baseline values. Greater percent decrease indicates better outcome.

  12 weeks

• Mean Change in Depression Severity Score (IDS-C30) After 12 Weeks of Treatment

  To evaluate whether EPA treatment produces a decrease in ratings of depression severity after 12 weeks of treatment, when compared with placebo-treated subjects. Comparison is made between pre-treatment and post-12 weeks treatment. Inventory of Depressive Symptomatology-30 item-Clinician Rated (IDS-C30) is a depression severity scale, where lower scores indicate less depressive severity and higher scores indicate greater severity. Minimum score is 0 (zero) and maximum score is 84.

  12 weeks

• Percent Change in IDS-C Score After 12 Weeks of Treatment

  To evaluate whether EPA treatment produces a decrease in ratings of depression severity, when compared with placebo-treated subjects; and whether the changes in IL-6 or mitogen- stimulated PBMC TNF-α expression will mediate changes observed in ratings of depression. Inventory of Depressive Symptomatology-30 item-Clinician Rated (IDS-C30) is a depression severity scale, where lower scores indicate less depressive severity and higher scores indicate greater severity. Minimum score is 0 (zero) and maximum score is 84. Change in score over 12 weeks (from week 0 to week12) is calculated as a percent change from baseline. Greater percent change in the negative direction indicates better outcome.

  12 weeks

Secondary Outcomes (3)

• Percent Change in Plasma Concentrations of Mitogen-stimulated PBMC IL-6 (pg/mL) and Plasma Tumor Necrosis Factor (TNF)-α (pg/mL)

  12 weeks

• Percent Changes in Levels of Expression of Inflammation-related Genes for Interleukin (IL)-6 and Tumor Necrosis Factor (TNF)-α (in ΔΔCt Units)

  12 weeks

• Percent Change in High-sensitivity C-reactive Protein (Hs-CRP) in mg/L

  12 weeks

Study Arms (4)

Placebo

PLACEBO COMPARATOR

Soybean oil placebo capsules, 4 capsules daily for 12 weeks

Other: Placebo

EPA 1 g/day

EXPERIMENTAL

Eicosapentaenoic acid (EPA) 1000 mg capsules, 1 daily (plus 3 placebo capsules) for 12 weeks

Other: Placebo; Drug: EPA 1 g/day

EPA 2 g/day

EXPERIMENTAL

Eicosapentaenoic acid (EPA) 1000 mg capsules, 2 daily (plus 2 placebo capsules) for 12 weeks

Other: Placebo; Drug: EPA 2 g/day

EPA 4 g/day

EXPERIMENTAL

Eicosapentaenoic acid (EPA) 1000 mg capsules, 4 daily for 12 weeks

Drug: EPA 4 g/day

Interventions

Placebo OTHER

Soybean oil placebo

EPA 1 g/day; EPA 2 g/day; Placebo

EPA 1 g/day DRUG

Omega-3 fatty acid extracted from fish oil, 1 g/day

Also known as: Eicosapentaenoic acid; omega-3 fatty acid

EPA 1 g/day

EPA 2 g/day DRUG

Omega-3 fatty acid extracted from fish oil, 2 g/day

Also known as: Eicosapentaenoic acid; omega-3 fatty acid

EPA 2 g/day

EPA 4 g/day DRUG

Omega-3 fatty acid extracted from fish oil, 4 g/day

Also known as: Eicosapentaenoic acid; omega-3 fatty acid

EPA 4 g/day

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Able to provide informed consent.
• Men or women aged 18-80 years.
• A primary psychiatric diagnosis of major depressive disorder (MDD), by Diagnostic and Statistical Manual-5th ed (DSM-5) using the Mini International Neuropsychiatric Interview (MINI v.7.0).
• A Screening and Baseline visit Inventory of Depressive Symptoms, Clinician rated (IDS-C30) total score ≥ 25.
• Currently overweight at screening, defined as BMI \> 25 kg/m2.
• Screening visit high-sensitivity C-reactive protein concentration ≥ 3 mg/L.
• Willing to not significantly modify their diet from the time they sign consent through the end of study participation.

You may not qualify if:

