Evolutionary Psychiatry

The Treatment of Depression with T3

2012-02-12T16:52:00.000-05:00

Psychiatry is one of the few specialties where we are "allowed" to use T3 (the active thyroid hormone, instead of the safer prohormone T4) for treatment of resistant depression. (Please see yesterday's post for a thyroid primer). The literature for its use is extensive but old. Much of it was done before there were very reliable lab tests for thryoid function, so symptoms such as pulse, insomnia, anxiety, palpitations and reflexes were measured to judge whether someone was made "hyperthyroid" with the treatment or not. I suppose that made them bolder, back in the day (also, there were very few options, medication-speaking, so all the people studying resistant depression did a little study on T3. For the same reason there is a ton of data on lithium for bipolar disorder. It was the only game in town for decades.)

In any event, I thought I would take the opportunity to catch up on the latest and greatest in T3 supplementation and safety issues, particularly since the very large STAR-D trial used T3 and found it equally efficacious in resistant depression to lithium use, and better than many other pharmaceutical tinctures. Fortunately there is an up to date review from the Green Journal, T3 Augmentation in Major Depressive Disorder: Safety Considerations. The article had a number of interesting points, particularly with regards to the standard endocrinology method of treating hypothyroidism with T4 monotherapy. I'll get to that in a bit.

All right. So the weakness of most of the studies is that they were short, typically 2-12 weeks. Also, most of them were studies of augmentation or acceleration with the old-fashioned antidepressants, the tricyclics (or TCAs). And when I think of the tricyclics, I think of a cruder but much more medication-stringent time. TCAs have lots of side effects (weight gain, dry mouth, fast heartbeat) and are fatal in overdose. However, they are effective for many, and folks with very serious depression where they were nonfunctional and suicidal who responded to the medicine would take them because being without proved worse than the side effects of being on them. The SSRIs, with fewer (but still not insignificant) side effects had not yet been invented, and mildly depressed women were still being given B12 shots by their primary care doctors, who also advised them to smoke to give them energy and motivation. (Or gave them a tiny bit of dexedrine in the morning and some barbituates at night.)

So we are dealing with a subset of very depressed people who do not respond to the tricyclics. They don't seem to be hypothyroid by physical symptoms or the lab tests of the time, but a certain percentage would respond to augmentation with active thyroid hormone. In addition, "accelerating" the tricyclics (which, like most antidepressants, take several weeks to kick in) with a dose of T3 up front (isolated to 2-4 weeks, then discontinued) seemed to work too. There are fewer studies of augmentation with SSRIs, but these are also short and the results are less definitive.

Why would T3 help? What does T3 do in the central nervous system? Well, a lot. The thyroid has fingers in almost every physiological pie, after all. And T3 not only may act as a direct neurotransmitter, but it also seems to increase the efficiency of serotonin signaling, much like a modern SSRI. T3 also enhances neurogenesis in the central nervous system and could also enhance noradrenergic signaling. The conversion from T4 to T3 occurs all over the body, but in the central nervous system it uses different active genes than in the periphery and occurs within the cells. These differences could explain my own clinical observations--that T3 augmentation seems to work best in folks already diagnosed hypothyroid that are on T4 monotherapy. And the literature (such as it is) seems to support my observation (1).

(I am ignoring selenium and iodine deficiency for the moment as does this literature. Much of North America has fairly selenium-rich soil except some of the Eastern Coastal plain. Given the wide geographic distribution of vegetables and other produce, frank selenium deficiency is rare. Also, with the advent of iodized salt, frank iodine deficiency is also rare so that babies are very rarely born with congenital hypothyroidism. These facts do not mean that our selenium and iodine levels are optimized, but, again, I would say a frank deficiency is rare).

So the good news is that T3 augmentation seems to help some and (relying on some limited longer-term data up to several years) it seems to be relatively safe (particularly in the short term), though post-menopausal women need to watch the possible side effect of osteoporosis, and there is a continued risk of heart arrhythmia. So in heart-healthy and strong-boned folks with a serious bout of depression, a small dose of T3 is a good option, even if they are clinically and by laboratory measure euthyroid (normal thyroid) particularly if they are the type to have serious episodes and then bounce back, rather than the more chronically low-grade depressed people.

The goal for longer-term treatment is to use a dose that keeps TSH at the low end of normal (or even somewhat below normal if there are no hyperthyroid symptoms) and free T3 at the high end of normal (I can tell you that the recommended dose of 25-50mcg almost always seems to overshoot this goal, but it probably reflects the long history of shorter-term studies), while monitoring bone density and cardiac side effects frequently, particularly in post-menopausal women. T3 augmentation does seem to work better in folks with higher TSH and lower free T3s at baseline, suggesting we are, indeed, treating a type of "subclinical hypothyroidism" with depression symptoms, maybe those who convert T4 to T3 just fine in the periphery but who are poor converters in the central nervous system. Again, this would support my clinical observation of long term treatment. Fairly useless in the euthyroid except for temporary severe exacerbations, but useful in the hypothyroid or subclinical hypothyroid.

And what about those endocrinologists who are so very down on combination therapy with T3 and T4 for hypothyroidism? I've had some tell me point blank (over the phone) there is no literature support for treatment of hypothyroidism with anything but T4 monotherapy. I've had to pull out the "psychiatric indication" card and then they will back off, mostly because most folks in medicine are a little scared of psychiatrists and psychiatric patients. There's a little bit of literature of psychiatrists as the last shamans of Western medicine. We don't typically wear the white coats. We treat the unexplained. We exist apart. We may well be witch doctors. In the US, insurance payments regard "mental health" and "medical" as separate entities. But I'm wandering a bit.

Well, what about that literature for combination therapy (T3 and T4) vs monotherapy (T4 alone) for hypothyroidism? Multiple studies and a meta-analysis have proven no benefit for combination therapy over T4 alone. However, in several studies, patients had a preference for combination therapy that could not be explained by lab results or quality of life measurements. In Denmark, one study using double-blind crossover methods treated patients with T3/T4 or T4 alone to equivalent TSH levels. 49% of the patients preferred combination therapy compared to 15% who preferred T4 monotherapy, and quality of life measures and depression and anxiety ratings were generally better on combination therapy than on T4 alone. T4 monotherapy is safer, less likely to result in hyperthyroidism. But to say there is no support for the alternative is incorrect.

From the evolutionary point of view in general a bit of seaweed and some selenium won't hurt. In the case of Hashimoto's one must take care with iodine supplementation lest one worsen the condition (this seems less likely to happen if selenium is topped off). Selenium excess is also a pretty bad idea.

But looking at the more modern basis of hypothyroid and depression treatment, the science behind T4 monotherapy is not yet ironclad. T3 might yet come back from its banishment to psychiatry.

Thyroid and Psychiatric Illness

2012-02-10T12:43:00.000-05:00

The thyroid is one of those glands that is hooked into everything. Mood, cognition, metabolism, bones, heart, cholesterol… all can be affected by perturbations among the thyroid hormones.

Chris Kresser has done a great series of articles and it's worth a look if you are unfamiliar with the thyroid or if you want a comprehensive refresher. In fact he did such a good job it seems hardly worth reinventing the wheel, so I thought I would start with psychiatric disease and then address any questions and chase the rabbit holes that will inevitably open up.

My information today comes from a review done for the American Journal of Psychiatry this month and pointed out to me by my fantastic colleague Dr. Hale: Abnormal Thyroid Function Tests in Psychiatric Patients: A Red Herring? This review is conventional to the extreme, but I find it is often very useful to start with conventional reasoning and pick apart where there may be issues or something missing.

I will begin with the briefest of primers so that we are more or less on the same page:

The Killers, All These Things That I've Done (right click to open in new tab)

All right. As with everything endocrine, there is a feedback loop, but for our purposes we will start with the hypothalamus, which makes a chemical called thyrotropin releasing hormone (TRH). This chemical toodles on down to the anterior pituitary, which produces thyroid stimulating hormone (TSH). TSH then directs the thyroid gland itself to release thyroid hormone. The two major ones are T3 (triiodothyronine) and T4 (thyroxine). High levels of T3 and T4 should feedback to the pituitary and cause it to decrease the amount of TSH secreted, thus nicely regulating itself. The other important thing to know is that iodine is essential for the creation of the thyroid hormones, and that T4 is actually a prohormone (and is the major hormone secreted by the thyroid) while T3 is the active hormone. Selenium is required to turn T4 into T3.

Courtesy Wikipedia Commons

Lots of things can go wrong within this complex system. For example, a nodule in the thyroid can start producing thyroid hormone like gangbusters and won't respond to feedback inhibition. This is hyperthyroidism, with classic lab results of high T3, high T4, and typically undetectable TSH. Symptoms are a racy metabolism, so weight loss, rapid heartbeat, somewhat elevated body temperature, insomnia, anxiety, etc.

In the opposite case, the thyroid can stop responding to the pituitary TSH stimulation and stop producing thyroid hormone. This is known as hypothyroidism, and will result in low T3 and T4 with a very high TSH. Symptoms can include weight gain, fatigue, depression, cold intolerance, hair loss, and slow heart rate among others.

These two primary thyroid disorders can cause a host of psychiatric symptoms, including depression, mania, dementia, and even psychosis. If someone comes to my office with weight gain, cold intolerance, fatigue, and depression, I'd better well check the thyroid and grab a pulse rate while I'm at it. I'd look pretty silly treating hypothyroidism with therapy or antidepressants.

Besides these basic thyroid problems, thyroid hormones can be off kilter in a variety of other ways. Chris Kresser's series goes into great detail, but with rare exceptions, these abnormalities are not due to thyroid problems in the actual gland. Alterations in thyroid function can occur in response to all sorts of systemic illnesses, stress states, and medications, and perturbations in the thyroid function tests not thought to be due to actual hypo or hyperthyroidism is called "nonthyroidal illness." In general, any pattern of tests that don't quite fit the classic hypo/hyperthyroid patterns will indicate a nonthyroidal illness.

Sepsis, heart attack, major surgery, autoimmune disease… all of these can lead to a characteristic pattern of thyroid tests including low T3, normal to low T4, and high reverse T3. TSH is often normal, but can be low and later become elevated during recovery. These abnormalities are extremely common and are seen in about 75% of hospitalized medical patients. The kicker is these abnormalities seem to be a physiologic response to the illness and they resolve without any intervention in a few months. The reason these changes happen is (as always) complicated, but inflammatory cytokines such IL-6, IL-1, and TNF alpha are likely involved, altering feedback regulation along the hypothalamic-pituitary-thyroid axis.

Starvation, fasting, or a very low carb diet can tend to lead to low TSH, normal or slightly elevated free T4, and low T3. There is nothing wrong with the thyroid and this is not "hypothyroidism" per se, but a normal physiologic response to perceived starvation, and it should resolve without other intervention once someone stops fasting or increases carbohydrate intake. Sepsis (severe infection) will often present with low TSH, normal free T4, and low free T3, a similar pattern. Again, once the infection is cleared, the abnormalities will resolve on their own. This "low T3" syndrome is a bad predictor in the case of cardiovascular disease (1), but that doesn't mean that treating with T3 would be smart. There is some reason to suspect that "low T3" may be a maladaptive response and T3 after a heart attack may be a good idea after all (2), but I think the proof will be in future research (3).

As we noted before, primary thyroid problems can cause psychiatric symptoms. However, the reverse is also true, and up to 33% of psychiatric inpatients will have abnormal thyroid tests. As in the case of the medical "nonthyroidal illness," these abnormalities will tend to be characteristic of the disorder and will also resolve on their own within a few months. In acute psychosis, for example, TSH is usually normal while total T4 is often elevated. In mania, total T4 and free T4 will be elevated. In depression, TSH may be a little low or high, with a high free T4 and low or high total T3.

In general, it is recommended that nonthyroidal illness is NOT treated with thyroid hormone. In nonthyroidal illness, the low T3 or other abnormality may be part of the adaptive inflammatory response (I've linked some thoughts about possible exceptions above). This reasoning is why conventional medicine suggests testing TSH alone, and checking other hormone levels only if the TSH is out of whack. Without multiple findings indicative of thyroid problems (a typical hyper or hypothyroid) symptom complex, it is unlikely to be a primary thyroid issue, except in the elderly, who can sometimes show few symptoms. Other folks with a history or family history of autoimmune disease, treatment with lithium, radiation exposure, goiter, etc. are obviously at higher risk for primary thyroid disease and one should have higher suspicion.

"Subclinical hypothyroidism" is a bit of a gray area between true thyroid illness and the nonthyroidal problems. TSH will be high, while free T4 will be low or normal. Usually multiple hypothyroid symptoms will indicate a thyroid problem, while no symptoms will indicate nonthyroidal illness and will resolve on its own, which should show up in serial lab tests over months.

From my perspective as a physician, I tend to rely on the TSH and not aggressively pursue mildly abnormal T4s or T3s, particularly if there are no other symptoms. However, I think low grade iodine and selenium deficiencies are rarely thought of by a conventional physician and may lead to thyroid symptoms and subclinical or confusing lab results. ("Are you eating too much millet? Is not a typical question in the standard medical interview). In addition, there is some controversy as to the appropriate range of TSH considered normal. In the past it was around 0.8 or 1.0-6. Now many labs have narrowed the threshold by reducing the upper limit to 3.5 or 4. However, in most true hyperthyroidism (99%) there will not be much of a question -- TSH will be undetectable. In true hypothyroidism, it is not unusual to see levels higher than 20.

TSH levels >2.5 are associated with a greater risk of cardiovascular disease. But is that due to other factors, such as systemic inflammation? Does it make sense to use thyroid hormone to treat a mere number? How is that different from treating a cholesterol number with a medicine for the specific purpose of getting the number into a "better" range? I think we are still coming to a consensus as to the right thing to do in the case of "subclinical hypothyroidism."

As we discussed in the comments of a previous post, psychiatry is pretty much the only specialty where we have a large amount of data and clinical reason for using T3 hormone to treat depression symptoms. Most primary care doctors and endocrinologists will use T4 exclusively. In general, T4 the prohormone is safer, and the body should be able to make about as much T3 as it needs (provided selenium levels and vitamin levels are okay). Conversely, being too aggressive with T3 can lead to death.

However, as I noted, I've found T3 to be generally ineffective or uncomfortable for most, and the only folks who seem to respond well already have diagnosed hypothyroidism and are on synthetic T4. I've also found that the recommended psychiatry doses (25 to 50 mcg T3) are way too high, and lead to mild hyperthyroidism symptoms within several months. I've had better luck with lower doses of T3 (around 5 mcg) combined with lowering the dose of T4. My anecdotes are hardly data, but I think I might have caught some poor converters from T4 to T3, or maybe they are selenium deficient. In conventional endocrinology these folks don't really exist, but I'm usually able to get away with treatment if I document "for psychiatric indication."

Upcoming Talks and Topics

2012-02-09T16:45:00.000-05:00

Foster the People, Don't Stop (right click to open in new tab)

Time is flying by and my clinic is very busy, and the phone is ringing off the hook, but I did want to take a moment to list the planned upcoming talks and panels for the year (so far):

March 14-18 at PaleoFX12. I will be on a panel about addressing the psychology of change. Very excited to have a reason to go down to Austin for a long weekend, as it is my home town and where many of my lifelong friends live.

May 23rd at the Massachusetts Psychiatric Society Geriatric Interest Group meeting in Wellesley, Massachusetts. I'll be doing a talk for psychiatrists who specialize in treating the elderly on Evolutionary Medicine and Alzheimer's Disease. I'm thrilled for this opportunity to speak to my peers, as I've trained in conservative institutions, and I have the tendency to believe that any psychiatrist who reads my blog will think I'm a crackpot. For this reason I'm sure the talk will be squeaky clean with regards to literature references and the best accuracy I can muster, and hopefully exciting and thought-provoking for the attendees.

August 9-12 at the Ancestral Health Symposium 2012 in Cambridge. I'll be doing a short presentation and will really enjoy seeing all my paleosphere friends again.

I have also been asked about possibly speaking for the Boston-area Paleo Interest group perhaps in the spring but I believe we were going to regroup after holidays/winter, as it is nearly useless making plans when there might be a big snowstorm (ironically the only one we've had was last October, the day before I spoke at Harvard Law School!)

My plan for upcoming blog topics: Finally, at long last, for real, the Thyroid, with a focus on psychiatric implications. The first in this series may even come tonight… but more likely tomorrow.

And then I plan to take on that interesting alt med diagnosis known as adrenal fatigue.

I still have stacks of other interesting papers, plus the new ones that come up. Always more interesting things than I could possibly have time to look into. And a number of books that need book reviews. Any tremendously wealthy reader willing to sponsor a year's salary so I can catch up is more than welcome to do so ;-) Of course then I would be spoiled for any future clinical endeavors and lose my usefulness as an active, front-lines interpreter of the literature, so perhaps I'm much better off with the status quo.

Magnesium Deficiency and Fibromyalgia

2012-02-04T16:44:00.001-05:00

Free the Animal's Richard Nikoley may have no use for government (I recommend the depressing but excellent book, Humanity, A Moral History of the 20th Century to get some measure of the amount of systematic human death and suffering caused by government even recently), but I must say I do appreciate the United States of America hosting the organized repository of online knowledge that is PubMed.

I'm old enough to remember hunting the Stacks in the undergraduate library. Even then we had Wargames-era computerized search engines. Half the time you would get sent to something on microfiche and you would give up. In medical school, Medline, MedlinePlus, Ovid, and LoansomeDoc were still ways to search (and you still had to comb the library for the actual paper journal nearly all of the time). In most cases we would do almost anything to avoid a literature search and generally gave presentations straight from textbooks.

Look at me now. Voluntarily doing literature searches for the purposes of gaining knowledge and stuff.

The Ting Tings: Hang it Up (right click to open in new tab--VEVO so there's an ad the first time through. Sorry about that, but I think this song is a new, and it is rockin'.)

Now if the whole shebang could be shifted to PubMed Central and free full text were the norm…well. I suppose my school (I'm not going to mention the name of it, because we all know what happened the last time) would have to find some other way to pay me for my teaching duties than academic journal access. Maybe money of some kind, a discount on malpractice insurance, a holiday basket, a free MRI or something. But for now I get PubMed's friendly My NCBI to email me automatically and regularly with searches of interest. And then I'm able to plug the search results into my school's online academic access for full text so the emails are not a horrible tease.

Sometimes I get a lot of results for boring articles about rats on ketogenic diets, or the latest review in Hungarian about sleep disorders. Sometimes I hit the veritable Evolutionary Psychiatry jackpot, relatively speaking.

Is magnesium citrate treatment effective on pain, clinical parameters and functional status in patients with fibromyalgia?

It's a small study, 60 women with fibromyalgia. Nothing definitive but certainly very interesting. Have I talked about fibromyalgia before? It's a disease characterized mostly by generalized muscle pains and body aches, fatigue, and poor sleep. Like irritable bowel syndrome, a good proportion of the folks I see in my outpatient clinic that I see for anxiety or depressive disorders have been diagnosed with fibromyalgia. I would say men tend to be more on the irritable bowel side while the afflicted women generally have a nice helping of both, in combination with long term anxiety, depression, and often some autoimmune arthritis or skin issues. Fibromyalgia is one of those debilitating conditions that many doctors (and lay people) consider the 21st century version of hysteria, partially because there are no definitive biomarkers, no x-ray findings, it tends to co-occur with depression and anxiety, and it can respond somewhat to certain antidepressants.

My guess is that fibromyalgia is a variant of depressive disorders that is mediated by a poorly regulated stress response combined with broken sleep, oxidative stress, and inflammation. There's very likely a gut microflora connection. I can further speculate that a program of stress reduction, a nutrient-rich, toxin-avoidant diet, sensible exercise and good sleep hygiene will go a long way to help a large percentage of those with fibromyalgia.

The diagnosis of fibromyalgia has become more popular recently because there is a shiny new Drug to treat it, Cymbalta (duloxetine), which is also FDA-approved for major depressive disorder. There are, of course, no studies as far as I know for paleo diets combined with intensive lifestyle interventions for fibromyalgia, so it is madness and pseudoalternative crap medicine to promote that idea on my blog, whereas there is growing literature evidence for Cymbalta (and pregabalin and milnacipram, the other two FDA-approved treatments). Cymbalta is one of the class of second generation mixed norepinephrine and serotonin-reuptake inhibitors. And I would have to say, in my experience working with people, it really does seem to help the annoying, constant aches of fibromyalgia in many. Cymbalta can also cause weight gain, sedation and a host of other irritating antidepressant side effects, and it is expensive.

Of course, the dirty little secret of expensive pharmaceuticals is that there are older, dirt-cheap antidepressants that are equally effective for fibromyalgia, called tricyclic antidepressants (TCAs). To be perfectly fair, the TCAs are fatal in overdose and cause much more weight gain, sedation, and deal-breaking dry mouth than the second-generation Cymbalta.

But what if there were an even cheaper, easier, less side-effect laden pill or supplement to take for fibromyalgia? How about magnesium? If you like more detail, go read my Psychology Today article, Magnesium and the Brain: The Original Chill Pill. It combines the information from several articles from this blog. To summarize, magnesium deficiency can cause us to be more vulnerable to a poorly regulated stress response, and magnesium is absolutely necessary to metabolize energy efficiently. Many on a Standard American (or whatever) Diet are likely to be at least somewhat magnesium deficient. Since most magnesium is stored within cells and bones, a simple serum level generally won't tell us much. Since we die rather quickly of heart problems if our blood levels are low, our regulatory systems pull out all the stops to make sure our blood levels remain within a certain range, even if our bodies are relatively deficient.

Back to the study. These researchers took 60 women with fibromyalgia and 20 controls. The patients were randomized into three groups, magnesium citrate 300mg daily, amitriptyline 10mg daily (a TCA), or Mg Citrate + amitriptyline for eight weeks. Number of tender points and a "tender point index" were assessed. Serum and red blood cell levels of magnesium were measured and followed. In addition, all the participants took standard scale questionnaires measuring depression, anxiety, and fibromyalgia symptoms. All of these measures were taken before and after treatment.

Why magnesium? The researchers were intrigued by the idea of fibromyalgia being a disease of oxidative stress, and mineral deficiencies are known to predispose folks to oxidative stress. Magnesium plays a critical role in the various processed turning the food we eat and our fuel stores into energy used by the cells. It was postulated that muscle cells could be low in magnesium while the blood levels were maintained with normal limits (to preserve the heart), and this low magnesium could cause problems with muscle cells turning fuel into energy, thus fatigue, weakness, and pain. A previous study showed that 300-600 mg of magnesium malate daily improved the symptoms of fibromyalgia (1). Another trial used a mix of magnesium supplements (low and high) with similar results to the previous study in the high-dose arm (2).

In the brand new study, here are the results:

...magnesium levels [both serum and red blood cell] were lower [in fibromyalgia patients] than in the control groups and there was a correlation between magnesium and VAS, the number of tender points, tender point index, the FIQ, the Beck depression and anxiety score and clinical symptoms such as fatigue, sleep disorder, headache, numbness and gastric disorders. All of these findings support the fact that magnesium plays an important role in the development of fibromyalgia.

That's pretty impressive. And here, then, appears to be the third trial showing clinical improvement with magnesium supplementation for fibromyalgia. The patients who did best were on a combination of magnesium and amitriptyline (the 10mg dose is quite low and would not expect to have much in the way of antidepressant effects).

Before we get too terribly excited, there are studies showing that sleeping medicines alone will help improve symptoms of fibromyalgia, and one of the most consistent reports of people taking magnesium is that sleep is improved. Similarly, amitriptyline in a 10 or 25mg dose is often used off-label as a prescription sleep aid. That might explain the improvement all on its own.

But however the magnesium seems to help, that it does could be significant for many. It certainly seems worth a try, considering the risks and benefits and costs of the FDA approved treatments (pregabalin, duloxetine, and milnacipram) and the multitude of benefits from getting one's magnesium levels up to snuff. These are not massive doses. Considering the average diet gives us maybe 250mg daily, adding 300mg daily puts us just a little above the RDA. Seems sensible enough to me, anyway.

Medicine Is Still an Art

2012-01-31T21:15:00.001-05:00

I'm going to go an unusual direction today and swerve from my normal focus on psychiatry to comment on the general direction of medicine. In some ways, psychiatry, with its drug-heavy focus, is the forefront of medicine (and not in a good way), so perhaps it is not so far outside my specialty that I will make a fool of myself.

Young the Giant. Cough Syrup (right click to open in new tab)

My thoughts are in response to a culmination of a number of recent news items in medicine. First, at the end of 2011, an expert panel convened by the National Heart, Lung, and Blood Institute recommended universal lipid screening in children 9-11 years of age and again at 17-21 years of age. On surface this seems innocuous enough… from a conventional medicine standpoint when one considers cholesterol to be an important marker of health. (Let's ignore for a little bit the fact that low cholesterol (along with exceptionally high) is associated with increased overall mortality in study after study after study.) No matter what, one of the most basic tenets of modern medicine is to consider the point of the test. If one runs a test, one must be prepared to do something with the information. If you aren't going to do anything about it, then why run the test in the first place?

I was pleasantly surprised by a JAMA editorial from earlier this month concerning these universal recommendations. The new NHLBI guidelines are linked to recommendations about both behavioral and drug therapies. The behavioral therapies are obvious -- increased exercise and a prudent diet (*cough*). And surely we should be recommending a diet focused on healthy, whole foods and avoiding processed foods for everyone. Healthy activity is also a universal and without too much controversy. But then you get to drug therapy for dyslipidemia, which in 2012 means statins for kids.

Here is where the JAMA editorial gets real. They note that in a meta-analysis of 10 primary prevention trials (primary prevention refers to people without prior cardiovascular disease, more or less the general population, whereas secondary prevention refers to drug treatment of folks who have already had a heart attack or stroke), statin use was associated with a 30% reduction in coronary events and a 12% reduction in total mortality (1). (Let's ignore the fact that these are relative risk rather than absolute risk numbers for now, more on that later!) Let's not ignore the fact that atherosclerosis begins in childhood, and that cholesterol levels track from childhood to adulthood. Reducing LDL cholesterol levels appears to extend the life of people with familial hypercholesterolemia.

