Inflammatory biomarkers for determining clinical response in people with major depressive disorder

Unhappy Depressed Woman

Major depression is acknowledged as having a strong inflammatory aetiology and the use of pure EPA as an anti-inflammatory mood regulator is supported by numerous intervention studies. One such study published earlier this year provides the most recent support for EPA’s anti-inflammatory therapeutic action in depression. The results indicate that the level of response to EPA supplementation may be dependent on the inflammatory profile of the individual, as those subjects with the highest levels of inflammatory markers experienced the most significant benefits from taking EPA. [1]

In this recent study, one hundred and fifty five subjects, diagnosed with major depressive disorder as defined by a Hamilton Depression Rating Scale (HAM-D-17) score of ≥ 15, were randomised to 8-weeks of a double-blind treatment with EPA (1060mg) or DHA (900mg) or placebo. Outcomes were determined using mixed model repeated measure analysis for ‘high’ and ‘low’ inflammation groups. Level of inflammation was determined by individual or combined IL-1ra, IL-6, hsCRP, leptin and adiponectin profiles. IL-1a and IL-6, and the acute phase protein c-reactive protein (CRP), are all positively associated with depression [2] whilst high circulating levels of leptin and low circulating levels of adiponectin, associated with insulin resistance and type 2 diabetes, are also considered to be indicators of inflammatory status. [3]

High inflammation = high EPA response

Subjects with one or more high biomarkers of inflammation improved more on EPA than placebo despite overall differences in response between the treatment groups being negligible. Subjects randomised to EPA treatment with one or more high biomarkers of inflammation consistently had an 11-point decrease in depression scores by treatment week 8. Subjects randomised to placebo were progressively less responsive as the number of high biomarkers of inflammation increased, showing a clear gradient of separation between EPA and placebo according to inflammatory status. Interestingly, those in the DHA group with high inflammation actually showed even less improvement in depression severity score than those taking the placebo. Also of note, however, was that individuals with no high markers of inflammation were less responsive to EPA than to placebo or DHA. These results clearly support the need to understand the biological and inflammatory basis of mood disorders and treat according to individual needs.

Pure EPA is a potent anti-inflammatory anti-depressant when needed

This latest study adds to the established role of EPA as the source of the anti-depressant properties of omega-3 fish oil, attributed to its anti-inflammatory effects and supported by several meta-analyses of dietary interventions using EPA, DHA and EPA/DHA blends. [4-6] The unique role of EPA was clearly confirmed by a 2013 study comparing the efficacy of EPA versus DHA as co-therapy to medication for mild-to-moderate depression. Mean HDRS scores of patients in the EPA group were significantly lower at study endpoint compared with those in the DHA or placebo groups; however, not all of the EPA group responded to EPA treatment, once again supporting the ‘correct use’ of the relevant omega-3 intervention. [7]

Inflammatory basis of depression

Clinical depression is associated with increased inflammation, elevated levels of pro-inflammatory markers, cortisol insensitivity and increased production of kynurenine and the neurotoxic metabolite quinolinic acid at the expense of serotonin.   It is through the manipulation of these pathways that EPA is thought to exhibit its multiple benefits by reducing inflammatory markers, reducing cortisol and increasing neuroprotective neurotrophins. [8-10] IFN-α therapy induces depressive symptoms in non-depressed individuals and thus provides a unique platform to study the potential of EPA as an anti-inflammatory agent. Pre-treatment with EPA for two weeks has been shown to be effective in the prevention of depression in hepatitis C virus patients receiving IFN-α therapy. [11]

Personalised treatment for depression based on omega-3 and inflammatory biomarkers

The evidence for using pure EPA either alone, or as an adjunct to pharmacotherapies for managing mood disorders continues to increase. With EPA’s multifaceted anti-depressant mechanisms of action, it is increasingly clear that identifying individuals who are ‘at risk’ (either due to low omega-3 levels or high inflammatory status) is a useful approach to maximise intervention success. Combining the omega-3 index, to identify baseline levels of EPA and DHA, with the AA to EPA ratio, to identify an individual’s potential ‘inflammatory status’, allows an omega-3 intervention to be designed specifically in line with current individual omega-3 needs and likelihood of response to the chosen intervention.


