New Study on Vitamin D and Depression

Quite a bit of feedback on my rant from yesterday.  In truth I would probably keep these rants to myself, except I keep getting asked about what I think about certain matters, so I'm assuming there is wider interest in these opinions.  The rants garner big audiences, for what it is worth.  If you don't like them but enjoy the more sciencey stuff, you can stick to my Psychology Today blog, as I doubt the rants will get cross-posted over there.

To answer and clarify some general questions from the comments: (Sleeper Agent Get Burned)

I'm not expecting to rain on anyone's parade.  There is an inevitable pull to the side of quasi-scientific posturing in the paleosphere.  Sometimes I just like to yank back.  The even-tempered bloggers (Paul Jaminet and Stephan Guyenet) have large blogrolls.  I do not.  Like Kurt Harris, I'm a bit more on the cranky side, and I consider my blogroll to be something of an endorsement, meaning I often find valuable information and interesting ideas on those blogs without a huge amount of garbage.  Of course nearly all of those on the blogroll have published something I vehemently disagreed with.  That's pretty cool, of course.  Differing opinions open the mind.  When it goes too far into the land of obvious pseudoscience and woo or dangerous advice or the endorsement of that, it is no longer my cup of tea, and I drop the blog.  I've dropped several blogs in the past but I just haven't mentioned it.  Sometimes, though, not mentioning or pointing out something is taken as tacit approval.

As to Gary Taubes' petition, I merely have a problem with the very specific nature of the treatise. He basically asks us to sign a petition endorsing his particular theory of obesity, which involves insulin and the adipose tissue as the main regulating mechanism.  It should be obvious to anyone reading my blog that I don't agree with that theory and feel it has been disproven.  That doesn't mean I don't think insulin is involved, or that low carb diets aren't helpful, or that I'm eating a 90% carb diet of unsalted potatoes.  I just wish Gary had been a tad less specific - more of a "let's study low carb diets and not be afraid of fat" petition, and "let's not give up on obesity just because most people fail at diets."  I'm 100% in favor of not giving up on obesity.

As to supplements, I take some myself and have written extensively about them.  However, I don't think they are the be-all, cure-all, and used pharmacologically, a risk-benefit analysis ought to be taken, though the full data will never be known.  In addition, supplements won't cure a crappy diet, crappy sleep hygiene, and complete other lack of self-care or stress reduction.  I like Stumptuous' rant for that reason.  It's a step back.  Let's evaluate as best we can the safety and efficacy, and more often than not the shiny new supplement with the promising data becomes the harmful supplement when more data is gathered.   The same is true for prescription pharmaceuticals.

Speaking of supplements, vitamin D is a tricky one.  It was the paleosphere darling for a while.  The unheralded sunshine vitamin the dermatologists wanted to take from us with their creams and sun hats.  And while getting a certain amount of D to keep from being deficient is clearly helpful, and it seems there is decent data to show that "deficient" for the IOM may be too low when one considers cancer data and being prudent,  it is also clearly problematic to go for the gold and have the highest vitamin D level around (not that anyone recommends that).  In the past year or so, the promising pro-Vitamin D papers have been followed by some disappointing findings.  Some very thoughtful editorials have been written in JAMA and Nature on the subject (not even by dermatologists).

I've posted on vitamin D and depression before (here and here).  It seemed very promising when I read the articles at the Vitamin D Council.  But when I looked up the actual scientific studies, there wasn't much at all.  I could honestly pull together a sober recommendation that there are plausible reasons to think D levels would effect mood, and since it also plausibly could prevent cancer and help bones, seems reasonable to stay in a nice healthy range.

But of course, I keep an eye out.  And this week on twitter a new paper came to my attention from my own alma mater (1).  This paper is a population study of vitamin D levels and depression scores.  5 previous population studies have been done, with 3 showing correlations between low levels and depression, and two showing no correlation.

As I've explained before, the brain needs vitamin D for neuronal repair.  As depressive disorders can be progressively neurodegenerative, in a similar way but with far less global neuron damage as dementia, it is very plausible that low vitamin D levels could hasten or worsen an existing depression, or perhaps even cause depressive symptoms.  Indeed, low levels of vitamin D have been associated with increased inflammatory markers, and inflammation is associated with depression.