But. But but but but but. Even a cardiologist would have to agree that most children with "dyslipidemia" will not develop early heart disease. Treating these children with statins exposes them to unwarranted risk and side effects. Drugs that lower cholesterol, such as fibrates, sterols, or the newer CETP inhibitors, are only associated with an increased or unchanged risk in cardiovascular events, suggesting that lowering cholesterol numbers itself is not a means to an end. The studies for the first CETP inhibitor, torcetrapib (which does a crackerjack job of lowering LDL and raising HDL at the same time! Whee!) showed a modest increased hazard ratio (only 1.25) which scarily enough would not have been detected if only the cholesterol measures were used, rather than overall mortality or cardiovascular events in the initial studies.

The JAMA authors go on to remark that statins have been tested in small numbers of children ( a few hundred, for studies ranging from 8 weeks to 2 years) for brief periods of time, and only the surrogate outcomes (cholesterol measures) have been assessed. So far, trials have lacked the size and duration to demonstrate any health benefits for children. If there are long term harms, it is unclear how these might be detected. Surely this uncertainly would be enough to give most pediatricians pause, to say the least.

So if one screens, there will be a compulsion to act quickly on the results. Do you give statins to children with NO data? Wouldn't you recommend whole foods, avoiding processed garbage and prudent exercise as staples for all children as a matter of course? "What this novel public health intervention in children clearly lacks is an evaluation to determine whether the long-term risk-benefit profile may in fact be favorable or harmful."

Let's move on from children to women, where statin use has also been controversial, as a very new meta-analysis was published in the Journal of the American College of Cardiology this very week: Meta-Analysis of Statin Effects in Women Versus Men. I imagine this study will be used in order to further pressure all of us with average cholesterol to go on medicine for primary prevention of heart disease. This meta-analysis (which brings together the data from a number of different studies) strives to do what no statin study has done before--prove any benefit in women, particularly in primary prevention. In the end the authors find in a compilation of data from 18 trials with sex-specific outcomes (141,235 people and 40,275 women) that outcomes were similar for women as for men. That is a statistically significant benefit for women as well as men of similar magnitude in both primary and secondary prevention. All-cause mortality was also lower with statin therapy both in women and in men with no significant differences between the sexes.

Well. Hallelujah. At last. The conclusion: "Statin therapy should be used in appropriate patients without regard to sex."

Of course, as we all know, the devil is in the details. And in a beautiful editorial in the very same edition of Journal of the American College of Cardiology we have "Controversy and Consensus About Statin Use: It Is Not About the Sex." The editorial says, yes, indeed, finally, and it is no surprise, that statin therapy should be of similar benefit to women and men, but what does that mean, exactly?

It means, with secondary prevention, those who have already had a heart attack for example, that statins do indeed impart benefit, and I'm willing to extend that benefit to women as well as men. But when we come to primary prevention (statins in people with risk factors for heart disease, not proven heart disease), we are talking a whole different kettle of fish.

First off, of more than 2300 studies identified by the doctors doing the meta-analysis, only 18 met all the inclusion criteria (meaning they were of high quality enough to be included). 8 were primary prevention trials, and 17 were funded by the pharmaceutical industry, and only 2 included sex-specific data on side effects (or "adverse events"). One of the included trials was JUPITER, which remains controversial as it was halted early and had a short follow-up.

The "devil" here is that women are considerably less likely to die of heart disease than are men. Thus any primary prevention in women will need to meet a more stringent requirement than in men, as by numbers alone primary prevention of heart disease will be of lesser benefit in women. The risks of diabetes, muscle problems, cognitive deficits, and perhaps increase in cancer would be expected to be more of an issue in women, with smaller lean mass thus higher relative statin dose (same issue is at play in children), longer lifespans and lower risk of heart disease and higher risk of cancer than men. While "relative risk" of decrease in heart disease (say a decrease of 2% to 1%, with a relative risk decrease of 100%!) might be promising, the absolute risk (that change from 2 to 1%) is unimportant. So here we get to the heart of the matter:

Women without CVD have lower annual mortality risk and lower CVD risk than men without CVD. Therefore, the absolute benefit of statins will typically be less for women than men, suggesting it might be appropriate that women receive statins less frequently than men in the setting of primary prevention. The current meta-analysis provides information about sex-specific relative risk benefit and not absolute benefit. Both absolute risk of CVD and the proportionate risk reduction associated with statin therapy are needed to make informed clinical choices with regard to the use of statins for primary prevention. Although the latter might be similar for the sexes, the former might be quite different.

As only 2 studies provided sex-specific risk data, we simply cannot evaluate the risk of statins for primary prevention in women Adverse outcomes are extremely clinically important when we are giving medicines to healthy people to prevent disease. More wisdom from the editorial:

Sex-specific results in cardiovascular prevention tirals should be provided for relative and absolute benefits, adverse outcomes, and cost-effectiveness. Only then we will know with less uncertainty whether what is good for the gander is also good for the goose. Medicine is still an art. [emphasis mine]

And, finally, some thoughts on some email conversations I've had with Kurt Harris on low dose naltrexone. We were discussing the use of LDN in allergy and autoimmune disease, and I had stumbled upon this skeptical webpost: Low Dose Naltrexone, Bogus or Cutting Edge Science? The truth is that LDN has shown a robust benefit for a very challenging illness, Crohns Disease, in studies at Penn State (2). In these studies, the inexpensive and by any rational observation low risk low-dose naltrexone performed better than the incredibly expensive noxious anti-TNF-alpha Humira. We certainly know much more about Humira's risks-- they are many, and yet it is somehow dangerous and "woo" to recommend a trial of LDN in comparison. LDN has real potential to modify the immune system to decrease deadly and intolerable immune reactions in diseases such as Crohns. Naltrexone has been in use for a decade or more, and while there is a dose-dependent risk of liver damage, that risk tends to happen at 150mg daily. LDN is about 4.5 mg a day. Sure, there is no argument that we should have more data, but how is it crazy and dangerous to recommend LDN for Chrons (as opposed to Humira or even steroids) and not crazy and dangerous to recommend statins for primary prevention, a very accepted practice?

In my mind, when we are considering difficult illnesses with only dangerous evidenced-based cures, we have consider common sense and the cost of large trials and the corrupt influence of money and the pharmaceutical industry. One such example is the vitamin supplement SAMe, which performed better in trials at MGH than any FDA approved adjunctive treatment for resistant depression. SAMe is not without risks (mania and elevated homocysteine), yet surely Abilify (which has FDA approval), 10X more expensive and with risks of permanent movement disorders, weight gain, metabolic syndrome, and diabetes should sensibly be a second-tier option in resistant depression compared to SAMe, with a decades-long track record of randomized controlled trials? Somehow that is not the case. Somehow we put Abilify ahead of the mere supplement.

I'm preaching to the choir. But I suppose that is what a blog is for. The papers march on, the money, the meta-analyses, the editorials. Does anyone demonstrate common sense in actual clinical practice? We shall have to see. Money (and time?) is running out for us to come to our senses.

(I read recently The Cholesterol Delusion by Ernest Curtis, M.D., a cardiologist, at the recommendation of Mike Eades. It's a short read, pointed, and interesting. Worth the time. One of his most important points of wisdom is that any study or news report touting relative risk in lieu of absolute risk has an agenda and is trying to make a dramatic statement when there may or may not be any reasonable difference in risk.)

More Evidence for a Gut-Brain Connection

2012-01-28T16:31:00.002-05:00

Someone (Stephen B) emailed me via Google +, which I didn't know was possible, mostly because I have yet to bother to figure out anything about Google +, mostly because my reading pile is dangerously high and Google+ wasn't very iPad friendly. If I'm going to figure out any new complex system of communication with circles, it had better be with my feet warm and snuggly under the covers, thus iPad friendly. Now you know my opinion, so go work on that, Google.

Neon Trees. Everybody Talks (right click to open in new tab).

The abstract of the paper Stephan sent me seemed mighty intriguing indeed (pardon the font hiccup here but I am too lazy to type it out rather than cut-n-paste and Blogger is dreadful about editing such things. My, I am certainly opinionated today!). Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve

I know that title might not make everyone's heart go pitter patter immediately, but it is actually Evolutionary Psychiatry exciting. As I noted in a couple of previous blog posts, it is clear that (in mice, anyway) the wee beasties of the microflora in the gut (comprising about 90% of the cells in our bodies) have something to say about behavior and moods. In addition, behavior and mood can affect the population of the gut flora. But how the communication proceeds is a bit mysterious. Hopefully this paper will shed some light.

First off, a little bit about GABA. It is the major inhibitory neurotransmitter in the central nervous system (glutamate being the major excitatory neurotransmitter). GABA is a nice glass of wine in front of the fire. GABA is restful sleep. GABA is tranquility and yoga. Not surprisingly, GABA plays a major role in conditions such as anxiety disorders and irritable bowel syndrome.

Now let's introduce Lactobacillus rhamnosus. These little bacteria can modulate the immune system via manipulation of TNF-alpha and IL-8, and can change T cell production. In addition, in rodents, it reduces the autonomic nervous system response to intestinal distention and alters small intestinal motility. That's a lot of long range action for a wee beastie.

So, for the study, the researchers gave some mice probiotics, and other mice got broth. Then the mice were tortured in various ways to induce a stress response. Some of the mice had surgery to sever the vagus nerve (which is the major communication highway between the gut and the brain). And mice ultimately made the ultimate sacrifice to have GABA levels and mRNA levels measured in the brain.

The results: mice who go the probiotics were, in general, more chilled out than the control mice. The probiotic mice had lower levels of corticosteroid release in response to stress. Steroids are something the body pumps out as an emergency reaction to stress, and while in the immediate timeframe they can save your life (grandma lifting the car off the toddler, for example), in the long run, chronically elevated stress hormones like steroids can lead to depression, anxiety, heart disease, you name it.

Mice who had their vagus nerves severed did not differ from the control mice so did not experience the anxiolytic effects of the Lactobacillus probiotic. This would suggest the communication from the bacteria (via its own neurotransmitters? or via immune modulation in the gut) definitely goes through the vagus nerve on its way to the brain to control behavior.

In addition, when the brains of the little mice were tested, the amounts of mRNA of various types of GABA receptors (reflecting the amount of messages from the genes to create the GABA receptors) were higher in certain key brain areas of certain key subtypes of GABA receptor.

So what does it all mean? Actually, the authors of the study summarize nicely (the "HPA axis" is the connection between the brain and adrenal glands and how corticosteroids are released and regulated, and there is more font hiccuping. Sorry):

Furthermore, in this study we observed that L. rhamnosus administration reduces the stress-induced elevation in corticosterone, suggesting that the impact of the Lactobacillus on the CNS has an important effect at a physiological level. Alterations in the HPA axis have been linked to the development of mood disorders and have been shown to affect the composition of the microbiota in rodents… Moreover, it has been shown that alterations in HPA axis modulation can be reversed by treatment with Lactobacillus and Bifidobacterium. However, caution is needed when extrapolating from single timepoint neuroendocrine studies. Nonetheless, these data clearly indicate that in the bidirectional communication between the brain and the gut, the HPA axis is a key component that can be affected by changes in the enteric microbiota.

So, once again, a common ancestral practice to consume fermented foods rich in probiotics is quite interesting. There is almost no evidence in humans as yet for psychiatric disorders (the only scientific evidence I'm aware of is discussed in my blog post here). But all in all the data and research looks to be very interesting, and perhaps promising.

Autism and Antioxidants -- A Wee Little Explanation

2012-01-22T16:46:00.003-05:00

To start off, here is Elvis Presley's last Number 1 hit: A Little Less Conversation (right click to open in new tab)

Yesterday I put up a little post discussing a very theoretical possible link between acetaminophen and autism. The main point is that acetaminophen is known to gobble up glutathione like gangbusters, and some of us will be more vulnerable to this glutathione destruction than others.

Glutathione is a major part of the body's detoxifying systems. When we burn fuel and various other biochemical things, we create toxic byproducts. These toxins can damage DNA and make systems inefficient and ragged, and call up our inflammatory army to clear the damage, which can cause its own problems. Since our body is a tiny little ecosystem, we have our own chemical clean-up crew that should be johnny on the spot to sop up free radicals and other untoward elements. We can measure how good our clean-up crew is in various ways, and a couple of very small studies have demonstrated that kids with autism don't seem to be very good at dispensing with toxins. In this Egyptian paper (1), kids with autism have lower rates of superoxide dismutase and glutathione peroxidase than matched control children (this could mean they make less or are dealing with more oxidation than other kids, so the enzymes are used up faster). These two enzymes clean up superoxide and the resultant hydrogen peroxide, reducing them to less dangerous downstream products. I have also reviewed a study showing inefficient and dirty mitochondria in children with autism compared to controls.

A free radical courtesy Flickr Creative Commons

Children under 3 not only grow at a rapid rate, they also seem to have naturally low glutathione levels, making them among those particularly vulnerable to oxidant injury (2). Children who have genetic inefficiency in the antioxidant system will therefore be even more vulnerable. The brain, being a high energy and relatively delicate organ (the liver has an astonishing capacity to regenerate cells, whereas the brain has almost no capacity to regrow cells but can modulate connections to bypass injured systems to some extent) will be especially susceptible to oxidative damage. Another area vulnerable to lack of glutathione? Our delicate airways -- one of the reasons perhaps some children eventually "grow out" of asthma.

Guess what else is exceedingly important in establishing an amazing and efficient antioxidant system? That's right. Micronutrient status. Copper and zinc need to be topped up in order to make plenty of superoxide dismutase, for example.

You know who else tends to have a less efficient antioxidant-making system and lower amounts of glutathione? Yes, the elderly. As I've mentioned in the past, the pathophysiology of autism and dementia seem to have some similarities -- a similar puzzling and devastating process of inflammation and neuronal cell death occurring at entirely different developmental stages.

These are all complex processes with many players, internal and external. That's why I don't think there is any "one" cause of the autism spectrum disorders (or the dementias, for that matter). However, combine a genetic vulnerability, low zinc status, maybe some acetaminophen, and inflammatory insult, and ultimately there is a straw that breaks the camel's back.

The good news is that most of us are resilient and can handle a bit of acetaminophen here and a bit of red #5 there, and some of us sail through life smoking cigarettes and chomping on funky fries. The bad news is that some of us aren't as resilient, and one way or another we will all have to pay the piper.

Tylenol and Autism?

2012-01-21T14:47:00.001-05:00

I know. The link seems silly. Tylenol is for babies, right? Far safer than aspirin for fever, after all. Pediatricians recommend acetaminophen (tylenol) all the time.

Let me not mislead you, for everything I am about to write about is tenuous. And yet all doctors will have a wrinkle-nosed reaction to tylenol, simply because if you overdose on the stuff, even in small amounts, you run the risk of dying a horrible death. Tylenol breaks down to NAPQI which breaks down the master antioxidant of the body, glutathione, in large amounts, and kills the liver and kidneys and brain. Who cares if it is the liver, which repairs itself at a rapid rate -- what about the lungs? Or the brain? "Real" antioxidants are more than a vitamin pill. We need to make our own.

In autism, there is an increased level of inflammation (1):

There are an increasing number of reports that anomalies in the immune system may play a role in autism. This has been found at the molecular, pathological, and epidemiological level. Altered lev- els of immunoglobulins, cytokines and inflammatory markers have been identified in the serum, cerebral spinal fluid, and autopsy brain tissues of autistic patients. Gastrointestinal inflammation in autism as well as pathological evidence of neuroinflammation involving activation of brain microglia has been shown. An increase in head circumference in autistic children, a consistent finding in autism, may involve neuroinflammation.

More interesting information (and a related blog post from some time ago):

Numerous studies have attempted to measure the prevalence of autism and asthma in the population. Both asthma and autism have had a similar apparent rise in the number of cases since approximately 1980, over the past 30 years, and in both disorders these have been repeatedly referred to as ‘‘epidemics”. In autism, this apparent rise in cases is highly controversial and may be whole or in part due to increased disease awareness and/or expansion and reclassification of diagnostic criteria.

The following discussion is not intended to judge the validity of disease prevalence studies in asthma or autism; it is simply to point out interesting minor anomalies in those curves. In disease prevalence curves of both autism and asthma in the US, the sharp rise in cases began in approximately 1980. In the period from 1980 to 1990 there were two slight downturns in the slope of the curves, after 1982 and after 1986. Both curves continue markedly upward after 1988 into the 1990s. In addition, there are similar slight downturns in slopes of the curves at the same times from independent and geographically disparate studies in both asthma and autism including; asthma hospitalizations, autism cases in Minnesota, autism in north east London, and autism in an urban area in Sweden.

Four significant events related to acetaminophen use occurred between 1980 and 1990. The first was the CDC caution in 1980 concerning the relationship of aspirin to the risk of Reyes Syndrome which was followed by a public and professional warning by the United States Surgeon General regarding a possible Reyes Syndrome–aspirin association. These cautions against the use of aspirin as a fever reducer in children were largely responsible for the replacement of aspirin by acetaminophen as a pediatric antipyretic. In 1982 and again in 1986 there were product tampering cases where acetaminophen tablets were laced with cyanide resulting in eight deaths. Acetaminophen sales collapsed after each tampering event, but recovered in less than a year in each case. These dates roughly correspond to the slight downturns in asthma and autism cases.

Personally, I do not give my children acetaminophen and I do not take it myself. It should be known that I think fevers come into play for a reason, to kill germs, and I do not administer medicines to my children explicitly for fever control unless the fever is dangerously high, or the children are in pain due to headache or ear infections or whatever.

The data I present here is definitely preliminary. The alternatives for fever reduction, aspirin and NSAIDS, all have downsides as well (NSAIDS can cause kidney and gut damage and aspirin can be deadly in children as well). I would just caution parents not to be too free with Tylenol. I know that many parents pre-treat their children prior to immunizations, for example, and I think that is a bad idea. Exercise prudence. That's my message, in a nutshell.

Good luck.

For more explanation about autism and antioxidants, please see my next post.

Diet and ADHD - A Literature Review

2012-01-15T16:50:00.000-05:00

Last Thursday I had to report for jury duty. Fortunately my number was on the higher side, so it involved me sitting in a room for a while reading some papers while the slots for the criminal case were filled. I'm glad I wasn't selected -- the case involved the deaths of small children in a fire. Ever since I had a couple of my own small children, I find it much harder to be "clinical" about violence and death when it comes to kids. I put down Blood Meridian five years ago and haven't picked it up since.

Grieg - Holberg Suite (Prelude)

One of the terrific articles released this month is The Diet Factor in Attention-Deficit/Hyperactivity Disorder, in Pediatrics. A couple of neurologists culled the literature, including not only the modern work done in Australia, England, and Belgium, but also the old Feingold stuff from the 70s. They offer both an historical and evidence-based perspective, which enables one to see not only the science, but the human story of dietary treatments for ADHD. Let's dive in, as there is a lot to cover.

The paper begins with a brief overview. Basically, when it comes to dietary treatments for ADHD, there isn't that much to choose from that has been studied. We start with the old anti-salycilate Feingold approach (which also avoids other major allergens, such as food dyes and other additives.) The diet involves avoiding apples, grapes, lunch meats, and any foods containing artificial preservatives or dyes. One could eat certain cereals, beef, lamb, pineapples, bananas, pears, grapefruit, milk, eggs, and color-free vitamins. Enthusiasm for Feingold was huge in the 1970s, however, clinical trial results weren't as impressive as the case reports. Occasionally, certain children would have an amazing response, but overall the treatment was not helpful to most.

After Feingold waxed and waned (20 articles in pubmed between 1979-1988, 2 between 1990-2010), a newer elimination diet approach has come to the fore (based on the Southhampton Study I've written about several times, with the follow-up INCA study that was quite impressive). The theory behind these diets and Feingold is that ADHD behaviors are, for some, a display of intolerance to certain foods. The Southamption study backed this theory up with some superfly demonstration that the kids who were sensitive to food dyes had histamine systems that seemed to be more brittle and less able to clear out junk than other kids.

Hypoallergenic diets are a version of your basic "paleo autoimmune" diet - no wheat, cow's milk, cheese, eggs, nuts, chocolate, or citrus fruits. Hypoallergenic foods include lamb, beef, potato, tapioca, carrots, peas, and pears. (Another example is a "few foods elimination diet" consisting of turkey, rice, pear, and lettuce, in which 62% of children had a >50% improvement in behavior on the diet). In pilot studies and the larger INCA trial, these diets typically resulted in significant improvement in 60% of the children who tried them.

The problem with elimination diets is that they are tough. You have to be very strict, and the whole family has to be on the same page. With every Disney character advertising a new processed food these days, it is harder than you think to keep the kids' diet clean even for a short duration of an elimination diet trial. I know when I show up at snack time at the preschool, most of the kids have spritely-colored gogurt and goldfish and juice boxes. My poor children (who don't seem to have behavioral or attentional problems) are stuck with water, prissy whole milk straight from the dairy delivered in glass bottles, fruits, meats, home fries, mashed potatoes, stew, veggies, and if they are lucky, the occasional organic pudding, yobaby full fat yogurt, or gluten-free pretzels. Frankly, the only way I get them to eat mostly healthy is by stuffing them full of good stuff first and bribing them with a small amount of bad.

BUT, considering that such diets, when done with care, are a relatively harmless maneuver, it seems worth trying. And considering that most of the moms I know seem to have at least one son with some real attention-related issues, I wish there were more public support for these diets. One mustn't have the expectation that the diets are a cure all, however. Typically, 40% of kids will not respond.

Grieg - Holberg Suite (Air) - Right click to open in new tab. I do like this piece. One of my all time favorites.

Besides elimination diets, supplements with iron, zinc, and omega 3 fatty acids have also been attempted in the treatment of ADHD. Long chain omega 3 PUFAs are lower in the RBC membranes of kids with ADHD compared to controls. Kids with ADHD may have low O3 intake as well as reduced conversion of other long chain PUFAs to the essential O3s. In the Oxford-Durham study, kids with coordination problems were given supplements made of 80/20 O3/O6. ADHD symptoms improved in most of the kids, whereas no change was found in the placebo group. Spelling and reading gains were also substantial in the experimental group over the 3-6 month follow up. There were no adverse effects. These authors, reviewing the 16 studies over the years, recommend doses of 300-600mg daily of Omega 3 with no more than 30-60mg O6 in the supplements (nordic fishes chews, nordic gummy bears, megared krill oil, and nature made were some examples of supplements used.) The authors note that in their clinic, most parents are enthusiastic about using omega 3 supplementation, but in almost all cases, additional medication treatment is required for meaningful symptom improvement.

Zinc! I like zinc. And in studies in Turkey and the Middle East, kids with zinc deficiency tend to be more hyperactive. These regions have endemic zinc deficiency, unlike the West in general. In a few US studies, zinc supplementation enhanced the benefit from d-amphetamine medicine. The optimal dose of stimulant was decreased by 30% when compared to placebo. Since zinc is a cofactor for the metabolism of many neurotransmitters and fatty acids, it would make sense that having zinc stores tip top would help in ADHD.

Iron - kids with documented iron deficiency or low ferritin do seem to have more problems with learning disorders and cognitive function (yes, your brain needs oxygen!), however, in a random sampling of kids with ADHD, ferritin and iron was no different than those of controls. It makes sense to check for iron deficiency in kids with ADHD, nevertheless.

Ketogenic diets have not been studied in ADHD, though in kids with epilepsy, attentional and behavioral problems often improve on the ketogenic diet.

Finally - sugar. Despite the sworn testimony of every parent and pre-school teacher everywhere, sugar has never been consistently shown to increase aggression or activity in children compared to placebo, aspartame, or saccharine. However, there is some data to suggest a cranky downward hypoglycemic response in some sensitive children. And while adults don't tend to show behavior symptoms at a blood sugar greater than 54, children consistently show changes on EEG and in behavior at blood sugar levels less than 75 mg/dl. Such a level is easily obtained by giving kids sugar only, while protein and fat can smooth the sugar spike and hypoglycemic aftermath.

Grieg - Solveig's Song (also very pretty).

And finally, the authors of the paper give a shout-out to the Australian study showing a link between Western Diet and ADHD symptoms. The diet pattern had a higher intake of "total fat, saturated fat, refined sugars, and sodium, and is deficient in omega 3 fatty acids, fiber, and folate." The "Healthy diet pattern... is rich in fish, vegetables, fruit, legumes, and whole-grain foods." Of course, a family eating ho-hos, icing, and cotton candy is going to be a different sort of family than the one who eats whole grains and fish. However, I'm all in favor of reducing processed foods. Duh.

And that wraps up the summary of the study of dietary factors and ADHD. GAPS was not mentioned. In general, I would say, avoid additives and processed food, make sure your kids are stocked up with minerals, and don't go nuts with the sugar. Elimination diets to determine special food sensitivities or gut bacterial overgrowth problems would probably be more helpful than harmful. Pick your battles, but good food is a worthy fight, I would say.

(A sublime soprano version of Solveig's song by Marita Solberg can be found here. Chills. And I'm a much bigger fan of orchestral music than opera.)

Just Eat Fish

2012-01-12T13:35:00.001-05:00

I've covered the importance of omega 3 fatty acids in the brain a number of times. However, when anyone asks me for specific recommendations, I've had to be distressingly vague. Typically I hem and haw and suggest that someone try to eat plenty of clean cold water marine fish, but if one wants to supplement, it's likely that a mix of EPA/DHA is better than DHA alone despite the fact that DHA is by far the major omega 3 in the brain. But how much do we supplement? Who knows? See, the literature on fish oil supplementation is such a mish-mash of different doses and results than one would have to dedicate a zillion hours scanning through the literature, and frankly, there are better things to do.

Warning, fishing at a young age may lead to future moralizing on the internet

But this month we are in luck! This paper was published in The Journal of Clinical Psychiatry, and it sheds a lot of light on the mysteries of fish oil supplementation and what is known about the efficacy when it comes to mental health. I love it when academics comb the literature so I don't have to.

The paper is a meta-analysis of fish oil supplementation trials in depression. There were straight up placebo controlled trials, trials of depression in Parkinson's, in pregnancy… the trials were many, and the results all over the place. This meta-analysis paper like any decent one is fairly excruciating to read. See, you have to take all the results and torture them with statistics until they reveal their secrets. There are statistics for the different types of data, for the particular hypothesis you are attempting to disprove in relation to the data, for the fact that a single author of multiple papers on the same subject will likely have an "author bias" … it's a mess. And with all that data and that torturing who knows what you have on the other side of the computation?

Well, a few findings keep popping up, and you can likely hang your hat on them:

1) High dose EPA alone is no good.