• Use of any psychotropic agents within 2 weeks of baseline or at any time during the study, with the exception of prescription hypnotics (eszopiclone, zaleplon, zolpidem, suvorexant, ramelteon), diphenhydramine, or a stable daily dose of a benzodiazepine.
• Breastfeeding or pregnant women, women intending to become pregnant within 6 months of the screening visit, or women of child bearing potential who are not using a medically accepted means of contraception (defined as oral contraceptive pill or implant, condom, diaphragm, intrauterine device (IUD), status-post tubal ligation, or partner with vasectomy)
• Patients who, in the investigator's judgement, pose a current, serious suicidal or homicidal risk.
• Serious or unstable medical illness that in the investigator's opinion could compromise response to treatment or interpretation of study results.
• History of seizure disorder, except for childhood febrile seizures.
• Meeting DSM-5 criteria at any point in their lifetime, for any of the following: Neurocognitive Disorder, Psychotic Disorder, Bipolar disorder, Anorexia Nervosa
• Meeting DSM-5 criteria in the 3 months prior to the screening visit for any Substance Use Disorder (except nicotine or caffeine).
• Meeting DSM-5 criteria at screening for current obsessive compulsive disorder or bulimia nervosa.
• Presence of psychotic features at any time during the current major depressive episode.
• Any conditions or medications (within 1 week of baseline or during the trial) that might confound the biomarker findings, including: Regular ingestion of NSAIDs or Cyclooxygenase-2 (COX-2) inhibitors, or any use of oral steroids, immunosuppressants, interferon, chemotherapy, or anticoagulants (Patients will be instructed not to take a nonsteroidal antiinflammatory drug (NSAID) or COX-2 inhibitor in the 24 hours prior to a biomarker assessment visit), Malignancy not in remission for at least 1 year, Active autoimmune disorder or inflammatory bowel disease, Insulin-dependent diabetes mellitus.
• History of allergy to PUFA supplements.
• Laboratory evidence of undiagnosed hypothyroidism or change in treatment for hypothyroidism in the 3 months prior to screening.
• Patients who have failed to respond during the course of their current major depressive episode to \>4 adequate antidepressant trials, defined as six weeks or more of treatment with the FDA-defined minimally effective dose.
• Patients who have taken a supplement of at least 1 g/day of omega 3 fatty acids for at least 6 weeks during the current major depressive episode.
• Patients who have had electroconvulsive therapy (ECT) during the current depressive episode or within 6 months of the screening visit.

Sponsors & Collaborators

• Massachusetts General Hospital: lead
• Emory University: collaborator

Study Sites (2)

Emory University School of Medicine

Atlanta, Georgia, 30322, United States

Location

Depression Clinical and Research Program at Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Related Publications (4)

• Mischoulon D, Nierenberg AA, Schettler PJ, Kinkead BL, Fehling K, Martinson MA, Hyman Rapaport M. A double-blind, randomized controlled clinical trial comparing eicosapentaenoic acid versus docosahexaenoic acid for depression. J Clin Psychiatry. 2015 Jan;76(1):54-61. doi: 10.4088/JCP.14m08986.

  PMID: 25272149 RESULT

• Rapaport MH, Nierenberg AA, Schettler PJ, Kinkead B, Cardoos A, Walker R, Mischoulon D. Inflammation as a predictive biomarker for response to omega-3 fatty acids in major depressive disorder: a proof-of-concept study. Mol Psychiatry. 2016 Jan;21(1):71-9. doi: 10.1038/mp.2015.22. Epub 2015 Mar 24.

  PMID: 25802980 RESULT

• Mischoulon D, Dunlop BW, Kinkead B, Schettler PJ, Lamon-Fava S, Rakofsky JJ, Nierenberg AA, Clain AJ, Mletzko Crowe T, Wong A, Felger JC, Sangermano L, Ziegler TR, Cusin C, Fisher LB, Fava M, Rapaport MH. Omega-3 Fatty Acids for Major Depressive Disorder With High Inflammation: A Randomized Dose-Finding Clinical Trial. J Clin Psychiatry. 2022 Aug 22;83(5):21m14074. doi: 10.4088/JCP.21m14074.

  PMID: 36005883 DERIVED

• Appleton KM, Voyias PD, Sallis HM, Dawson S, Ness AR, Churchill R, Perry R. Omega-3 fatty acids for depression in adults. Cochrane Database Syst Rev. 2021 Nov 24;11(11):CD004692. doi: 10.1002/14651858.CD004692.pub5.

  PMID: 34817851 DERIVED

MeSH Terms

Conditions

Depressive Disorder, Major; Overweight; Inflammation; Depression

Interventions

Eicosapentaenoic Acid; Fatty Acids, Omega-3

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders; Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Pathologic Processes; Behavioral Symptoms; Behavior

Intervention Hierarchy (Ancestors)

Dietary Fats, Unsaturated; Dietary Fats; Fats; Lipids; Eicosanoids; Fatty Acids, Unsaturated; Fatty Acids; Fish Oils; Oils

Limitations and Caveats

Smaller than projected sample due to challenges in recruitment led to smaller analyzable treatment arms. Results should be considered preliminary.

Results Point of Contact

• Title: Dr David Mischoulon, Director, Depression Clinical and Research Program, MGH
• Organization: Massachusetts General Hospital

dmischoulon@mgh.harvard.edu

617-724-5198

Study Officials

• Maurizio Fava, MD

  Massachusetts General Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: All the above were blinded to the interventions. Placebo and EPA capsules had identical appearances.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: Study compared 3 dosing regimens of eicosapentaenoic acid (EPA), 1 g/day, 2 g/day, and 4 g/day versus an inactive placebo.

Study Record Dates

• First Submitted: September 16, 2015
• First Posted: September 18, 2015
• Study Start: December 1, 2015
• Primary Completion: July 13, 2018
• Study Completion: March 31, 2022
• Last Updated: May 2, 2022
• Results First Posted: November 18, 2019

Record last verified: 2022-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)