The current study is the largest population-based study to date, of 12,600 some odd relatively healthy patients at the Cooper Clinic in sunny Dallas, Texas between 2006 and 2010.  The sample was 68% men with a mean age of 52.  All participants had baseline 25 (OH) vitamin D (actually D2+D3, though D2 levels are typically negligible in my experience unless someone is taking a prescribed D2 supplement) and had level of depression tested with a standard 10 item questionnaire.

Patients with a history of depression were analyzed separately.  There were significantly more women in that group, as well as a significantly higher number of people with history of diabetes, cardiovascular disease, and cancer.  Those with a history of depression had a lower education level, were less likely to exercise, and had a higher BMI.  Age, smoking history, and vitamin D levels were not significantly different in the patients with a history of depression compared to those without.

Among these 12,600 folks, low vitamin D (less than 20 ng/ml) was very common - 50.7% of the sample was affected.  Those who exercised regularly were much more likely to have normal vitamin D levels than those who did not.  Those with high levels of vitamin D were significantly less likely to have current depression symptoms than those who had deficient vitamin D.  The effect was stronger in the group with prior history of depression, and was also stronger in October to March than in the sunnier times of the year.

The study was limited by the observational nature and the relatively brief screening tool used to diagnose depressive symptoms.  But the findings are interesting, and certainly it is still reasonable not to be deficient in Vitamin D, whether you are depressed or not.

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The Glorious Cause

Evolutionary medicine is important.  A common sense, evolutionary based approach to general preventative health care and diet advice  could possibly prevent your obese, demented and expensive nursing-home future, change the debt burden, create a healthy, productive, and prosperous individual subset amongst the oppressive planetary burden of 7 billion agricultural-dependent humans.

The stakes are high.  The adversaries (conventional wisdom and conventional commodities) well-funded and more or less articulate.  The doctors in the trenches are gun shy but pressured to adhere to "evidence-based medicine."  And by pressured, I mean, will be sued or not meet some evidenced-based "standard care marker" (such as a certain percentage of folks with high cholesterol taking statins) and will make less $$ if they don't adhere to "standard of care."  By gun-shy, I mean they were excited by vitamin E.   They were excited by B vitamins lowering homocysteine.  Then it turns out that vitamin E made everything worse.  Lowering homocysteine didn't prevent heart problems.  Chromium maybe hurts the liver.  The glorious Stumptuous put it best in her blog post - "F%^$ supplements."

If you think you will make your primary care physician happy by showing up with a list of non-standard labs to be checked and some half-baked theories as to why they are important, you are going to be disappointed.

Music:  Never Miss A Beat by the Kaiser Chiefs (right click in new tab, sorry about the ads!)

Doctors are conservative because we have to be conservative.  We are the last bastion of sense against shark cartilage injections and calcium as the cure for everything.  If you want to shoot across the bow of conventional wisdom, you need some hard core rigorous evidence and medicine.

Gary Taubes sent me (and many, many others) an email for a petition in support of insulin and hormonal fat regulation at the level of the adipocyte being the cause of obesity.  He wrote the petition in repsonse to Tara Pope's article about the difficulties maintaining fat loss after an initial bout of obesity.

Gary, I'm all for eating well as a long-term cure for obesity, but I'm not going to sign something blaming insulin alone. I can't do it.  There's too much evidence against it.   And I'm not sure I buy the "lean mass protection" gig Paul Jaminet endorses.  Why so many thin people with vitamin deficiencies, after all?  And I'm not going to sign up for the Harvard School of Public Health omega 6 fest of a food plate, either.  Epidemiology be dammed.  Show me the coronary arteries.  Hard evidence for such a departure from the ancestral norms of low omega 6.

And yes, I removed Perfect Health Diet from the "Of Like Minds" list at the right  (probably temporarily - depends on my mood) after one too many posts praising Dr. Mercola.

I can't do it.  I can't have my blog linking to direct endorsements of frauds.   Paul isn't an MD and is not in clinical practice.  He can give clinical advice on his blog whereas I, as an MD, cannot due to ethical and legal obligations.  He can feel free to consider the fringe of alternative medicine "on the same team" whereas I cannot.  I can't be on the same time as quackery because I am one phone call away from the front lines of the gun-shy primary care doctors.  I think Paul and Shou-Ching are amazing and thoughtful, but they never went through the humbling experience of clinical medicine training.  As many times as we are right, we are wrong.