2) Any dose of DHA alone is lousy, and may even be harmful.

3) A fish oil supplement worth its salt for depression symptoms, anyway has at least 60% EPA, and EPA may be the most helpful of the two components. Fortunately, fish and mollusks and whatnot come supplied with fish oil in ratios of EPA higher than DHA, so it does not surprise me that our brains are optimized to run on a mix and not weird, farmed vegan algae DHA (sustainable though it may be).

I KNOW. There is hardly any EPA in the brain. HOW CAN THIS BE?

Well, the authors conclude that EPA is the active component, stating that low dose EPA has been shown to be effective, and that it may be that EPA and DHA fight 1:1 for receptors, so in the mixed supplements, the EPA in excess of the DHA is the actual active ingredient. Like most supplements (or anything, really), too high or too low is bad, so high dose EPA on its own passes some sort of goodness threshold on a U-curve and ceases to be healthful.

Interesting item number 1: The effect of dietary DHA supplementation on human brain levels has not been studied. That's right. It's entirely possible that dietary DHA might not lead to increases in cerebral DHA. If one injects radiolabeled DHA into healthy humans, however, it is incorporated into the brain at an extremely slow rate (about 3.8 mg/day), with total brain turnover occurring after 2.5 years. Guess how many randomized controlled fish oil trials lasted 2.5 years? (The fifteen trials included in this meta-analysis lasted from 4-16 weeks).

Interesting item number 2: EPA is a precursor for DHA. Given that fish sources tend to have more EPA than DHA, it could be that we are optimized to use the dietary EPA to make the DHA in such a way that it is incorporated into our brains. (A bit of cloudy weather for this interesting item: There have been studies of dietary EPA in humans and rats and it has not been shown to increase plasma or RBC DHA in humans or brain DHA in rats.)

Interesting item number 3: EPA does enter the brain. A tiny bit. The ratio of EPA:DHA in the brain is actually 1:274. And brain EPA in rat studies has been shown to help with neurogeneration and neuroprotection. EPA for 9 months in a human case study study in brain atrophy seemed to increase the ratio of neurogenerative factors in the brain.

Interesting item number 4: EPA's effects could be in the body and these effects secondarily influence the brain. EPA/arachidonic acid ratios seem to effect membrane fluidity, and EPA seems to increase the burning of polyunsaturated fatty acids which will produce ketone bodies. And we all know that our brains love ketones.

Interesting item number 5: In trials of DHA alone, the DHA takers tended to do worse than placebo and it might actually lead to a pro-inflammatory environment.

So what is the dose? All positive trials in the literature had a dose of EPA between 200-2200mg daily (with one lonely successful trial at 4000 mg/d). In the trials with a mixed supplement of DHA and EPA, when you subtract the DHA from the EPA, the dose was also between 200-2200 mg.

What do I make of it?

Here's a diagram of our metabolism.

Yes, it's complicated.

Sometimes the best generalized advice is to keep things simple.

New Study on Vitamin D and Depression

2012-01-07T16:05:00.001-05:00

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.

The Glorious Cause

2012-01-06T16:14:00.002-05:00

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.

More on Diet and Dementia

2012-01-01T15:47:00.002-05:00

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?

Ring in the New Year

2011-12-31T14:39:00.001-05:00

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!

Time to Freak Out. Sensibly.

2011-12-16T15:31:00.000-05:00

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.

Evolution and Anorexia Nervosa

2011-12-10T17:39:00.001-05:00

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...

Beyond the Chemical Imbalance Part 2

2011-12-03T16:18:00.001-05:00

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.

Depression - Beyond the Chemical Imbalance (Part 1)

2011-11-28T15:59:00.001-05:00

Today we go back to the basics of depression. Borodin's Nocturne (right click to open in new tab).

I would say there are three main theories held by the general public about the causes of depression:

1) Bootstrap theory: you are a lazy good-for-nothing who just needs to snap out of it and get up and get yourself better.

2) Trauma theory: too much stress, death, trauma, etc.

3) The chemical imbalance: You have an SSRI deficiency and your serotonin needs to be regulated (see this memorable old zoloft commercial)

Of course, I don't subscribe to any of these theories entirely, though there are elements to each of them that hold a kernel of truth - my belief and one that is largely supported by the literature is that stress and genetic susceptibility leads to depressive symptoms, which are mediated by inflammatory means in the brain. And certainly if one is capable, getting up and getting out and exercising and eating right can be very helpful, but sometimes asking a depressed person to wake up early and exercise is like asking someone with a broken ankle to go for a run. The frontal lobe isn't firing on all cylinders. There's no motivation, no zazz.

The scientifically minded probably are most familiar with theory number three. In medical terms, the "chemical imbalance" theory is called the "monoamine hypothesis" of depression. The monoamine theory is (I would say) largely accepted by doctors of a certain age (even psychiatrists), but it holds about as much water as the carbohydrate-insulin theory of obesity. Back in the day there was a medication for blood pressure called reserpine. Among other things it depletes the brain of serotonin, and does indeed tend to cause depression (it is rarely used nowadays).

The first antidepressant, a drug used to treat tuberculosis, was found serendipitously. One of its actions was to change the concentrations of monoamines (such as serotonin and norepinephrine) in the synapse between nerves. And thus, the monoamine hypothesis of depression was born along with a billion dollar antidepressant industry. All the antidepressants affect the monoamines one way or another, and they work… if you are lucky, often with side effects, and maybe they protect your brain during one episode of depression, but they don't seem to protect you from the next episode if you go off the medicine when you feel better (talk therapy when compared to medicines seems to have more long term benefit, not surprisingly).

Along the way, the monoamine theory picked up a bunch of other diseases (called the affective spectrum disorders) including major depressive disorder's anxious twin, generalized anxiety disorder, migraines, irritable bowel syndrome, bipolar disorders, social phobia, PTSD, OCD fibromyalgia, and chronic fatigue syndrome among others (1). All of these diseases have been shown to respond (somewhat) to three or more different classes of antidepressant medication.

Problem is, when you measure serotonin in depressed people, the levels are often all over the map. In fact, low serotonin doesn't really correlate with depression very well at all, though low serotonin in the central nervous system does correlate with suicide, violence, and insomnia. Brain researchers quickly figured out that the monoamine hypothesis has some pretty big holes, and the mechanism of antidepressants is not about increasing serotonin and other monoamines in the synapse but rather changing the efficiency with which monoamine signals are transmitted.

Instead, the current literature-supported theory of the brain pathology of depression and the other affective spectrum disorders leads us to two things going awry - the immune system (inflammation) and mitochondrial dysfunction.

How messy is the study of depression? Consider these facts - if we look at the modern criteria, the classic unipolar major depression is a smallish subset of the whole. 31-62% of people with depression have symptoms of "atypical depression" (leaden feelings in the arms and legs, increased appetite, increased sleep, as opposed to the classic weight loss and insomnia). 64-72% of those with atypical depression meet criteria for bipolar spectrum disorders. Depressive disorders are often comorbid with ADHD, anxiety, and substance abuse disorders. You can see if we try to study a group of patients with "major depressive disorder" by criteria that represents the typical clinical outpatient, we will get a mix of people with various complicating neuropsych problems, and any studies of so-called "pure" major depressive disorders where other problems are excluded (which is typical for pharmaceutical studies) will not necessarily be generalizable to the actual population.

Add in frequent comorbid medical conditions, and you have a whole soup of pathology. 92% of depressed inpatients have pain, typically headaches or muscle aches. Irritable bowel and migraines are often found, along with metabolic syndrome, pre-diabetes and diabetes, and obesity.

However, rather than be taken aback by the complexities, theories of mitochondrial dysfunction and inflammation can scoop up the entire variable pathology (which makes these theories very pleasing to me).

So let's start with mitochondria. As we know, these are the energy factories of the cells, and their primary mission is to make the cellular equivalent of gasoline, ATP. Problems with the mitochondria tend to show up as symptoms with the most energetically hungry cells of the muscle and nerves. Nutritionally, CoQ10, carnitine, B-vitamin, and selenium deficiencies can also cause mitochondrial dysfunction directly. Mitochondria desperately need these micronutrients to do their work efficiently.

Symptoms of mitochondrial dysfunction can be non-specific, but the cognitive symptoms are very similar to those found in depression, including impairments in attention and executive function and memory. Tellingly, in families with known genetic problems with mitochondria, the symptoms worsen around times of stress - overwork, fasting, over-exercise, and environmental temperature extremes. Children with mitochondrial disorders are more likely to be depressed than control children, and among adults, folks with known mitochondrial disorders are more likely to have depression, chronic fatigue, major depressive disorders, bipolar disorder, and panic disorder than the general population.

But all of that is the typical chicken and egg clinical stuff. Maybe people with genetic mitochondrial problems have a lot of stress, and are thus more depressed. What's the biochemical evidence for mitochondrial dysfunction in major depressive disorders (and bipolar disorder)? Autopsies show all sorts of interesting problems with mitochondrial proteins, unusual mitochondrial DNA mutations, and poor mitochondrial complex activity (2). ATP production rates and respiratory chain enzyme ratios seem to be decreased in the muscle of biopsied patients with major depressive disorder and pain. In fact, several studies have shown that patients with a high degree of somatic complaints (typically muscle aches) have much lower ATP production than average in the muscle. In chronic fatigue patients, some similar abnormalities have been found.

And finally, in some mouse models of mitochondrial dysfunction, the mice have bipolar-like symptoms and altered levels and turnover of the monoamines. The researchers worked out that the mitochondrial dysfunction was the cause of the monoamine depletion, leading to the mouse mood disorders.

So mitochondrial problems (which can be brought about genetically, but also by micronutrient deficiencies) can cause oxidative stress, and eventually lead to nerve damage and psychiatric symptoms. More on the specifics of this pathology and the role of inflammation in the next post.

Tales of the Metabolically Deranged

2011-11-24T10:18:00.001-05:00

Happy Thanksgiving! I'm probably in too good of a mood to write this post properly, but I have a moment right now and must seize the opportunity, and I'm going to try to make this short but cogent. A few days ago I noted that I don't agree with Mercola and Rosedale about their characterization (paraphrased, as it wasn't quite as black and white) of glucose as toxic and human beings as on a linear path to diabetes. Whether or not anyone cares about my opinion as a psychiatrist is another question :-) Commenter js290 wrote the following:

You should read more carefully what Dr. Rosedale wrote in the link you supplied. Your characterization of it is entirely [sic] accurate.

I wrote that I read the articles a couple of times, and found them flabbergasting. Js290 wrote back:

The way I read it, Dr. Rosedale offered the most generalized solution. The abstraction he makes is we simply define a gradient of metabolic derangement from 0% (healthy) to 100% deranged (diabetic). His argument seems to be simply, the diet that is therapeutic for fully metabolically deranged cannot be unhealthy for the metabolically healthy.

Analogously, it's similar to most of the paleo stance on gluten grains: just because it's tolerable doesn't make it optimal.

Given that you have written about brains function on ketones, that for the same number of carbon atoms, fatty acids produce more ATP than glucose, that the body is capable of producing all the glucose it needs, Dr. Rosedale's view is by far the most generalized and better abstraction from a health perspective.

Why come up with many different models for different use cases when a single model will work? This is how evolution and natural selection does things: the best abstraction wins.

I think js290 encompasses in a nutshell exactly why I find the theories so puzzling. I don't see why we should use sick people to tell us what is optimal for all people. Nor do I know the definition of "metabolically deranged" - do we mean pre-diabetic and type II diabetic? Obese? Metabolic syndrome?

I disagree with the characterization that the "derangements" are linear. My understanding of physiology is that those with healthy beta cell function can do very well with a wide variety of carbohydrate intake and it shouldn't matter that much for optimal health. We are obligated to use glucose for fuel - we have systems in place to deal with physiologic amounts of glucose. I also don't think that post-prandial glucose "spikes" are particularly abnormal or dangerous unless they are very high and last a long time. I don't think glucose or carbohydrates as a macronutrient class per se cause diabetes. Once you get past a tipping point and start taking out beta cells, hyperglycemia, insulin resistance, and increasing damage occurs, then you have fewer options, dietarily speaking. Even then, a hard core ketotic zero carber who never cheats may be in good stead, but those who cheat are now (physiologically) even more insulin resistant than they would have been if they ate enough carbs to keep them out of deep ketosis all the time… so glucose "spikes" and area under the curve for glucose and insulin would be even higher than if there were more carbs eaten on a regular basis.

In addition, since the liver will make a bunch of glucose via gluconeogenesis, I don't see much harm in eating moderate amounts of glucose so our liver doesn't need to make it, unless you are needing to stay in deep ketosis for medical reasons. Six of one, half a dozen the other.

And, of course, I think there are certain brain illnesses that could very well benefit from deep ketosis (for some of these conditions it is merely theoretical, for others there are case studies or even pilot data, for epilepsy there is a lot of data) - brain cancers, migraines, epilepsy, bipolar disorder, dementia, autism, and schizophrenia.

In general, I think it is reasonable that fasting and autophagy should be engaged in on an intermittent basis for all individuals, including heathy ones - I know that if on one particular day I personally eat high carb or low carb, I wake up the next morning in ketosis. That is a sign of metabolic flexibility, which is a positive sign of a healthy metabolism.

Well, that is my opinion. Starchy root vegetables and fruit are good sources of nutrients and in general less expensive than good quality meat, though perhaps not less expensive or easier to store than than good quality fat, calorie for calorie. The nutrients in starch tend to be somewhat different than the ones in fat. I find them pleasurable to eat, personally, and my kids certainly prefer the starch and fruit to just fat, green leafy vegetables, and meat. Perhaps they would truly want mountains of candy and chocolate and their preferences shouldn't guide our health speculations… well, that's my opinion. I simply don't think there is enough evidence to suggest that zero carb diets are optimal for everyone for longevity and health, either from an experimental perspective or from a common sense, physiologic perspective.

Soda Begets Zombies

2011-11-22T20:01:00.001-05:00

Okay, not likely. But the sugary variety might well be causing depression in those vulnerable to fructose malabsorption. Have a look at my previous post on the subject.

Today I have a mere observational study that adds to a pile of evidence that soda ain't the best thing in the world to be drinking, behaviorally speaking. "The Twinkie Defense: the relationship between carbonated non-diet soft drinks and violence perpetration among Boston high school students."

Here's an appropriate song (right click in new tab to open): Kiss With a Fist

Some bad news about behavior and soda, associatively speaking: In Norwegian adolescents, soda consumption correlated with poor mental health. Among American college students, those who drank more soda were less likely to be social, less able to understand emotional cues, and more likely to favor individualism (is that bad?). There are several reasons soda might cause problems - the sugar could lead to a low blood sugar "crash" which is associated with violence (as I discussed in this post). In addition, soda is a pretty poor source of nutrition other than straight-up calories, so if it replaces more nutritious food in the diet, big soda-drinkers could end up with micronutrient deficiencies. And yeah, micronutrient deficiencies could lead to more violence. No one measured if anyone was a fructose malabsorber.

The experimental design of the Boston study was pretty simple - Boston public high school students were randomly selected and asked to answer a survey. Those who answered that they drank five or more cans of non-diet soda every week comprised 30% of the sample. They controlled for a bunch of covariates (but I can think of several million more). Alcohol, age, gender, race, sleep, smoking, family dinners.

Heavy soda drinkers had similar BMIs to less heavy soda drinkers, and were no more likely to have less than 6 hours sleep. White, Black, and Hispanic kids are all equally likely to be heavy soda drinkers, but Asians were significantly less likely to be quaffing 5 or more cans a week.

Heavy soda users were far more likely to smoke or drink alcohol, and were far more likely to carry around a knife, have been violent with a sibling, a date, or another young person. When the sample was split into 4 quartiles rather than two, the violence link remained linear, suggesting a dose response relationship.

And that's pretty much it. A rather limited self-report study with some statistical crunching, no causal relationship can be inferred; though there are some sensible physiologic explanations as to why soda could make you knife your sister, it isn't proven here. Brain-eating was not examined.

More posts this week! I need to answer js290 regarding the whole linear glucose thing, and I figured it would warrant a short post rather than a comment. Jamie has sent me a few papers, and I pulled some reviews on inflammation, atopy, and behavior.

Handel and the Biology of Allergy, Atopy, and Suicide

2011-11-19T13:51:00.001-05:00

With respect to classical music, I'm a much bigger fan of the classical and romantic composers (Mozart, Beethoven and all those Russian guys like Rimsky-Korsakoff) than the earlier baroque composers (such as Bach and Handel). Baroque is beautiful and often awe-inspiring, but too structured for my taste -- like a doily or a stained glass window in a church. Back then gardens were arranged into strict geometric designs. We caged nature. Then pastoralism came into vogue, and we get landscape architecture that was meant to be natural and pleasing rather than quite so civilized, and the music of the time reflects this aesthetic as well. The structure and expectations of the preceding baroque era seemed to squeeze the lyricism out of baroque music, though not the beauty.

But a baroque giant, Handel, wrote the Largo from Xerxes, a selection of music that seems to wrest poetry from rigidity. It's an amazing piece, before its time. A game-changer - who knew Handel could be passionate? According to Wikipedia, Mozart said of Handel, "[He] understands affect better than any of us. When he chooses, he strikes like a thunderbolt." Right click to open in new tab.

We have our biology, our natures. And yet we dare impose the structure of agriculture and pharmacology upon it… with an incomplete understanding, at best, particularly in the brain. Such incomplete understanding will lead seemingly learned folks to suggest that we are all diabetic. (We are not). And that glucose is not a toxin but foods that raise blood sugar levels are toxic (er, what?). I probably should not stick my foot into this one, as I am not a metabolism blogger, but for heaven's sake. Without glucose in the bloodstream we are dead. With too much glucose we are poisoned.

Physiology is all about Goldilocks, the right amounts, and the case that all starches are toxic for the vast majority of people is a very, very poor one. And if fasting glucose and overall levels of circulating glucose are important, the strict low-carber who cheats every once in a while might be in more trouble than the healthy starchy-carb eater who will be more exquisitely insulin-sensitive. As Kurt Harris and Melissa McEwen have noted, there is no evolutionary precedent for lifelong very low carb diets, and plenty of examples of healthy cultures who eat starchy carbs. So with our incomplete understanding of physiology, I feel it is a safer bet to use reasonable precedent rather than a zero-carb theory of an optimal longevity diet as a prescription for most people. Certainly there are likely exceptions - seizures, dementia, the first stage of weight loss, in many folks with diabetes. Personally I think calling starch a poison for the majority of people makes about as much sense as demonizing saturated fat.

So. Back to allergies and suicide. This part of the post is for me, really. I need a spot to look back and see the nitty gritty stuff organized in a way that makes sense to me. Actually, this is the point of the entire blog. My self-taught fellowship in Evolutionary Psychiatry.

In the beginning, there were Th1 and Th2 helper cells. These are soldiers of our immune system, called lymphocytes, with different capabilities and called into action in different circumstances. The call to war comes in the form of the release of inflammatory cytokines. There are a whole soup of these chemosignals, released also primarily by T lymphocytes, mostly named interleukins, which are shortened to IL-1, IL-2, IL-3, etc. etc.

In general - the release of inflammatory cytokines can lead to reduced activities and social interaction, and it can activate the HPA axis which can lead to supernormal responses to stress, which can further ramp up the inflammatory response. Elevated pro-inflammatory cytokines can activate the IDO enzyme, reducing serotonin production (this may explain the link between allergy and suicide). Certain types of Th2 related cytokines also increase insomnia. Allergy, then, does not increase the risk of suicide by making people feel sick, but directly through inflammatory means, leading to people withdrawing from social activities and over-react to stressful situations.

What are some more specific features? Well, proinflammatory cytokines released at the time of the allergic reaction activate the HPA axis - the glucocorticoids and catecholamines cause a suppression of Th1 and a shift to Th2 activity by inhibiting IL-12 and promoting IL-10. The pro-inflammatory cytokines also cause dysfunction of corticosteroid receptors. The Th2 lymphocyte produces IL-4, which can effect serotonin metabolism as well - and IL-4 is known to have more effect in people with some genes than others.

En anglais, we are talking here a direct mechanism by which a certain kind of stress, allergy, can affect the neurochemicals in the brain and therefore behavior, and it seems that some people are genetically more vulnerable to this stress than others. That said, other researchers have postulated that the Th1 cytokines impair the serotonin machinery even more than the Th2 ones… we're back to not too hot, not too cold, not too soft, not too hard. It all has to be just right. And what is just right? Depends on your genes and your epigenetics. Superimposing an emulation of the evolutionary milieu is only a first approximation and a good guess.

Sniffles and Suicide

2011-11-17T16:12:00.001-05:00

Let's revisit the basic premise, my hypothesis we are searching to disprove. Humans are not broken, but we are not optimized for our current environment, whether it be modern stress, modern social structure, modern diet, modern sleep, or modern activity. Perturbations from the homo sapiens "norm" of paleolithic life (minus the few adaptations we have accumulated in the recent years) lead to modern human disease, mental and physical.

In a broad stroke, pathology in the human body is mediated via abnormal immune response - thus autoimmunity and inflammation. This piece of the theory has mounting evidence both for physical and mental health diseases. Inflammation in the brain can lead to disturbances of human behavior - to anxiety, extreme depression, and even suicide.

Today an interesting paper newly out in the Journal of Clinical Psychiatry, Suicide and Prescription Rates of Antiallergy Medications: An Ecological Study.

I know. That sort of a title will make any Evolutionary Psychiatrist's ears prick up.

First, though, suicide. With any human condition, sometimes the best place to look for clarity and understanding is Steinbeck, who won the Nobel and Pulitzer prizes for literature. And, like many men of the 20th century, John Steinbeck died of heart disease in his 60s.

He wrote a sympathetic portrayal of a suicidal man in what I consider to be his best work, East of Eden:

On another sheet he wrote, "Dear Will, No matter what you youself may think -- please help me now. For Mother's sake -- please. I was killed by a horse -- thrown and kicked in the head -- Please! Your brother, Tom."

...In his bedroom he broke open a new box of shells and put one of them in the cylinder of his well-called Smith and Wessen .38 and he set the loaded chamber one space to the left of the firing pin. His horse standing sleepily near the fence came to his whistle and stood drowsing while he saddled up.

It was three o’clock in the morning when he dropped the letters in the post-office at King City and mounted and turned his horse south toward the unproductive hills of the old Hamilton place.

He was a gallant gentlemen.

Certainly many suicides are planned -- often if family members get letters or phone calls ahead of time, it can be prevented. Sometimes though, suicidal urges come on in an unbearable wave, and if someone has access to lethal means (typically firearms, hanging, or jumping), the urge becomes deadly. A very interesting examination of people who survived jumping from the Golden Gate Bridge showed that only 10% of people who survived went on to complete suicide later. Most of the time, the urge to kill oneself is impulsive. Often there are biological markers - increased inflammation and low serotonin, among others.

Allergies, of course, are very common. And if suicide is in part an inflammatory issue, then one would suspect that people inflamed with allergies are more likely to commit suicide. There are, indeed, correlations between allergy and suicide. And while I tend to think of spring and fall as suicide seasons (spring in particular) due to rapid change of sunlight during those times, spring and fall are also allergy seasons, with spring being the peak of hospitalizations for those with severe allergy problems. It turns out that the link between suicide and seasons (particularly the springtime) is stronger in those with allergies.

The authors of the allergy medicine and suicide paper had an interesting premise. They looked at the theory between the connectedness of allergy and suicide in a very biological way. They looked a data showing increased gene expression of cytokines that mediate the activity of a of a certain type of immune cell, Th2 (T-helper cells type 2) in the prefrontal cortex of postmortem suicide victims. Then they looked at the main treatments for allergies/asthma - antihistamines (like claritin) and intranasal steroids (like rhinocort). An antihistamine won't change Th2 helper cell activity. A steroid will decrease it via direct means. The authors went county by county in the US comparing non-sedating antihistamine prescription data and inhaled corticosteroid data with reported suicides, antidepressant prescription data, availability of psychiatrists, urban vs. rural, demographics, within-country vs. intra-county and crunched numbers. And man, they crunched numbers to a degree that is way beyond my ken. They used logarithms and differential equations and basically took the huge amount of data and crunched the heck out of it. I can't speak to the veracity of the crunchedness as I am no statistician. It sounds reasonable but any mathematical skeptic who wants to look at the paper and pull it apart, feel free to get in touch.

They found that antihistamine prescriptions (and they excluded sedating antihistamines such benadryl or vistaril which are often prescribed for sleep, not allergies) were positively correlated with suicide rates (p=.0001) and that intranasal corticosteroids prescription rates were inversely associated with suicide rates (p=.0004). So if prescriptions for inhaled corticosteroids were to increase by 1%, the suicide rate should decrease by 0.16% (0.04 suicides per 100,000 people). The use of decongestants was neutral with respect to suicide risk.

The discussion in the paper is complex, noting that systemic steroids are known to cause problematic psychiatric side effects (which is certainly true) but that intranasal steroids (for the most part) seem to bypass this problem and have minimal systemic effects, merely decreasing inflammation in the nose, where it counts. Some data suggesting that intranasal steroids do cause jitteriness, anxiety, agitation, insomnia, and depression in certain people makes the findings of this study even more interesting. Could Th2 suppression in certain cases more than compensate for the negative psychological effects of nasal corticosteroids, at least with respect to suicide?

In East of Eden, Tom knew what his mother felt about suicide:

[She] had a strong distaste for suicide feeling that it combined three things of which she strongly disapproved -- bad manners, cowardice, and sin.

Inflammation is, indeed, unmannerly, but I think we go too far to call it cowardice or sin. We should look closer, look further, and truly delineate this pathology. Suicide is the 10th leading cause of death in the world, and the 11th in the United States. Inflammation is the number one cause of death in the modern world.

Is Postpartum Psychosis an Autoimmune Disease?

2011-11-13T09:59:00.001-05:00

Here's an article for the "everything is connected" file. Also for "yes, psychiatric disease has biologic underpinnings and is medical illness" file. Also the "inflammation in the wrong place at the wrong time is super-bad" file. And it may be of interest to anyone who has had symptoms of autoimmune disease helped by an anti-inflammatory (paleo-type) diet.

Postpartum psychosis is rare and scary. About 1 in 1000 women become psychotic in the first months after having a baby (though anything up to 12 months after is considered "postpartum" the greatest risk is in the first month). The most typical presentation is one of manic psychosis, with prominent insomnia, irritability, and delusions of grandeur. However, some women will also be depressed and be delusional and suicidal, or even with delusions that lead a women to kill her baby.

