Zinc, Depression, and Everything

Today I will review more specific and up-to-date information about the interplay between zinc and depressive disorders and inflammation. Let's summarize the human evidence thus far (1):

1) Depressed patients in studies have a lower serum zinc level than normal controls.
2) The more depressed the patients are, the lower the zinc level.
3) Low zinc levels in pregnant women are associated with pre- and postpartum depression.
4) Treatment with antidepressants normalizes zinc levels (I've been a little loose with the terminology, I admit, and this finding helps us keep in mind that zinc level can be just a biomarker for depression, not necessarily a cause or effect per se.)
5) Zinc supplementation plus antidepressant therapy can work better for depression than antidepressants alone.
6) Zinc supplementation alone can have antidepressant effects.

Now let's try to clarify a bit more about zinc and the brain. As I noted in my last post, the hippocampus seems to be the most vulnerable to zinc deficiency. The hippocampus is a center of memory, and it also plays a big role in nerve plasticity and repair. Recall that nitric oxide and antidepressants seem to work by increasing the production of brain derived neurotrophic factor in the hippocampus. BDNF is one of many nerve growth factors in the hippocampus, and is part of several different neurochemical pathways which help in nerve recovery, adaptation, and repair.

Scientists have been able to cobble together the following pathway in rat brains: Zinc deficiency leads to decreased zinc in the synapse, which results in an increase in the NMDA receptors (these receptors respond to glutamate, an excitatory neurotransmitter that can be responsible for toxic effects in the brain if there is too much). At the same time, the inhibitory (in this case, neuroprotective) neurotransmitter GABA is decreased, along with BDNF and another nerve growth factor, NGF. The glutamate level in the synapse is higher, so calcium mediated stimulation of the nerves is primed. Do this too much, and you get "excitotoxicity." This same mechanism is thought (in acute vs chronic and in differing areas of the brain) to be responsible for seizures, migraines, dementia, anxiety, depression, and bipolar disorder (and is why pharmaceutical GABA receptor modulators can be effective for certain symptoms of any of those conditions).

Getting down to the real nitty-gritty, Zinc works in conjunction with nearly all of the different membrane signaling and second messenger systems you might have learned about in molecular biology classes. Membrane gated ion channels, p53 signaling, g-proteins, zinc-fingers (obviously) - the whole lot. This is why even though a lot of these different nerve chemicals work via different mechanisms, or multiple mechanisms, zinc can have a hand in all of these up regulating and down regulating events. Zinc is a cog in the machine all along the way.

So there are clear mechanisms by which absolute zinc deficiency can have a hand in all sorts of bad brain syndromes, and vegetarians, dieters, the elderly, those with malabsorption or intestinal issues, and the two billion people on the planet who (due to poverty) pretty much subsist on grains alone (rich in zinc-binding phytates) are all at risk for absolute zinc deficiency.

But robust presumably zinc-replete meat-eaters of a Western diet are at risk for depression, diabetes, dementia, and cardiovascular disease along with the whole diaspora of the Western chronic diseases. I contend (along with many others) that inflammation is the primary driving mechanism behind the whole shebang. Could there be a mechanism by which inflammation could affect brain zinc levels (or vice versa) as a part of the pathway leading from inflammation to bad brain disease?

Wanna put some money on it? Did I mention that pancreatic beta cells in particular run on a lot of zinc-dependent pathways too (2)(3)?

It's common knowledge that zinc supplementation can help ameliorate a cold (at least if you take the zinc within the first day of symptoms (4)), and, as I mentioned in the last post, zinc has a lot to do with mediating our body's immune response. We use zinc to activate the immune pathways that zap viruses (like colds), but zinc can influence the activity of 2000 (yeah, two thousand) different immune transcription factors. The baddest of these factors is NFkappaB. NFkappaB hangs around in the nucleus of immune cells and helps them make all sorts of inflammatory cytokines to fight off the perceived bad guys - good old inflammatory frenemies such as IL-6, IL-2, TNFalpha and many, many more. (Yesterday I noted that zinc deficiency is associated with increased IL-6, and on review of several articles, it seems that high and low zinc is associated high IL-6. It is probably a part of what I discuss in the next paragraph, but I'll look into it more, as a lot of the work is done by the Polish group or Maes, and they seem to cite each other all the time). Zinc not only directly promotes the synthesis of NFkappaB, it helps it get into the nucleus where it can work, and it helps it bind to the DNA to promote inflammation.

It isn't so simple as that. Turns out that zinc also has a hand in down regulating inflammation too! It even activates a protein that helps inactivate NFkappaB. And IL-6, an inflammatory cytokine which needs zinc the be born, will then activate a protein in the liver called metallothionein, a protein that holds on to zinc and keeps it in the liver, so that even if you eat a lot of zinc, it won't be available in your blood or brain for other uses. A lot of biochemical systems are like this - too little zinc (such as in people born without the ability to absorb it (5) and you get immune dysfuntion and vulnerability to infection, as your protective inflammatory response won't work. But if inflammation gets high enough, it has its own down regulating systems (sequestering zinc via IL-6 and metallothionein, for example) that cool things off.

