Do Omega-3 Fatty Acids Have an Antidepressant Effect in Patients With Signs of Peripheral Inflammation?
Condition: Major Depressive Disorder
MeSH terms: Inflammation; Depressive Disorder; Depressive Disorder, Major
Study type: Interventional

Summary: 
      In this study, the investigators will stratify depressed subjects a priori based on CRP
      levels to test the hypothesis that eicosapentaenoic (EPA) would be more efficacious to treat
      depression in subjects with high CRP levels compared to subjects with low CRP levels.

      Depressed subjects, with ongoing stabilized antidepressive treatment who remain clinically
      depressed, will be enrolled in an "Inflammation group" or in a "Non-inflammation group"
      depending on baseline levels of CRP. Subjects in both groups will receive EPA enriched
      omega-3 fatty acids for 8 weeks, added to their pre-stabilized antidepressant medication.
    

Detailed description: 
      Background

      Increased mean levels of peripheral inflammatory markers have repeatedly been reported in
      individuals with major depression compared to controls, although there is considerable
      overlap between groups. As further evidence for a role of inflammation in major depression,
      20-60% of patients receiving treatment for viral hepatitis and certain forms of cancer with
      the cytokine interferon-alpha will develop depressive symptoms. Interestingly, some authors
      have suggested that the association between inflammation and depression is symptom specific,
      i.e. there might be a subtype of "inflammation-related depression" with a specific phenotype.
      Although it still remains unclear if the immune abnormalities often seen in depressed
      subjects derive from changes in the periphery or in the central nervous system (or both),
      animal studies have shown that by counteracting the effects of pro-inflammatory cytokines in
      either the blood or the brain, depressive-like behavior in animals can be mitigated. These
      animal studies, along with data from several clinical studies pertaining to this, suggest
      that interventions primarily targeting peripheral inflammation may be useful in treating
      psychiatric symptoms. Although the exact mechanisms by which increased inflammation may give
      rise to depressive symptoms remain unclear, there are several potential downstream pathways
      that may be involved including accelerated cellular aging, mitochondrial dysfunction, and
      oxidative stress.

      In search for a potential antidepressant that could be tested in clinical trials in which
      subjects are selected a priori based on inflammatory markers, the investigators turn to
      eicosapentaenoic (EPA), an omega-3 (n-3) fatty acid with anti-inflammatory properties. The
      ability of dietary n-3 fatty acids to mitigate the inflammatory response has been shown in
      human and animal studies. EPA and Docosahexaenoic acid (DHA) are the two major n-3 fatty
      acids found in oily fish and fish oil supplements, and both have shown anti-inflammatory
      properties. Supplementation of EPA and DHA in individuals with cardiovascular disease results
      in decreased plasma levels of CRP. N-3 fatty acids also have several other anti-inflammatory
      properties including i) Decreased chemotaxis of neutrophils and monocytes, ii) Decreased
      expression of adhesion molecules (e.g. ICAM & VCAM) on the surface of immune cells and in the
      circulation, iii) Decreased production of prostaglandins, iv) Increased synthesis of
      anti-inflammatory molecules such as resolvins and protectins, and v) Inhibition of T-cell
      proliferation. The mechanisms underlying these effects are not fully understood but likely
      involves n-3 fatty acids acting via cell surface and intracellular receptors controlling
      inflammatory cell signaling and gene expression patterns. In addition to the well-established
      anti-inflammatory effects of n-3 fatty acids, they may also have beneficial effects on
      oxidative stress and cell aging parameters such as leukocyte telomere length and telomerase
      activity. However, more research is needed in order to confirm these relationships, and
      therefore the investigators will, in addition to assessing inflammatory markers, also study
      the effects of n-3 fatty acids on markers of cellular aging and oxidative stress.

      Some, but not all, previous studies have shown that EPA is superior to placebo in treating
      unipolar or bipolar depression. Several caveats have, however, been issued when interpreting
      the results from these studies, including small and perhaps clinically irrelevant effect
      sizes, as well as potential publication bias. Generally, n-3 preparations with high doses of
      EPA relative to DHA have been shown to be more efficacious in treating depression.
      Interestingly, a double blind placebo-controlled RCT showed that that EPA (but not DHA) was
      effective in preventing interferon-alpha induced depression in hepatitis C subjects,
      consistent with the notion that EPA may have antidepressant effect in "inflammatory
      depression". In line with this notion, a recent a proof-of-concept study showed that high
      inflammation at baseline was associated with a better antidepressant effect of EPA, but not
      DHA, enriched n-3 compared to placebo. That study stratified subjects post-hoc based on
      inflammatory markers, whereas our approach will be to select study subjects a priori based on
      validated cut-offs for CRP. This is the next step in developing a personalized medicine
      paradigm for depression.

      The main aims of the study are to test if i) EPA enriched n-3 (added to stabilized ongoing
      treatment) is efficacious in treating depressed patients, but only in subjects with
      prospectively ascertained elevations in baseline CRP, ii) Changes in inflammatory markers
      over the course of treatment mediate this effect, and iii) Clinical trial designs utilizing
      prospectively-ascertained biomarkers to predict response are feasible and thereby pave the
      way for personalized medicine in psychiatry.

      Specific objective 1: To determine whether the antidepressant effect of n-3 EPA is greater in
      the Inflammation group than in the Non-inflammation group, controlling for baseline
      depression rating.

      Hypothesis (H) 1: The antidepressant effect of n-3 EPA is greater in the Inflammation group
      than in the Non-inflammation group.

      Specific objective 2: To determine whether changes in inflammatory, oxidative stress and cell
      aging markers from baseline to end of treatment correlate with antidepressant effect.

      H 2: Change in inflammatory and cell aging markers with n-3 EPA treatment will be directly
      correlated with changes in depression ratings.
    

Intervention name(s): Eicosapentaenoic acid enriched omega-3 fatty acids, 2 g/day
Intervention type(s): Dietary Supplement
Intervention description(s): Eicosapentaenoic acid enriched omega-3 fatty acids, 2 g/day, added to pre-stabilized antidepressant medication
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Intervention model description: Match/mismatch design (based on CRP levels), all subjects receive the same dose of EPA, no one receives placebo. Raters are blind to "Inflammation group" or "Non-inflammation group" allocation
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Treatment