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

Study Overview
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Brief Summary
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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.

Detailed Description
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This study will evaluate the anti-inflammatory effects and antidepressant efficacy and tolerability of EPA versus placebo in the treatment of MDD. The study design is a randomized, placebo-controlled, double-blind parallel-group dose-finding 12 week outpatient clinical trial. The study population will consist of outpatients who are overweight and suffer from MDD, who also demonstrate systemic inflammation. Three doses of EPA (1 gm/d, 2 gm/d, and 4 gm/d) will be compared against placebo. The study will be conducted at two sites: Emory University School of Medicine and Massachusetts General Hospital. The study will be conducted under the Food and Drug Administration Investigational New Drug (IND) 074150. One hundred adult MDD patients (ages 18-80) will be randomized to enter the 12-week double-blind treatment period. Each of the four study arms (3 EPA arms and one placebo arm) will have 25 patients, with the expectation of 20 completers per arm, based on a 20% early termination rate. The subjects will be recruited through advertisements and clinical referrals from psychiatrists and general physicians who are treating overweight outpatients with MDD. Participants must agree not to significantly modify their diet during the 12 weeks of the study. Due to the need for participants to have a hs-CRP ≥ 3 mg/L to be eligible for the study, two screening visits will be used to minimize expenses associated with screening. The screening period may extend up to 28 days prior to the baseline visit (Visit 3) if necessary to allow for time need for participant scheduling and allow for any required repeat laboratory testing. Patients screened for the study and found to be eligible will return for their baseline visit after one week, during which no psychotropic medication or PUFAs will be administered. Patients must have an Inventory of Depressive Symptoms, Clinician rated (IDS-C30) total score ≥ 25 at the baseline visit in order to be eligible for randomization. Patients will be randomized to one of four treatment arms: 1) EPA 1 mg/day; 2) EPA 2 mg/day; 3) EPA 4 mg/day; or 4) Placebo. Randomization will be in blocks of 4 with separate randomization schedules for each site. Study materials will include: Study capsules containing EPA-enriched omega-3, 1000 mg tabs, supplied by Nordic Naturals. Placebo capsules matching the EPA 1000 mg tabs, also to be supplied by Nordic Naturals. Documentation of the presence of any side-effect or adverse event (AE) will be completed by one of the treating psychiatrists at every visit by recording all spontaneously reported AEs, which will be classified as either mild, moderate, or severe. Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA) terms. Patients shall be allowed to contact the investigator or a member of his staff at any time between visits concerning adverse events or worsening of symptoms. All concomitant medications taken during the study will be recorded in the case report form, along with dosage information and start and stop dates. Drugs that may be taken by the patient include any prescription or over-the-counter medication not specifically excluded by the protocol. Patients requiring excluded drugs (including antidepressants, benzodiazepines, antipsychotics, psychostimulants, and mood stabilizing agents) will be discontinued from the study. Patients may choose to withdraw from the study at any time. Participants may be withdrawn by the investigator should any of the following occur: severe, persistent intolerance to study medication worsening of depressive symptoms such that the subject's safety is endangered (e.g. suicidality) development of mania or psychotic symptoms a serious adverse event (SAE) that is either: i) considered by the investigator to be possibly, probably, or definitely related to the study medication, or ii) places the subject at increased risk of harm if she were to continue in the study persistent non-adherence to the study medication, defined as not taking between 80-120% of the study medication pills for two consecutive visits development of pregnancy Patients with MDD may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality), whether or not they are taking antidepressant medications, and this risk may persist until MDD remission occurs. This guidance is consistent with global class labelling for antidepressants. Although there has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain subjects, a causal role for antidepressants in inducing such behaviors has not been established. Nevertheless, subjects being treated with study medication will be observed closely for clinical worsening and suicidality, especially at the beginning and end of the course of treatment, or at the time of dose changes, either increases or decreases. Consideration will be given to possibly discontinuing the investigational product in subjects whose depression is persistently worse or whose emergent suicidality is severe or abrupt in onset or was not part of the subject's presenting symptoms. To assess suicidal ideation and behaviors, the CSSRS will be used in this trial. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in patients being treated with antidepressants for MDD. Consideration will be given to possibly discontinuing the study medication in subjects for whom such symptoms are severe, abrupt in onset, or were not part of the subject's presenting symptoms. Research participants are exited from the study should any of the following occur: Any emergent Columbia Suicide Severity Rating Scale (CSSRS) defined suicidal behavior A suicidal ideation score of 5 (indicating active suicidal ideation with specific plan and some level of intent) on the CSSRS In the absence of a CSSRS suicidal ideation score of 5 or CSSRS-defined suicidal behavior, the investigator determines the patient to have a significant short-term risk for a suicide attempt. Any participant who becomes pregnant during the study will be withdrawn from the study. The investigator will collect pregnancy information, record it on the Pregnancy Form, and submit it to the lead site PI, Mark Rapaport, MD, via email within 2 weeks of learning of a participant's pregnancy. The participant will also be followed to determine the outcome of the pregnancy. Follow-up is expected to end approximately 8 weeks following the estimated delivery date. Any premature termination of the pregnancy will be reported. While pregnancy itself is not considered to be an adverse event (AE) or SAE, any pregnancy complication or elective termination of a pregnancy for medical reasons will be recorded as an AE. A spontaneous abortion is always considered an SAE and will be reported as such. All randomized participants who terminate the trial prior to the Week 12 visit will be asked to return for an early termination visit. The study team should complete all the Week 12 assessments at the study termination visit. All subjects who complete the trial or discontinue because of lack of response or side effects will receive treatment as clinically appropriate and will then be referred for appropriate follow-up care. Blood will be collected and analyzed for the screening tests and biomarker analyses. Urine samples will be collected and analyzed with a toxicology screen and urinalysis. We will collect physical records in the form of questionnaires, phone screenings, and psychiatric interviews. We will request access to participants' medical records only for reasons related to patient safety. Participant case report forms will be kept in locked file cabinets in the offices of each study site. Biological specimens are linked to the individual patient only through a unique research code. All documents that directly reveal the participant's identity, such as signed consent forms, are stored in charts that are marked on the outside only with the participant's code number.