Our inflammatory and fight or flight systems were built for acute insults. Viruses, injury, bacterial invasion, angry lion attacking the camp. When the insults are chronic (unalleviated stress, gallons of inflammatory-promoting omega-6 fatty acids, weird glutens and lectins, chronic depression-causing viral infections such as herpes, borna disease, HIV, or Epstein Barr), the whole system becomes dysregulated. What should be up is down. So zinc ought to be in the central nervous system, helping out with nerve repair and plasticity, and instead it is crusading with NFkappaB or stuck with metallothionein in the liver, and your poor hippocampus is shorting out on glutamate and calcium. Extra zinc might help. As might antidepressants, GABA receptor modulators, and other neuroprotective chemicals. But those are bailing buckets. What we really need is to correct the problem causing the boat to sink. We need to reduce the inflammatory insults in the first place.

There's more. Always more!

Zinc!

When one makes a study of evolutionary medicine-type issues (that is, all chronic Western disease mediated by inflammation and diet and lifestyle so far removed from the life our bodies were designed for), the same nutrients keep popping up again and again. Fish oil is a good example. Yes, for heaven's sakes. I'm taking my fish oil. Shut up about it already.

When examining the small unexplored niche of nutritional evolutionary psychiatry, however, another trace mineral nutrient keeps bobbing to the top. This warrants a post, of course (or two, or three). Yup, no surprises here - I'm talking about zinc.

Let's start with the basics. This first bit of info comes from a rather abruptly titled "Zinc and depression. An update." from Poland in 2005. No cutesy titles in Poland! They get down to business. Good. I'm from Texas. I prefer cute yet vaguely threatening, myself (i.e. "Don't mess with Texas" as an anti-littering campaign - Also, driving out in the hill country, a large sign with scarecrow: "No trespassing. We don't call 911.") Gulp.

Zinc is a trace mineral (like magnesium, iodine, selenium, et al) that is essential for our continued life. Turns out that 300 or more enzymes in our bodies use zinc as a buddy to help them do their thing. DNA replication, protein synthesis, cell division - basic, mondo important, reliant on the presence of zinc. And guess what - the highest amount of zinc in our bodies is found in the brain - specifically in our hippocampus and cerebral cortex. Zinc deficiency can therefore lead to all sorts of unlovely consequences, such as ADHD, depression, alterations in behavior, learning, mental function, and seizures.

Turns out scientists of yore did all sorts of horrible tests on rats to figure out how zinc might be related to depression. Antidepressants seem to increase the ability of zinc to work as an anti-inflammatory agent in rat brains, zinc alone seems to be an antidepressant for rats, and the combination of zinc + small amounts of different classes of antidepressants (TCAs and SSRIs) enhanced the ability of the antidepressants to do their thing (helping the rats swim longer in hopeless situations, for example, or endure being held by their tails. Is reality TV really any different?).

Zinc therapy in rats also increases the amount of BDNF in rat hippocampi. Readers of the archives will note I am a big fan of BDNF in the hippocampus. And zinc reduced the fighting behavior of rats (and prisoners) too!

Yes, humans. Turns out Maes (my new hero - churned out a 62 page article on inflammation and depression this year, which I now have in my hot little hands!) discovered that zinc is low in the serum of humans with depression. Also, that low zinc seems to affect inflammation and immunity. Our T-cells (members of the immune system who hunt and kill infection) don't work well without zinc, and seem to release more inflammatory cytokines (IL-6 and IL-1) with low levels of zinc. Also, one of zinc's special actions is to inhibit the NMDA receptor in the brain. In suicide victims, there seems to be an alteration of zinc's ability to affect the NMDA receptor. (Turns out, BDNF + zinc helps calm down the NMDA receptor, leading to antidepressant effects.) Can zinc supplementation have antidepressant effects in humans? You may not be surprised at this point that the answer is yes (1).

There is more, much, much more to the story of zinc and psychopathology, but for now, let's end with good sources of zinc in our diets. Not surprisingly, the best sources of zinc are protein-rich meats, such as beef, pork, lamb, shellfish (especially oysters), chicken, turkey, etc. Pumpkin seeds are also a good non-meat source, and while grains have zinc, the absorption is strongly affected by the phytic acid in grains (2). Vitamin C, E, and B6 help you absorb zinc also. Seems that people with intestinal problems (celiac disease, inflammatory bowel), vegetarians, those with chronic kidney and liver diseases, alcoholics, and the elderly are most likely to suffer from zinc deficiency (3). Intake of more than 50mg a day (both from diet and from supplements) can lead to improper copper metabolism, altered iron function, reduction of HDL and reduced immune function.