So when Mat Lalonde gives a talk endorsing real science and hard evidence as a basis for Ancestral Health, I am in complete agreement (more or less).  I understand Andrew's reticence for the general population of folks and bloggers, but those who find "paleo" and have improvement will build it and spread the word on their own amongst their friends.  The real inertia to be lifted is with the primary care doctors and the incentives to keep pumping our processed food and vegetable oils.  No amount of enthusiasm and crappy anti-wheat polemics will change that.  Primary care doctors aren't stupid.  They need good evidence to turn the tide.

Here is the sordid truth - conventional wisdom is not wrong.  It is only skewed in favor of the vested interests. Cardiovascular disease has been dropping with the advent of the vegetable oil.  We have to get people caring about obesity, autoimmune disease, and mental health but the funding is problematic, to say the least.

Once doctors such as myself are linked with the lunatic fringe, we are done for.  Credibility, critical thinking, and scientific evidence are harsh mistresses.  I can have my little mistakes, but if I post anything showing major fallacies of critical thinking, I'm done for.  As it should be.  I'm a Harvard-trained physician, after all.  There are certain expectations, even in my hobby of a blog.

I'll try not to be blinded by science.  I'm not going to praise paleo for the sake of paleo (eat a g$$d%#@^ed banana already, and I don't have time to hunt and kill a boar).

Let's not throw the baby out with the bathwater.  Life is good and only getting better without the processed food, without the seed oils.  Let's protect it, nurture it, and not shove it out into the rocky shoals of the lunatic fringe too soon.

* The Glorious Cause is an excellent history of the American Revolution.  I highly recommend it.

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More on Diet and Dementia

Thanks to Oregon, another diet and dementia study hit the press (or internet-prior-to) last week.  A modest number of seniors were tested for levels of all sorts of vitamins and fatty acids, given cognitive testing, and then some had MRIs as well.  The punch line is that those seniors with the highest levels of B vitamins (B1, B2, B6, B12, and folate) and vitamins C, D, and E had the best scores on cognitive function and some mighty fine lookin' brains.  Those with high omega3 marine fatty acids also did well.  The cohort with high trans fats did poorly.  Exactly what we might expect!  Imagine that.  What we eat might impact the brain after all.

The seniors tested were all white, educated Oregonians who joined an aging cohort study back in 1989.  293 healthy older folks agreed to be poked, prodded, questioned, imaged, and measured until their deaths.  At the time of this study, circa 2006, 104 subjects were left, with an average age of 82, 62% female.  The population was originally chosen to be healthy, and after 16 years those that remained were pretty healthy, with a relatively low amount of comorbid illness such as high blood pressure.  Only 10% were ApoE4 carriers. Only 7% had B12 deficiency (<200 pg/ml) and 25% were 25 (OH) vitamin D deficient (<20 ng/ml) - meaning that as a whole, the population was pretty well stocked up on vitamins.  Eating well is exactly what I would expect from a bunch of older, educated Oregonians.

The weaknesses of the study are the small number and the lack of ethnic or socioeconomic diversity and the observational nature.  The strength is that multiple nutrients were measured via blood tests rather than relying on the more classic (and classically unreliable) food frequency questionnaires (FFQs).  The multiple nutrients were then statistically arranged into certain nutrient patterns - on one hand, this makes it easier to apply the results to real life diets, as people eat food, not isolated nutrients.  On the other hand, this type of statistical manipulation can lend itself to data mining.

With imaging, various memory and cognitive tests, 30 plasma biomarkers and 8 biomarker patterns (for example, the B, C, D, E vitamins, marine omega3s, omega6 + retinol, lutein + HDL, saturated fat, trans fat (mostly linolelaidic acid (18:2omega6t)), carotenoids, etc.) there were quite a lot of associations to be had.  The most interesting are the previously mentioned generally better global findings in the BCDE group and the omega3 group, and the generally worse findings in the trans fat group.  In addition, folks in the lutein-HDL group had better memory, and those in the omega6 + retinol group had poorer memory and language scores.  In adjusting for comorbid factors, age, education, gender, APOE4 status, and other health factors didn't seem to impact these findings that much.  The only major link between health problems and nutrients was a link between hypertension and trans fats and low B vitamins, which makes physiologic sense (remember, lousy B vitamin status leads to high homocysteine, which is likely a cause of hypertension).