Not surprisingly, a prior diagnosis of bipolar disorder is the greatest risk factor for developing postpartum psychosis. However, most women with postpartum psychosis have no history of psychiatric illness at all (1). Often the illness requires hospitalization, and though there are no "consensus treatment guidelines," in almost all cases benzodiazepines (sedative, anti-anxiety meds, such as lorazepam) are used to help stabilize sleep-wake cycles, and in most cases antipsychotics are also used, typically with good effect. If those aren't helping, lithium is added.

Here's another bit of info about pregnancy. The fetus is obviously genetically different than mom, so women develop a depressed immune system during pregnancy, in order to protect the growing beastie from mom's antibodies and killer cells. This is why I was told to studiously avoid unpasturized cheese and raw eggs and deli meat during pregnancy, and why healthy women in the third trimester are much more likely to develop severe complications and die from the flu than women who are not pregnant.

It is well known that in women with a dysfunctional immune system (the autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, and autoimmune thyroiditis), the autoimmune symptoms are generally greatly ameliorated during pregnancy. However, this time of relatively low autoimmune symptoms is followed in the post-partum period by a "rebound" with greatly increased symptoms and greater autoantibody titers measured in the serum.

So is post-partum psychosis a symptom of autoimmune disease? Specifically autoimmune thyroid disease, as thyroid disease (both hyper- and hypothyroidism) is well known to cause psychiatric symptoms, even psychosis?

Well, those societies with socialized medicine were able to gather data in such a way as to start to give us an answer to that question. In the Netherlands, all the women in a certain area of the country who developed post-partum psychosis and ended up in the hospital were checked for autoimmune thyroid antibodies and thyroid function upon admission to the hospital. A larger control group of other post-partum women were also checked. Critically, women who were medicated at admission (particularly with lithium) were excluded from the study, as lithium is known to depress thyroid function. All women with a previous history of thyroid disease, bipolar disorder, schizophrenia, or psychosis were excluded. That left a group of 29 women with new-onset post-partum psychosis and 117 controls.

Here is what the researchers found. 5% of post-partum women in the control group had measurable autoimmune thyroid autoantibodies at 4 weeks after delivery, a sign of autoimmune thyroid disease. This is comparable to surveys of a general population of women in the Netherlands. None of them had measurable abnormalities in thyroid function or any symptoms. In contrast, 19% of the post-partum psychosis patients had measurable thyroid autoantibodies at admission (again, prior to receiving any lithium or antipsychotic medication treatment), and half of those women also had measurable thyroid abnormalities. In the following 9 months, 67% of the postpartum psychosis women with autoimmune thyroid antibodies went on to develop measurable thyroid problems (abnormal TSH or free thyroxine). None of the control women did. The odds ratios for these findings were all >2, some as large as 9, which is quite significant, especially considering the size of the sample).

Even though patients with previous bipolar disorder were excluded from this study, the researchers note that the 19% prevalence of autoimmune thyroid antibodies in these psychotic women is similar to the prevalence in women with bipolar disorder (2). And, to really get your noggins going, twin studies of bipolar disorder show that the presence of autoimmune thyroid antibodies are correlated not only to the illness itself, but to the genetic vulnerability to the illness (3).

The researchers in this study strongly recommended that all women with postpartum psychosis be monitored for thyroperoxidase antibodies and thyroid function abnormalities, and furthermore that all women at high risk for postpartum psychosis be monitored before and throughout pregnancy and the postpartum period. Though this was a small observational study, the advice seems very reasonable.

And, as always, we find that "post-partum psychosis" like many psychiatric symptoms is the equivalent of a fever - signaling underlying abnormalities, but not always caused by the flu. Sometimes fevers are caused by different bugs, or cancer, or autoimmune disease. Differentiating the underlying pathology will go a long way to informing our treatments (and helping in prevention) in the future.

Psychiatrists and other doctors reading this article will be interested in one directed more to healthcare professionals about the same study at the MGH Center for Women's Mental Health blog by Ruta Nonacs, MD PhD. Thanks to Dr. Trevisan for the link to the blog post!

Evolutionary Psychiatry and Bipolar Disorder

2011-11-11T13:01:00.001-05:00

A couple of papers came to my attention this week that relate to what I consider "real" evolutionary psychiatry. That is, what are some evolutionary reasons we might have genes that make us vulnerable to psychiatric disorders. The "real" evolutionary psychology academics consider this discussion to be "Abnormal Psychology," and like all evolutionary psychology, it is somewhat controversial. I actually don't think about the disorders much as evolving in an evolutionary light… I tend to think in terms of the human body and gut and neurons working outside design specs, thus breaking down (that is "my" version of evolutionary psychiatry). But the overlap between one ev psych and another deserves some scrutiny, because certainly I can make the case (and often do, to patients, particularly those with bipolar and ADHD and OCD) that there are elements of these disorders that are quite adaptive to certain situations, as long as the maladaptive parts don't derail everything.

Part of my major hypothesis is that the industrial/digital age and processed, low-nutrient food has brought out more severe and different phenotypes of underlying vulnerabilities, and has also brought out seemingly new illnesses ("atypical depression"). Thus a less destructive phenotype (a mildly paranoid schizotypal person, for example, who will be more creative than the average person, as compared to full-blown schizophrenia, which impairs functioning to a terrible extent) will persist in the population due to selective advantage for certain traits.

My only previous article on "real" evolutionary psychiatry can be found here: The Creative Advantage.

Well. It is fitting the first of the two papers today comes from Medical Hypothesis. Melissa McEwen sent it to me - I think she likes that journal because it is crazy and it makes her laugh. (Here is advice for those aspiring to be published there: The purpose of Medical Hypotheses is to publish interesting theoretical papers. The journal will consider radical, speculative and non-mainstream scientific ideas provided they are coherently expressed.)

I have no publications, myself, though I have assisted in some research efforts. My mentor would like me to cobble something together from all the research I've done for the blog on affective disorders, or something. I never did fancy myself much of an academic… thus never felt the motivation to write anything boring enough to be published in a journal ;-)… however, it would certainly add to my street cred. I don't know that I can write the exotic papers for Medical Hypothesis, however (Melissa sent me a paper previously about some sort of reptile origin theory of illness? I can't remember, but it was hysterical, and it must have slipped through part of the editorial process as it was also mostly incoherent). Back to evolutionary psychiatry!

Evolutionary origin of bipolar disorder - revised (EOBD-R) is the paper in question, by one Julia A. Sherman of Madison, Wisconsin. A quick google search brings up her original EOBD (sans R) from 2002. And as much as I make light of Medical Hypothesis, I do have to admire the originality of the paper, noting that it is wildly speculative and the basic premise is most likely incorrect.

Ms. Sherman connects the dots between the circadian rhythm issues and vulnerability to bipolar disorder (manic episodes are known to peak in the spring time, when the light increases exponentially day by day in extremely northern or southern latitudes.) In a nutshell, the EOBD suggests that bipolar disorder developed as an adaptive trait in the northern temperate zones which had more extreme winters during the ice age. If you were hypomanic all spring and summer, you got a lot of stuff done, and then you could slow down and "hibernate" (be depressed) during the winter and not use much energy. The "R" or revision in question actually brings in the interesting bit of Neanderthal DNA that all of us non-San Bushmen (or otherwise directly derived from Africa without side-stepping through Europe or Asia and coming up close and very personal with other hominids) seem to have. Ms. Sherman thinks that bipolar disorder is a Neanderthal trait.

Hmmm. She brings in the observations of a German psychiatrist from the early 20th century, E. Kretchmer, who noted that folks with bipolar disorder tended to be of a certain "pyknic" constitutional type. They have a "thick trunk, relatively short limbs, and a big head on a short, thick neck." Apparently, several other researchers in the early 20th century, when they were really into measuring heads and body sizes and making silly claims based on the measurements found that manic-depressive patients were more likely to be pyknic (endomorphs), and schizophrenics were more likely to be "leptosomic" (ectomorphs). A much newer study in 2003 also confirmed this finding. Sherman believes it is striking that Neanderthals are also described as having big bellies and short limbs. Interesting. In addition, people of African descent apparently have lower incidence of bipolar disorder in some studies Sherman cites. However, there is no reliable data among truly purely African populations such as the San.

There is more to the paper, but I hit the highlights. I'm not entirely sure what to think. There is no question that bipolar disorder has a seasonal component and that light and dark therapies can be useful. Hypomania, with the extended bursts of drive, energy, and creativity can also be very adaptive. And one can imagine being moderately depressed during a cold, dark winter might keep a small tribe of Neanderthal out of each other's hair, when there might have been nothing much to do anyway. I think the pyknik bit is a little ridiculous - as we know, actually, both schizophrenia and bipolar disorder are related to metabolic syndrome, even in people who have never been on medicines. I also would bet a poodle that there are San bushmen with some bipolar disorder out there, but symptoms might be attenuated by their latitude and hunter-gatherer lifestyle with plenty of socialization and exercise (though they do like those omega 6-filled mongongo nuts), according to my own wildly speculative theorizing…

The second paper is far less... imaginative and was published in the much more staid Journal of Affective Disorders. Creativity and affective temperaments in non-clinical professional artists: An empirical psychometric investigation. These researchers looked at 152 undergraduates in art school (or other creative majors) vs. 152 undergraduates who were in majors predicted to lead to professions "mostly requiring the application of learned rules" (like accounting, I suspect). The students were tested with several standard measures to detect subclinical and clinical manifestation of cyclothymia (a mild variation of bipolar disorder), and also other scales of general health and demographic data. I don't think it will surprise anyone to know that the creative students were significantly more likely to score into the cyclothymic range on these scales.

An interesting quote from the paper:

Positive mood, and happiness in particular, was postulated to fuel creativity. Enhanced positive affect is a feature of both hypomania and mania, which are core symptoms of bipolar disorder and may predispose people within the manic-depression/bipolar disorder spectrum to creativity. By contrast, postulated that depression might provide fresh insights which can be executed into the artistic oeuvre during the energized phases of cyclothymia.

So it appears that bipolar disorder is linked to creativity, which may have an adaptive advantage. I don't think that is particularly controversial, but it is nice to see more studies on the subject. Now were Neanderthals more creative than homo sapiens? At least in the springtime? That might help Julia Sherman's hypothesis!

Edited to add - a Neanderthal winter love song? By Primitive Radio Gods (right click to open in new tab).

Is Some Psychiatric Disease a Manifestation of Lyme Disease?

2011-11-07T16:38:00.002-05:00

Hello there! I’ve been offline at home for the past week, ever since the big snowstorm that came through the northeast in late October. The wet, heavy snow landed on trees that still had their leaves, leading to incredible amounts of damage and fallen limbs. That night as the snow fell, we listened to branches cracking and snapping and falling and saw arcing electricity light up the sky as wires were torn down. By morning hundreds of thousands of people were without power, including us — our wires were pulled off the side our house by falling branches. 30 foot tall trees were snapped in half, like toothpicks. (That picture is of the end of our driveway)

On the Friday before the storm I received my order of 60 pounds of grassfed, high quality beef from Paidom Ranch in Texas. On Sunday morning I filled 20 freezer bags full of the fresh snow and stuffed them in the powerless freezers and fridge, so the meat was still nice and frozen even after a few days without power. Without heat and daytime temps in the mid-fifties, it might have been just fine as it was. Halloween was put off until the following Friday night, though the neighborhood is still a mess. Power came back in two days, but our wires were still on the ground, caught in a turf war between the utility company, local electricians, and the town inspector. Back in Texas where I’m from, the utility company is responsible up to the meter — here there is something of a gray area between the property line and the meter, which would be okay, except you are at the mercy of the utility company as to when the power comes on and off so you can repair the lines on your property, leading to the ridiculous situation where we had live wires ready to electrocute anyone unlucky enough to trespass for several days, until the town inspector intervened and made the power company fix the problem.

Well. As I write this article, we are still offline at the house with respect to cable TV, landline phone, and internet (so-called bundled services are so much fun!). I’m hoping it will be back in the next several days so I can publish — fortunately the smartphone works for email and the like.

But enough of our tale of first world woe, except the disease I am about to discuss has long been maligned due to the attention it has received affecting wealthy Connecticut kids. However, I’ve seen many afflicted folks in my practice here in Massachusetts, and several family members and friends have been treated for it. So I take Lyme Disease, or Borrelia burgdorferi very seriously. Borrelia, along with several other nasty organisms, such as the microbes that cause babesiosis, ehrlichiosis, Rocky Mountain Spotted Fever, and rickettsia, are all spread by dirty tick bites.

(Quick and easy tic repellant for the spring and summer - 2 tbs coconut oil, 1 tbs aloe vera gel, 25 drops gardenia or rose oil, 25 drops lavender oil. The essential oils can be found at Whole Foods. Stir and smear on ankles, wrists, forehead, nape of neck, belly, and anywhere else tics are liable to climb in. Last summer prior to use of this ointment we had 6 tics found on kids and husband (tics and mosquitos do not like me - I am too sour) - afterwards no tics whatsoever. Thanks to @OldSalt72 for the link to the recipe)

Lyme disease is endemic to the area in which I now live, and if transmitted, can become a multisystem inflammatory disease that can affect the skin, joints, heart, and nervous system. Borrelia burgdorferi is a spirochete gram-negative bacteria in the Treponemataceae family, like the agent that causes syphilis, rather famous for its neurological findings, Treponema palidum.

Syphilis and tuberculosis are known in medicine as the “great imitators,” meaning these infections can be mistaken for many other problems, from psychiatric disorders to heart disease. Lyme disease is very tricky as there are supposedly many false negatives when you check serology. If you have a suspected deer tick attached for more than 24-48 hours here in Massachusetts, you are better off getting an extended antibiotic regimen just in case (for adults, doxycycline, for young kids, amoxicillin), considering the nastiness of the illness if not treated early.

In a paper from 2002, Hajek et al screened for antibodies to Borrelia in 926 Czech psychiatric patients between 1995 and 1999. 884 healthy persons were recruited at the same time from the general healthy population. 36% of the psychiatric patients were positive in at least one antibody class for exposure to Borrelia. Only 18% of the healthy controls were positive. That’s a rip-roaring difference, to put it in scientific terms. Since the psychiatric group was older, statistically, than the healthy group, age-matching was done (statistically), and the results were similar.

An older study in the US showed very low seropositivity in a group of psychiatric patients - however, the general population in the US has much less exposure to Lyme (1% as opposed to a much higher percentage of folks in Europe), and the assay used to detect the antibodies was rather old-fashioned in the older study. (Western blot in 2002 was gold standard, ELISA a close second, and flourescent immunoassay was used in the older US study).

The first immune response to Borrelia will be IgM antibodies, which peaks 4-6 weeks after infection, followed by the more specific IgG response, which peaks at 6 weeks, but like IgM can persist for months to years. Antibodies circulating in immune complexes are likely to signify ongoing disease activity.

If Borrelia burgdorfi is related to psychiatric problems, there are two main mechanisms which could be responsible. Patients vulnerable to psychiatric disease may also be more susceptible to Lyme or neurotoxic effects due to genetic or other factors. Second, Borrelia may cause psychiatric symptoms, which is the most parsimonious explanation. PCR analysis and other advanced methods ought to be employed in the future, and more surveys run on the population to better clarify this phenomenon.

In short, Borrelia burgdorfi is one of those suspicious, long-term, nasty and sneaky pathogens that could contribute to inflammation and issues in the brain for years or decades. It may be well one of the many inflammatory activators that are increasing our psychiatric diagoses in recent times, along with diet, lack of sleep, lack of sunshine, increased stress, and lack of exercise. The problem with Lyme is that many people who seem to have symptoms (and even those with known tic bites and classic rashes) do not test as positive. But is it really a solution to give everyone a course of doxycycline? This issue is my question with respect to any infection that may have neuropsychiatric symptoms - we need more data. In the mean time, I like anti-inflammatory, nutrient rich diets and plenty of sleep, sunshine and stress reduction.

Offline

2011-11-06T16:45:00.001-05:00

Hi all! A snowstorm took out my
home Internet service a week ago, and it is still not repaired. I have a post written for when service is restored, but in the mean time, be sure to check out the "map" at the upper right for some pertinent archives.

- Posted using BlogPress from my iPhone

Brain Shrinkage and B Vitamins

2011-10-27T21:08:00.002-04:00

As we discussed before, humans are rather unique among primates in that our brains appear to shrink as we age. When I first posted the article, Steve Parker, M.D.* noted that there was a recent article on PLOS1 about B vitamins decreasing brain shrinkage, so I thought I would investigate the matter further. Recently I've been going through this years' issues of The Carlat Report** to get some CMEs, and they mentioned the B vitamins and that study too.

Snow Patrol: Called Out in the Dark (right click in new tab to open)

But before we get to that study, let's look at an older one, from 2002: Homocysteine and Brain Atrophy

(I KNOW. Homocysteine. That bad boy of the folate cycle. Always hanging out when everyone wants him to be recycled and go home. Possibly cleaving your disulfide bridges and leaving your arteries and cartilage all crispy and brittle. Maybe just a sign that you aren't eating all your B vitamins, amino acids, and various co-factors that you need.)

Homocysteine (Hcy) has been implicated as a risk factor for vascular disease as well as brain atrophy. There is evidence to implicate Hcy in increased oxidative stress, DNA damage, the triggering of apoptosis and excitotoxicity, all important mechanisms in neurodegeneration. Hcy… also causes damage to the vessel wall… the high prevalence of hyperhomocysteinemia in the population and its easy treatability [via B vitamin supplementation - ED] make Hcy an interesting amino acid for future intervention studies in the prevention of degenerative brain disorders.

So if we want to break it down, homocysteine is part of the one-carbon metabolism cycle. B12 and folate are also an important part of this cycle, and deficiencies in these are clearly related to nerve damage and neural tube defects in infants. Deficiencies in either of these vitamins will lead to an increase in homocysteine, which is also apparently directly neurotoxic.

The brain might be particularly vulnerable to higher levels of homocysteine because it lacks two major metabolic pathways for eliminating it (biochem nerds, hold on to your hats), remethylation and transsulfuration.

All right. There's theory, and lots of it. What about the observational evidence? Well, a number of cross-sectional studies have examined a relationship between too much homocysteine and brain atrophy. In an Australian study of stroke patients, high homocysteine was related to increased brain atrophy, and the OPTIMA and Rotterdam studies replicated this finding in healthy elderly. Other observational studies have shown a correlation between higher homocysteine level and Alzheimer's disease, to the point where homocysteine levels seemed to be able to predict the speed of progression of the disease.

If we look at specific cognitive impairment trials, higher homocysteine levels have been shown to correlate with poorer performance on a number of cognitive tests - story recall, spacial coping, etc. In fact, homocysteine levels accounted for "7-8% of the variance in late-life cognitive ability."

In a prospective observational study (the Framingham heart study), higher homocysteine at baseline was related to an increased risk of developing Alzheimer's later on. Several other smaller studies have repeated this finding.

Moving onto trials - B vitamins lower homocysteine levels. Folic acid supplementation can lower homocysteine by 25%, B12 by a further 7%. Betaine is somewhat less effective. These B vitamins have been used in mild cognitive impairment and dementia. In small, open-label trials, B vitamin supplementation (typically folate and B12) have been helpful in some tests of cognitive impairment and homocysteine levels…

Fast forward to 2010, when the freely available study at PLOSone came out: Homocysteine-Lowering by B Vitamins Slows the Rate of Accelerated Brain Atrophy in Mild Cognitive Impairment: A Randomized Controlled Trial

Sounds cool, right? Well, turns out the first author has a patent for a folate or B vitamin something or other in the treatment of Alzheimer's so keep that in mind. But still cool. 168 folks with mild cognitive impairment were randomized to placebo or B vitamin supplementation (0.8 mg/d folic acid, 0.5mg/d vitamin B12, and 20 mg/d vitamin B6). Both groups of people underwent baseline and serial follow up MRIs and cognitive testing.

In the end, the B vitamin supplementation seemed to slow the brain atrophy compared to the control group. The treatment response was related to baseline homocysteine levels - the rate of atrophy in patients with a homocysteine level at baseline of >13 micromol/L was 53% lower in the active treatment group than in placebo. A faster rate of atrophy was associated with lower cognitive testing scores.

So, pretty interesting. And certainly treating our elders with B vitamin supplementation seems to have few downsides. A lifetime of offal eating might leave us well-served in that regard.

* Steve Parker MD is the go-to person where I send my patients leery of my wild and wooly evolutionary approach who are looking for something a bit more… conservative. He has a great set of evidenced-based blogs and books on the Mediterranean Diet, with some ketogenic options, and has recently started up a Paleo Diabetic blog as well.

** The Carlat Psychiatry Report is my go-to source for unbiased, evidence-based round-ups of everything in psychopharmacology and beyond.

Quick Talk Update

2011-10-27T14:42:00.003-04:00

Just a quick reminder that I will be speaking to the Harvard Law School Food Law Society at Noon on Monday, October 31, 2001. Further details about the event are here: http://hlsfoodsociety.weebly.com/events.html

I am told it is open to the public.

I've been deluged at work, but have managed to pull a few interesting papers today, so cross fingers that I will get a moment to blog about them later tonight or tomorrow.

Conventional Wisdom and the Lunatic Fringe

2011-10-22T18:51:00.001-04:00

This weekend I had a terrific opportunity. Nathan Rosenberg is an exceptional fellow who is co-president of the Harvard Food Law Society and a key organizer of next year's Ancestral Health Symposium. He found me at AHS11 and asked me if I might be interested in speaking at Harvard Law School - I said sure, though I wondered what I would say, seeing as how doctors and lawyers are natural enemies. (Kidding. Sort of. Actually I have a GREAT lawyer. He probably sleeps better not knowing about this blog.)

My talk is next week, on Halloween - the link is here. I'm really looking forward to it. My focus will be on how diet is likely a large actionable component of our mental health problems, and how mental health is both expensive and disabling.

However, on October 21st, the Harvard Food Law Society sponsored a great event - TEDx talks on obesity, with some of the foremost obesity researchers in the country (including Willet, Ludwig, Lustig, and Guyenet) along with many lawyers and policy makers talking about their efforts to encourage local agriculture and vegetable consumption over promotion of the commodities crops and CAFO operations.

The talks will be freely available some time - maybe follow the TEDx website? They were fascinating - I was, frankly, shocked by Willet's dietary prescription based, for the most part, on epidemiologic evidence. He advocates cereal fiber and polyunsaturated fats as a major portion of a "prudent" diet. He was very pro-Mediterranean diet and whole foods, but was quick to say "it's all digested to the components" - so does he think a whole grain cracker fried in seed oil and sprayed with some vitamins is equivalent to nuts and legumes? He was anti-saturated fat and red meat, but pro-poultry and fish. He mostly stuck to obesity and heart disease, but used epidemiology and small, short randomized controlled trials as evidence. Willet is, apparently, the 2nd (or 6th? I forget) most cited person in the scientific literature. He is HUGE. He is conventional wisdom, in a nutshell, though Stephan Guyenet told me Willet is pro-egg, and Willet himself says that the food pyramid, demonizing fats and, in effect, promoting low-fat processed carbohydrates in favor of whole foods, was a public health disaster.

If we rely on epidemiology alone we would still have 90 y/o women taking hormone replacement therapy. But Willet seemed convinced that confounders are easy to account for. His confidence was… breathtaking. Willet also dismissed anecdotes of traditional diets as the weakest form of evidence (which isn't entirely wrong, but ignores the compelling congruence of these healthy human diets across many cultures). Willet also said that ancestral diets are not useful because "those people only lived to 50-55 and we don't want that." Sigh. Willet eats kashi grains for breakfast, apparently.

Ludwig's talk began, very promisingly, with an evolutionary history, but ended with the basic Harvard School of Public Health prescription for a healthy diet. (Ludwig got a lot of media flack recently for suggesting that obese kids should be taken from their parents - the actual editorial he wrote suggests that foster care could be an option in intractable cases and I feel was taken out of context). I was puzzled how we got to cereal fiber (how do we have cereal fiber, on a viable level, without processed foods?) and seed oils, but that's epidemiology for you. He was quick to point out that if we substitute nuts and legumes for a big mac, once a week, we would have a measurable difference in obesity over time. Okay - Stephan Guyenet was quick to point out the sleight of hand. The substitution does not mean that red meat is bad for you. Well - Ludwig looked great (very slender, not-inflamed looking at all) and apparently might be interested in speaking at AHS12. It seems he is thinking in evolutionary health ways, but has not strayed from the conventional wisdom fold as of yet. Very interesting.

Stephan's talk was excellent; it was mostly a historical review of the changes in the American diet over the past 150 years. He pointedly showed the increases in fat (primarily polyunsaturated), poultry consumption, and linoleic acid over the last 50 years, coinciding with the obesity and diabetes epidemics. His major point was that we have gone from all home-cooked foods to a high level of fast food, restaurant food, and pre-prepared convenience foods at home. Does convenience kill? Most likely...

(An important note - heart disease has been in decline for the past 30-40 years, though it might be leveling off now. It is unclear if that is due to aggressive control of high blood pressure, dietary changes, or even statins. But don't make the false proclamation that heart disease is increasing lately, because it is not).

Lustig did his anti-sugar talk (which also pointed out the problems with epidemiology as a prescription, I am told) on Thursday night, when I could not attend. He did attend the panel discussion, when he came out as neutral on sat fats, pro-omega3, anti-omega6, anti branched chain amino acids, and anti MCTs. And, of course, anti frucrose, and while he would not come out against whole fruit whole hog, he did discuss the anecdote of the "fruit orgy" of orangoutangs where they seasonally develop insulin resistance and put on fat. Lustig seems to feel that fructose, MCTs, and BCAAs are damaging to the mitochondria and lead to insulin resistance (thus he is anti-corn fed beef, as corn-fed beef is higher in BCAAs than grassfed, apparently. I don't know enough to say whether that is wacky or not.) Ludwig was quick to point out that there is no evidence linking fruit consumption to any chronic illness. I'm quick to point out that I eat 1-2 bananas a day, and I rely on 1/2 banana before and after crossfit for happy lifting.

What we can all agree on - eat "real" food, and from a policy and preventative perspective, perhaps the most important, simple message is to eliminate sugar-sweetened drinks in the diet. I think everyone would pretty much agree on that one too.