More on zinc to come!

A Closer Look at Tartrazine

Tartrazine, also known as Yellow #5, is a coal-tar derivative azo dye found in a lot of processed food, including Kraft Macaroni and Cheese, Doritos, Mountain Dew, Peeps, and many soups, custards, mustards, baked goods, cotton candy, ice cream and tons and tons more. It's also in a million and one other products we may use on a daily basis - lotions, face soaps (including the one I used this morning), body soaps (including the one I used this morning!), cosmetics, shampoos, hand stamps - you name it! Despite this multimodal ingestion and cutaneous exposure, only a very small amount of the dye is used in each product, so total exposure might be around 1 teaspoon in a year (from wikipedia, so take that number with a grain of salt) (The CSPI site says around 12.75mg a day on average based on usage data - but probably more for kids and those who live on Mountain Dew). There's no reason, though, to freak out and empty out the pantry and medicine cabinet. Dose is important. But, as we well know, some of us can bathe in toxic substances and come out smelling like a rose, and others are sensitive to very small amounts.

The reason I'm looking at it more closely today is because if you hunt around the internet searching for possible creepy things about industrial food dyes, tartrazine has the worst reputation. And, indeed, it was one of the several dyes used in the Southampton Study I discussed earlier this week - and the whole study cocktail of dye and preservative did lead to increased hyperactivity in kids. Its use as a food additive is subject to a ban in the UK and voluntary bans in other European countries, like Norway. In fact, the Center for Science in the Public Interest in the US called for the FDA to ban Yellow Number 5 on June 30, 2010. (Here's a cute PDF from CSPI - Food Dyes, a Rainbow of Risk.)

But how might tartrazine cause problems? Well, some people (around 1/10,000, more or less) are definitely allergic to it. Hives, purpura, anaphylaxis, the real deal. This is why the FDA declared that it has to be on the labels of food if it is used - for people with hypersensitivity, and you can run afoul of the FDA if you include tartrazine in your product and don't label it (1). Not unusual - lots of natural and manmade chemicals cause allergic reactions in some people. It would be an unfortunate allergy to have, as yellow number 5 is in all sorts of things you wouldn't expect. Also, there seems to be a cross-reactivity in some people with asthma between tartrazine and aspirin - people with asthma caused by aspirin also seem to have asthma caused by tartrazine (2), and using desensitization techniques (gradual increasing exposure) to reduce aspirin sensitivity in one case study protected against the effects of tartrazine too. (3). Hmmm.

What about other actions of tartrazine? I couldn't find much. One study showed that application of small amounts of tartrazine caused contraction of intestinal muscle cells in guinea pigs, and the effect was blocked by atropine. That clues us in that tartrazine seems to be able to activate the parasympathetic nervous system, either directly or indirectly, via the muscarinic receptor (4). Now that is quite interesting, as the central nervous system has lots of muscarinic receptors of all types known (M1-M5). Various activating agents of these receptors can cause things such as confusion, convulsions, restlessness, and psychosis - in high enough doses. At lower doses they can sometimes do the opposite, and cholinesterase inhibitors (which increase the CNS activity of acetylcholine, a muscarinic activator) are used to treat dementia. We've taken several big leaps at this point, but it is theoretically possible that if tartrazine gets into the central nervous system, this muscarinic receptor activation might be a mechanism for some sort of psychiatric reaction (like increasing hyperactivity).

The most intriguing information comes from this study from 1990 about how tartrazine influences the zinc status of hyperactive children. Now I'm still trying to get my hands on the full text - institutional access website is being coy the last few days, and it seems this journal is only available online from 1995 on anyway. But the abstract is telling. 20 hyperactive boys and 20 "aged matched controls" were tested for zinc levels in their saliva, urine, 24 hour urine, scalp hair, fingernails, and blood. The hyperactive kids had decreased zinc everywhere but the saliva. Then 10 control kids and 10 hyperactive kids were given a tartrazine-containing drink. In the hyperactive kids, the blood levels of zinc went down and the urine levels of zinc went up, and their behavior got worse, suggesting that tartrazine caused them to pee out some much-needed zinc. It's a bit hard to tell from the abstract, but the way I read it, it looks like the control kids zinc levels didn't change, and neither did their behavior. So that might be the mechanism by which yellow number five influences hyperactivity in certain kids. Ironically enough, Concerta, a formulation of Ritalin, has yellow number 5 as a colorant in the capsule!

The only other dirt I found on yellow number five is that it was implicated also in reducing the absorption or metabolism of vitamin B6, leading to carpal tunnel syndrome, of all things (at least according to Dr. Murray). (Here's the link between B6 deficiency and carpal tunnel, anyway). The rumor that the yellow number 5 in Mountain Dew causes your testicles to shrink? Well, that's not true.

