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
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.
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