Title: Omega-3 fatty acids as an aetiological factor in depression


Key words: depression, immune system, inflammatory response, cardiovascular disease, autoimmune, omega-3, omega-6, phospholipids, cell membranes, PUFA, polyunsaturated fatty acids, eicosapentanoic acid, EPA, prostaglandins, cytokines, docosahexanoic acid, DHA, arachidonic acid, dopamine, serotonin, homocysteine, oxidative damage, cancer, diabetes, neurodegenerative disease, fish oils, fish consumption, myocardial infarction, oily fish, oily nuts, flaxseed oil, seeds,  


Date: Oct 2006




Nutrimed Module:


Type: Article


Author: Morgan, G


Omega-3 fatty acids as an aetiological factor in depression

There is now much evidence to support the theory that clinical depression is a manifestation of a disturbed immune system and inflammatory response, along with a broad spectrum of other conditions such as cardiovascular and autoimmune disease (Simopoulos 2002). This review will consider the evidence that supports this conclusion and the attendant public health implications.


The important role played by essential fatty acids (EFAs) in modulating normal cell membrane phospholipid composition and function has been confirmed by many studies. Reduced omega-3 polyunsaturated fatty acid (PUFA) composition and a reduced omega-3 to omega-6 PUFA ratio of cell membranes has been linked to depression (Smith 1991, Maes 1996). The long-chain omega-3 PUFA eicosapentaenoic acid (EPA) has been shown to inhibit the production of inflammatory prostaglandins from cell membrane-derived arachidonic acid (AA)(Durrington 1995), lower omega-3 to AA ratios being related to the level of clinical depression (Adams 1996).


Conversely, higher ratios of the omega-6 PUFAs are associated with increased levels of proinflammatory cytokines such as IFN-gamma and TNF-alpha (Maes 1995, Maes 2000). Reductions in long-chain structural omega-3 PUFAs such as docosahexaenoic acid (DHA) (Peet 1998) are known to produce changes in cell membrane fluidity affecting membrane channel activity, cell signalling, and the configuration and composition of key neurotransmitters such as dopamine and serotonin involved in depression (Litman 1996).


Abnormal cholesterol metabolism associated with depression also affects the cholesterol content of cell membranes, their fluidity, and cell signalling transduction (Maes 1997). Methylation problems, commonly related to elevated homocysteine levels, are also frequently present in depression and lead to oxidative damage to EFAs and cell membranes (Horrobin &Bennett 2003). These changes in cell membrane EFA composition and the presence of inflammatory markers are indicative of dysfunctional changes affecting the immune system, changes mirrored in other conditions such as cardiovascular disease, diabetes, cancer and neurodegenerative disease, and has led some commentators to talk of a ‘cytokine theory’ of depression (Smith 1991). A close correlation between cardiovascular disease and depression, in particular, has been noted (Booth-Kewley 1987).


Studies have shown that fish oils, with their high content of omega-3 PUFAs, are able to restore imbalances in the omega-3 to omega-6 ratio in cell membranes (Smith 1991) and to lower levels of cytokines and other inflammatory markers associated with depression (Meydani 1993). Five double-blinded trials looking at the effect of fish oils in depression have now been carried out. Three were carried out in groups already on antidepressant medication (Stoll 1999, Nemets 2002, Peet &Horrobin 2002), and two in groups on no form of therapy (Edwards 2002, Su 2003). The trials lasted up to 4 months and all showed positive benefit. Inflammatory markers were not monitored in any of the trials. These results are in line with epidemiological evidence linking cross-national fish consumption with rates of depression (Hibbeln 1998) and with other surveys linking fish consumption and depression within subgroups on a national level (Tanskanen 2001).


Increased rates of depression in the developed world since the early 20th century have been linked to decreasing levels of fish consumption in these populations (Smith 1991). The associations between depression and cardiovascular disease seen in developed countries adds weight to the theory that such conditions are manifestations of systemic inflammatory disorders whose evolution can be modified by the increased omega-3 PUFA content of a fish based diet (Horrobin 2002). Ingestion of fish oils has experimentally been shown to suppress the production of the proinflammatory cytokines linked to such conditions (Meydani 1993). Studies looking at the beneficial results of fish consumption on the rate of such inflammatory conditions as myocardial infarction (GISSI 1999) and stroke (Gillum 1996) help to support this hypothesis.


In conclusion, epidemiological, experimental, and intervention studies support the theory that depression is closely associated with cell membrane dysfunction caused by imbalances in the ratio of omega-3 to omega-6 PUFAs in the cell membrane. Release of proinflammatory prostaglandins and cytokines is closely linked to such imbalances. Increased consumption of the omega-3 PUFAs, either in the form of fish or supplements, has been shown to both modulate this inflammatory state and to lead to improvements in clinical depression. The public health issues stemming from this research are clear. The public needs to be encouraged to increase significantly its consumption of fish, especially oily fish, if the high rates of depression and other chronic inflammatory disorders currently prevalent in developed countries are to be reduced.