My stance is - for most kids there is no need to make a big scene at a birthday party by grabbing the bag of rainbow candy out of your kid's hand. But on a day to day basis, processed food should be avoided in favor of whole, real food anyway. Doing that will reduce exposure to the rainbow soup of chemicals in processed food. Not to mention the mountains of fructose, trans fats, and genetically modified ingredients. Real food is a win/win. Weirded out by yellow number 5 in shampoos and soap? Check the labels if it bothers you. Or use baking soda and apple cider vinegar as cheap alternatives to shampoo and conditioner.

Vegetarianism and Eating Disorders

A study from the Journal of the American Dietetic Association hit the press in April of 2009 with a rather provocative association - young adult and adolescent vegetarians have an increased risk of eating disorders.

Let's examine the data for a moment. 2516 participants from Minnesota schools (in 1999 and 2004) aged 15-18 and 19-23 answered questionnaires regarding food, exercise, weight, binge eating behaviors, dieting behaviors, demographics, and substance abuse. A huge cohort was originally recruited in ethnically diverse high schools, but many of them (around 50-60%, depending on the cohort) were lost to follow up. The "EAT-II" sample (of 2516 participants) who answered both surveys were more likely to be female and were less ethnically diverse than the overall study sample, which is important to know, as the EAT-II folks were used for the article I'm reviewing here.

Of the 2516 folks, about 15% labeled themselves as current or former vegetarians, but very few were vegan, as 95% of them consumed milk products, 87% consumed eggs, 46% consumed fish, and 25% consumed chicken. Most were vegetarian because they wanted a more healthful diet, and a slightly lesser percentage didn't want to kill animals, didn't like meat, wanted to help the environment, to lose or maintain weight, or were vegetarian for family or religious reasons. In the older cohort, vegetarians were thinner (not true of the younger ones), and all of the vegetarians tended to eat more fruits and vegetables and ate less fat than non-vegetarians. Overall exercise patterns were about the same between vegetarians and non-vegetarians, and younger vegetarians were less likely to drink or smoke cigarettes, but more likely to use "non-marijuana" drugs than non-vegetarians.

Here's where it gets interesting - vegetarians were more likely to engage in "extreme unhealthful weight control behaviors" (p<0.005) and "binge eating with loss of control" than the nonvegetarians (p<0.001). The extreme weight control behaviors included use of vomiting, diet pills, laxatives, and diuretics, and approximately 1 in 4 current adolescent and young adult vegetarians admitted to using one or more of those methods to lose weight. Only 1 in 10 of never-vegetarians admitted the same. So what comes first - the decreased consumption of chicken or the semi-avoidance of eggs? Well, this article (or the abstract anyway - the original article is in Hebrew!) suggests that vegetarianism precedes eating disorders, though if one talks to patients with eating disorders, many will explain that they told people they were vegetarians so they could avoid eating in social situations.

The authors of the 2009 study, in an editorial in the same issue, expressed their belief that vegetarianism did not cause eating disorders, but could be used as a marker by concerned parents and health care practitioners to be more suspicious of an eating disorder in a young adult or teenager who is vegetarian. Lierre Keith (not surprisingly) has a different view in her book, The Vegetarian Myth: Food, Justice, and Sustainability (p230-4) Nutrition therapists at eating disorder clinics in in Indiana, Boston, and Los Angeles reported that between 30-50% of their patients were vegetarian. Julia Ross, a nutrition writer, thought the reason might be due to lower amounts of tryptophan in a vegetarian diet (1). Recall that tryptophan is the precursor to serotonin, so that without enough of it, we are vulnerable to anger, anxiety, depression, and addictive behaviors. Zinc is a mineral tough to come by in a vegetarian diet (it is found mostly in egg yolks and red meat), and zinc deficiency is known to cause depression, obsessive and compulsive behavior, and eating disordered behavior. Supplementation with zinc is a known and extremely helpful treatment for anorexia nervosa, helping sufferers regain weight faster than those without the supplement (2). Binging and vomiting can trigger an endorphin rush, which can temporarily mask anxiety and depression (bulimics given an opiate blocker, naltrexone, report symptoms of opiate withdrawal, according to Ross). Fasting and extreme dieting lower other vitamins, like thiamine, which can cause loss of appetite, making it easier to fast, on and on and on.

Lierre Kieth has her axe to grind, but I do think her book is an important counterpoint to the milder view (and worth a read for vegetarians and meat-eaters alike). Julia Ross' theories and her clinical experience are also intriguing. Vegetarians tend to be healthier and thinner than those who eat a standard American diet (which I'll say is not saying much), but there may be a hidden cost, and when a young person is a vegetarian, it seems that one should be somewhat suspicious that there is a darker reason than not wanting to kill animals.