Omega-3 Fatty Acids for Major Depressive Disorder With High Inflammation: A Personalized Approach
Condition: Major Depressive Disorder; Overweight; Inflammation
MeSH terms: Overweight; Inflammation; Depressive Disorder; Depression; Depressive Disorder, Major
Study type: Interventional
Phase: Phase 2/Phase 3

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.
    

Detailed description: 
      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:

        1. Study capsules containing EPA-enriched omega-3, 1000 mg tabs, supplied by Nordic
           Naturals.

        2. 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:

        1. severe, persistent intolerance to study medication

        2. worsening of depressive symptoms such that the subject's safety is endangered (e.g.
           suicidality)

        3. development of mania or psychotic symptoms

        4. 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

        5. persistent non-adherence to the study medication, defined as not taking between 80-120%
           of the study medication pills for two consecutive visits

        6. 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.
    

Intervention name(s): Placebo; EPA 1 g/day; EPA 2 g/day; EPA 4 g/day
Intervention type(s): Other; Drug; Drug; Drug
Intervention description(s): Soybean oil placebo; Omega-3 fatty acid extracted from fish oil, 1 g/day; Omega-3 fatty acid extracted from fish oil, 2 g/day; Omega-3 fatty acid extracted from fish oil, 4 g/day
Other intervention name(s): Eicosapentaenoic acid; omega-3 fatty acid; Eicosapentaenoic acid; omega-3 fatty acid; Eicosapentaenoic acid; omega-3 fatty acid
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention 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 (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Omega-3; EPA; Depression; Overweight; Inflammation; Eicosapentaenoic acid