Recognised as a disorder of both immune and inflammatory function, clinical depression is believed to be accompanied by sustained activation of the HPA-axis, possibly through induction of chronic stress. The immune system responds to stress by releasing pro-inflammatory cytokines that alter the activity of enzymes involved in serotonin production and uptake. Omega-3 fatty acid deficiency, which is common in clinical depression, influences the delicate balance of omega-6 and omega-3 fatty acids. The resulting accumulation of membrane arachidonic acid (AA, omega-6) composition has a corresponding effect on pro-inflammatory mediators and central serotonin production, all of which appear to be normalised by eicosapentaenoic acid (EPA, omega-3) supplementation. As the evidence for the role of pure EPA in treating depression, and the impact of EPA in normalising dysregulated inflammation, increases, so does the promise for successful alternatives to standard pharmaceutical interventions for this crippling condition. The most recent evidence for EPA’s regulatory role in the inflammatory pathways linked to depression is published in the October edition of the Journal of Biological Psychiatry where pre-treatment with EPA was shown to prevent depression induced by interferon (IFN)-α therapy associated with chronic hepatitis C virus infection.
Inflammation and depression
Inflammation is the body’s protective response to injury, pathogens or irritants. Whilst the absence of inflammation would compromise health, chronic inflammation is known to be linked to the development of numerous disease states, including cardiovascular disease, cancer, neurodegenerative disease, diabetes and disorders of the gastrointestinal system. With some conditions such as rheumatoid arthritis (RA), inflammatory bowel diseases (IBD) and asthma, the central role of inflammation is well recognised, with heavy infiltration of inflammatory cells at the site of disease activity (e.g. the joints, the intestinal mucosa, the lungs) with elevated concentrations of inflammatory mediators found both at the direct site and in the systemic circulation. Notably, when these individuals are treated with anti-inflammatory drugs there is a corresponding improvement in symptoms correlated with a reduction of these inflammatory mediators and a reduction in inflammation. In contrast to these aforementioned examples, the link between chronic inflammation and the development of mental health conditions, such as depression, schizophrenia and bipolar disorder, is less palpable and yet it does exist. There is, therefore, huge potential to target inflammation as a therapeutic means of managing these disorders.
Fatty acids and cytokines
It is well established that omega-6 and omega-3 fatty acids can influence cytokine production. AA for example is a long-chain omega-6 fatty acid that increases the production of pro-inflammatory eicosanoids and, consequently, pro-inflammatory cytokines. In contrast, the long-chain omega-3 fatty acid EPA has the opposite effect and can significantly reduce the production of a number of inflammatory products, including tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-2 (IL-2). Unsurprisingly, a high omega-6 to omega-3 (and specifically AA to EPA) ratio is associated with high pro-inflammatory cytokine production; in combination with the stress hormone cortisol, this can directly influence the inflammatory stress response.
Inflammation and mood disorders
Both cortisol and inflammatory cytokine production increase the risk of developing depression by altering the activity of enzymes from key metabolic pathways including indoleamine 2-,3-dioxygenase (IDO) tryptophan 2,3-dioxygenase (TDO) and kynurenine monooxygenase (KMO). Kynurenine is the catabolic product of IDO- and TDO-induced tryptophan metabolism and is an alternative tryptophan pathway that can result in reduced production of the neurotransmitter serotonin. The chronic up-regulation of the kynurenine pathway results in an imbalance in critical neuroactive compounds, including a reduction of tryptophan, a reduction of serotonin and elevation of tryptophan-derived metabolites. In addition to lowering serotonin, the activation of KMO shuttles the production of the neuroprotective product kynurenic acid (from kynurenine) and increases the production of quinolinic acid, which has potent neurotoxic effects. Activation of TDO is up-regulated by cortisol, whilst cytokines activate the enzymes IDO and KMO.  A number of pro-inflammatory cytokines capable of initiating this pathway are consistently found to be increased in major depression.  Indeed, the shift of tryptophan metabolism from serotonin to kynurenine formation has been observed in depression, resulting in a high kynurenine/tryptophan ratio that is significantly associated with symptoms.  Elevated quinolinic acid has also been reported in depressed patients, where it accumulates in certain areas of the brain tissue and has the potential to cause significant neuronal damage.  Indeed, magnetic resonance imaging (MRI) scans show structural brain grey matter abnormalities in major depression, bipolar and schizophrenia. Furthermore, in addition to reducing serotonin production by driving the tryptophan metabolism kynurenine pathway, pro-inflammatory cytokines also increase serotonin transporter (SERT) activity (involved in recycling serotonin for reuse), thus further reducing overall serotonin activity. [10, 11] As an example, exposure to TNF-α in cultured cell lines resulted in a dose- and time-dependent increase in SERT-mediated serotonin uptake. 