The policy/lawyer talks were terrific -- they were very interesting, and exciting, as these lawyers and seasoned politicians are going forth to help farmer's markets and soil preservation, water preservation, sustainable agriculture and align government policy incentives with the supply and availability of local, real foods. Some of the real initiatives include penning legislation to abolish state sales tax at local farmer's markets (just as most states do not charge sales tax for staple food items at the grocery store), and streamlining state and local regulations to allow for farmer's market and production and sale of homemade low-risk specialty items (such as jams or apple pies). As the current farm bill heavily supports the commodity crops (corn, wheat, soybeans, etc.) and downgrades vegetables to "specialty crops," some changes would be nice!

I left the talks a little shaken. I felt (as always) the standard anti-obesity message is not practical for a non-Mediterranean culture and likely to be a terrible failure here in the U.S., land of the processed health food, and the pro-egg, fat-is-okay (albeit *cough* polyunsaturated) message has certainly not been carried to clinicians, nutritionists, and doctors in the field. That Willet and Ludwig were not willing to support whole dairy or red meat/pigs was unfortunate. The "whole foods" message gets really lost when we are parsing out red meat and even dairy. Forget the "nuts and legumes" (seriously, legumes? The only beans worth eating are refried in lard, amirite? - to clarify, this is my little joke, as beans upset my tummy) - how to we kick red meat and dairy to the curb without eating a crapload of disgusting kashi? I can't fathom it - Stephan I think would advise in consideration of sustainability and a large scale policy level for us to add potatoes (not fried, but whole, baked or boiled potatoes) and use traditional methods to prepare grains.

However, today I was fortunate enough to be invited to a lunch with Stephan Guyenet, Mat Lalonde, and friends and significant others. It was very refreshing to be with Mat and Stephan, who seem to be aligned with me about not supporting the some paleo fringe extremes (meaning acceptable carb levels vary, gluten and dairy levels vary in tolerance on an individual basis, etc.). We were also concerned about ideologues who seem to support one aspect of a diet as the end all, be all to ill health (fructose, or wheat, or carbohydrate), when the scientific truth is far more complex.

One of the most interesting aspects of the discussion was reflection upon genetic adaptations to agriculture - hemochromatosis (a disorder where humans can't properly get rid of iron, which was likely protective in grain-eating, low iron situations but which would make a classic low-carb, ruminant heavy, offal heavy diet dangerous), lactose tolerance in adulthood, and variations in folate metabolism. Evolution did not end with the paleolithic, of course, and while the generalities of "eat real food" are true for everyone, the specifics can vary a great deal depending on context - insulin resistance, obesity, large exercise volume, etc.

I don't have a specific prescription on this blog for a very important reason, but let me be explicit - for the most part, go archevore, exercise, tighten up the sleep, learn stress reduction, and that will help a great deal, and if all those things aren't in order, meds and strict ketogenic diets and supplements may well be shoveling sand against the tide. This all doesn't mean I'm entirely anti-meds or anti-ketogenic diets - indeed, if the issues are substantial and significantly impair functioning, I want to help in whatever rational and evidenced-based way possible… but don't look for magic. For the most part, it fails us.

How You Like Me Now? The Heavy

You Are What You Eat

2011-10-19T21:06:00.005-04:00

Did you know that diet could affect mental health? Okay, that is, perhaps, putting it too strongly. Diet is correlated with mental health, especially in Australia.

Mental health disorders tend to be pretty chronic and can be debilitating. And, unlike many chronic diseases of Western Civilization, they tend to strike young. Autism in babyhood, anxiety disorders often before age 10, mood disorder in the teens, schizophrenia in the late teens and early adulthood… psychiatric disorders cost us so much in terms of productivity and health.

Y'all already know what I think. (Donnie Darko, Mad World right click to open in new tab).

There is every reason to believe a modern, processed, nutrient-poor diet could have a lot of influence on mental health. Of course, no one knows what to tell anyone to eat except for "fruits and vegetables." And that is what PLOS1 tells us today…

A Prospective Study of Diet Quality and Mental Health in Adolescents

In this study, several thousand Australian adolescents filled out surveys about diet, health, and mental health several years apart.

Here is how diet quality was assessed:

As such, a point was allotted for each of the following: eating breakfast at home on school days; eating lunch brought from home; consuming two or more fruit serves per day; four or more vegetable serves per day; fruit and/or sandwiches as after school snacks; generally avoiding biscuits, potato chips, pies, hot chips, fried foods, chocolate, sweets, ice-creams as after school snacks; and, finally, both consuming healthy after school snacks and avoiding unhealthy after school snacks.

(Chocolate????)

It is not terribly surprising that an unhealthy diet score in the first survey correlated with a poorer rating of mental health in the second survey several years later. Covariates were assessed for but can never really be extinguished completely… interestingly, mental health at baseline did not predict diet several years later, strengthening the findings of the study.

But I rather love these researchers, and will quote some of the interpretation in full here:

...the prevalence of emotional and conduct problems in adolescents increased in the period between the mid 1970's and 1999, while a new meta-analysis, reporting on data collected at many time points and, thus, free of confounding by age and/or recall bias, has reported large generational increases in self-reported psychopathology in American high school and college students between the 1930s and 2007. These increases did not appear to be explained by social response biases, economic cycles or changes in student populations, and the authors concluded that changes in unidentified cultural factors have resulted in increased rates of psychopathology among American youth.

Paralleling this possible increase in the rates of psychological illness among young people are data indicating a reduction in the quality of adolescents' diets over recent decades. A report based on trends in adolescent food consumption in the US identified a reduction in the consumption of raw fruits, high-nutrient vegetables and dairy foods, which are important sources of fibre and essential nutrients, between 1965 and 1996, with an associated increase in the consumption of fast food, snacks and sweetened beverages. Concurrently, population surveys demonstrate a substantial increase in overweight and obesity among children and adolescents over recent decades. Obesity does not necessarily indicate nutritional repletion, as high-energy foods typically have poor nutrient content.

Could it all be connected? Increasing muffin tops and increasing psych hospitalizations in children and increasing psychopathology? And how expensive is it to society when a lean cuisine is the epitome of healthy eating?

A very very mad world indeed.

Crisco and Cocaine, or A Fun Saturday Night

2011-10-14T15:32:00.001-04:00

As usual there is a stack of papers awaiting my attention, but Dr. Aaron Blaisdell just tweeted this sparkling brand new one that just couldn't be ignored -- A History of Bingeing on Fat Increases Cocaine Seeking and Taking. (Boy, rodent researchers really know how to make an intriguing combination of ~~industrial lubricants~~ "heart healthy vegetable oil" and cocaine sound boring.)

Song - an oldie but a goodie - The Dandy Warhols: Bohemian Like You (right click to open in new tab)

I've discussed the rodent bingeing literature before: see here and here and a little bit here. Rats and mice, like humans, will binge on sugary snacks. Unlike humans, rats and mice will binge on Crisco alone, whether it is the old fashioned trans-fat kind or the modern however-it-is-they-make-vegetable-oil-solid-at-room-temperature kind we can buy in the supermarket now. The sugar-fat combo seems to be the most damaging - though in all of these studies, a variety of vegetable oil was the fat used, so it is hard to know whether it is an omega 6 thing or a fat thing in general.

A little reminder - not all binge-eaters are obese, but 67% of them are. And not all obese people are binge-eaters, far from it. It seems that about 1/3 of those who seek medical treatment for obesity have binge-eating behavior, however. If we are considering the prospect of disordered "food reward" pathways, perhaps looking at binge-eaters will help us to understand one extreme of the continuum. Or perhaps the pathology behind binge-eating and the supposed disordered food reward leading to obesity are really different concepts. I suspect they aren't entirely separate, but it isn't a simple comparison, either. And certainly, exploration of binge-eating and addiction can hopefully inform our treatments of those disorders.

In this new study, researchers added the interesting twist of seeing if a history of fat-bingeing made their rodents more vulnerable to becoming addicted to cocaine in the future. As I've noted from my clinical experience (and as is noted in the literature), binge eaters can (but don't have to) have a hard time controlling behaviors in several areas - bulimia and binge-eating often occur together with substance abuse in humans.

Let's start with what all the folks agree upon - massive doses of sugar (really, sugar - sucrose, meaning glucose + fructose) are a bad idea, particularly in those who are vulnerable to addiction of bingeing behaviors.

Rat researchers know their bingeing and drugging. A correlation between liking sweets and drugs of abuse (including alcohol, cocaine, and amphetamines) is known in humans, and in rats, repeated exposure to sucrose seems to enhance behavioral susceptibility to cocaine later on. Sucrose is, in this paradigm, a "gateway drug." Let's not forget that in sugar-bingeing rats, taking away the sugar leads to opiate-like withdrawal syndromes and worsens the withdrawal from morphine. So let's say you are a binge-eater withdrawing from a sugar-fest -- are you more likely then to have a bottle or two of wine, some meth, or cocaine? Could be. Even though these different drugs of abuse affect different reward neurotransmitters, they all end at one common pathway, which makes sorting out some of the specifics rather difficult.

Here is a money excerpt from the paper:

Offering further support for the connection between the intake of sugar and fat and the intake of drugs of abuse are several studies investigating the neuroanatomical and neurochemical changes that accompany sucrose and fat consumption. Not surprisingly, these sugar and fat consumption-induced changes occur in the mesocorticolimbic dopamine system, a major component of the brain’s reward pathway, and many of the changes mimic those that occur after exposure to drugs of abuse, including turnover and release of DA, D2 receptor binding and expression, and dopamine transporter binding and expression. In addition, differential responsiveness in rats bingeing on fat has been reported when a D2 receptor antagonist is administered peripherally, or directly into the prefrontal cortex.

In short, eating fat and sugar seems to engage our reward systems in the same way that drugs of abuse do. This is not terribly unsurprising - we have a reward system for our survival. Protein is easy to find in the paleolithic world (ask any bug or lean rabbit) - but what about our fuels of sweet and fat? We need it, we love it, and our big brains encourage us to find it and consume it, and drives us to find it and consume it again. My suspicion (not first thought of by me in any respect!) is that, like cocaine, Snackwells, Oreos, Big Gulps, potato chips, peanut M&Ms and deep-fried twinkies stimulate our reward centers in ways our brains were never designed for, like a magnitude 9 earthquake taking out at magnitude 7-rated nuclear reactor. To parse matters even further - the actual substances may be less important than the manner in which they are consumed. A sugar binge (with all the sweaty anticipation, consumption, aching stomach and crashing blood sugar later on) is a far more worrisome issue than eating the same amount of sugar over the course of a day, at least in rats. Here we separate those who are (for whatever reason - environment, genes, etc.) vulnerable to addiction and those who are not.

So what happened to these rats with the cocaine and the crisco, anyway? The methods are a bit boring, but in short, we have some rats on standard rat chow, and then some rats on standard rat show plus access to fully hydrogenated Crisco (not sure where you can get your paws on that nowadays! J.L. Smuckers must have a special research repository in the basement. Actually, wasn't it the partially hydrogenated Crisco that was the bad stuff? Poisons are so confusing...) All the rats were then transported to another lab 90 miles away (in Hershey, PA, which is a lovely community of nostalgia and chocolate), where there was no Crisco, but there was some high quality blow (actually it was IV cocaine, and the rats could control the administration by licking a certain spout, leading to an infusion of the drug. Interestingly enough, a study was once done on humans comparing IV cocaine, IV amphetamines, and IV caffeine, and the humans could not tell the difference.)

You will not be surprised to learn that the indulgent, gluttonous crisco-bingeing rats were mostly the same ones who had a bit too much affection for the cocaine. The other, abstaining rats were rather like Meg Ryan in "When Harry Met Sally" "I don't like to eat between meals." So superior, so sure that all you have to do is exercise some self control, as they do, and you could wear size 2 jeans, no problem.

I know, it is a big leap from a few crisco-loving, coke-addled rats to 60% of the population being overweight or obese. But certainly there is something there. And for the love of all that is precious and good, DO NOT EAT HYDROGENATED CRISCO (even though it is much better than the partially hydrogenated stuff**).

Ever.

** In the US, anything less than 0.5mg trans fat per serving can be listed as "0g trans fat." Does anyone know the fully hydrogenating process for New Crisco and how good it is at getting all the double bonds saturated? Or are quite a few missed and you end up with a small dollop of trans fat each time, still?

More on Infections at Psychology Today

2011-10-11T12:32:00.002-04:00

Updated another post (with some new research findings) at Psychology Today that is pertinent to my most recent post here:

Could Alzheimer's Dementia be Caused by a Virus?

Also new(ish) at Psych Today:

Parkinson's, CoQ10, and Creatine

Brain Energy

More new posts soon!

Infections and Schizophrenia Risk

2011-10-09T10:15:00.002-04:00

Whew. Quite a response over my disappointment in Wheat Belly. And Melissa gives us an informed and reasoned review (mine was more of a visceral reaction). It's hard for me to see the merit in a book just because the idea of wheat not being ideal for human consumption agrees with my own views.

On the interesting papers front, a couple of new articles shine more light on the relationship between infections and mental disorders. I consider this type of thing "evolutionary psychiatry" as it brings us closer to finding the true pathology of illness, inflammation, and disease. In addition, the typical evolutionary prescription of nutrient-rich and anti-inflammatory diets and appropriate amounts of vitamin D ought to increase resistance to infection and resilience to the inflammation and autoimmune issues that may be spurred on by such infections.

The first paper is from Denmark, Toxoplasma Infection and Later Development of Schizophrenia in Mothers, from August's American Journal of Psychiatry. There is also an enlightening editorial in the same issue.

Toxoplasma gondii is a parasite that one can pick up from contaminated cat feces, from eating undercooked meat containing the infectious cysts or contaminated vegetables, and from being a fetus whose mother is infected. Infection in pregnant women can cause major birth defects in offspring, and this fact is the origin of the common advice for pregnant women not to clean litter boxes. Studies have linked infection with toxoplasma with schizophrenia since the 1950s. More recently the association was confirmed in a 2008 study of the US military. All these early studies were retrospective and observational, which is the weakest sort of experimental data this side of the anecdote. Meaning folks with schizophrenia were compared with normal controls, and it turned out that people with schizophrenia have a higher rate of previous exposure to toxoplasma.

A step up from the retrospective, after the fact sort of study is the observational cohort study. In this type of study, a group of people are followed for many years to see what develops. This type of experiment presumably takes away what sorts of bias can be introduced by finding cases after the fact. (For example, do people with prodromal symptoms of schizophrenia engage in behavior that makes it more likely for them to be infected with toxoplasma - washing hands less, or not cooking meat as thoroughly?) Scandinavian countries are hotbeds of these studies, as they've collected all sorts of medical data on pretty much all of their citizens for a generation now.

In Denmark, 45,609 women were followed from childbirth, when antibodies indicating prior prenatal exposure (or not) to toxoplasma in their babies were measured by heel-stick 5-10 days after being born. All these antibodies circulating in the baby's bloodstream were made by the mother, not the baby, as a baby won't make too much in the way of these sorts of antibodies (IgG) until the immune system is a bit more mature, by 3-6 months. Therefore mothers with babies who were positive for T gondii exposure were presumed infected themselves. Some, but not all, of the mothers had been tested for IgG levels in the first trimester of pregnancy - these levels correlated with the newborn levels that were available for all the mothers.

Over the following years (the women were followed from 1992-2008), 80 of the mothers developed schizophrenia. The ones whose babies had the highest IgG levels had a higher risk of developing schizophrenia than those who had babies with the lowest levels (the risk was increased by 1.73-fold, which was statistically significant - though with a population risk of approximately 1%, toxoplasma seems to increase the risk to about 1.7%). Other meta-analysis have shown odds ratios of around 2.54-2.73 (odds ratios above two are considered a significant finding). In the Danish study, adjustments were made for confounders (such as age, urban or rural, and other known risk factors), and women already diagnosed with schizophrenia at the beginning of the study were obviously excluded.

Why would infection with T gondii increase the risk of schizophrenia? Active infection in the central nervous system can certainly cause huge problems (such as seizures) and inflammation. In addition, our immune reactions to these infections can cause problems, especially if something on the infectious particle looks a bit like something in our own cells. The classic example of this type of problem is rheumatic heart disease, most likely caused by our own antibodies attacking heart tissue after a strep infection. It is also thought that neurological symptoms of lupus are caused by these neuro-specific auto-antibodies. In the case of toxoplasma, it is a possibility that the anti-toxo IgG antibodies react with neural tissue and might help the immune system attack the NMDA receptors in particular.

The paper Progressive Gray Matter Loss and Changes in Cognitive Functioning Associated With Exposure to Herpes Simplex Virus 1 in Schizophrenia: A Longitudinal Study appeared in the same August, 2011 issue of the American Journal of Psychiatry. In this study, there were four groups of folks - schizophrenic patients (none of whom were on antipsychotic medication) who were seropositive for HSV1 infection or not positive, and normal healthy controls who were also positive for HSV1 infection or not. All these folks were followed with some cognitive testing and neuroimaging at the beginning of the study and at one year. It was found that the schizophrenic folks with HSV1 infection had significant worsening of certain measures of cognitive functioning and shrinking of gray matter in certain regions (meaning the brain cells are dying off). The other three groups of people didn't have these changes.

Here is what the researchers had to say about the possibilities:

There are several plausible explanations for the observed changes. In the rodent and rabbit models of CNS HSV1 exposure, latent infection and reactivation directly affected functioning through neuronal death or dysfunction. Neuronal death resulted from apoptosis. Neuronal dysfunction during reactivation and latency resulted from modulation of apoptosis and autophagy, host cell translational shutoff, oxidative damage, and/ or neurotransmitter alterations. Even with peripheral infections, HSV1 could alter neurotransmission through release of cytokines, especially chemokines, which may be elevated in HSV1-exposed individuals. Human studies support some of these observations. These processes occur throughout the life of an infected person.

In short, infection (even a smoldering latent infection without obvious active signs) in the brain or periphery can lead to all sorts of changes in the way the cell handles energy and self-destruction and general inflammatory badness.

Monitoring, modulating, and avoiding these infections seem like different ways to decrease the risk of central nervous system symptoms.

Slam-dunked and Wheat Belly

2011-10-06T16:54:00.002-04:00

All right. Work has been really, well, working me lately, so I've barely had time to sleep, much less to review papers, keep up with the blogosphere, and write.

I do like this song, though (right click to open in new tab): Days are Forgotten (and it is getting very difficult to find songs on youtube that will play without ads upfront - sorry if there is an ad on this one! It had a glitch and skipped the ad but might not work for everyone :()

Despite the time crunch, I did manage to squeeze in Wheat Belly over the weekend (most of it), and read the rest last night.

No, I don't like it.

No, I don't eat wheat as a rule, and I am not a grain industry shill.

But I don't feel I have to put my name out in support of a shoddy, sloppy book just because the overall message "wheat sux" agrees with my thoughts that wheat gluten and other wheat proteins likely are inflammatory in many people and cause problems for more than just those with celiac disease. I think most physicians and researchers with critical thinking skills will find this book useless and full of hyperbole. For those not taken in by the confident tone, it may do more harm than good.

Why don't I like Wheat Belly? In short, it is the carelessness and simplicity of the message. Hyperbole and poorly supported, confident claims. Obesity and chronic illness is a complicated subject. It doesn't come down to wheat. Wheat isn't responsible (entirely) for "moobs" or the other too-cute phrases Dr. Davis churns out ad nauseum throughout the book.

An example? In chapter 4, Dr. Davis spends a bit of time discussing the evidence linking wheat to schizophrenia and addiction. I've discussed this issue at some length and noted the obvious circumstantiality of the evidence and the need for more research. (see Wheat and Schizophrenia and Wheat and Serious Mental Illness). And while Dr. Dohan (who was the major researcher who championed the wheat causes schizophrenia meme) felt he had evidence that schizophrenia has increased incidence in wheat-eating populations, most modern schizophrenia researchers make note that schizophrenia is pretty consistent in incidence across many populations - around 1%-1.3% incidence, in the developing world and in the Western world, in rice eating Chinese areas and the wheat-eating American Midwest.

Dr. Davis says: "while it seems unlikely that wheat exposure caused schizophrenia in the first place, the observations of Dr. Dohan and others suggest that wheat is associated with measurable worsening of symptoms." I don't get that quote at all. Is the incidence of schizophrenia higher in non-wheat eating countries or not? Do exorphins cause psychotic symptoms or not? Schizophrenia, after all, is defined by the symptoms. Something that "worsens" schizophrenia will cause schizophrenia, a symptomatically defined illness, as I've discussed earlier in my posts on cannabis.

But where I find the book to be critically annoying is in the discussion of addiction and opiates. Wheat, as we know, has break-down components that are exorphins, which activate the opiate receptors in the brain and nervous system (the same receptors that are activated by our natural endorphins, opium, morphine, heroin, percocet, and other opiate painkillers). The opiate pathway is part of the reward pathway in the brain, and is actually activated by anything "rewarding" - such as sex, exercise, drugs, gambling, and rock and roll.

Where I agree with Dr. Davis is that I have seen clinical evidence that some people seem to be "addicted" to wheat. Particularly night bread binge-eaters. They talk about bread much like one of my opiate addict patients would talk about oxycontin. They can't stop eating it even after they are full, and even when they desperately want to lose weight. They will leave their cozy house and pick up crackers, pretzels, fast food with fluffy bread, or a fresh loaf to eat at night. Critically, in certain cases (where more evidence-based methods have been tried), I've managed to stop these cravings and binge behaviors with naltrexone, which blocks the opiate receptors and short-circuits reward. The problem is, ALL reward is mediated through opiate and dopamine, so using naltrexone doesn't tell you that you've blocked specific wheat exorphins - maybe the person has a real jones for fresh steaming lovely bread for simple reward sake - like some people love chocolate, Pringles, or cocaine.

It's a good message, though, and something that should be researched. But then Dr. Davis comes up with this sentence (and also states he has seen the withdrawal and "brain fog" from wheat in "thousands of people"then later "I've personally witnessed hundreds of people…"), which is incredibly jarring and ruins the credibility of the message: "Let's pretend you're an inner-city heroin addict. You get knifed during a drug deal gone sour and get carted to the nearest trauma emergency room. Because you're high on heroin, you kick and scream at the ER staff trying to help you. So these nice people strap you down and inject you with a drug called naloxone, and you are instantly not high."

Naloxone (and it's orally administered cousin, naltrexone), is an opiate blocker, or "opiate antagonist." It will immediately knock opiates off the opiate receptor and put someone high on opiates into instant withdrawal. This is not only extremely unpleasant, it tends to make people very agitated, unhappy, and even violent. If you have to do it to save someone's life, you do it. If someone is overdosing on opiates and loses the chemical signal to breathe, it will be lifesaving. If someone is alert and active and still high on heroin, injecting someone with naloxone would be a galactically stupid thing to do, particularly if you were just injured in a knife fight and needed some painkilling. Injecting someone with naloxone will mean that the strong painkillers will not work in someone who will have a high tolerance to hospital painkillers.

Any emergency room physician, nurse, or doctor with a shred of ER experiecne will read that sentence in "Wheat Belly" and go, "huh? What is this guy talking about, and is he galactically stupid?"

Honestly, I think it is a throwaway line that was carelessly written and carelessly published. And other "paleo" books like "The Vegetarian Myth" are full of lines like that. But you know what, I have a much higher standard for a cardiologist than I do for a non-scientist like Lierre Keith. I want real science, real risks, real data. Not hyperbole and nonsense.

So no, I don't recommend Wheat Belly. And I don't recommend eating wheat either.

(Nor am I saying that Dr. Davis is stupid - far from it - just careless in his phrasing. If you are going to take on Conventional Wisdom of Healthy Whole Wheat, you really have to "bring it." It was not brought.)

Of Like Minds

2011-10-02T08:26:00.001-04:00

As you may recall from my AHS - The People Post, one of the best experiences from my visit to Los Angeles was meeting a few other like-minded psychiatrists there. Evolutionary medicine, as sensible and evidenced-based as I try to make it, can feel very lonely and off the beaten path. So it is lovely to meet people who see the innate reason of it all. The northeastern US is both protective and stifling in its conservative medical atmosphere - so to have others thinking in ways apart from psychopharmacology and psychodynamic or behavior therapy as the end-all, be-all is, well, glorious.

Beethoven - Symphony No. 9, 4th Mvt (one of the finest pieces of music ever written, though choral music is not always my favorite, I make an exception for this one - right click to open in new tab)

Not long after I returned from AHS, I received an email from a psychiatrist I had seen on Jimmy Moore's low carb doctors list, Judy Tsafrir, M.D.. She works maybe 30 miles away and has a holistic psychiatry practice in Newton (a city just to the west of Boston, which, I'm told has the highest number of psychiatrists per capita in the world - and yet we could still all be working 24/7 and turning people away. Remarkable). Dr. Tsafrir has extensive experience and training in both child psychiatry and psychoanalysis (unlike myself - I am a pretty run-of-the-mill adult psychiatrist). In more recent years she has turned to dietary therapies and has become an expert in the GAPS diet.

I met Dr. Tsafrir for lunch a few weeks ago, and like most analysts she is a patient and serene sort of person - rather the opposite of myself in some ways (as I can be somewhat impatient and directive). We talked a bit about our training and experiences and our frustration with the restrictive (and sometimes disastrous) mold that encompasses "evidenced-based medicine." And of course we are interested in the best data and best evidence for our patients, yet the money and the studies seem to be spent and performed with a different agenda.

Dr. Tsafrir has started a blog, and I am adding her to my "Of Like Minds" group to the right. Her latest entry is about her thoughts on "Wheat Belly," entitled One Size Does Not Fit All. I encourage any readers with GAPS questions especially to take a peek, as I have only started reading the book and have no clinical expertise in that area.

People often ask me if I know of like-minded psychiatrists where they live. There is Ann Childers, MD in Oregon, the two psychiatrists I met at AHS (I did not ask them about sharing their names or details so will not do so), and now Dr. Tsafrir! And maybe more and more, every year. We shall see.

Happy Happy Coffee!