Interestingly, if the study subject had depression, the link between omega3 status and white matter density in the brain was lost.  In subjects without depression, there was a significant link between omega3 levels and a healthier white matter density compared to whole brain volume.

So when the researchers broke it all down, they found that age, gender, APOE4 status, education years, hypertension and depression accounted for 46% of the variation in cognitive scores, and the nutrient status was responsible for an additional 17%.  They found nutrient status to account for 37% of the total brain volume and 9% of the white matter density compared to whole brain volume variation.

What, then, would constitute the supposed diet of the healthiest brains?  Dark leafy green and cruciferous vegetables, fruits, and fish were on the good side, bakery foods such as cookies, pies, doughnuts, fried foods, margarine, red meat, and offal were on the "trans fat" side.  (Red meat and offal seemed to be added to this group due to the previous dietary pattern study done in Manhattan implicating offal consumption in worsening cognitive status.  Chris Masterjohn had something to say about that study here.  "When holism goes horribly wrong -- the perils of dietary pattern analysis" will give you a clue as to his thoughts!)  There are, indeed, trans fats in red meat and offal, but they tend to be CLA: the 18:2 isomers implicated in this newest study are the baked goods/margarine variety of trans fats.  As you know, red meat and offal are fantastic sources of B vitamins.

The mechanisms by which the specific nutrients may be helpful or harmful are ones we have discussed many times on this blog.  The B vitamins are necessary for proper functioning of the folate cycle, which has all sorts of downstream effects with relation to neurotransmitters, oxidative stress, inflammation, etc.  I've also discussed vitamin D a number of times, and while I haven't covered much on vitamin E or C, I suppose I should get to that.  Omega3s have also been reviewed at length.

Trans fats, on the other hand, may well replace omega3s in the cell membranes, and are associated with systemic inflammation, cardiovascular disease, and endothelial dysfunction.  All those processes could have an impact on memory, brain structure, and cognition.

To break it down, eat "real food," not cookies and doughnuts.  How hard is that?

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Ring in the New Year

Whew.  A bit of a hiatus there.  I hadn't quite realized how much I had overextended myself until decamping to Texas for some serious sitting around.  There I had all sorts of unrealized ambitious plans to read and get caught up, visit some local Crossfits, answer some emails, etc.  I did very little at all besides the holiday stuff, a handful of morning runs, and reading some fiction.  Since the whole family was recovering from a steady onslaught of viral preschool nastiness that began before Thanksgiving, I sorely needed the rest.  A very mild but persistent case of walking pneumonia had settled in, so it was nice to take it easy and finally get well.

In the midst of the sitting around, I was able to visit two Austin "real food" restaurants, Hudson's on the Bend (where I had rattlesnake cakes - not gluten-free but very tasty, and Hudson's has several gluten-free options) and Foreign and Domestic (steak and pigs brains.  I have to say the brains at Animal were better, but the steak at F&D was fabulous, the yogurt with dill sauce sublime, and the atmosphere quintessential Austin).  I'm told the Noble Pig is also excellent (though it is a sandwich restaurant).

One of Lance Armstrong's yellow jerseys at Hudson's on the Bend

Pig brains and huckleberries

   

Yogurt with dill sauce

Perhaps the most ambitious thing I did all week was to go to the rail yard for the Austin Steam Train Association.  We were able to get a behind the scenes tour, and the kids were thrilled (kids love trains,  as do the adults at the Austin Steam Train Association).   

At this point I have numerous articles and a large stack of books waiting to be read.  I'm hoping that without my class, my schedule will be a bit more forgiving.  You never know what will turn up, however, and the backlog of emails and to-dos--formidable!

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Time to Freak Out. Sensibly.

There is a reason I stick to relatively easily modifiable practices and how they might (possibly!) improve health and prevent disease.  I like fun exercise, real food, wool socks in the wintertime, and sunshine.  I don't like to think about the years of farm pesticide waste seeping into the groundwater, or the estrogenic compounds in plastic.  Plastic compounds are ubiquitous and incredibly convenient.  In all our packaged foods.  Sippy cups.  Tupperware.  IV bags and tubing.  Coating paper receipts.  In the lining of canned foods and soda.  The most famous is BPA (found primarily in receipts and number 7 plastic), but all sorts of plastic contain all sorts of weird compounds.

