Friday, July 2, 2010

Oils Aint Oils: EPA for Depression

One of the more remarkable features about depression is the number of therapies that have proved beneficial. I explored that issue in this post. This latest study highlights the importance of prostaglandin regulation in depression. This latest study, the largest ever trial on omega 3 fats in treating depression, demonstrates a careful delineation that helps clarify the role of omega 3's in treating depression. The nutshell is this: they focused on EPA, typically at 120mg in your fish oil tablets, and boosted that intake to a big 1000mg per day. That's a lot but given the role of EPA in regulating prostaglandin pathways makes good sense.

The researchers deserve credit for focusing on EPA. This study is a good example of how ongoing research keeps digging deeper and deeper and so improves our understanding of what is going on. Previous research on omega 3's for depression had produced conflicting results. By focusing on EPA, and recognising that an important variable was anxiety comorbidity, the researchers have managed to tease out the discrepancies in prior results and so provide valuable information that can be put to good use at a clinical level. Or at least could be if high EPA concentrations in fish oil supplements were available!

To understand the importance of prostaglandin regulation in depression we need to look at the role of fatty acids and how these specifically impact on inflammatory mediators, which are increasingly perceived as being cardinal players in depression onset. Wiki provides a good overview of this. Omega 3 fatty acids, especially EPA, induce the production of less inflammatory prostaglandins. Additionally, while the body can manufacture DHA and EPA from small chain omega 3's, such as found in flaxseed, the prevailing view is that humans have limited ability to make this conversion and so should rely on food sources with the longer chain omega 3's. I don't share that view, I vaguely recall studies indicating that our liver is quite capable of generating EPA which can be taken up by the brain. Nonetheless let prudence rule and eat oily fish.

What is important here is what is referred to as the Arachidonic Acid cascade. Arachidonic acid is an abundant fatty acid that is stored in cell membranes and via PLA2 is released from these stores. It is strongly associated with inflammation but keep in mind it performs a multitude of functions. The inflammatory potential of Arachidonic acid is mediated by its being a precursor for inflammatory mediators and its ability to affect transcription of inflammatory cytokines. There are some foods high in arachidonic acid content(eg. pork) and it probably is advisable to limit our intake of the same, especially if we are suffering from depression.

One of the interesting things about biomedical research is that when new research pops up and if you have kept your head buried in the literature for an extended period  you often find that research findings are prefigured in prior research. In this instance ...

Addition of Eicosapentaenoic Acid to g-Linolenic Acid–Supplemented Diets Prevents Serum Arachidonic Acid Accumulation in Humans
ABSTRACT Previous studies reveal that supplementation of human diets with g-linolenic acid (GLA) reduces the generation of lipid mediators of inflammation and attenuates clinical symptoms of chronic inflammatory disorders such as rheumatoid arthritis. However, we have shown that supplementation with this same fatty acid also causes a marked increase in serum arachidonate (AA) levels, a potentially harmful side effect. The objective of this study was to design a supplementation strategy that maintained the capacity of GLA to reduce lipid mediators without causing elevations in serum AA levels. Initial in vitro studies utilizing HEP-G2 liver cells revealed that addition of eicosapentaenoic acid (EPA) blocked D-5-desaturase activity, the terminal enzymatic step in AA synthesis. To test the in vivo effects of a GLA and EPA combination in humans, adult volunteers consuming controlled diets supplemented these diets with 3.0 g/d of GLA and EPA. This supplementation strategy significantly increased serum levels of EPA, but did not increase AA levels. EPA and the elongation product of GLA, dihomo-g-linolenic acid (DGLA) levels in neutrophil glycerolipids increased significantly during the 3-wk supplementation period. Neutrophils isolated from volunteers fed diets supplemented with GLA and EPA released similar quantities of AA, but synthesized significantly lower quantities of leukotrienes compared with their neutrophils before supplementation. This study revealed that a GLA and EPA supplement combination may be utilized to reduce the synthesis of proinflammatory AA metabolites, and importantly, not induce potentially harmful increases in serum AA levels. J. Nutr. 130: 1925–1931, 2000.