2011-09-29T22:10:00.001-04:00

I'm really falling behind my stack of papers. Fortunately, life is good and busy, and there are always new, catchy songs to listen to:

The Temper Trap: Fader

That song really puts a spring in my step. Rather like a strong cup of coffee. Full disclosure - more of a tea person, but I've been known to drink a cup of joe every now and again. Maybe I ought to drink a bit more… the evidence is mixed, frankly. And certainly I can't tell you how many times I've had patients complain of insomnia, only to find out they are drinking 6 large iced coffees a day, or 12 Mountain Dews (no matter how much I exercise, I don't seem to be able to take this weight off, doctor…).

But what does the research say about, say, depression and coffee? A brand spanking new piece of epidemiology from the Nurses' Health Study was published in the Archives of Internal Medicine this month - Coffee, Caffeine, and Risk of Depression Among Women.

Some facts from the article - 80% of the caffeine in the world is consumed as coffee. Interesting. Prospective studies of men and caffeine use showed a strong inverse association between coffee drinking and depression, with no association for tea or cola. Three cohort studies showed an inverse relationship between coffee consumption and suicide (though in a Finish study, there was a J-shaped curve with both very high (>7 cups of coffee daily) and low consumption of coffee seemingly less protective than moderate amounts.)

So, in the Nurses' Health Study (following 121,700 American female nurses starting in 1976), women filled out questionnaires every two years. 97,000 filled out questionnaires in 1996, 98, or 2000, and those with no history of depression at that time (50,739 women) (those with unknown history were excluded) were followed over the next decade.

Regular coffee drinkers in this cohort were more likely to be smokers, drinkers, and not go to church! They also tended to have lower rates of diabetes and obesity. Average consumption for the whole group was about 1&1/2 cups of coffee a day.

Among the 51,000 women, about 2600 developed clinical depression in the 10 year period. There was a dose dependent, inverse relationship between the amount of coffee consumed and the risk of developing depression over the years. When covariates (such as age, health, smoking, divorces, etc. etc.) were all adjusted for, the inverse relationship became even stronger! No associations were found between tea consumption, chocolate consumption, decaf coffee, or soda consumption and depression.

So what's up? Is coffee an antidepressant?

I Know What I Am: Band of Skulls

Well, maybe. This is no randomized controlled trial, so causation cannot be determined, but caffeine (1,3,7-trimethylxanthine) antagonizes the adenosine A2A receptor. This is thought to have pro-dopamine effects. By taking out adenosine, we might also be affecting the transmission of norepinephrine and serotonin, both known targets of antidepressant medicines.

Since coffee is known to cause insomnia and anxiety, both features of depression, a weakness of the study is that women prone to insomnia and anxiety might limit their intake of coffee, thus biasing the results so that women who can tolerate a truckload of coffee also happen to be the ones less prone to depression.

But… all told, it seems that this study is another notch in coffee's bedpost. Though less than 8 cups a day seems prudent. And I really can't recommend Mountain Dew :)

Anger and Serotonin

2011-09-24T13:45:00.001-04:00

My buddy Jamie Scott is a research machine. It's all I can do to keep up with the interesting papers and links he emails my direction. Today's article is yet another one we owe to his sharp eye. He also has brand new digs at a wordpress blog (*brief moment of jealousy*) - so edit/add him to your blogroll and check it out:

That Paleo Guy

Some music - I rather adore the Yeah Yeah Yeahs. Here's an oldie but a goodie: Gold Lion (right click to open in new tab). Favorite comment on youtube: "i think I just got whiplash rocking out to this song" [sic].

Want something a bit more classical? How about a Chopin Nocturne played by none other than Rachmaninoff from 1927? (You will not be rocking out, but it is quite lovely).

The paper is in Biological Psychiatry: Effects of Acute Tryptophan Depletion on Prefrontal-Amygdala Connectivity While Viewing Facial Signals of

Aggression

It's kinda cool. Involves humans, which is always a plus. It is one of those "view angry faces whilst in a functional MRI machine" which has some limitations, but it is pretty much the only way to see what's going on in real time in the old noggin, seeing as how it's rather awkward to test gene expression and neurotransmitter levels other ways without decapitation (not likely to pass the institutional review board any time soon, unless you were unfortunate enough to be born as a research rodent). (Random aside - Andrew tweeted this REAL MIND READING finding yesterday. Wow.)

How many segues is that? Welcome to my left-handed, small child-raising brain. As we know, depletions in serotonin, especially in a particular communication circuit between the frontal lobes (the policeman) and the amygdala (the emotional/rage center of the brain) leads to anger and aggressive behaviors. Now, there are some people who are just aggressive altogether - I'm thinking Drew Barrymore's boyfriend in one of the Charlie's Angels movies. We're not talking about that. We're talking about impulsive aggression. All the sudden, you just want to jump out of your car and strangle the other driver who cut you off (please don't do this). Impulsive aggression can be unexpected and very scary, and can certainly ruin lives.

So what if it happens just because you forgot to eat your banana this morning??? Oh, don't worry, we are likely more resilient than all that… but in an experimental setting, one can pretty much abolish serotonin via a weird laboratory tryptophan-depleting drink. Then you get into an MRI machine. Then you look at pictures of angry faces (if I were running this experiment, I would pipe in some hard core metal, and not one of Chopin's Nocturnes). Of course, I read A Clockwork Orange in high school. The tryptophan-depleting drink significantly reduced both plasma tryptophan levels (remember, tryptophan is the precursor to serotonin) and the ratio of tryptophan to other long-chain neutral amino acids (remember, tryptophan competes with these other amino acids for entrance into the brain).

In the end, the reactions of the tryptophan-depleted individuals to the angry faces vs. controls was statistically significant. Tryptophan-depleted folks had a higher response to the angry faces within the amygdala (the rage/anger part of the brain) compared to controls, and compared to the response to neutral faces. These findings would suggest that, as suspected, serotonin helps you chill out and assess the situation when faced with an angry hoarde.

Between the mind reading and the availability of a rapid acting tryptophan-depleting anger drink that will affect our aggressive reactions, I'm a little worried about the future of our free will. But I'll try to eat some protein, micronutrients, a banana, and put my trust in the incompetence of bureaucracy in order to be less paranoid.

Carbohydrates, Gut and Autism

2011-09-23T19:28:00.001-04:00

If you haven't already, go read the latest Psychology Today post about Alzheimer's and High Blood Sugar and Alzheimer's and Omega3s. Page views on my Psychology Today posts help support the paper, toner, textbook, and time that goes into Evolutionary Psychiatry.

Jamie sent me this link from PLOS1 (which, admittedly, is not the Rolls Royce of journals, but does have some interesting stuff every now and again):

Impaired Carbohydrate Digestion and Transport and Mucosal Dysbiosis in the Intestines of Children with Autism and Gastrointestinal Disturbances

Hmm. The text is very large and doesn't seem amenable to editing. One more reason to move over to wordpress…

So y'all have heard of the GAPS diet, right? Natasha Campbell-Mcbride is a doctor who had a kid with autism. I haven't read her book yet, but the general theory is that folks with certain issues with gut microbiota and carbohydrate malabsorption will end up with psychological/psychiatric symptoms, including autism. Dr. Campbell-McBride had great success with this approach, as, apparently, do many others.

In this PLOS1 paper, patients with autism and patients with GI disturbances were examined for different carbohydrate malabsorption.

Kids with autism often have gastrointestinal problems (survey studies report comorbidities of 9-91%, which isn't all that useful a percentage spread, but certainly given clinical experience and thinking about autistic kids I know in the community, higher seems more likely than lower). Pathologic findings of gut issues in autistic kids include gastritis, esophagitis, inflammatory markers at the gut lining, gut lymphatic system hyperplasia, increased intestinal permeability, abnormal gut microbiota findings, increased enzyme secretion, and carbohydrate malabsorption. Indeed, autistic children with severe gastrointestinal symptoms are more likely to have severe autistic symptoms (1).

So what happens if you don't have efficient digestion of disaccharides, for example, for whatever reason (damage to gut, unlucky genes, other illness)? Well, any carbohydrate that goes undigested will float down and feed the hungry masses of gut bacteria. This feeding can result in bloating, discomfort, diarrhea, and proliferation of pathogenic bacteria, which can presumably affect both inflammation and behavior.

The researchers from the latest studies biopsied the intestines of autistic children with gastrointestinal symptoms (AUT-GI), finding the following (among other things:)

Pyrosequencing analysis of mucoepithelial bacteria revealed significant multicomponent dysbiosis in AUT-GI children, including decreased levels of Bacteroidetes, an increase in the Firmicute/Bacteroidete ratio, increased cumulative levels of Firmicutes and Proteobacteria, and increased levels of bacteria in the class Betaproteobacteria...

Metabolic interactions between intestinal microflora and their hosts are only beginning to be understood. Nonetheless, there is already abundant evidence that microflora can have system-wide effects and influence immune responses, brain development and behavior.

When there is a devastating illness with only supportive treatment, a harmless intervention, such as adjusting the types of carbohydrates in the diet (this will not be a completely "paleo" intervention - sweet potatoes, for example, are off limits on GAPS I believe - I will post some more when I get the book), seems to be an approach that ought to be supported and attempted. Sure, it might not help everyone, but what is there to lose?

Interesting Findings in Eating Disorders and Alzheimer's

2011-09-17T17:18:00.001-04:00

First off, everyone take a couple of hours and hop on over to Robb Wolf's blog and listen to his podcast with Dr. Kurt Harris. As usual, Kurt pulls it all together with fun and flair and a hefty serving of common sense. He gives me and my blog a few mentions, which is very much appreciated, as always :)

I've been anticipating excitement hunting down a couple of papers that came out in the last couple of weeks - the first one: An Update on Hospitalizations for Eating Disorders, 1999-2009. As expected from a statistical brief, there is little there besides the numbers - so it is not all that exciting. Overall, eating disorders as a primary or secondary diagnoses have increased 24% in that period, cost of hospitalizations have increased 29%, and hospitalizations for children under 12 have increased 72%, and for people 45-65 88%, and for men 53%. Weirdly, hospitalizations for pica (compulsively eating non-food items, such as dirt or soap or whatever) have increased 93% but are still rather unusual. If you look at eating disorders as a "principal" diagnosis only, the number has actually fallen 1.8%, and I've seen some funny headlines as a result - "eating disorder hospitalizations fall, but pica hospitalizations double."

An important caveat is that these numbers are generated from billing codes. If someone comes to see me at the office, I am obligated (if I want to be paid by the insurance company) to generate a code based on a DSMIV diagnosis that I put on a billing form. The same is true for inpatient hospitalizations. And in the past 13 years, a number of states and the federal government have issued rules to prevent insurance companies from rejecting paying for psychiatric diagnoses that are so-called "biologic." This change is a part of the mental health parity act. "Biologic" diagnoses vary from state to state depending upon the laws, and even depending upon the insurance company, but generally include major depressive disorder, bipolar disorder, schizophrenia, etc. Sometimes anxiety disorders are not included. Addiction used to be not included, now it is I believe, and often autism and eating disorders are not included. Therefore if I am a doctor who would like to get paid and not have patients stuck with bills when they pay their insurance premiums, and someone meets criteria for major depressive disorder (MDD) AND an eating disorder (which in the inpatient world will very often be the case), the MDD will always be the "principal" diagnosis to avoid issues down the line. I know that anorexia is often more likely to be covered for inpatient care than bulimia, depending upon the medical status of the patient… in short, the overall trend of primary and secondary diagnoses and increase in men and children and older people I find very interesting more than the drop in "principal" diagnosis.

It is actually rather difficult and getting more difficult all the time to be hospitalized for psychiatric disorders in general. For the most part you must be an obvious imminent risk to self or others or completely unable to care for yourself in order to get a bed, which are in scarce supply. In 1999 it was easier to get the slightly less ill hospitalized. So with this background, I find it rather remarkable the eating disorder hospitalizations have increased to such a degree. Binge eating rarely results in psychiatric hospitalization, and outpatient rates of binge eating and bulimia are rising also (though inpatient bulimia hospitalization dropped - the severe cases are often readily managed in intensive outpatient day programs nowadays, however.) As obesity has also increased over the same period of time, I can't help but suspect the two trends are related, but I can't prove it.

The second article I was excited to hear about is probably a watershed paper in the treatment of Alzheimer's dementia: Intranasal Insulin Therapy for Alzheimer Disease and Amnestic Mild Cognitive Impairment. This paper discusses a pilot trial of 104 adults with amnestic mild cognitive impairment or Alzheimer's disease vs controls with a couple of doses of intranasal insulin.

Why intranasal? None of the subjects had diabetes, and obviously systemic insulin could cause dangerous hypoglycemia. The intranasal dose goes pretty much straight to the central nervous system via the olfactory and trigeminal nerve perivascular channels, and none of the subjects had hypoglycemia during the trial.

Why insulin? Well, as I've discussed at great length (I really ought to repost some of those dementia articles up on Psychology Today…), there are very clear issues with the ability of a dementing brain to metabolize glucose (the example in that article is Parkinson's disease, but the principle is very similar for Alzheimer's). This problem results in inefficient use of energy, free radical generation, and neuronal toxicity and death. There are several ways to (theoretically) improve this issue - one of them is to use a therapeutic ketogenic diet. The other way is to jack up insulin in the central nervous system to improve the ability of the cells to pull in and utilize glucose, theoretically. In addition, insulin seems to have an effect on amyloid-beta peptides that may protect the neurons, and insulin and insulin activity are generally low in the CNS of folks with dementia (though hyperinsulinemia with insulin resistance seems to be a long-term risk factor for developing Alzheimer's dementia eventually).

My question is - and this is highly speculative - without improving the energetics, does jacking up the insulin help in the short term but hasten the problems in the long term? No long term studies have been done. In the absence of insulin resistance and with insulin in the CNS low already, perhaps not? I'll have to think a little more on that one.

Back to School Again

2011-09-15T15:38:00.000-04:00

I've started teaching my small section of the introduction to psychiatry class for the medical students again, which has added a measure of increased chaos to the week. Not always a bad thing. However, blogging frequency may diminish for the fall (but who knows - depends upon what I see that interests me, and the class time for the lectures I don't teach does give me time to catch up on some journals, as I'm not taking a test at the end of the semester, I don't always need to pay attention…)

A few weeks ago I recorded a podcast with Superhuman Armi Legge and Bulletproof Exec Dave Asprey. Here is the podcast, so enjoy! I'm not entirely certain I am a paleo "brain hacker" - I'm more into emulating the evolutionary milieu(™)* than throwing MCT oil and butter into coffee for a kickin' breakfast, but that could be my likely dairy intolerance talking. We all share enthusiasm and interest in human health - the search for optimization of human health and performance is preliminary but intriguing. Thanks for the opportunity, Armi and Dave! Very happy to be on your podcast.

I also have another post up on Psychology Today about vitamin D, birth weight, and schizophrenia. All clicks are very helpful and help me finance my textbook addiction.

A few interesting articles in the queue - stay tuned for brand new posts. In the mean time, here's a boppin' rock tune (can't get enough of it):

Brooklyn is Burning by Head Automatica

*lovin' Kurt Harris's new picture.

Carbs and Serotonin, A Connection After All?

2011-09-11T16:20:00.004-04:00

A few weeks ago in Do Carbs Keep You Sane, I reported from a couple papers that disagreed with the textbook theory that a high carb, low protein and low fat diet would increase tryptophan in the brain. The Wurtmans from MIT have designed a whole pharmacologic diet around this theory, so it was interesting to read the rebuttal, especially since the rebuttal included data from Dr. Judith Wurtman's own papers.

In short, the theory goes that carbohydrate ingestion stimulates insulin production, which in turn causes protein to be driven out of the bloodstream and into the cells. Tryptophan, the rarest amino acid in the diet and the precursor for serotonin, is mostly bound in the blood to another protein called albumin, which makes it immune to insulin's effects. Therefore a carb bolus will increase the ratio of tryptophan to other amino acids competing for the same receptor, tryptophan shoots into the brain, and you get a nice hit of satiating, serenity-making serotonin.

If we follow the lines of this theory, a high protein diet will increase the amount of other amino acids and increase the competition for the receptor, leaving tryptophan a loser and the brain relatively "low" in serotonin. Fat in the diet will also delay gastric emptying and lower the overall glycemic index, lowering the insulin response and therefore reducing the insulin mechanism for driving tryptophan into the brain. Pretty simple.

Except in nutrition, nothing is ever simple. Turns out this mechanism works a bit differently in rodents than in humans or other primates, and any natural food and even flour and potatoes should have too much protein for it to work in humans. You can get this effect after a night's fast by eating or drinking something that is pure carbohydrate - such as marshmallows or lemonade. Not exactly an evolutionary model. In fact, in the primate models, the amount of tryptophan that made it into the brain depended on a higher amount of protein, not a lower amount with higher carbs.

But Mr. Jamie Scott sent me the Pubmed link for this paper a few weeks ago, and I certainly don't like to ignore papers, even if they tell a different story than the majority of the papers I had seen thus far:

High glycaemic index and glycaemic load meals increase the availability of tryptophan in healthy volunteers

Interesting study. 10 healthy human male university student volunteers are given several diets of varying macronutrient composition on different days. The first meal was a high GI meal consisting of 768 calories of jasmine rise and a tomato pureee - this meal was 1.6% fat, 8% protein, and 90.4% carbohydrate. The glycemic index of the meal was 117 and the glycemic load 200. That's 171 grams of carbohydrate, in case you were wondering. The other two "mixed macronutrient" meals served were lower in calories (about 457 each) of either a lower glycemic rice + or a high glycemic rice with a Lean Cuisine chicken. (I kid you not). The latter two meals were about 16% fat, 18% protein, and 66% carbohydrate give or take a rounding up or down, and each meal had 75 grams of carbohydrate.

(Okay, another hysterical sentence in this paper - each volunteer was tested with a standardized glucose drink to calculate glucose and insulin response to the different meals - the standard was the 75 grams of glucose bolus, and the figures were extrapolated to estimate the response to the 171 grams of carbohydrate meal because "it was considered unethical to give a glucose reference drink of 171.4g CHO.")

The results? The young men found the two mixed macronutrient meals palatable, whereas the (double calorie) high carb, high GI meal was more satiating, but less palatable. Sleepiness did not differ when measured immediately after the meal.

Only seven of the participants participated in all the blood draws, so only seven data sets were used for comparison of the ratio of tryptophan (TRY) to other "large neutral" amino acids (LNAA) in the study. At baseline (which was fasting), the ratio did not differ between the subjects. After the high carbohydrate, high GI meal, TRY:LNAA ratios increased by 23% and remained high for the next 8 hours. The Lean Cuisine folks with the low GI rice had an increase in TRY:LNAA of about 8%, and the high GI Lean Cuisine folks had an increase in TRY:LNAA of 17%.

The high carbohydrate bolus in several studies brings out robust high insulin responses - several hundredfold percentage increases over baseline (in this study the increase in insulin was 650% over baseline). In another study, plasma platelet serotonin levels were increased 3.5 fold after a similar high carb meal. Of course, high amounts of serotonin floating around in your periphery may not be exactly good for you - it is thought the high levels of serotonin caused by the diet drug combination fen-phen caused the aortic calcification risk from those drugs and possibly the risk of increased pulmonary hypertension.

In other studies, there are interesting implications. Recall that serotonin is the precursor for melatonin - in this rather recent study, a high carbohydrate, high GI meal (high GI rice, very very low fat) four hours before bedtime decreased sleep onset by 50% compared to those who consumed a low GI rice meal (also very low fat).

So it looks that you can increase tryptophan ratios in the periphery with high glycemic index meals, even with a more realistic macronutrient mix than jasmine rice and tomato puree. Presumably this may increase tryptophan intake into the brain. Tryptophan has several fates in the brain, serotonin being one, kynurenic another depending upon your state of inflammation and what drugs you may be on. Once again we have one fragment of a hugely complex picture.

And, since this mechanism depends on insulin, if one is contending that a high carb "serotonin cure" diet is helpful for depression, one must take into account that people with severe hyperinsulinemia are more likely to be depressed than people without, not less (though there are other confounding factors - since inflammation is one, the high carb diet in an (inflamed) type II diabetic might lead to increases in kynurenic rather than serotonin, explaining the diffference… but you see there is way too much unknown to make any general prescription for high carb diets in this context.)

Anger and Homocysteine (A Folate Cycle Ditty)

2011-09-09T18:15:00.001-04:00

Happy Friday! I actually have a whole stack of interesting papers from email and links (as usual) - Paleo Wunderkind Jamie Scott sent me an email about homocysteine and anger earlier this week, and the papers are pretty cool.

Quick and catchy brand new tune by Girls - Honey Bunny (right click to open in new tab)

All right. Homocysteine. If you recall, in protein we eat an amino acid named methionine. Methionine plus various derivatives of the B vitamins, including folic acid vitamin B6 and vitamin B12 helps us make all sorts of stuff from other proteins like DNA, neurotransmitters, etc. Lots of important stuff. Homocysteine is an intermediate in the pathway, that is supposed to be recycled back into methionine (see this diagram) so that the cycle can begin again. Older people and men are likely to have higher homocysteine. Older folks also tend to eat less B vitamins. And folks with hyperinsulinemia are also more likely to have high homocysteine (if you really want your mind blown, check out this anonymous commenter who sounds and awful lot like Dr. K on my latest Psychology Today post linking insulin, homocysteine, selenium, B vitamins, choline, NAC and basically all the pathology of disease in Western Civilization.) Those who are obese are also more likely to have high homocysteine (in some studies but not in others), even with normal serum B6, B12, and folate levels (3).

If you don't have all the B vitamins in the right amounts, or if you are on medications that change the effectiveness of the enzymes in this pathway, or if you are one of 10% of of folks genetically deficient in the MTHFR enzyme, you will end up with extra homocysteine hanging about. And that, my friends, is not good. It's a bit murky, but homocysteine is thought to do all sorts of bad things, like stiffen arteries and increase the proliferation of smooth muscle cells leading to high blood pressure and increased risk of stroke. Homocysteine is also thought to be associated with joint and cartilage stiffness, weak bones, and is probably directly neurotoxic. High homocysteine is associated with increased risk of heart attacks both in baseline healthy folks and in people with previous heart disease, and it is thought to directly damage the blood vessel endothelium and is also probably prothrombic (2). High homocysteine (indicative of an inefficient folate cycle) (the actual level that is high is greater or equal to 11.3 micromol/L, in case you were wondering) means may be low in SAMe. SAMe (as we discussed earlier) is needed in the brain to make many neurotransmitters.

Over the years, high homocysteine has also been associated with anger (1). In fact, each 10 point increase in the Hostility and Hostility Direction Questionnaire is associated with a 2.9 micromol/L increase in homocysteine. Women under psychologic stress have higher levels of homocysteine also. Homocysteine has been investigated a number of times with respect to major depressive disorder, and it was found that only those with the disorder who also have anger attacks (approximately 40%) had significantly higher levels of homocysteine.

Anger on its own is also highly correlated with risk of heart attack. In one study of Koreans getting treatment for blocked coronary arteries, 60% of the patients met criteria for significant hostility on standard scales. This is in contrast to a much lower hostility score in healthy Koreans or Americans using the same scale. Both hostility and homocysteine level correlated with earlier return to the hospital with a new coronary event when the Korean patients were followed over time.

All right. So that is just a whole truckload of correlations, without a lot of explanation. And in the papers, there are some interesting suggestions (that the stress hormones deplete the B vitamins, thus raising homocysteine, that homocysteine is directly neurotoxic, causing anger. That homocysteine is associated with higher levels of pro-oxidants and represents an inflammatory state, also neurotoxic.

In the end we have the same prescription to address all the correlations and genetic variations - eat a healthy, nutrient rich diet. Avoid obesity and stress, or engage in stress reduction. Keep your folate cycle humming, and a lot of good things fall into place. Once it is out of whack, a cornucopia of bad juju starts to happen.

Further Evidence that Mental Illness Exists

2011-09-08T17:50:00.001-04:00

Long, long, long ago, I wrote several posts that were later updated for Psychology Today, mostly because it is the basis for my understanding of the pathology of depression with regards to that Big Bad of Diseases of Civilization, inflammation. A nice tie-in to all those posts is here:

Depression Crashed Your Party

It is not, perhaps the friendliest of posts with all that biochemistry and all. But rest assured it is of vital importance. Especially this diagram (right click to open in new page and take a look). And this post will not be particularly friendly either. Mostly because I have caught up on a recent skirmish in the war between medicine and psychiatry, begun by the book reviews by the former editor and chief of The New England Journal of Medicine, Dr. Marcia Angell, and all the big names in psychiatry writers, specifically an article in Psychiatric Times by Ronald Pies, M.D. "Misunderstanding Psychiatry (and Philosophy) at the Highest Level."

In case you do not happen to be a clinical psychiatrist and do not care to dive into the debate, let me paraphrase (and allow me to take extreme liberty with my own interpretation of the stance of the two sides): Dr. Angell: "Psychiatrists are witch doctors." Psychiatrists: "You are ignorant and misinformed."

Music - Danse Diabolique (right click to open in new tab)

It is hard to be misunderstood. Rest assured that I do not rely on incantations to treat my patients, but I do dislike equating psychiatry with the DSMIV. The DSMIV, the cookbook describing all the diagnoses for research and insurance billing purposes, is not psychiatry. A good psychiatrist listens and measures and watches for neurologic disorders, medical symptoms, experience, emotions, emotional expression, tremor, eye contact, muscle tone, gait… most of these are not ever mentioned in the DSMIV. I consider the DSMIV a necessary evil, for now. A very clever former teacher of mine once said, "If all the copies of the DSMIV dropped to the bottom of the ocean, all the better for us, and all the worse for the fishes." He asked that I not repeat that to anyone. I won't attach his name, and details are changed to protect the innocent, as always...

So how do I cope with being a well-meaning witch doctor? I write this blog. I tear apart the pathologies of the DSMIV in the context of biology, biochemistry, nutrition, lifestyle and evolution. For me, it is a more sensible and tenable approach than the random crapshoot of modern medicine epidemiology and the biased minefield that is psychopharmacology research. And in my own little corner of the blogosphere, I feel all is safe and honest and going the right direction. Most of the time.

Back to depression crashing the party. I've talked quite a bit about serotonin, a term, I think, with which everyone is familiar. Here is a nice article about serotonin in case you missed it.