Omega levels in the depressed patient
Alterations in fatty acids in clinical depression include a decrease in omega-3 fatty acids and an increased omega-6 to omega-3 ratio, specifically AA to EPA, correlating positively with symptom severity.[13, 14] Deficiencies in omega-3 and increased omega-6 AA concentrations can result in increased levels of prostaglandin (PGE)2, known to directly activate the HPA-axis, increase cortisol and drive the production of inflammatory mediators. Chronic dietary omega-3 fatty acid deficiency significantly increases membrane AA composition, correlating with a corresponding increase in pro-inflammatory cytokine IL-6, tumour necrosis factor (TNF)-alpha, c-reactive protein (CRP) production and increases in central serotonin turnover.  Supplementation with EPA can reduce inflammation through its direct competition with AA, through the suppression of PGE2 and subsequent reduction of pro-inflammatory end products. [10, 16]
Omega-3 and depression: evidence from clinical trials
Although there has been considerable variation in findings, the evidence for a role of omega-3 in preventing and/or treating depression has been well supported by numerous trials. Two major meta-analyses have reported the efficacy of EPA-dominant oils over EPA/docosahexaenoic (DHA) oils and concluded if DHA is the predominant fatty acid within a treatment product, omega-3 supplementation will be ineffective in depression and that many studies simply do not take into account the possible differential effects of EPA versus DHA.[17, 18] The striking result of both meta analyses show that as the proportion of EPA increases within a preparation, so does the efficacy, with those studies using pure ethyl-EPA at a dose of around 1g/daily the most efficacious. Supplements containing EPA ≥ 60% of total EPA + DHA, in a dose range of 200 to 2,200 mg/day of EPA in excess of DHA, are clinically effective against primary depression. In a recent direct comparison of EPA and DHA, 1g pure EPA was found to be signifcantly more effective than 1g DHA in treating depressive symptoms, yet further supporting the use of purifed EPA over EPA/DHA combinations.
Cytokine administration induces depressive symptoms
Cytokine therapy is well known to induce depressive symptoms. For example, data derived from treating cancer or hepatitis C patients with IFN-α based immunotherapy shows cell-mediated immune activation at the onset of IFN-α-induced depression leading to full blown major depression in a number of patients.  Phospholipase A2 (PLA2) and cyclooxygenase 2 (COX2) are the two key enzymes in the metabolism of polyunsaturated fatty acids, which in turn play an important role in cytokine-induced depression. Genetic variations in the COX2 and PLA2 genes increase the risk of IFN-α–induced depression, possibly by affecting the levels of EPA and DHA. Thus the role of EPA, known for its anti-depressant activities in preventing treatment induced depression, is of interest partly because omega-3 polyunsaturated fatty acid deficiency has been associated with an increased risk of IFN-induced depression. In the recently published 2-week, double-blind, placebo-controlled trial, Su and colleagues compared the capacity of EPA, DHA, and placebo to prevent IFN-α-induced depression in 152 patients with chronic hepatitis C virus infection. EPA pre-treatment increased both EPA and DHA erythrocyte levels and was found to be effective in preventing IFN-α-induced depression, whereas the effects of DHA only had modest effects that were not sustained.
EPA has numerous anti-inflammatory properties. EPA directly competes with AA, inhibits COX2 enzyme activity and reduces PGE2 synthesis, with favourable outcomes on pro-inflammatory cytokine production. Interestingly, a reduction in COX2 activity not only has a general anti-inflammatory action but also specifically down-regulates the IDO enzymes cascade and the production of potentially neurodamaging metabolites. As AA-derived pro-inflammatory cytokines and the initiation of the IDO cascade are known to be involved in the mechanisms relating to depression, identifying those individuals with high AA and low EPA (AA to EPA ratio) offers great potential, not only as a treatment for depression but it may also help identify those at risk of developing depression. Ideally, the AA to EPA ratio should be no more than 3:1 and can be determined by our simple blood spot fatty acid test – the Opti-O-3. Combined with the use of purified EPA treatment, this is a viable and safe oral treatment to optimise this ratio.