Official Title
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Omega-3 Fatty Acids for MDD With High Inflammation: A Personalized Approach

Conditions
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Major Depressive Disorder, Overweight, Inflammation

Intervention / Treatment
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* Other: Placebo
* Drug: EPA 1 g/day
* Drug: EPA 2 g/day
* Drug: EPA 4 g/day


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Exclusion Criteria: 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. Patients who have taken supplements with omega-3 fatty acids (see Appendix A for list of products) within sixty (60) days of the screening visit. Patients who, at baseline, are consuming a diet that contains more than 3g/day of omega-3 FA, or who consume more than 3 meals of fatty fish per week. Patients who have a history of a bleeding disorder. Patients who have participated in another clinical trial of an investigational medication within 1 month of the screening visit. Patients who are currently in psychotherapy that was initiated within 90 days prior to the study screening visit.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Study compared 3 dosing regimens of eicosapentaenoic acid (EPA), 1 g/day, 2 g/day, and 4 g/day versus an inactive placebo.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Soybean oil placebo capsules, 4 capsules daily for 12 weeks | Other: Placebo<br>* Soybean oil placebo<br>|
| Experimental: EPA 1 g/day<br>Eicosapentaenoic acid (EPA) 1000 mg capsules, 1 daily (plus 3 placebo capsules) for 12 weeks | Other: Placebo<br>* Soybean oil placebo<br>Drug: EPA 1 g/day<br>* Omega-3 fatty acid extracted from fish oil, 1 g/day<br>* Other names: Eicosapentaenoic acid; omega-3 fatty acid;|
| Experimental: EPA 2 g/day<br>Eicosapentaenoic acid (EPA) 1000 mg capsules, 2 daily (plus 2 placebo capsules) for 12 weeks | Other: Placebo<br>* Soybean oil placebo<br>Drug: EPA 2 g/day<br>* Omega-3 fatty acid extracted from fish oil, 2 g/day<br>* Other names: Eicosapentaenoic acid; omega-3 fatty acid;|
| Experimental: EPA 4 g/day<br>Eicosapentaenoic acid (EPA) 1000 mg capsules, 4 daily for 12 weeks | Drug: EPA 4 g/day<br>* Omega-3 fatty acid extracted from fish oil, 4 g/day<br>* Other names: Eicosapentaenoic acid; omega-3 fatty acid;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change in Plasma Concentrations of Mitogen-stimulated PBMC IL-6 (pg/mL) and Plasma Tumor Necrosis Factor (TNF)-α (pg/mL) | To evaluate whether EPA treatment produces decreases in plasma levels of mitogen-stimulated PBMC IL-6 and TNF-α (both in in pg/mL). Percent change calculated by comparing week 12 to week 0 (baseline). Greater decrease (change in negative direction) indicates better outcome. | 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) | To evaluate whether EPA treatment produces decreases in the expression of inflammation pathway-related genes for IL-6 and TNF-α (in ΔΔCt units). Levels compared at week 0 (baseline) and at week 12 to obtain percent change from baseline. Greater decrease (change in negative direction) indicates better outcome. | 12 weeks | 
| Percent Change in High-sensitivity C-reactive Protein (Hs-CRP) in mg/L | To evaluate whether EPA treatment produces decreases in plasma hs-CRP in mg/L. Levels compared at week o (baseline) and week 12 to obtain percent change. Greater percent decrease in the negative direction indicates better outcome. | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Omega-3, EPA, Depression, Overweight, Inflammation, Eicosapentaenoic acid