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

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.