But serotonin is only a small piece of the whole story. Our friendly neighborhood amino acid tryptophan can become all sorts of things - happy satiating serotonin, or enervating irritating kynurenic. Many, like the pioneering researcher Dr. Maes (who has hopped from Case Western Reserve (very respectable) to Antwerp (I'm sure, very respectable) to Thailand (well, let's reserve judgment until we know the whys and wherefores, though Thailand is a lovely place it is not a hotspot of respectable biomedical research!)) have been talking about inflammation and kynurenic for a decade or more. And, finally, other researchers have been looking into it. They call it kynurenine, but I'm not going to quibble.

The new generation of researchers working out of the very respectable New York State Psychiatric Institute measured kynurenine levels in healthy controls, patients with major depressive disorders, and patients with major depressive disorders who have had suicide attempts in the past (all controls and only three of the depressed patients in this study were medication-free).

And, low and behold, it was found that those with a previous suicide attempt were significantly more likely to have higher levels of serum kynurenine! Let's back up - activation of the inflammatory cascade (theoretically via autoimmune or other mechanisms, like, say, to go out on a paleo limb, wheat or omega 6 fatty acids) increases the activity of an enzyme called IDO (indoleamine 2,3 dioxygenase) which will change the amino acid tryptophan into kynurenine rather than fat-n-happy serotonin.

Serotonin levels actually have closer (negative) correlation with violence and suicide than depressed mood - and this study of kynurenine is no different - suicide attempters had the higher levels, and depressed patients without attempts had similar levels to healthy controls. Interestingly, kynurenine levels did correlate with BMI and tryptophan levels, and more robustly in males than in females (males have a higher risk of suicide completion than females, though females have more suicide attempts).

In previous studies, autopsies of suicide victims and CNS samples of suicide survivors have shown increased levels of kynurenine in both.

In mouse studies, increased kynurenine has been associated with activation of the neurotoxic (in excess) glutamate and even dopamine (which increases motivation and drive). Stress seems to increase the activity of IDO (leading to increased conversion of tryptophan to kynurenine) and general suicide badness.

In the end, I have to say that all that is psychologic is biologic. And psychiatrists must keep an eye out for signs and symptoms, and while the DSMIV (and psychiatry skeptics) ignores signs, we do not. Otherwise we remain guilty of the criticisms that the likes of Dr. Biffra will levy - which according to my comment (number 17) shows that he has very little understanding of the job of a psychiatrist. (Normally I like Dr. Biffra's ideas, but clearly he needs to consult with more expert psychiatrists if he is writing such posts!)

But ultimately I am not surprised. Mental illness is not understood, and psychiatrists hold some of the keys to the temple. Sometimes it is easier to eject what is misunderstood rather to absorb and understand it, regardless of biology or morality.

****
A little editorial addition on 9/9/11

I thought about not writing about the ongoing controversies in psychiatry as 1) it may not be of interest to many readers (though I do have several clinical psychiatrists who follow the blog, and hey, it's my blog and I will write about what interests me), and 2) it opens me up (fairly enough) to be a defender of modern clinical psychiatry, as I am critiquing the critic. I'm not interested in the role of defender, as certainly some aspects of modern psychiatry (and indeed modern medicine) are indefensible, and the role is ably taken up by Drs Altschuler, Nierenberg, Friedman, and Pies (among others) who have written responses to Dr. Angell's reviews.

However, I do think that critiques of psychiatry are important and, again, not entirely unreasonable. There is a risk with an atheoretical document like the DSMIV, with diagnosis based on a list of symptoms divorced from pathology (on purpose!) and a profit-driven pharmaceutical research community to create more and more diagnoses and make pills to fit the diagnoses. The ultimate argument of this critique is that a lot of mental illness is essentially made up. My main objection to Dr. Angell's stance is to this sentence of hers (quoted from Dr. Pies' article linked above), where she starts by saying that psychiatry is different than other medical specialties: "First, mental illness is diagnosed on the basis of symptoms (medically defined as subjective manifestations of disease, such as pain) and behaviors, not signs (defined as objective manifestations, such as swelling of a joint.)"

As I mentioned above, mental illness presents with many objective physical signs that have a known neuropathologic basis, and these signs are used all the time in clinical psychiatry. That Dr. Angell would not know this fact betrays a rather shocking ignorance. In addition, there are biomarkers for mental illness. Zinc is one, kynurenine now likely another, various cytokines… in fact biomarker tests are now being marketed to psychiatrists for diagnosis of depression, but it is hard to convince a psychiatrist to jab someone with a needle and spend money on the test when you can merely ask the person about the symptoms of depression and find the same answer. I suppose it might eventually be useful in cases where people are feigning depression for monetary gain (such as a faked disability case).

And I will suggest that just because there is an objective "sign" and "known pathology" doesn't make pharmacology less of a Faustian bargain in other more "objective" medical specialties. Sure, for reflux you can send a scope down someone's esophagus and measure pH, and the medicine used to treat it will indeed change the pH via blocking the proton pump, but is it helping the overall pathology of acid reflux in the long run? Statins will, indeed, lower cholesterol through a known mechanism, but despite the standard line that doctors have no idea that cholesterol is less important than the statin commercials will tell you, every well-trained and intellectually curious primary care doctor I speak with on a regular basis knows that statins work via their somewhat mysterious anti-inflammatory effect, not their cholesterol-lowering effect. And what about sulfanylurea drugs used to boost insulin production in type II diabetes? Sure, you improve the situation in the short term (and could possibly avert some long term hyperglycemia damage) - but you are making the patient more hyperinsulinemic in the process, and looking at longer term risks of worsening diabetes, and depending on the medication, there seems to be increased risks of pancreatic cancer and heart disease.

I would suggest that "knowing" the (almost invariably incomplete) pathology and having lab tests to check gives modern medical doctors a false sense of security in many cases. I'm not saying we should throw the baby out with the bathwater, but we can't scapegoat psychiatry without holding other specialties of modern medicine accountable in our critique as well. Pharmacology, whether it is with psych drugs, medical drugs, or pharmacologic use of supplements will always have unknown risks along with any benefits.

Add the risks of not using pharmacology (whether medical or psychiatric) - and you have a complicated picture of risks and outcome. One that takes good training, a bit of humility, honesty, and time to figure out.

Intriguing Links Between Depression and Cholesterol

2011-09-05T14:46:00.001-04:00

Today's paper comes from the Journal of Clinical Psychiatry: Serum Lipoproteins Improve After Successful Pharmacologic Antidepressant Treatment: A Randomized Open-Label Prospective Trial. Turns out that depression researchers are thinking about the whole body and not just the brain. My basic premise is that it is all connected, folks. Inflammation, heart disease, diabetes, obesity, metabolic syndrome, depression, IBS… Let's lump, shall we?

(Music - Ravel, Jeux d'eau - right click to open in new tab)

So the truth of the matter is that people suffering from depression have lower overall cholesterol than average. I know, crazy, right? Here's where I really blow your mind - people with major depressive disorder, despite the lower cholesterol, have higher rates of death from heart disease, whether or not you had heart disease before or after the diagnosis of depression.

But anyone in the primal/paleo community will know that total cholesterol doesn't mean much - we want to know about HDL and the subfractions of LDL - the big fluffy new fresh LDL are not associated with increased risk, whereas the old, rancid, small dense LDL are certainly associated with increased risk of heart disease. Here is a quote from the article (though I'm not entirely sure I agree with the pathology description):

"small dense" LDL particles, resulting from packing of LDL particles with higher amounts of triglycerides, have a higher propensity to be oxidized, to be trapped in the subendothelial space, and, subsequently, to form the seed of an atherosclerotic plaque."

In favor of further lumpage, it is known that depression is associated with insulin resistance, which is associated with more small, dense LDL, and thus higher triglycerides and higher apolipoprotein B. Successful antidepressant treatment will just so happen to to improve insulin sensitivity and all those bad metabolic markers.

In the paper, lipoprotein composition of various folks with major depressive disorder were recorded and compared to healthy controls. Then depressed subjects were randomized to treatment with either mirtazapine (an effective antidepressant known to cause weight gain) or venlafaxine (another antidepressant less likely to cause the same).

Results: not surprisingly, total cholesterol was lower in depressed patients compared to healthy controls (surely the total cholesterol amount and how important robust cholesterol levels are to the brain has nothing to do with that. I'm sure it is just a confounder.) Both HDL and LDL were significantly lower. There was also a higher ratio of nasty, small, dense LDL particles to HDL particles in depressed patients compared to controls. Depressed people are much more likely to have rancid LDL lingering in their bloodstream. To me, not surprising.

Let's add the psychotropics - predictably, folks taking mirtazapine gained some weight, and folks taking venlafaxine lost some weight (serotonergic antidepressants such as venlafaxine will tend to cause short-term weight loss, likely though increasing satiety signals to the hypothalamus, of course some folks consider the hypothalamus to be of secondary importance with respect to weight gain or loss).

So what happened with the interesting subfractions of lipoproteins among the antidepressant treated groups? With fat-inducing mirtazapine (which causes weight gain through a central histamine or anticholinergic mechanism, most likely), total cholesterol and triglycerides increased. Under venlafaxine treatment, total cholesterol remained stable and triglycerides decreased. With both groups (and these are both powerful antidepressants who tend to actually work and help people feel a bit better - the study showed about 60-65% response, which is typical for these agents), the HDL levels improved, and HDL to LDL ratio and apolipoprotein B (a measure of old, dense, rancid cholesterol) decreased. The mirtazapine group gained weight (as expected), the venlafaxine group did not. In both groups, responders had a slight increase in total cholesterol.

What do we learn? Depressed folks who responded to antidepressant treatment tend to increase their HDL levels and had favorable changes decreasing old small dense LDL. Oddly enough, those on the fattening mirtazapine had similar good lipid changes (if the medicine worked) compared to the short-term slimming venlafaxine. (Editorial note: inflammation is inflammation, my friends, and an anticholinergic or histamine mechanism will make you fat regardless of how inflamed you are - and while most of this work has been done with antidepressant medication, I have linked studies in the past showing that therapy has also been shown to be anti-inflammatory, though to be honest it has not been looked at robustly).

Wildly enough, this study says "to the best of our knowledge, the composition of LDL particles has not been studied previously in depressed patients." WHAT? Small dense LDL vs large fluffy LDL was only discovered, like, 20 years ago, right? Mental health research is always lagging! And antidepressants might actually be anti-inflammatory as suspected… dare I say like statins? Both classes of drugs have evidence for some modest benefit in certain situations, and major drawbacks.

Phytic Acid - Mineral-grubbing Nuisance or Magic Food?

2011-09-03T14:03:00.003-04:00

Chris Kresser emailed a link to an interesting paper published at the beginning of this year (thank you very much! Hope little Sylvie is allowing you just a bit of sleep): Phytic acid as a potential treatment for Alzheimer's pathology: evidence from animal and in vitro models.

Music - Satie's Gnossienne #1 (right click to open in new tab).

A few caveats - it's a mouse study, and even worse, part of it is just a mouse cell study. But it has some interesting bits and is worth a close look.

The authors begin by reviewing the current thinking about the cause of Alzheimer's (amyloid beta plaques, neuronal death, slow progression, etc. etc.) and the current treatments (several FDA approved acetylcholinesterase inhibitors, oh by the way they don't work very well and are not a cure). Then they go on to talk about the real cause of Alzheimer's (inflammation and crappy energetics - leading to cell death, slow progression, etc. etc.) and mention a funny little compound that might help with that, phytic acid.

Whoa. All the paleo peeps just squealed. PHYTIC ACID??? FROM WHOLE GRAINS??? Yes, that phytic acid. The one that binds all your minerals and leaves you anxious, insulin resistant, and fat. One of the reasons you don't eat oatmeal anymore. (via Dr. BG) Yes, phytic acid, why Stephan Guyenet has mysterious rice soaking in his fridge. (Honestly, I think traditionally prepared grains could be healthy enough if you are desperate, but they don't taste as good as meat and it takes so much effort… and I do worry about folks who are relatively sedentary or immobile and need the most nutrient-rich calories available.)

I actually wrote a bit about therapeutic uses of phytic acid before, but I was pretty sneaky, in my post on inositol.

So here's the scoop about phytic acid. Turns out that many nutrients and even anti-nutrients have multiple effects. I know. Shocking. I will quote the paper as they do a good job of writing here:

In this study, we investigated a novel protective treatment for AD pathology with phytic acid (PA, inositol hexakisphosphate). PA is structurally a myo-inositol sugar ring attached to 6 phosphate molecules. It is found naturally and ubiquitously, as a phosphate-storage phytochemical in unprocessed whole food grains, vegetables, and fruits, and as a key signaling molecule in mammalian cells. The Ca/Mg form of PA found in most plants is known as "Phytin" with its salt form known as "Phytate." Although PA is often described as a metal chelator, growing literature indicates that PA influences multiple processes, including antioxidant functions, anti-apoptotic effects, clathrin-coated endocytosis, DNA repair, and mRNA export from the nucleus. Phytic acid also lowers serum cholesterol and triglycerides. These studies suggest that PA possesses much broader functions than simply the originally-presumed metal binding properties

So what the authors suggest is that phytic acid is one of the many things (such as ketosis, calorie restriction, etc.) that can promote clean, happy, humming mitochondria. Happy mitochondria are one of my favorite things here at Evolutionary Psychiatry.

To get more detailed, there are many things that are postulated to increase SIRT1 (which is a class III histone and has epigenetic effects). High SIRT1 levels are found in long-lived yeast, flies, worms, and mice, and levels of SIRT1 are lower in folks with dementia. Calorie restriction and Red Wine Magic Food Resveratrol increase SIRT1 in animal models. The end result of increased SIRT1 seems to be increased autophagy. An awesome, dedicated clean-up crew keeping your neurons sparkly, as it were. Will phytic acid do the same for the brain as calorie restriction or resveratrol?

Well, in mouse cells, application of phytic acid seemed to do all the right things, increasing the expression of SIRT1 and other autophagy-promoting biochemical stuff. And, in Alzheimer's model mice given phytic acid-laced drinking water for six months, levels of SIRT1 increased, amyloid beta accumulation decreased, and other indicators of decreased oxidative stress and more efficient mitochondrial function were evident compared to control mice. AND brain levels of copper, zinc, and iron were no different between the control and phytic-acid mice.

(I'm wondering if any of that had to do with increasing the efficiency of second messengers, as inositol is thought to do, as I described in my previous post linked above).

So, the take home message is to eat whole grains to prevent Alzheimer's. Haha. Just kidding. Actually, the take home message is that nutrition and biochemistry are really complex. A molecule that has some downsides may also have some positives. Phytic acid seemed like the least noxious part of the chemical warfare that grains (and nuts and fruits and other plants) play. Since I don't pretend to have complete knowledge of the chemistry of the human brain, I like the evolutionary fallback position of an ancestral health lifestyle. Forget novel industrial foods created by a chemical company, and I won't be going to cute supplements (outside of the basic minerals and sunshine) unless I'm desperate.

Have a great Labor Day Weekend, everyone!

***

Just want to add on a bit to address Rudolf's very astute comment (the eighth comment, below): : Isn't there another confounder, namely that rats, mice etc express phytase, and we don't?

Rudolph is saying that mice are better adapted to eating grains and have the enzyme phytase in their guts, which will cut up phytate into its components (inositol and a bunch of phosphate molecules). The authors do address this issue (sort of, though they don't make it that clear that humans do not metabolize phytic acid) - here's another paragraph from the paper - I'm a little irritated they didn't measure the phytic acid levels in the mouse brains when they had them, though:

It is important to emphasize that the effects of PA demonstrated here are distinct from those that have been attributed to its “backbone” and metabolite, inositol. Stereoisomers of myo-inositol (the non-phosphorylated backbone of PA) inhibit Aβ fibril assembly and protect neurons from Aβ-induced cytotoxicity in vitro. The stereoisomer scyllo-inositol inhibits Aβ aggregation, reduces soluble and insoluble Aβ, reduces plaque size and inhibits cognitive defects in a transgenic model of AD. Scyllo-inositol (ELND005) has been tested in animals and has entered phase 3 clinical trials for AD by Elan Corporation, plc. Recently, however, it had been shown to cause severe adverse drug effects in humans in two arms at doses 1 and 2 gram twice a day leading to death of 9 patients and discontinuation of both arms of this clinical trial. Interestingly, 6–7.4 g/day of phytic acid administered to patients did not have any adverse drug effects for up to 24 months. Our study indicates that phytic acid works by independent mechanisms. Additional support for the hypothesis that phytic acid may have effects beyond those of inositol come from studies showing elevated brain levels of phytic acid in rats fed a high phytate diet, indicating that some unmetabolized phytic acid is delivered to the brain, in addition to other species of phosphorylated inositols.

So - it's not all the inositol or other metabolized products from a mouse consuming phytic acid (which is synonymous with phytate, by the way). Phytate itself gets through in the mice, and, it seems, the question in humans (who shouldn't absorb much phytate at all - the phytate gets pooped out with the minerals, remember), is whether administration of phytate orally would make a difference in the brain. One interesting note in the paper is that the regular mouse diet had NO phytate, and the experimental diet was 2% phytate, and a diet rich in legumes, grains, and seeds would be about 5-6% phytate. The authors postulate that we humans in the developed world would be fine (hahaha quite an assumption given what is known about mineral consumption in epidemiologic studies in the developed world!) but that those in third world countries with marginal food consumption ought not to eat so much phytate…

It is something to consider to be studied as an injectable, if one has Alzheimer's. (Do not try this at home - in the quote above you will note that 9 people died taking scyllo-inositol in the clinical trials of that drug for dementia).

A "paleo" diet in humans will have its share of phytic acid (likely not the 5-6% of calories, though, I would imagine), especially if you don't soak all your nuts (I don't - I don't eat that many nuts and don't have the time or the space to mess with them - just like grains). See Melissa McEwen's latest post for more information.

Suicide, Omega 3, and the Military

2011-08-30T21:36:00.003-04:00

Another one for the marine-derived highly unsaturated fatty acids are probably really important for proper brain function files: This new paper has been tweeted quite a bit lately: Suicide Deaths of Active Duty US Military and Omega-3 Fatty Acid Status: A Case-Control Comparison

It is an observational study, but large for a suicide study (suicide is, fortunately, quite rare). All told, 800 randomly selected suicide victims in the armed services were selected between 2002-2008, and compared to 800 matched controls. Cases were matched for time and theater of deployment, exposure to stress during deployment, report of mental health status, and demographics among other data points. (Though later the paper says 99.1% of the controls had been deployed vs. only 61.9% of the suicides, so the deployment location and duration were not added as covariates to the end calculations).

So, fatty acid of the blood of the participants - in short, the lower the DHA in the blood, the more likely the person was to have committed suicide. The relationship was linear and true of all octiles studied. There were only 70 women in the samples, and they tended to have higher DHA levels than the men, and lower suicides (among women, the omega 3 status to suicide relationship was not statistically significant as it was clearly so among the men). Men in the lowest DHA octile were 62% more likely to commit suicide than those in the highest octile.

Other fatty acids of interest - lower levels of stearic acid (saturated! My goodness! Found in chocolate! And steak!) were found to be associated with increased risk of suicide (my preliminary conclusion - eat more chocolate - though it is only observational - I'll risk it and eat your chocolate if you are uncertain). Also, higher palmitoleic acid (a monounsaturated acid made from the saturated palmitic acid) levels correlated with a lower level of suicide risk.

In this study, US military personnel were found to have, on average, a lower DHA level than average North American, Australian, Mediterranean, and Asian populations (unlike the medical students I wrote about a few articles ago, who had higher levels than the general population). In fact, among Chinese suicide attempters, nearly all of them had higher levels of omega 3 DHA than the highest octile of the US military personnel studied. And when both populations were studied together, the lowest DHA levels coincided with a 5-6 fold increased risk of suicide. For perspective, this risk increase coincides with the risk of undergoing severe stress under deployment (seeing wounded, killed, or dead comrades, for example) and the risk of suicide.

We can't determine causality, but common sense and and evolutionary perspective should surely make us suspicious - eat those marine omega3s and keep your 6:3 ratio minimal. The paper recommends 2 grams daily of marine omega 3s.. Seems reasonable.

Folate! The Beginning.

2011-08-27T14:48:00.002-04:00

Did I ever mention that I'm not a big fan of the folate cycle? Not because it's not important, but because it is intensive, poorly understood, and hard to remember. Probably a bad reason to dislike it, as far as those things go…

Let's just start with a diagram, and an explanation for those of us who were taught some basic organic chemistry. Folate does not equal folic acid. I know. It's weird. For all the other acids, -ate equals -ic acid (such as phytate and phytic acid), but for whatever reason, folate = dihydrofolate, and folic acid equals synthetic folate that is used to fortify foods in the US and in multivitamins. Let me supply you with a handy diagram:

Please click on the diagram to make it bigger!

The blue formulations are those that can be had by prescription or supplement. The yellow are the natural forms. Folic acid is put into grains and multivitamins. Folinic acid is used in chemotherapy. 5-MTHF (methyltertrahydrofolate, or the active enantiomer l-methylfolate) is a "medical food" pharmaceutical grade folate one can get by prescription.

Now why would a psychiatrist care about this pathway? Well, folks with depression have increased risk of having crappy dihydrofolate reductase activity (meaning they have a hard time turning synthetic folic acid into dihydrofolate - this enzyme is also inhibited by the medication lamotrigine). In addition, folks with depression are more likely to have issues with the MTHFR enzyme (I know - it stands for methylenetetrahydrofolate reductase but that's not what I call it in my head either). So if you prescribe medications meant to maximize the efficiency of neurotransmitter* transmission in order to treat depression or anxiety, or if you just want nature to maximize the efficiency of neurotransmitter transmission (which everyone would agree is preferable, if possible), you want plentiful tetrahydrobiopterin in the brain.

You can see from the diagram that cheap, plentiful folic acid may not aways become the final active product in the brain. You can also see that expensive, prescription 5-MTHF (deplin) might be useful for some people, though you may be annoyed if you know that deplin has never been tested head to head against folic acid.

5-MTHF and folinic acid have had some decent studies increasing response rates to antidepressant therapies, and decreasing cognitive symptoms of depression. The results for folic acid supplementation itself have been mixed. And, given some genetic polymorphisms (such as C677T, affecting the MTHFR gene), a peripheral folate level (which I have drawn routinely) will not necessarily tell us about folate levels in the brain.

But why not just pour tons of folic acid into the system - well folic acid has some risks. For one, it has been shown to mask some of the first symptoms of B12 deficiency (which I have seen - none of my patients with low B12 have had the classic hemotologic signs that doctors have long relied upon to help diagnose B12 deficiency - possibly because folic acid supplementation is now abundant in the food system). In addition, folate is a growth factor, and one has to be careful about pouring growth factors into the system, lest one risk cancer - the risk of colorectal cancer being the most studied and the most likely (1) caused by widespread folic acid supplementation. (The results of the epidemiological studies are mixed however, with this large US study showing no correlation).

Now, if you take a ton of folic acid (more than 800 mcg daily - 800 mcg being the normal dose in prenatal vitamins), it has been shown that the excess folic acid won't be metabolized, and that excess folic acid in the serum actually reduces the amount of l-methylfolate that reaches the brain, with a potential increase in depression. Supplementation with l-methylfolate will not mask B12 deficiency and is less likely to be a risk for colon cancer (since the upstream agent, folinic acid, is used to kill cancer). But… the cost. A thirty day supply of deplin can cost as much as $80 at the pharmacy, and the cheapest I have found it is $70 for a 3 month supply direct from the manufacturer. As a "medical food" it is not covered by insurance. And yes, in my clinical experience, I have some patients who have not responded to folic acid supplementation who have done very well on deplin.

Folate, real, natural happy dihydrofolate from food is most plentiful in leafy green vegetables, fruits, and (ahem) legumes. Cereals and grains are fortified with synthetic folic acid.

Hopefully this article will clarify some things… or maybe we will consume few more leafy green veggies and fruit along the way...

*serotonin, dopamine, and norepinephrine are neurotransmitters

Fava, M and Mischoulon, D. Folate in Depression: Efficacy, Safety, Differences in Formulations, and Clinical Issues. J Clin Psychiatry 2009;70[suppl 5]:12-17

Frankenburg, FR, Folate supplementation: is it safe and effective? (letter) J Clin Psychiatry. 2008;69(9):1352-1353

More About Thiamine

2011-08-26T16:57:00.002-04:00

Some of the most harrowing stories of nutrient deficiencies come from the 18th and 19th century British Navy. Perhaps because the officers on the long voyages had nothing better to do than document the slow, desperate and horrific progression? Recently there was a PBS special on the Erebus, a ship that left Britain in 1845 under Captain Franklin to look for the Northwest Passage. This voyage occurred during a century of Arctic and Antarctic exploration that included Shackleton's famous doomed voyage (the memoir, South, is well worth reading). Those poor sailors on the Erebus, though. See, just before their planned expedition, the process of food canning was, um, perfected. The Admiralty was thrilled - now they could send the ships around the world and not worry about local conditions or foraging for food. They would include plenty of canned fruits rich in vitamin C so that most horrible sailor's disease, scurvy, would not affect the crew. Scurvy is a horrible way to die - your connective tissue degrades and you spend a great deal of time in terrible pain as you slowly bleed to death internally. Go civilization! Let's conquer the Arctic!

Well, the ship sailed off with Franklin and a crew of 128 and was nearly never heard from again. There were a few accounts of sightings, and rumors of mutiny and cannibalism reached Britain. Turns out that the cans were soldered with lead, and the water supply may also have been contaminated. And it so happens that the vitamin C in canned foods only lasts about a year, so after the ship bogged down in ice for several seasons, the sailors who weren't weakened, crazed, and killed by lead poisoning succumbed to hypothermia and scurvy. The luckier sailors on the Shackleton expedition brought some guns along and hunted and fished for the years they were stranded after their ship was crushed in the ice (one can't help but notice that all those cute sled dogs present at the beginning of the voyage are gone by the end). And they got through okay - Shackleton didn't lose a single man. The crew of the Erebus may be some of the first victims of modern processed food.

While thiamine deficiency was described as "sailor's asthma" in the Navy, this disease was better known in Japan as "Kakke" and had been described as early as year 808 (1). In the early 20th century, 30 per 100 Japanese died of the disease. Once thiamine was discovered, mortality dropped to 0.5 per 100 Japanese. The major symptoms were poor reflexes, swelling, low diastolic blood pressure, and tender calf muscles. Cardiovascular symptoms include a weakening and enlargement of the heart, called "cardiomyopathy" which will eventually result in heart failure (and lung symptoms as the circulation backs up in the lungs - thus "sailor's asthma.") Peak deaths, both in adults and infants, occurred between August and September, even more so when humidity was high.

