Depression 2 - Inflammation Boogaloo

It is well known that symptoms of clinical depression 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-alpha, 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 antidepressant 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 cute. Here's one - the amino acid tryptophan is a precursor to Eli Lilly's second favorite neurotransmitter, serotonin*. Turns out that tryptophan is also the precursor to kynurenic. When the inflammatory cascade is activated, more tryptophan is made into kynurenic, which leaves less tryptophan around to make into Eli Lilly's second favorite neurotransmitter, serotonin. And everyone knows that without serotonin, we're unhappy (and angry). SSRIs work, in part, by undermining the effect of the inflammatory cytokines, pushing more tryptophan to be made into serotonin.

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 (2). The horse tranquilizer (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) (3). 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 psychiatrist's tool, indeed.

Finally, inflammatory cytokines also push the brain from a general environment of happy "neuroplasticity" (mediated finally by our old friend, BDNF) towards an environment of neurotoxicity (sounds bad, and it is!).

In my post on vegetable oils, I made note of a popular theory that 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, low side effect, cheap treatment for depression, if it worked. Some studies have been disappointing (4)(5). However, the largest study yet, hot off the presses, does show benefit (equal to a prescription antidepressant) for those who have depression, but not concurrent anxiety, at a daily dose of 150mg DHA and about 1000mg EPA. (DHA and EPA are fish oil omega 3 fatty acids).

Well, neat! But adding extra omega 3 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 fatty acid 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 (6)).

As far as I know, there haven't been any major studies testing both a dietary decrease in omega 6 and supplementation with omega 3 for depression, but it would be an interesting intervention. 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 lots of Western disease. Hunter gatherers, such as the Kitavans, consume less than 1% of calories from omega 6 fatty acids. Right now, in the US, about 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.

*Eli Lilly's favorite neurotransmitter is, of course, dopamine.

Read More..

Vegetable Oils and our Brave New World

A quick review of the basic premise, this new lens through which I examine nutrition, general health, and mental health: humans beings will have the best chance of good physical and mental health by staying true to the diet and activities that we are evolved for. Let's get back to diet for the moment and focus on some of the differences between what we eat today, and what physically healthy peoples and cultures ate. Much of the following information is taken from Food and Western Disease (never leave home without it).

We know from several hundred years of good observation and anthropology that healthy peoples ate a wide variety of different foods, with vastly differing percentages of macronutrients (primarily differences in carbohydrates and fats - protein is usually around 15-30% of calories). The types and quality of the food they ate, however, universally differed from our current diet in the following ways:

1) no wheat, and if grain-based the grains are carefully prepared to minimize antinutrients
2) minimal amounts of omega 6 fatty acids balanced with omega 3 fatty acids (or vast amounts of omega 3)
3) reliance on whole foods with no industrial processing (therefore no highly refined carbohydrates or sugar other than perhaps seasonal raw honey and wild fruits)

In my opinion, one doesn't need to understand the science or biochemistry of these differences to go forward with a paleolithic-style diet based on the time-tested diets of healthy cultures. However, I'm interested in what it is about these differences that might cause Western disease.

I'm going to focus on #2 at the moment, and introduce a fading star of the "heart-healthy diet," vegetable oils. (Or not so fading star - this recent article trumpets vegetable oil as the second coming, though, as always, Stephan at Whole Health Source has a reasoned review.)

Corn oil, safflower oil, sunflower oil, peanut oil and/or soybean oil are ingredients in pretty much all processed food. Just check the list on the back. They are in breakfast cereal, bread and other baked goods, and also in fried items, salad dressings, mayonnaise, sauces, and are used (along with canola oil) in the fryers at most restaurants. They are cheap and relatively tasteless, which makes them perfect for certain industrial and restaurant food applications. They are also universally high in omega 6 fatty acids, and therefore we eat a ton of them in the Western diet, especially since throwing out butter, lard, and beef tallow 30-40 years ago.

How could this possibly matter? Omega 6 fatty acids are a type of PUFA (polyunsaturated fatty acid), which are required by the body to make certain hormones and signaling molecules. Omega 6 PUFAs are "essential" fatty acids - we can't make these signaling molecules without them, and we need them to live. PUFAs are made into HUFAs (highly unsaturated fatty acids - which isn't all that vital to this discussion but I like to say 'HUFA'), and omega 6 PUFAs (in particular linoleic acid) are made into the HUFA arachidonic acid. Arachidonic acid (AA) is the precursor for all sorts of *inflammatory* signaling molecules, including (as an example) COX-1 and COX-2 (which are blocked by ibuprofen and other NSAIDS that decrease pain and inflammation). (Here is a very understandable review of eicosanoids.)