- Raison CL: Inflammatory depression: a trifecta of trouble. J Clin Psychiatry 2014, 75(6):663-664.
- 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(7):559-566.
- Noto C, Rizzo LB, Mansur RB, McIntyre RS, Maes M, Brietzke E: Targeting the inflammatory pathway as a therapeutic tool for major depression. Neuroimmunomodulation 2014, 21(2-3):131-139.
- Heyes MP, Saito K, Crowley JS, Davis LE, Demitrack MA, Der M, Dilling LA, Elia J, Kruesi MJ, Lackner A et al: Quinolinic acid and kynurenine pathway metabolism in inflammatory and non-inflammatory neurological disease. Brain 1992, 115 ( Pt 5):1249-1273.
- Oxenkrug GF: Tryptophan kynurenine metabolism as a common mediator of genetic and environmental impacts in major depressive disorder: the serotonin hypothesis revisited 40 years later. Isr J Psychiatry Relat Sci 2010, 47(1):56-63.
- 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(2):171-186.
- Swardfager W, Herrmann N, Dowlati Y, Oh PI, Kiss A, Walker SE, Lanctot KL: Indoleamine 2,3-dioxygenase activation and depressive symptoms in patients with coronary artery disease. Psychoneuroendocrinology 2009, 34(10):1560-1566.
- Steiner J, Bogerts B, Sarnyai Z, Walter M, Gos T, Bernstein HG, Myint AM: Bridging the gap between the immune and glutamate hypotheses of schizophrenia and major depression: Potential role of glial NMDA receptor modulators and impaired blood-brain barrier integrity. World J Biol Psychiatry 2012, 13(7):482-492.
- Kempton MJ, Salvador Z, Munafo MR, Geddes JR, Simmons A, Frangou S, Williams SC: Structural neuroimaging studies in major depressive disorder. Meta-analysis and comparison with bipolar disorder. Arch Gen Psychiatry 2011, 68(7):675-690.
- 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(1):112-115.
- Song C, Li X, Kang Z, Kadotomi Y: Omega-3 fatty acid ethyl-eicosapentaenoate attenuates IL-1beta-induced changes in dopamine and metabolites in the shell of the nucleus accumbens: involved with PLA2 activity and corticosterone secretion. Neuropsychopharmacology 2007, 32(3):736-744.
- Malynn S, Campos-Torres A, Moynagh P, Haase J: The pro-inflammatory cytokine TNF-alpha regulates the activity and expression of the serotonin transporter (SERT) in astrocytes. Neurochem Res 2013, 38(4):694-704.
- Maes M, Smith R, Christophe A, Cosyns P, Desnyder R, Meltzer H: Fatty acid composition in major depression: decreased omega 3 fractions in cholesteryl esters and increased C20: 4 omega 6/C20:5 omega 3 ratio in cholesteryl esters and phospholipids. J Affect Disord 1996, 38(1):35-46.
- Adams PB, Lawson S, Sanigorski A, Sinclair AJ: Arachidonic acid to eicosapentaenoic acid ratio in blood correlates positively with clinical symptoms of depression. Lipids 1996, 31 Suppl:S157-161.
- McNamara RK, Jandacek R, Rider T, Tso P, Cole-Strauss A, Lipton JW: Omega-3 fatty acid deficiency increases constitutive pro-inflammatory cytokine production in rats: relationship with central serotonin turnover. Prostaglandins Leukot Essent Fatty Acids 2010, 83(4-6):185-191.
- Jazayeri S, Tehrani-Doost M, Keshavarz SA, Hosseini M, Djazayery A, Amini H, Jalali M, Peet M: Comparison of therapeutic effects of omega-3 fatty acid eicosapentaenoic acid and fluoxetine, separately and in combination, in major depressive disorder. Aust N Z J Psychiatry 2008, 42(3):192-198.
- 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(5):525-542.
- 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(12):1577-1584.
- 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(7):636-644.
- Haroon E, Raison CL, Miller AH: Psychoneuroimmunology meets neuropsychopharmacology: translational implications of the impact of inflammation on behavior. Neuropsychopharmacology 2012, 37(1):137-162.
- Su KP, Huang SY, Peng CY, Lai HC, Huang CL, Chen YC, Aitchison KJ, Pariante CM: Phospholipase A2 and cyclooxygenase 2 genes influence the risk of interferon-alpha-induced depression by regulating polyunsaturated fatty acids levels. Biol Psychiatry 2010, 67(6):550-557.