Image from Flickr Creative Commons

I like to live a relatively processed food and gluten free life - but philosophical ramblings about candy cigarettes aside, I don't dive across the table and grab the birthday cake out of my kid's hand at the party.  (I'm not generally tempted by the birthday cake myself, as it is generally of the grocery-store azol-dye soybean oil frosted variety.  There was an incredible ice cream cake at a recent party that I'll admit to stealing a few bites from).   There's a line between living a somewhat normal life and being completely obsessed and anxiety-ridden about food, and I certainly don't want the kids to be obsessed and anxiety-ridden about food.   Nor would I lie about my kids having celiac or peanut allergies - the last thing I want is a terrified preschool teacher calling me about the goldfish cracker my kid snatched from some other kid's lunch, and should she call an ambulance or what.  Nothing is totally off-limits within reason, though the healthy stuff has to be consumed first, before the leftover Halloween candy.  And yes, they do get gluten-free pretzels as a snack (they are cooked in palm oil).  And sometimes those sugar-bombs otherwise known as raisins.

So we muddle through, minimizing harm, and the way I approach plastics is to slowly transition away from them and avoid heating anything (or putting hot food) in them.  (I try not to think about those years and years of microwaved lean cuisines).  I get milk delivered from a local organic dairy in glass bottles.  Is that enough?  Some (many of you, perhaps) would say no.  But aluminum lunch containers are expensive (and have plastic lids that tend not to fit as closely as plastic on plastic), and many of the plastic ones I have are still serviceable and attractive.  Canned foods are also tricky - on a mostly "paleo" "real foods" "avoiding processed food" diet the major canned foods will be coconut milk and tomato products (maybe canned pumpkin?).  In general I made an effort to avoid these except for maybe once per week, figuring, again, the dose makes the poison, and tomato sauce makes anything more palatable for the kids (a variation of the old parenting trick of putting ketchup on everything.)

Ignorance is bliss, really.  At the end of November a research letter was published in JAMA- "Canned Soup Consumption and Urinary Bisphenol A: A Randomized Crossover Trial." In this little Harvard School of Public Health Study, student and staff volunteers consumed 12 ounces of either fresh (prepared without canned ingredients) or canned (Progresso brand) soup daily for lunch (they were vegetarian varieties of course - this is HSPH!).  For the first 5 day period, the soup was consumed daily.  After a 2-day washout, the treatment assignments were reversed.  Urine samples were taken on the 4th and 5th days of each phase.  Urinary BPA was found in 100% of Progresso consumers and 77% of fresh soup consumers, and following the 5 days of canned soup, urinary BPA was 1221% higher than the urinary BPA of the fresh soup consumers.

"The increase in urinary BPA concentrations following canned soup consumption is likely a transient peak of uncertain duration.  The effect of such intermittent elevations in urinary BPA concentration is unknown.  The absolute urinary BPA concentrations observed following canned soup consumption are among the most extreme reported in a nonoccupational setting."

I have to admit I'd canned (heh heh) Progresso and other pre-prepared soups from my eating list a long time ago due to the biochemistry-happy omega-6 fest in the list of ingredients� as expected from any processed food maker trying to scratch a profit by using the least expensive commodity items.  I try to use marinara sauce from a glass jar whenever possible (we'll ignore the plastic seal around the top), and I'm looking for good convenient alternatives to canned coconut milk� but the pantry still has some canned items, to be sure.  And certainly the cardboard box variety of foods has plastic in the lining as well, right?  I make more and more of my own bone broth, but sometimes you just need a bit of stock on hand.  Am I being hopelessly neurotic and silly worrying about plastics, BPA, and canned items (and handling receipts as little as possible)?

Well, 2011 has not been a friendly year for BPA.  A month before the research letter in JAMA alarmed the Progresso soup executives, another scary article was published in Pediatrics: Impact of Early-Life Bisphenol A Exposure and Executive Function in Children (free full text!).  A prospective observational study, so the typical caveats apply.