  1. Rapaport MH, Nierenberg AA, Schettler PJ, Kinkead B, Cardoos A, Walker R, Mischoulon D: Inflammation as a predictive biomarker for response to omega-3 fatty acids in major depressive disorder: a proof-of-concept study. Molecular psychiatry 2015.
  2. Howren MB, Lamkin DM, Suls J: Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosom Med 2009, 71:171-186.
  3. Lopez-Jaramillo P, Gomez-Arbelaez D, Lopez-Lopez J, Lopez-Lopez C, Martinez-Ortega J, Gomez-Rodriguez A, Triana-Cubillos S: The role of leptin/adiponectin ratio in metabolic syndrome and diabetes. Hormone molecular biology and clinical investigation 2014, 18:37-45.
  4. Martins JG: EPA but not DHA appears to be responsible for the efficacy of omega-3 long chain polyunsaturated fatty acid supplementation in depression: evidence from a meta-analysis of randomized controlled trials. J Am Coll Nutr 2009, 28:525-542.
  5. Sublette ME, Ellis SP, Geant AL, Mann JJ: Meta-analysis of the effects of eicosapentaenoic acid (EPA) in clinical trials in depression. J Clin Psychiatry 2011, 72:1577-1584.
  6. Grosso G, Pajak A, Marventano S, Castellano S, Galvano F, Bucolo C, Drago F, Caraci F: Role of omega-3 fatty acids in the treatment of depressive disorders: a comprehensive meta-analysis of randomized clinical trials. PLoS One 2014, 9:e96905.
  7. Mozaffari-Khosravi H, Yassini-Ardakani M, Karamati M, Shariati-Bafghi SE: Eicosapentaenoic acid versus docosahexaenoic acid in mild-to-moderate depression: a randomized, double-blind, placebo-controlled trial. Eur Neuropsychopharmacol 2013, 23:636-644.
  8. Jazayeri S, Keshavarz SA, Tehrani-Doost M, Djalali M, Hosseini M, Amini H, Chamari M, Djazayery A: Effects of eicosapentaenoic acid and fluoxetine on plasma cortisol, serum interleukin-1beta and interleukin-6 concentrations in patients with major depressive disorder. Psychiatry Res 2010, 178:112-115.
  9. Balanza-Martinez V, Fries GR, Colpo GD, Silveira PP, Portella AK, Tabares-Seisdedos R, Kapczinski F: Therapeutic use of omega-3 fatty acids in bipolar disorder. Expert review of neurotherapeutics 2011, 11:1029-1047.
  10. Balanza-Martinez V, Cuesta MJ, Arango C, Crespo-Facorro B, Tabares-Seisdedos R: Longitudinal course of cognition in schizophrenia. The British journal of psychiatry : the journal of mental science 2009, 195:84; author reply 85.
  11. Su KP, Lai HC, Yang HT, Su WP, Peng CY, Chang JP, Chang HC, Pariante CM: Omega-3 fatty acids in the prevention of interferon-alpha-induced depression: results from a randomized, controlled trial. Biol Psychiatry 2014, 76:559-566.


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Personalising omega-3 treatment for optimal results using a biomarker-based approach, by Dr Nina Bailey
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Dr Nina Bailey

About Dr Nina Bailey

Nina is a leading expert in marine fatty acids and their role in health and disease. Nina holds a master’s degree in Clinical Nutrition and received her doctorate from Cambridge University. Nina’s main area of interest is the role of essential fatty acids in inflammatory disorders. She is a published scientist and regularly features in national health publications and has featured as a nutrition expert on several leading and regional radio stations including SKY.FM, various BBC stations and London’s Biggest Conversation. Nina regularly holds training workshops and webinars both with the public and health practitioners.