It is well known that symptoms of clinical are likely mediated by inflammation in the brain. A number of lines of evidence support this idea, including that depressed people, old and young, have elevated levels of certain inflammatory proteins in the plasma and cerebrospinal fluid. Anti-inflammatory agents treat depression, and pharmacologic agents such as interferon, that cause depression, also lead to increases in the inflammatory proteins IL-6 and TNF-alpha. In addition, when someone who is depressed responds to an treatment, these same inflammation markers decrease (1). People with generalized inflammatory syndromes (such as acute viral illness, rheumatoid arthritis, insulin resistance, and cardiovascular disease) have higher rates of depression than the general population too. I also notice in my clinic that people who have had bone surgery tend to get depressed for a few weeks after the operation, more so than people who had other kinds of surgery. I always wonder if sawing through the bones releases an enormous wave of inflammatory cytokines.

There are several suspected mechanisms of how this inflammation leads to depression, many of them very intriguing. Here's one - the amino acid tryptophan is a precursor to the neurotransmitter serotonin. Turns out that tryptophan is also the precursor to another, far less famous neurotransmitter, kynurenic. When the inflammatory cascade is activated, more tryptophan is made into kynurenic, which leaves less tryptophan around to make into serotonin. And everyone knows that without serotonin, we're unhappy (and angry). SSRIs work (when they do), it is thought, by undermining the effect of the inflammatory cytokines, pushing more tryptophan to be made into serotonin rather than kynurenic.

Here's another mechanism - inflammatory cytokines also interfere with the regulation of another neurotransmitter, glutamate. Glutamate is an excitatory neurotransmitter that, if left to go wild, can pound our NMDA receptors in the brain and wreak major havoc. No one wants overexcited NMDA receptors, and clinical depression is one among many nasty brain issues that can be caused by overexcitement. Astrocytes, little clean-up cells in the brain, are supposed to mop up excess glutamate to keep it from going nutso on the NMDA. Turns out inflammatory cytokines interfere with the clean-up process. The (and club drug) ketamine, when administered IV, can eliminate symptoms of severe depression pretty much immediately in some cases (do NOT try this at home) (2). Ketamine helps the astrocytes mop up glutamate, and it is assumed that this is how ketamine instantly cures depression. Unfortunately, the effects of ketamine don't last, otherwise it would be a nifty tool, indeed.

Finally, inflammatory cytokines also push the brain from a general environment of happy "neuroplasticity" (mediated in part by a type of natural brain fertilizer called "BDNF") towards an environment of neurotoxicity (sounds bad, and it is!).

At this point It shouldn't surprise you that psychological interventions (such as therapy) have been shown to reduce chemical markers of inflammation. Yoga has also been shown to do the same. I think it makes sense to assume that any successful antidepressant treatment will also be anti-inflammatory.

So, back to the "vegetable oil" theory: a relative imbalance between the consumption of anti-inflammatory omega 3 fatty acids (fish oil) and inflammatory omega 6 fatty acids (vegetable oil, such as corn oil) predisposes us to inflammation. The omega 6 fatty acids are the precursors for many of the nasty, depressing cytokines mentioned above (such as IL-6).

Well, an absolute flurry of research has been done in this area in the last decade or so, because omega 3 fish oils would be a nifty, natural, presumably no or low side effect, and inexpensive treatment for depression, if it worked. Some studies have been disappointing (3)(4). However, the largest study yet does show benefit (equal to a prescription antidepressant) for those who have depression, but not concurrent , at a daily dose of 150mg DHA and about 1000mg EPA. (DHA and EPA are fish oil omega 3 fatty acids).

Well, neat! But making sure we get omega 3 (and I personally prefer to get my fish oil included in my fish rather than take supplements) is just one half of the omega 6/omega 3 balancing act. What if we decreased dietary omega 6 at the same time? Researchers looked at the blood levels and tissue levels of all the different kinds of in this recent paper. Turns out that depressed people had higher amounts of omega-6 fatty acids, but the amounts of monounsaturated fats, saturated fats, and omega 3 fats were about the same between depressed and non-depressed individuals. (Other studies showed a decreased amount of omega 3 and an increased amount of omega 6 (5)).

As far as I know, there haven't been any studies testing both a dietary decrease in omega 6 and making sure you get appropriate omega 3 for depression, but it would be an interesting intervention to test. Dr. Guyenet uses the work of Dr. Lands to make a case that reducing omega 6 PUFAs to less than 4% of calories would be a great way to reduce overall inflammation, and in the process lots of Western disease. Many hunter-gatherer populations consume less than 1% of calories from omega 6 fatty acids. Right now, in the US, at least 7% of our calories are omega 6 PUFAs.

In summary - inflammation is depressing! Fish oil may make it better, but avoiding corn/safflower/sunflower/soybean oil (theoretically) makes it all better still, and is the natural state for which we are evolved.

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Copyright Emily Deans, M.D.