Urine was collected from pregnant women at 16 and 26 weeks, and at birth) and later from the resultant babies at 1, 2, and 3 years of age.  The results?  Well, BPA was detected in >97% of the gestational and child urine samples.  With adjustment for confounders, each 10-fold increase in gestational BPA concentrations was associated with more anxious and depressed behavior on standardized scales, along with poorer emotional control.  This was true more of girl babies than of boys.  The urinary levels in the children themselves didn't make much difference in behavior, and there was no difference between girls and boys.

There was another scary article about exposure of infants to breastfeeding moms replete with BPA that I can't find now, and this cute article from January in JAMA about nematodes and BPA.  I avoid gluten (for the most part) due to some skin effects and general creepiness, and I don't see why I should feel differently about estrogenic compounds leaching from plastics.

But no, I don't leap across the table and grab the Capri Sun out of my kid's hand at the birthday party either.  Nor will I add a machete to my list of standard kitchen tools so that I can make coconut milk from scratch.   I drink from a plastic-free water container at the gym and the next set of lunchbox containers will be metal� but life has to be lived.  And at least I can worry about these things affecting my children, rather than tuberculosis, mines, or revolution.

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Evolution and Anorexia Nervosa

There was a bit of a dust-up in the paleo and low carb blogosphere about some comments Gary Taubes apparently made about anorexia and insulin in an interview.  He noted that insulin was used as a therapy for anorexia, thus suggesting that (perhaps) anorexia, like obesity, is a disorder of fat metabolism. My suspicion is that Gary was using those studies as an example of how insulin could cause weight gain.   On the other hand, one doesn't need exogenous insulin to refeed anorexics  - the time-tested method is to keep those far gone enough to have medically dangerous symptoms (unstable blood pressure, dropping electrolytes, or super slow heart rate) under lock and key and get calories in whatever way possible (including via a tube inserted into the stomach.)

One of my attendings in at Children's Hospital characterized anorexia as "a desperate disease."  Often purging and starvation are combined (though this combination would be more correctly called "eating disorder not otherwise specified" or "anorexia nervosa, bingeing-purging subtype" than strict anorexia nervosa), and there were many cases of young teenagers hiding vomit and stool in places in their rooms to conceal purging and to get laxatives (not surprisingly, constipation is a symptom of anorexia).

Cowboy Junkies - Bea's Song (one of the better songs ever written - right click to open in new tab)

My evolutionary psychiatry interest has always been in how psychiatric disorders have changed over the past 100 years of rapidly changing lifestyle and diet.  Anorexia nervosa is one of those illnesses that was exceedingly rare until 50 years ago, then escalated rapidly, then leveled off so far as prevalence, though those who are affected encompass more children and more men now than ever before.  My educated guess is that only a small percentage of us are capable of starving ourselves outright without being under lock and key, and that vulnerable population shows symptoms earlier and earlier in life as societal pressures and the obesogenic environment increases.

A quote from my previous blog post linked above (the medical literature references can be found there):

All eating disorders remain relatively rare [though in total they are more common than schizophrenia and bipolar I disorder]. Anorexia afflicts about 0.5% of women and 0.1% of men. Bulimia around 1-3% of women (also 0.1% of men), and binge eating disorder 3.3% of women and 0.8% of men. Anorexia nervosa remains the most deadly of all psychiatric disorders, with a 5-10% death rate within 10 years of developing the symptoms, and an 18-20% death rate within 20 years. Anorexia is endemic in the fashion industry, to the point where models are now being airbrushed to add curves. Another model, Isabelle Caro, died at age 28 of anorexia, and Ana Reston of Brazil died at age 20, still modeling with a BMI of less than 14.

Photo of Isabelle Caro from Wikipedia

The current state of the art treatment of anorexia begins with refeeding, mostly because we know that semi-starvation itself causes obsessions, depression, and fixation on food.   In the hospital, patients work closely with dietitians, trying to learn how to eat a healthy amount and to establish a better relationship with food.  While medicines that promote weight gain are prescribed, antidepressants and other agents are fairly useless in a starvation situation.