Too much inflammation mediated by a high dietary percentage of the omega 6 fatty acid linoleic acid (the predominant fatty acid in corn oil) can be reasonably associated with coronary vascular disease, insulin resistance, cancer, hypothyroidism and other autoimmune diseases, thrombotic stroke, headaches, asthma, arthritis,(1) melanoma, depression, and psychosis.

But why do I keep harping on "balance" and those omega 3 PUFAs? Well, turns out the omega 3s (wild fish oil is the best source, but it is also available in grass-fed animal fat, other kinds of seafood, flax, and in more balanced levels with omega 6 in walnuts and macadamia nuts) compete in the body with the omega 6s in every which way. Omega 3s are precursors for anti-inflammatory signal molecules (which, obviously, counteract the inflammatory signal molecules). We can only store so much of either, so if we eat omega 3, we displace some of the omega 6 from our systems. Supplementing with omega 3 fatty acids has been shown to be beneficial in a number of major diseases (2). Again, we need both to survive, but if we max out on the omega 6 without any omega 3, we end up with a highly inflammatory soup of chemicals stored and floating around in our bodies predisposing us to that list again - cancer, diabetes, obesity, depression, heart disease, and autoimmune diseases.

Here are some numbers from Food and Western Disease about ratios of of omega 6 to omega 3 fatty acids in different populations (from page 46):

Omega 6/ Omega 3 ratio
Coastal fishing populations: <1
Hunter-gatherers: 2-3
Greece in the 1900s: 2
Japan today: 4
Northern Europe today: 15
USA today: 17

And here's the real kicker about the modern diet - first we load ourselves up with vegetable oils to create a large reservoir of pro-inflammatory molecules, and then add a soup of what are thought to be highly allergenic and pro-inflammatory proteins (gluten, gliadin, beta casein A1, proteins from peanuts and similar proteins from genetically modified soy, etc. etc.). Our modern diseases can almost always be linked back to inflammation of some kind. In my mind, this combination explains why my schedule is full every day.

How can you eat less omega 6 and more omega 3? One way is to eat more paleo. Get rid of the processed food. Use olive oil and vinegar instead of supermarket salad dressing. Balance out nuts (relatively high in omega 6 too) with some fish oil from wild caught fish. Poultry fat is relatively higher in omega 6, so eat grass fed beef and wild caught fish in a nice balance with your chicken and turkey.

And here's where I really part ways with the Grand Poohbahs of nutritional recommendations - you can eat more saturated fat. (Really. It won't kill you.) Instead of baking with industrial seed oils, use butter or coconut oil. They are neutral players in the omega 3 omega 6 fat war, and plenty of healthy cultures eat a reasonable or even high amount of saturated fat (the Masai, the Kitavans, the Tokelau) and they don't drop dead of heart attacks at age 50. Or 75. Pastured butter, bone marrow, and other yummy, more traditional treats are high in saturated fats are also the best sources of some vitamins we need but just don't get in our modern diet. But more on that later.

See, here's what has happened with the nutritional recommendations over the years. First we were told not to eat saturated fat and foods high in cholesterol. It was figured out almost immediately that foods high in cholesterol (such as eggs) don't cause heart disease or even elevated cholesterol in humans, but that was deemed confusing, so the message changed to don't eat saturated fat. At first everyone was moved over to the PUFAs - vegetable oils, including all that deadly trans fat margarine, but then it was discovered that PUFAs cause cancer and trans fats are horrible, so the message switched to 'eat low fat!' We're fairly restricted in the amount of protein we can eat anyway, so a low fat diet is therefore very high in carbohydrates (our particularly vicious mix of sugar and wheat). Then everyone following this advice got REALLY fat and diabetes incidence exploded. So THEN there was more backpedaling, and the message has changed to "healthy fats" (the omega 3s and olive oil), and "whole grains" (which when eaten without careful preparation as we eat them now *may* contribute to the problem) of a Mediterranean diet. (Though a true Mediterranean diet has plenty of saturated fat too. Cheese. Butter. France. Synonymous.) And consider that most of the disease states I'm looking at require two hits from the diet to make them happen - for example, wheat lectins to open the gut, and casein protein in the blood to predispose beta cells to autoimmune destruction in type one diabetes.

But one can see that all these nutritional recommendations backflip over themselves to catch up with science, and everyone is confused, sick, fat, and unhappy. But one doesn't need to stress over food, or make food the enemy. All one has to do is to go to a basic, default paleo style diet and then add in more modern foods (such as dairy) based on observations from other cultures (like the Masai) who ate them and don't have the diseases of modern civilization. All the work has already been done for us! We just have to pay attention.

Read More..