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.

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 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 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.