You can imagine the typical well-meaning dietician designed diets for these sick young people.  It's the food pyramid with way too many grains, too little fat, and a focus on "healthy" rather than good old fashioned farm fresh food.  And while I don't really have any objections a food pyramid Mediterranean-style whole foods diet (autoimmune issues with grains notwithstanding), I know that what happens in real life is not skipping breakfast, a light lunch, and a late supper of mussels, olive oil, roasted peppers, tapenade and homemade sourdough bread, but rather three meals and two snacks a day, a version of Weight Watchers� with Skinny Cow ice cream sandwiches, whole grain Rice o Roni, cans of beans, omega-6 laden commercial salad dressing, boneless skinless chicken breasts,  and "lite" yogurt.

The problem with so many meals a day is that one has to think about food constantly.  I don't think that is the best way to recover from an eating disorder, though one would have to be careful with fasting as well.  I believe intermittent fasting is a valuable practice, a way to lower food reward and to ultimately establish a good relationship with food - I don't have to have it right now, but later would probably be fine too - however, fasting can trigger binges in those who are vulnerable.  It is not verboten in those of normal or excess weight, but should be undertaken with care and support.  In my mind, the healthiest diet is one that you don't have to think about all that much - poached eggs, a beef stew with some liver chunks you cook once and eat all week long.  Cold potatoes and butter.  Forgetting to eat every now and again.

M83  Midnight City (right click to open in new tab)

I believe Jamie sent me this recent paper, Role of the evolutionarily conserved starvation response in anorexia nervosa.  It is a fascinating piece, with an in-depth consideration of biology, evolution, and insulin.

The authors speculate that "AN [anorexia nervosa] may be caused by defects in the evolutionarily conserved response to food and nutrient shortage associated with reduced calorie intake."

Some more facts about eating disorders - in 10-20% of patients, the disorder is short-lived.  In 20-30% it is chronic and unremitting.  The most seriously affected are at greatest risk for hypothyroidism, loss of bone density, electrolyte disturbances, low blood cell counts, amenorrhea, suicide, and death.

In anorexia, the physiology of starvation is paramount.  Both brain and peripheral metabolism responses come into play, orchestrated by the brain and the endocrine system (I don't think obesity is far different - I see no reason that obesity would be regulated by fat tissue or the liver when the brain and endocrine system are doing their thing).

The goal of the starvation response is to conserve energy, delay growth, preserve ATP (by increasing efficiency of energy metabolism) and to minimize oxidative damage.  In starvation, changes in the hypothalamus of the brainstem result in a fall in blood insulin levels and a suppression of other anorexogenic factors.  Once ketosis occurs with the depletion of glycogen stores, there is an increase in output from the sympathetic nervous system and stimulation of food-seeking behaviors.  These multiple pathways explain why fasting can be healthy, but also stressful.

One of the major biochemical pathways activated is the IGF-1/FOXO response (an insulin growth factor 1 pathway).  So the authors of this paper postulate something a bit similar to Gary Taubes - anorexia arises when there is defective regulation in the starvation pathway, similar to how insulin deficiency (due to insulin resistance) is a factor in diabetes.  Meaning there is a lot going on with respect to home life, environment, stress, and temperament in eating disorders, but only a select few have the genetic capability to deliberately starve themselves is response to the environment, and those few may have differences in the IGF-1/FOXO pathway.  The researchers were able to find some yeast, fruit flies, worms, and mice with defects in that pathway who tend to restrict food and develop more slowly (or, alternatively, eat more and spontaneously gain weight), and who have genetic differences in the IGF-1/FOXO pathway.

Evidence for genetic vulnerability to anorexia includes the fact that eating disorders are highly heritable. (Uruguayan model Luisel Ramos and her sister both died from anorexia in recent years).   When doing genome-wide linkage analysis of families with eating disorders, many components of the starvation response pathway are located in highly suspect genetic areas.  In practical terms, the increased impetus on thinness and subsequent dieting brings out the reinforcing starvation response as a result of the genetic vulnerability.  A single episode of excessive caloric restriction seems to bring out long-term changes in the neurotransmitter production mediated by FOXO.

Thus caloric restriction and weight loss predispose to additional episodes of dieting, especially in susceptible individuals wih defective regulation of their starvation response, or with perseverative bias in behavior, reflected in obsessive thoughts and compulsivity.

How do these general ideas affect treatment?  Family therapy, distress tolerance, and cognitive behavioral therapy around distorted body image is a cornerstone of therapy for eating disorders, along with the refeeding.