Promotion of fish oil supplements and other omega-3-rich foodstuffs such as oily nuts, seeds and flaxseed oil is also to be encouraged if, for social or other reasons, an increased consumption of oily fish appears to be an unattractive option.



1. Simopoulos AP (2002) Omeg-3 fatty acids in inflammation and autoimmune diseases. J Am Coll Nutr 21: 495-505

2. Smith RS (1991) The macrophage theory of depression. Medical Hypotheses 35: 298-306

3. Maes M, et al. (1996) Fatty acid composition in major depression: decreased omega-3 fractions in cholesteryl esters and increased c20:4omega-6/c20:5omega-3 ratio in cholesteryl esters and phosholipids. J Affect Disord 38: 35-46

4. Durrington PN (1995) Lipids and their metabolism. In: Hyperlipid- aemia, diagnosis and management, pp 4-24, Horrobin DF (ed.). Cambridge: Butterworth-Heinemann

5. Adams PB, Lawson S, Sanigorski A, Sinclair AJ (1996) Arachidonic acid and eicosapentaenoic acid ratio in blood correlates positively with clinical symptoms of depression. Lipids 31: S157-S161

6. Maes M (1995) Evidence for an immune response in major depression: a review and hypothesis. Progr Psycopharmacol Biol Psychiatry 19:11-38

7. Maes M, Christophe A, Bosmans E, Lin A, Neels H (2000) In humans, serum polyunsaturated fatty acid levels predict the response of proinflammatory cytokines to psychological stress. Biol Psychiatry 47: 910-920

8. Peet M, Murphy B, Shay J, Horrobin DF (1998) Depletion of omega- 3 fatty acid levels in red blood cell membranes of depressive patients. Biol Psychiatry 43: 315-319

9. Litman BJ, Mitchell DC (1996) A role for phospholipid polyunsatur- ation in modulating membrane protein function. Lipids 31: S193- S197

10. Maes M, et al. (1997) Lower serum high density lipoprotein cholesterol (HDL-C) in major depression and in depressed men with serious suicidal attempts: relationships to immune-inflammatory markers. Acta Psychiatr Scand 95: 212-21

11. Horrobin DF, Bennett CN (2003) Phoshpolipid metabolism and the pathophysiology of psychiatric and neurological disorders. In: Phospholipid spectrum disorders in psychiatry and neurology, 2nd ed., pp 20-24, Peet M, Glen I, Horrobin DF (eds.). Marius Press

12. Booth-Kewley S, Friedman HS (1987) Psychological predictors of heart disease: a quantitative review. Psychol Bull 101: 343-362

13. Meydani SN, et al. (1993) Immunologic effects of National Cholesterol Education Panel Step-2 Diets with and without fish- Derived n-3 fatty acid enrichment. J Clin Invest 92: 105-113

14. Stoll AL, et al. (1999) Omega 3 fatty acids in bipolar disorder: a preliminary double-blind, placebo-controlled trial. Arch Gen Psychiatry 56: 407-412

15. Nemets B, Stahl Z, Belmaker RH (2002) Addition of omega-3 fatty acid to maintenance medication treatment for recurrent unipolar depressive disorder. Am J Psychiatry 159: 477-479

16. Peet M, Horrobin DF (2002) A dose-ranging study of the effects of ethyl-eicosapentaenoic acid in patients with ongoing depression in spite of apparently adequate treatment with standard drugs. Arch Gen Psychiatry 59: 913-919

17. Edwards RW (2002) Studies of omega-3 polyunsaturated fatty acids in depression. PhD Thesis, University of Sheffield

18. Su KP, Huang SY, Chiu CC, Shen WW (2003) Omega-3 fatty acids in major depressive disorder. A preliminary double-blind, placebo-controlled trial. Eur Psychopharmacol 13: 267-271

19. Hibbeln JR (1998) Fish consumption and major depression. Lancet 351: 1213

20. Tanskanen A, et al. (2001) Fish consumption and depressive symptoms in the general population in Finland. Psychiatr Serv 52: 529-531

21. Horrobin DF (2002) Cardiovascular disease, affective disorders and impaired fatty acid and phospholipid metabolism. In: Vascular disease and affective disorders, Chiu E, Ames D, Katona C (eds.) London: Martin Dunitz

22. Gruppo Italiano per lo Studio della Streptokinasi nell’Infarto Miocardico (GISSI) (1999) Dietary supplementation with n-3 Polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Lancet 354: 447-455

23. Gillum RF, Mussolino ME, Madans JH (1996) The relationship between fish consumption and stroke incidence. The NHANES 1 Epidemiologic Follow-up Study (National Health and Nutrition Examination Survey). Arch Int Med 156: 537-42