Kathy Mankofsky and I recently published a 7-part series on fish oil and depression. So I won’t rehash that here. See parts 1, 2, 3, 4, 5, 6, 7.
Pure EPA Omega-3 or formulas that contain more than 60% EPA reduce depressive symptoms while formulas that are mostly DHA Omega-3 do not appear to reduce depression. Source: Sublette et al., 2011.
I want to elaborate on a couple of topics not previously addressed:
- If the brain is so full of DHA, then why does EPA (and not DHA) help with depression?
- The concept of ‘Unopposed EPA’
The best summary of the state of the science was published by Dr. Sublette of Columbia University Medical Center. She also has a website called MoodStudies.org
Dr. Sublette found that depression was significantly improved when a fish oil formula had 60% or more EPA.
If the fish oil contained equal parts EPA and DHA or mostly DHA, there was no improvement in depression.
Actually, DHA is contraindicated for depression per this publication.
But this flies in the face of two facts:
- DHA is the major component of the brain – there is hardly any EPA in the brain
- Depressed people have less DHA in their brain
So…what gives?
We don’t have all the answers yet, but here are a few possible reasons:
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Depression may not be just brain-related
- We think of depression as being exclusively brain-related. I’ve argued that depression is partly gut-and-diet related. If you eat crap (sugar, wheat & vegetable oils), then your gut will be leaky and inflamed.
- The concept of the gut-brain axis is still fairly new to western medicine. Progress is slow. Our grandchildren will hear a lot more about it than we do. Listen to Chris Kresser talk about it on his podcast.
- Makes you rethink the term ‘gut feeling,’ doesn’t it?
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EPA possibly enters brain and improves function
- Just because there is very little EPA in the brain does not mean it is not absorbed and/or rapidly used up (rapid turnover.)
- We know this happens in mice. No proof yet if it happens in people – wanna volunteer?
- EPA supplementation increases N-acetyl aspartate, a marker of nerve health and phospholipid turnover.
- EPA supplementation reverses brain atrophy.
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EPA indirectly increases DHA levels in the brain
- EPA is a precursor to DHA.
- EPA could increase production of DHA but the evidence here is weak.
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Depression could be an inflammatory condition
- We already talked about EPA and its preventive role in inflammation.
- There is an inflammatory hypothesis of depression – in a nutshell: physical and mental stress causes inflammation, markers of inflammation are increased in depressed individuals, and these inflammatory markers (cytokines) can cause depression.
- There is quite a bit of evidence that shows anti-depressants also lower inflammation. (Hey Cletus, this is startin’ to sound like your statin drug!)
- Read ‘Cytokines sing the blues’ by Raison et al., 2006. IL-6 and TNF-alpha are classic markers of inflammation…and depression.
But there’s more!
- Ratios of Omega-6 to 3 are increased in the depressed (never hurts to flog that dead horse!)
- Our bodies make serotonin (the happy chemical) from tryptophan. But if you’re inflamed, your body will convert tryptophan into anxiety-and-agitation-causing molecules (kynurenic and xanthurenic acid.) Groovy diagram explains this. Oh, turns out suicide attempters have high levels of kynurenine. Inflammation-suicide connection!
Since EPA is very effective at reducing inflammation, the inflammation-depression link is the strongest argument for EPA having a role in managing depression.
[Question: if I'm reading this pathway correctly, isn't supplementing with 5-HTP or Tryptophan by hyper-inflamed persons a bad idea? You'd be providing additional substrate for cytokine-mediated conversion to KA and QA...bad juju, no?]
OK, but why does excess DHA hurt?
The Sublette paper suggests it could be due to EPA and DHA competing for some unknown binding site where EPA in excess helps and DHA in excess hurts. And Maes et al., says it could be because DHA induces a Th-1-like immune response, which makes DHA contraindicated for depression. (I’d love to explain that but it’s above my pay grade. And I like being awake. Thanks for asking.)
What is Unopposed EPA?
The concept of unopposed EPA comes from the understanding that fish oil formulas that contained 60% or more EPA reduced depressive symptoms.
The higher the percent of EPA in the formula, the more likely it was to help.
So if your fish oil supplement contains 500 mg total Omega-3, of which 300 mg is EPA and 200 mg is DHA, then the unopposed EPA = mg EPA minus mg DHA. 300 – 200 = 100 mg of unopposed EPA.
OmegaVia supplement facts panel: mg EPA minus mg DHA = Unopposed EPA.
More is not better. Again.
Don’t gulp down 20 fish oil pills after reading all this.
Turns out, there is a sweet spot: between 1000 mg and 2200 mg of unopposed EPA per day. One study noticed benefits with just 200 mg of unopposed EPA per day.
Too much unopposed EPA, and no benefit.
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About the Author: Vin Kutty, M.S., is OmegaVia’s Scientific Advisor and Chief Blogger. He is a nutritionist, author, and Omega-3 expert with over 20 years of experience.
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