Should we use insulin to treat anorexia?  Well, the reactive hypoglycemia and other risks are problematic.  A more sophisticated approach is to use IGF-1 itself - it can increase appetite and reverse bone loss seen in anorexia.  Long term treatment tends to result in hyperplasia of the lymphatic tissue, tumor promotion, and excess accumulation of body fat.  

Better that we never begin dieting in the first place.  Skipping the processed foods and ensuring there are plenty of healthy fat and nutrients for the brain and muscles seems like the optimal and common sensical approach in that regard.  I'm not sure what to do about the fashion industry...

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Beyond the Chemical Imbalance Part 2

Love the new song from the new album by the Black Keys:  Lonely Boy (from El Camino)   I know this guy's video will get slashed soon enough, but for now� enjoy!  The Black Keys said Lonely Boy is a departure from their typical style, as it is up-tempo.  I wish they would do more like this one!

Are you peppy yet?  You ought to be, because we are going to dive back in to this paper (sent to me by Jamie some weeks ago):  Beyond the serotonin hypothesis: Mitochondria, inflammation, and neurodegeneration in major depression and affective spectrum disorders.

There's all this talk about pathogenesis, chickens, and eggs.  Well, I know where it ends.  We chase the trail back to the beginnings (is it abuse?  temperament? soda?  ho-hos?  winter? rancid vegetable oil?  bad reality TV?  the jury is still out).

But here is where it ends.  Ground zero.  Ratty neurons, smoking mitochondria, and brain damage.  Inflammation.

Inflammation is the term for the complex biological response of tissues to harmful stimuli, such as pathogens, damages cells, or irritants.  Inflammation is a protective attempt by the organism to remove the injurious stimuli as well as initiate the healing process for the tissue.

I knew there was a reason I liked this paper so much.  Two sentences of real wisdom.   The paper continues on to talk about cell death, mitochondria, and the cell "executioners" called capases.  They are cysteine proteases that bring it when a cell needs offing.  These are the cellular equivalent of the Necro-whatevers from Chronicles of Riddick.   Overproduction of reactive oxygen species by shoddy, inefficiently-acting mitochondria is a central feature of neuron cell death.   The tricky wicket is that mitochondrial dysfunction and cell death leads to more inflammation, dysfunction, and cell death.

The presence of an inflammatory response in major depression� is evidenced by, amongst other things, increased plasma levels of pro-inflammatory cytokines and acute phase reactants, oxidative damage to red blood cell membranes and serum phospholipids, and lowered serum zinc.

Pro-inflammatory cytokines can induce depression in 70% of people treated with such agents.  Elevations of cytokines have been reported in depression, anxiety, fibromyalgia, migraines, IBS, chronic fatigue syndrome, diabetes, autoimmune arthritis� of course, says any doctor.  The so-called "mitochondrial cocktail" can improve mitochondrial function after a few months and includes the following:  CoQ10, riboflavin, and at least one additional antioxidant (vit C, E, or alpha lipoic acid), and l-carnitine or creatine.

Older school psychopharmacologists will try the following:

Tricyclic antidepressants - they act as classical mitochondrial decouplers by hindering ATP synthesis and enhance ATPase activity.  They tend to change how mitochondria function in a neuroprotective way.

SSRIs: some seem to be toxic to mitochondria at large doses, but protective at lower doses.  In animal models, all antidepressants attenuate inflammation-induced brain cytokine production and prevent the development of depression induced by high dose interferon.  In fact, antidepressants seem to have this effect regardless of mechanism (SSRI, tricyclic, lithium) - which is a major argument against the monoamine theory of depression.

Lithium: seems to enhance mitochondrial function in humans and rats.  Long-term is even better than short-term.  Lithium is the favored medicine of the gray-haired psychopharmacologist.  Between the neuroprotective effects and the anti-suicide benefit, you might expect people to encourage lithium to be in the water�

Shock therapy:  Yes, it is still around.  Frankly, there is no faster treatment for depression and it works in refractory cases, thus is often a lifesaver.  It has terrible side effects, there's no denying it.  And it seems to increase the mitochondrial efficiency in rats.

Up to 50% of patients with major depression are unresponsive to medications� here is a poem from old Egyptian papyrus (from the anchor paper)

Disease has sneaked into me.  I feel my limbs heavy.  I no longer know my own body.  Should the master physician come to me� My heart is not revived by his medicines. 

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