Omega-3 Fatty Acids for MDD With High Inflammation: A Personalized Approach
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 61
- 试验地点
- 2
- 主要终点
- Percent Change in Plasma Concentration of Inflammatory Biomarkers IL-6 (pg/mL) and PBMC TNF-α (pg/mL)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
All the above were blinded to the interventions. Placebo and EPA capsules had identical appearances.
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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 ≥
- •Currently overweight at screening, defined as BMI > 25 kg/m
- •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.
排除标准
- •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.
研究组 & 干预措施
Placebo
Soybean oil placebo capsules, 4 capsules daily for 12 weeks
干预措施: Placebo (Other)
EPA 1 g/day
Eicosapentaenoic acid (EPA) 1000 mg capsules, 1 daily (plus 3 placebo capsules) for 12 weeks
干预措施: Placebo (Other)
EPA 1 g/day
Eicosapentaenoic acid (EPA) 1000 mg capsules, 1 daily (plus 3 placebo capsules) for 12 weeks
干预措施: EPA 1 g/day (Drug)
EPA 2 g/day
Eicosapentaenoic acid (EPA) 1000 mg capsules, 2 daily (plus 2 placebo capsules) for 12 weeks
干预措施: Placebo (Other)
EPA 2 g/day
Eicosapentaenoic acid (EPA) 1000 mg capsules, 2 daily (plus 2 placebo capsules) for 12 weeks
干预措施: EPA 2 g/day (Drug)
EPA 4 g/day
Eicosapentaenoic acid (EPA) 1000 mg capsules, 4 daily for 12 weeks
干预措施: EPA 4 g/day (Drug)
结局指标
主要结局
Percent Change in Plasma Concentration of Inflammatory Biomarkers IL-6 (pg/mL) and PBMC TNF-α (pg/mL)
时间窗: 12 weeks
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.
Mean Change in Depression Severity Score (IDS-C30) After 12 Weeks of Treatment
时间窗: 12 weeks
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.
Percent Change in IDS-C Score After 12 Weeks of Treatment
时间窗: 12 weeks
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.
次要结局
- 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)
研究者
David Mischoulon, MD, PhD
Principal Investigator
Massachusetts General Hospital