Look at the date, year 2000! One of my old archive files, Google desktop is great!

As noted in the abstract EPA has a direct impact on Arachidonic acid synthesis. Now with your typical fish oil supplements there may be a problem because these typically contain 180mg of DHA ...

1. Neuro Endocrinol Lett. 2007 Dec;28(6):875-80.
Why fish oils may not always be adequate treatments for depression or other inflammatory illnesses: docosahexaenoic acid, an omega-3 polyunsaturated fatty acid, induces a Th-1-like immune response.
Maes M, Mihaylova I, Kubera M, Bosmans E.
Clinical Research Center for Mental Health, Antwerp, Belgium.
BACKGROUND: We have shown that a depletion of omega3 polysaturated fatty acids (PUFAs) plays a role in the pathophysiology of depression, in part because omega3 PUFAs have anti-inflammatory effects. omega3 PUFAs are frequently employed to treat depression. Most if not all antidepressants have negative immunoregulatory effects by decreasing the production of proinflammatory cytokines, such as interferon-gamma (IFNgamma) and/or increasing that of anti-inflammatory cytokines, such as interleukin10 (IL-10). AIM: The aim of the present study was to examine the immunoregulary effects of the omega3 PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and the omega6 PUFA, arachidonic acid (AA), on the production of interferon-gamma (IFNgamma), interleukin-10 (IL-10) and tumor necrosis factor-alpha (TNFalpha). METHODS: This study examines the ex vivo effects of EPA (4.5 microM, 9 microM, 18 microM and 45 microM), DHA (1.3 microM, 3 microM, 6 microM and 13 microM) and AA (8 microM, 16 microM, 32 microM and 80 microM) on the LPS + PHA-stimulated production of IFNgamma, IL-10 and TNFalpha, and on the IFNgamma/IL-10 production ratio. Results: We found that EPA did not have any significant effects on the above cytokines. DHA significantly increased the IFNgamma/IL-10 production ratio, caused by a greater reduction in IL-10 than in IFNgamma. AA significantly decreased TNFalpha production. DISCUSSION: The results show that DHA induces a Th-1-like immune response and that AA has anti-inflammatory effects by decreasing the production of TNFalpha. Thus, the immune effects of omega3 PUFAs are not compatible with what is expected from antidepressive substances. The results of the present study show that treatment with fish oils, containing DHA, should be avoided in the treatment of depression. Toward this end, highly concentrated and pure EPA seems to be indicated.

PMID: 18063921 [PubMed - indexed for MEDLINE]

The above study also highlights the conflicting results from prior studies. So all those people who eat fish all the time could be creating a problem for themselves. I have seen other studies like the above, I can visualise a chart showing how omega 3's were boosting two key inflammatory mediators, il-1 and tnfa, but I'm too lazy to dig that out of my archives because Google desktop aint that great.

There is another issue with high omega 3 intake that we rarely hear about. I first became aware of it when I read how eskimos "bleed like cut pigs", have a reputation for dying from cerebral hemorrhages in their 60's, and a Japanese study which showed an decreasing trend towards cerebral hemorrhages as they Japanese moved towards a diet of more saturated fat, the downside there being an increase in other pathologies ... .
Good fats, bad fats, nonsense stuff, with the exception of trans fats but even then there is an exception. One trans fat that has demonstrated value is conjugated linolenic acid, found in dairy products. Many studies now point to benefits from moderate diary intake.  Note that CLA is both a trans and cis fat.

I've carried on long enough. What is the relevance of this to those suffering depression?

Take your fish oil, but keep in mind the above abstract because it appears that DHA and EPA may have counteracting influences. To that end, it may be better to also increase your intake of small chain fatty omega 3 fatty acids, flaxseed, hemp oil, walnuts, ... .

  1. Lower your saturated fat intake because it has a direct impact on inflammatory mediators. 
  2. Reduce your omega 6 intake. 
  3. In preference to the usual fish oil supplements, see if any supplements that focus on EPA are available. 
  4. In apparent contradiction to the above advice regarding dairy products, the high saturated fat content may be in advisable during periods of depression. 

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