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Treatment Resistant DepressionPhase 2NCT05774665

Specialized Pro-resolving Lipid Mediators and Treatment Resistant Depression

A Phase 2 study testing Omega 3 in people with Treatment Resistant Depression and Inflammation, run by Massachusetts General Hospital at 3 sites in United States.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record
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Trial 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: 1. Read more about this study

Who is it for?
Ages 18 to 65 years
What is being tested?
Omega 3
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
14 participants
Where
3 sitesUnited States
Study dates
30 Jan 2025to 31 Mar 2027
Phase
Phase 2
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 65 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Age: 18 to 65 years
  • Patients with treatment-resistant MDD who have not responded to at least 2 and no more than 5 antidepressant trials of at least 8 weeks duration 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 and ≤ 40 kg/m2
  • 17-item Hamilton Depression Rating Scale (HAM-D) score ≥15, and <25% decrease in score between screen and baseline

Who cannot join

  • Diagnostic Exclusions:
  • Meeting lifetime DSM-5 criteria for: a neurocognitive disorder, psychotic disorder, bipolar disorder, obsessive compulsive disorder, bulimia nervosa, or anorexia nervosa in the 3 months prior to the screening; any substance use disorder (except for nicotine or caffeine use disorder).
  • 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, pregnant women, or women of childbearing ability, who do NOT agree to use a study approved method of birth control (described in the MOP) for the duration of the study.
  • Currently or within 90 days of screen participating in another clinical trial (excluding large natural cohort trials such as 'All of Us').
Show all 20Show fewer
  • 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: - Patients with the following conditions: history of atrial fibrillation or atrial flutter, left ventricle hypertrophy, stroke, cardiovascular disease (including coronary artery disease, heart failure, and moderate or severe valve disease or prior valve procedure), uncontrolled hypertension, 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)
  • Sustained atrial fibrillation or atrial flutter of greater than 30 seconds detected by Holter monitor between V1 (screen) and V2 (baseline)

Trial locations and contacts

3 sites in 1 country.

United States3 sites

  • Emory University School of Medicine

    Atlanta, Georgia, 30322

  • Depression Clinical and Research Program at Massachusetts General Hospital

    Boston, Massachusetts, 02114

  • University of Utah

    Salt Lake City, Utah, 84108

Other trials in United States

About this study

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:

  1. Do omega-3 fatty acids added to ineffective antidepressant treatment increase production of compounds that reduce inflammation?
  2. Is the increase in these anti-inflammatory compounds associated with a stronger antidepressant effect?
Read more

Participants taking antidepressants that have not worked completely will be assigned at random for a 12-week period to one of the following:

  1. an omega-3 preparation
  2. 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.

Read the 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 ≤ 40 kg/m2, and inflammation (high sensitivity C reactive protein [hs-CRP] ≥ 3 mg/L and ≤ 10 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 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 (secondary biological endpoint).

Being tested
Omega 3, Placebo
Keywords
omega-3, fatty acid, major depressive disorder
Medical subject headings
Depressive Disorder, Treatment-Resistant, Inflammation, Overweight, Depressive Disorder, Major

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Omega 3Drug

    Also called EPA

    Omega-3 fatty acid enriched for eicosapentaenoic acid (EPA)

  • PlaceboOther

    Placebo consisting of soybean oil (about 54% omega-6 and 6% omega-3, but no EPA or docosahexaenoic acid (DHA)).

Study groups in NCT05774665
Study groupRoleWhat they receive
Omega-3ExperimentalOmega-3 fatty acid (ProEPA Xtra) capsules containing a total of 4 g/day of eicosapentaenoic acid (EPA), administered for 12 weeks.
Receives: Drug: Omega 3
PlaceboPlacebo comparatorPlacebo 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.
Receives: Other: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 18-HEPE (18-hydroxy eicosapentaeoic acid) Change

    Evaluate change in plasma 18-HEPE (18-hydroxy eicosapentaeoic acid) levels associated with 12 weeks of 4 g/day EPA-enriched n-3 treatment vs placebo.

    Measured: 12 weeks

Secondary outcomes (1)

  1. 18-HEPE (18-hydroxy eicosapentaeoic acid) Change in Treatment Responders

    To evaluate changes in plasma 18-HEPE (18-hydroxy eicosapentaeoic acid) level in relation to sustained clinical response status on the MADRS measure of depression severity.

    Measured: 12 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted20 Mar 2023
  2. Study start30 Jan 2025
  3. Primary completion31 Mar 2027 (estimated)
  4. Study completion31 Mar 2027 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
Double blind randomized placebo controlled clinical trial
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
14 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05774665
Sponsor's protocol ID
R33AT012329
Status last verified
Jun 2026
First submitted
6 Mar 2023
Last updated
1 Jul 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Yes: Data will be stored password-protected in REDCap. Following publication, data will be available to external researchers upon request for replication or secondary analysis. Subject confidentiality will be protected per HIPAA policies. Internal and external requests will be handled by the PI to ensure equitable access, fairness and safeguards. After reviewing a proposal from an external investigator, PI will approve requests with appropriate experimental design, scientific merit and IRB approval and recommend revisions if necessary. Database searches are completed by the study statistician following PI approval, and reports will be provided to investigators. Information can be printed directly from database or exported in spreadsheets in various formats. Format will be controlled by the study statistician. Distribution of data is controlled and de-identified as much as possible.

Publications

  • 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.

    PubMed 36005883

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Omega 3 in people with Treatment Resistant Depression and Inflammation, run by Massachusetts General Hospital at 3 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 5 inclusion and 20 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: under way, not looking for participants, as of the sponsor's last update on 1 Jul 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

18-HEPE (18-hydroxy eicosapentaeoic acid) Change (time frame: 12 weeks). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05774665, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Jul 2026.

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