Before thiamine was isolated, it became obvious (from voyages of the Japanese Navy and from birds fed a strict diet of white rice) that polished rice was the major contributor to beriberi, and that adding red beans, dried meat, rice bran, or barley to sailor's rations prevented the disease. It is the original "empty calorie" disease. Thiamine, first isolated in 1926, is now known to have some plentiful sources: meat, wheat germ, liver, organ meats, poultry, eggs, fish, beans, nuts, and whole grains. Cooking and processing depletes the vitamin, but you don't need much - just 0.5mg per 1000 calories consumed. Polyphenols in coffee and tea can inactivate thiamine, so stick to red wine (just kidding - alcohol interferes with the absorption of thiamine, remember?)

Like most vitamins, thiamine is taken up into the body and then immediately modified into a number of derivatives. The most famous is thiamine diphosphate (also known as TPP) - this thiamine is the one that plays a part in a bunch of energetic reactions in glucose metabolism. If you want your citric acid cycle to run (and believe me, you do), you need thiamine diphosphate. Bodybuilders and BCAA chuggers take note - you also need TPP to decarboxylate the keto acids derived from the branched chain amino acids. You also need TPP in the pentose shunt, which is an important extra-energy and detox pathway. Deficiency of TPP is what eventually shows up as Wernike's encephalopathy and Korsakoff's psychosis among the present day severe alcoholic set.

What is interesting about these old-fashioned deficiency syndromes is that thiamine deficiency today (most commonly seen as Wernike's) isn't the same thing as beriberi. Just as strict vitamin D deficiency isn't quite the same as rickets. With beriberi, there is a clear relationship between the classic symptoms and the amount of carbohydrates in the diet. With Wernike's we know we can bring it on with a bolus of D5W after someone has been living on booze, but Wernike's is missing many of the essential features of beriberi. The modern form is almost entirely confined to the central nervous system.

(It is an assumption nowadays that we have conquered the major deficiency syndromes with science. And, indeed, rickets is rare, beriberi is unknown in the Western world, and anyone ever see a case of pellagra? But my suspicion is that many of our modern diseases are primarily caused by or exacerbated by micronutrient deficiencies. We shouldn't be so complacent. *off soapbox*)

Thiamine, with its key role in central nervous system energy production, can give us clues as to the pathology of syndromes such as Alzheimer's Dementia. Folks with AD have normal thiamine levels, but low levels of the metabolically active TPP, suggesting problems with energy regulation. Giving people with AD extra thiamine can sometimes help the symptoms.

In Japan, there has been a long historical interest in thiamine, and they have come up with a number of synthetic thiamine derivatives. One of them, a disulfide derivative called sulbutiamine, crosses the blood brain barrier more readily than regular thiamine. I don't know much about it, but given the impact of energetics on disorders such as Parkinson's Disease and Alzheimer's, it seems an obvious candidate for further research.

In the mean time, eat your meat, especially if you are a big fan of white rice (though white rice in the US I believe is fortified with thiamine), or alcohol.

Do Carbs Make You Crazy? PCOS and Type II Diabetes Edition

2011-08-25T15:53:00.000-04:00

Previously, we discussed the question of Do Carbs Make You Crazy?, reviewed some literature to suggest that a bolus of sugar to a fasting person could certainly make some people crazy (or at least rather rotten-tempered), and yet MIT researchers suggest the same carby bolus will keep people sane with a nice happy squirt of serotonin. Personally I think the MIT advice to snack on marshmallows and pretzels for serenity's sake to be misguided, whereas I agree with the wise orthomolecular doctor from New York who told the young Mr. Ellsberg, suffering from insomnia, grandiosity, and bouts of suicidal depression, to cut out the coffee, alcohol, and sugar already.

(Music - Beastie Boys/Santigold Don't Play No Games That I Can't Win - right click in new tab)

We all agreed, I think, in the comments of the previous posts, that these studies are weakened by some lack of accounting for confounders (nutritional status, alcohol, sleep, insulin resistance, etc. etc. etc. etc.), and of course one can never just change carbohydrates - one has to alter another variable. AND of course I think inflammation and industrial food and micronutrient deficiencies cause or increase insulin resistance and violence and depression… so when one just examines blood glucose level and mood state, one is missing the electrified third rail, so to speak.

And I have to say, the state of the literature ain't that great. Among 15 papers I read for this series, there was one great review paper. Everything else was rather distractingly haphazard. And so we go to two more papers (thanks to Jamie Scott, Jackie, Ambimorph, and Zooko for helping me with the paper chase!): Daily Negative Mood Affects Fasting Glucose in Type 2 Diabetes and The impact of eating behavior on psychological symptoms typical of… (long title - it's about PCOS and blood glucose and mood).

The first paper is about a study following 206 people who kept daily food diaries, morning fasting blood sugar measurements, and daily mood records for 21 days. What is nice about this study is that the participants were phoned every night to get the data for that day. They were also paid $35 for the first week, $45 for the second week, and $55 for the third week, so motivation to keep up with the information gathering was pretty good.

After gathering all the data, there was really only one major finding. There were no real significant correlations between meals, daily mood, and blood glucose - except… if you had a crappy mood one day, you were more likely to have a higher fasting glucose on the morning of the next day. This makes sense if a crappy mood coincides with cortisol increasing, worsening glucose control that is reflected in the next morning's fasting glucose. It doesn't seem to say much about a correlation between carbohydrates and mood in diabetics. There was no relationship between glucose level on day one, for example, and mood on day two.

The second paper with the exhausting title is a little more interesting (well, sort of). This study looked at women with polycystic ovary syndrome (PCOS - known to coincide with insulin resistance), reactive hypoglycemia symptoms, mood, and diet. PCOS affects 10% of women, and between 50-70% of women with PCOS (particularly the lean ones) have symptoms of reactive hypoglycemia. That is, they have a "sugar crash" feeling about 90-120 minutes after a high carb meal. In this study, 24 women with PCOS, 299 controls, 47 self-reported women with symptoms of PCOS, and 92 men filled out an online survey.

Interestingly, 58% of the PCOS group reported having "binge and/or comfort eating" compared with 32% of the control women. More of the PCOS women were also reporting being on a "low-GI diet" - presumably at the advice of their doctors or nutritionists to help control PCOS symptoms. Of the participants, 53% were on no medicines, 13% were on contraception, 5% were on psych meds, 2.2% were on metformin, and 10% were on other meds (typically vitamins or allergy meds). 13% reported psychiatric issues (usually anxiety or depression), and 1.9% reported insulin resistance. The PCOS group was more likely than the controls to have mood or behavioral issues and to have reactive hypoglycemia symptoms.

In a subset of the study, 12 women with PCOS were matched with 12 healthy controls. The women with PCOS were, again, significantly more likely to have reactive hypoglycemia symptoms. Women with PCOS were more likely to have less energy, more tension, less happiness, and more behavioral symptoms associated with hypoglycemia. These differences remained significant after controlling for age, BMI, and "eating behavior."

So what do we find? Women with poor glucose control have, well, poor glucose control, and they have moods and fatigue to match, though underlying inflammation and hormonal badness could cause all of the above. And, not surprisingly, women with poor glucose control have more bingeing and emotional eating - again, perhaps a symptom and a cause wrapped all in one. There were not enough folks on the "low GI" diet to make any intelligible statistical conclusions.

Here's my conclusion. If you have PCOS or type II diabetes, do not eat 300 grams of carbohydrate a day. Don't do it. Keep it low, keep it nutrient rich*, keep it basic happy natural food. I'm guessing your moodiness and your glucose control will improve.

* my idea of nutrient rich and the USDA's idea of nutrient rich are rather different. I think bone marrow and grassfed beef liver are nutrient rich. They prefer skim milk and whole grains. You do the math.

Nutritional Brain Bomb - Thiamine Deficiency

2011-08-21T13:43:00.001-04:00

Yes, I will get back to the carbohydrate insanity series shortly. But in the comments of the second post, Jack Kruse and Itsthewooo noted that studies with respect to alcohol, blood sugar and violence could be confounded by other nutritional deficiencies. Which is absolutely true. I have to say, it is rare to see scurvy or other famously maritime deficiency diseases aside from the serious long-term alcoholics who frequently populate the emergency room. As one of my attendings in medical school put it, the "Three B diet" (beer, bologna, and bread) is not one likely to come up roses when thrown into a nutritionist's calculator.

So since I seem to be blogging an awful lot right now, I thought I would throw in an instructional primer on brain issues and thiamine deficiency, also known as Wernike's Encephalopathy (and if you are very unlucky, Korsakoff's Psychosis). And a new subset of patients aside from chronic alcoholics need to worry about this issue too - as I mentioned in ~~The Healthy Skeptic Podcast~~ Chris Kresser Dot Com Podcast Episode 13, there are many case reports in the literature of psychosis and weird psychiatric and neurologic syndromes popping up in gastric bypass patients several years after the surgery - though copper, iron, and B12 are all problematic for post gastric bypass patients, so, apparently, is thiamine (vitamin B1).

Wikipedia Commons

Alcohol interferes with the intestinal absorption of thiamine, so that people who obtain the majority of their calories from alcohol are unlikely to get quite enough thiamine. A "clinical pearl" taught in medical school is to double (in your mind, not in the chart!) the amount of alcohol someone tells you he or she drinks. (Hundreds of honest people now vow to halve the amount of drinking they admit to… then realize in truth they already have been…). I've heard every sort of vast quantity of alcohol use daily from "a quart of Jack" or "a 30-pack of beer" to "17 boilermakers" and "whatever I can get my hands on." (Shoot - another "clinical pearl" segue, for any medical students or residents reading this blog - the opposite is actually true for any savvy opiate abusers - often the dose of methadone given to prevent withdrawal is scaled to the amount the patient says he or she uses, rather than using vital signs and clinical picture as is the gold standard, so he or she will often increase the self-reported amount to get more methadone off the bat. And ALWAYS call the methadone clinic to confirm the chronic dose before you write the order for the hospital stay - 160 mg of methadone is a common clinic dose but can stop the breathing of someone not used to that much.)

So who cares if you don't get enough thiamine? Well, as we know, your brain loves energy. As do the rest of your nerves. And good old vitamin B1 is a cofactor to a zillion energetic reactions. If you burn glucose, you desperately need your thiamine. To quote Harrison's Principles of Internal Medicine, 14th Edition (yes, I am old, page 2455):

Thiamine is a cofactor of several enzymes, including transketolase, pyruvate dehydrogenase, and alpha-ketoglutarate dehydrogenase. Thiamine deficiency produces a diffuse decrease in cerebral glucose utilization and results in mitochondrial damage… electron microscopy shows disintegrating mitochondria, chromatin clumping, and swelling of degenerating neurons…consistent with excitotoxicity.

Yikes! Even if the bigger words are mysterious, let me assure you that the picture is very bad. Dying, rotting neurons and a smokey ruin of your precious brain. Certain areas of the brain, such as the mammilary bodies and parts of the cerebellum seem particularly vulnerable, as they may have some of the highest glucose utilization in the brain. The heart, being a high energy-using fellow itself, is also vulnerable to thiamine deficiency. Nervous system symptoms from thiamine deficiency is also called "dry beriberi" whereas cardiovascular involvement is known as "wet beriberi" or "sailor's asthma."

What are the symptoms? Classically, the clinical triad is paralysis of certain eye movement muscles known as "ophthalmoplegia," problems with balance and walking (often a wide-based, shuffling gait) known as "ataxia," and confusion. Only 1/3 of patients will present with all three - most are very disoriented, inattentive, and sometimes agitated. If a profoundly thiamine-deficient patient shows up in the emergency room and is given straight-up D5 IV drip (D stands for dextrose - which is basically glucose) - this will confound the problem and worsen the symptoms - which can include stupor, coma, and death. (ER docs and nurses really try hard not to kill folks by giving them the standard IV in the emergency room). This is why someone with a history of alcoholism will instead be given a "banana bag" - which contains folate, 100 mg thiamine, magnesium, and a multivitamin solution, which makes the bag yellow instead of clear like most IV solutions (thus the name). Acute thiamine deficiency (Wernike's encephalopathy) can be cured with 50mg thiamine a day until normal eating resumes.

Chronic thiamine deficiency is not curable and can result in a particular type of brain syndrome called Korsakoff's psychosis. The afflicted will have poor memory and confabulate like crazy - meaning, you ask him a question, and he will not know the answer, but he will make one up!

Well, most of you who are not members of the antique navies of the world and also without a 17 boilermaker a day habit or other genetic deficiencies of the pentose phosphate pathway will never experience such severe thiamine deficiency that you will get such dramatic symptoms. But the case of vitamin B1 does serve to illustrate the importance of appropriate nutrition for our noggins to work correctly.

Do Carbs Keep You Sane? Midmorning Post-Bagel Slump and the Wurtmans

2011-08-20T14:09:00.003-04:00

We are going to rely more on this most excellent review paper by Dr. David Benton of Swansea, UK, Carbohydrate ingestion, blood glucose, and mood to continue our exploration of the question of how ingestion of carbohydrates affects mental state.

First off, some of the short-term studies. We all can guess the results, but a dozen or so studies have shown comparisons between a meal of say, turkey breast versus starch-based meals, or placebo versus a sucrose or glucose containing drink. Not surprisingly, mood/energy measurements at 14-30 minutes after the sugar drinks shows an increase in energy levels, followed by a slump at two hours. In the protein meals versus starchy meals, subjects report a decrease in subjective sense of energy two hours after eating the starchy meal compared to protein. All of these studies were done while subjects were resting quietly.

In studies done of subjects asked to do demanding cognitive tasks (presumably slurping up all available glucose as the noggin is burning nitro), falling levels of reported energy directly correlated with falling blood sugar levels. Subjects with low blood glucose at 30 minutes and 2 hours doing demanding cognitive tests had higher tension ratings than those with high blood glucose. In diabetics, blood glucose levels (measured continuously) have been associated with immediate mood changes, with low corresponding to a more negative mood state than high levels. (There are some interesting perturbations of this phenomena over measurements of days and weeks, however, which I will address in detail in the next post).

Now on to that theory I've actually already discussed at some length in previous posts - via insulin and albumin effects, ingestion of carbohydrate leads to the preferential shuttling of the rare amino acid, tryptophan, into the brain. Since tryptophan is the precursor to serotonin, eating carbohydrates will presumably make one more serene, sleepier, and more sated than someone whose brain is starving for serotonin (low cerebrospinal fluid (CSF) serotonin levels are associated with violence, insomnia, hunger, and suicide, partly because serotonin and its metabolite melatonin play a major role in the mood, appetite, and sleep centers).

Richard and Judith Wurtman of MIT are the ones who originally proposed the theory, and they suggested that humans (particularly premenstrual women and those afflicted with seasonal affective disorder) crave carbs for the serotonin-boosting pharmacologic effect (1)(3). I've seen this theory in textbooks and in research papers many, many times, and I rather took it as fact. Judith Wurtman is a big carb proponent and is likely to give rather strongly-worded quotes to the media damning low-carb diets for causing depression. In the comments, Zooko pointed me to this, er, interesting article by Dr. J. Wurtman for the Huffington Post. Also to her twitter feed, which advises the dubious practice of snacking on pure carbs in between meals for a "serotonin surge" - with specific recommendations for pretzels, rice cakes, and marshmallows. Long term I would say that anyone wanting to lose fat who also has mental health problems should really pretty much avoid adding any processed, micronutrient-poor calories to the mix. What is interesting about the good Dr. Benton's review paper is that he leaves the Wurtmans' tenuous theory crumbled into dust when we look at the context of carbohydrate ingestion in the real world.

It is absolutely true that a carbohydrate only meal after a fast will increase the entry of tryptophan into the brain in rodents, humans, and other primates. The problem is, the moment you eat a bit of food protein, this effect no longer takes place. Dr. Garner was able to increase serotonin in mice brains via a mixed diet, but he fed the little critters extra tryptophan supplements to do the trick (which resulted in increased mouse brain serotonin and a deadly increase in scratching and subsequent skin infections). Without the extra tryptophan boost, as little as 4% of protein in the meal will eliminate the carbohydrate tryptophan-boosting effect. To put that amount of protein into perspective, potatoes, rice, chocolate, and flour all have too much protein for them to increase tryptophan entry into the brain. Bascially, one has to eat pure starch (or a sugary drink) to achieve the pharmacologic carb-serotonin effect, long enough after a previous meal that no protein remains in the gut. That also means that pretzels and rice cakes wouldn't work for a "serotonin surge," and one must stick to marshmallows and jelly beans, which doesn't have much of an evolutionary precedent. This teensy amount of protein killing any "serotonin surge" is true in studies of rats, other primates, and humans (2).

In monkeys, Grimes et al. contrasted protein and carbohydrate breakfasts and found no impact on the levels of cerebrospinal fluid (CSF) tryptophan or serotonin turnover from individual carbohydrate-heavy meals. He went from protein being 25% to 6% of calories, and as protein declined, so did plasma and CSF levels of tryptophan due to lower amounts of raw material protein consumed. There was no immediate change in serotonin turnover or CSF tryptophan levels to individual meals. In the case of the monkeys, higher protein chronically is associated with higher serotonin, not higher carbohydrate, and blood changes of the ratio of tryptophan to other amino acids did not predict CSF tryptophan levels as it does in rats (which are what the Wurtmans studied). I must say the Wurtmans' studies are cited a good deal more often than Benton or Teff or Grimes.

So the carbohydrate = serotonin-increasing theory is likely bogus for humans, especially in the real world (yes, even on Thanksgiving), unless you happen to have a glass of lemonade for breakfast every morning, excluding all other food. BUT, that doesn't mean that carbs don't affect mood. What do studies without such ridiculous attention to actual mechanisms show?

In one study, a drink with 48 grams of carbohydrate and no protein decreased depression, anger, and confusion in women suffering PMS. Judith Wurtman also found that women increased their intake of carbohydrate and fat in the premenstrual stage, and experimental meals with only 4% of the energy as protein did improve the mood of women with PMS. (She did find these women had no higher ratios of tryptophan in their blood than women given control meals, and that women who had improved mood also had no increase in blood levels of tryptophan, suggesting that is not the mechanism for the improved mood) (4).

What do other researchers find? In several reviews, it was found that women generally report an increased craving for sweets and increased appetite in the pre-menstrual period. In humans and animals, there are also changes in basal metabolic rate in the different parts of the cycle, corresponding to the appetite changes, which makes sense. However, a review of studies of what women actually eat showed no difference in the total amount of carbohydrate consumed in any part of the menstrual cycle. Some studies have shown an increase in sweets, chocolate, and cake consumption before and during menses compared to ovulation (which occurs mid-cycle). So there is definite evidence that appetite increases just before and a bit during menstruation, but this corresponds to a higher metabolic rate, and it is foods generally containing a combination of carbohydrate and fat that are craved, not strictly carbohydrates.

In other studies, carbohydrate ingestion has been associated with better mood. De Castro had subjects keep food diaries and mood journals for 9 days, and found that on the days when more carbohydrates were consumed, mood was better (5), and people felt more energetic. He also found a cumulative effect - the more carbohydrate consumed over the week, the happier the person tended to be. In a study of 686 folks who reported their mood at mid-day and what they ate that morning, the more absolute carbohydrate the male subjects consumed that morning, the happier their morning mood. Absolute and relative amounts of protein and fat had no impact on mood in this unpublished study by Benton.

Finally, studies of experimental low carb vs. high carb diets of one week (6), three weeks (7), six weeks (8), and one year (9) show a better comparative mood and increased serenity in the high-carb dieters. The one year study was complicated by the fact that twice as many people in the low-carb group were on antidepressants, and the other studies may have been of too short a duration to bypass the "low carb flu" - and all of those low carb diets may have been high in omega 6. I don't have the energy to chase down all the full texts of all these studies right now (I've seen the year-long one, however), and the one-week one was done in cyclists, who might be cranky in the first week of a low-carb diet while training!

So what have we learned? Well, the Wurtmans and the carbohydrate-tryptophan-serotonin boost theory are scuttled, for now*. But carbohydrates don't seem to cause craziness, and for some people, they seem to help. Is the story any different for folks who have insulin resistance? We'll find out next time (though there might be a quick intervening review of a related topic in between that post and this one).

Please see the later post, Carbs and Serotonin, A Connection After All

Do Carbs Make You Crazy? More About Blood Glucose, Violence, and Mood

2011-08-19T14:56:00.001-04:00

I began this series yesterday with a bit of an introduction and some exposure to some differing theories about carbohydrate consumption and mental health (basically they run the gamut from very low carb will spare your mood to you absolutely need carbohydrates for sanity). I didn't take much of a stand, myself, other than to note that in my personal experience, a bit of healthy fat and protein has kept me from experiencing some of the uncomfortable weakness, tremulousness, and crankiness I had a few hours after sugary meals years ago, when, ironically, Stop The Insanity was in vogue.

(Music - Alexander Borodin, Polovtsian Dances, right click to open in new tab)

I noted in my last post that somewhere between 1966 and the early 1990s, it became very unfashionable for medical professionals to endorse the idea of "hypoglycemia," outside of a super low measured blood glucose level of around 40 or less. "Relative (or reactive) hypoglycemia" had been consigned to a psychosomatic diagnosis. So my relative hypoglycemia which predictably occurred at expected physiologic intervals after ingestion of exclusively high-sugar foods or drinks must have been all in my head. :-) In fact, the year before I was born, the American Diabetes Association, the Endocrine Society, and the American Medical Association issued a joint statement on hypoglycemia, stating that widespread publicity "has led the public to believe that there is a widespread and unrecognized occurrence of hypoglycemia in this country… These claims are not supported by the medical evidence." The American Dietetic Association stated: "Valid evidence is lacking to support the hypothesis that reactive hypoglycemia is common cause of violent behavior."

However, when blood glucose falls to quite low levels, the body does tend to react rather aggressively in order to prevent death. Stress hormones, including catecholamines and glucocorticoids, growth hormone, and glucagon are all released. This high-powered combo would no doubt cause sweating, palpitations, anxiety, weakness, crankiness, and other symptoms traditionally associated with hypoglycemia (but can also occur whenever high levels of these hormones are released for any cause) (1 - amazing paper, by the way. I highly recommend it). If the blood glucose falls low enough that the brain is impaired, certainly very bizarre behavior (such as psychosis) can be observed.

How common is such low glucose outside very rare insulin-producing tumors or accidental overdoses of diabetic medications? Well, actually, in oral glucose tolerance tests (the gold standard is when you are given 50 grams of dextrose after an overnight fast, and then blood glucose is measured continuously for up to six hours - often the absolute nadir is missed if the glucose is not measured continuously, but rather at half hour intervals, as is also common), there is a wide range of glucose nadirs in the blood levels of those tested. The average level is about 65, but 10% of people fell below 47, with 2.5% of people below 39. That means that 1 in 40 people could expect to have "true" hypoglycemia in the context of a pure carbohydrate snack after a fast. This effect can be accentuated by caffeine and alcohol.

However, when one goes around measuring glucose levels of typical human beings eating mixed meals (not participating in oral glucose tolerance tests) levels almost never fell below 70. In these healthy subjects, levels pretty much stayed between 70-100 all day long, before and after meals, and overnight. It was a combination of these findings and studies of so-called hypoglycemics whose blood glucose levels did not correlate to symptoms that consigned "relative" or "reactive" hypoglycemia to conservative medical never-never land. However, in my own case, the symptoms were predictable, and the predictable treatment of switching to a higher-protein, higher-fat, less crappy diet cured it, which I would find odd if it were entirely psychosomatic. Also interesting and pointing to a physiologic cause is that the symptoms returned for me during pregnancy - where insulin reactions and "relative" hypoglycemia will tend to be of larger magnitude than in the non-gravid state, in order to promote glucose uptake by the growing fetus.

But there are other very interesting correlates between hypoglycemia and behavior and mood. A researcher named Bolton studied the Peruvian Quolla Indians, who are apparently known as "perhaps the meanest and most unlikeable people on earth." (2) These people, particularly the men, seemed to act out in irrational acts of violence, and also seemed to have very strong sugar cravings. Bolton happened to do glucose tolerance tests in many of the men, and he noticed a statistically significant correlation between the most aggressive subjects and those who had the lowest blood glucose values during the GTT (3). Another researcher, Virkkunen, studied men who had committed serious violent assaults. Their GTTs were also remarkable for higher peak glucose values and subsequently lower glucose nadirs than controls (4). Folks with antisocial personalities have also been noted to have low blood glucose levels, and, once again, it is important to note that many of these men perpetrated the crimes under the influence of alcohol, which will accentuate the hypoglycemic effect. Similar studies in the general population show that both men and women whose blood glucose fall more rapidly during a glucose tolerance test will tend to have higher ratings of aggression (5)(6). In these studies, a glucose level of 63 or lower was strongly associated with the aggressive tendencies. This is still outside a normal healthy humans' blood glucose range eating normal food, but much, much closer to the normal range than 40.

Wow. I guess rapidly fluctuating blood glucose does cause behavioral changes… wait a minute, there, buckaroos - as I had noticed in my perusal of the rather badly reasoned behavior/blood glucose/insulin resistance literature (which I will go over in the next post), and which Inthewooo noted in her comment on the first post in this series, these are mere correlations. Why is the blood glucose changing more rapidly in certain people than others to the same food or glucose stimuli? Could an underlying mechanism explain both aggression and hypoglycemia?

Virkkunen's more violent reactive hypoglycemics had enhanced insulin response to the oral GGT. And it has been found that impulsive offenders who act aggressively, particularly when intoxicated, have lower levels of serotonin turnover (measured low levels of the metabolite of the serotonin metabolite 5-HIAA in the CSF (7)). Low levels of brain serotonin are associated with enhanced insulin secretion and a tendency to develop low blood glucose levels. The data is a bit tenuous, but at least this mechanism makes some sense in the big picture.

Next up - carb craving and chocolate and PMS and Wurtman's rodents! Women with PCOS, reactive hypoglycemia, hyperglycemia, and mood relationships. You might be surprised at what the science shows...

Do Carbs Make You Crazy?

2011-08-18T17:05:00.005-04:00

Perhaps I should be more circumspect in my title. After all, there are several popular ideas out there - one that carbohydrates cause blood sugar spikes and crashes, leading to mood swings and general crankiness. The second is that sugar (that special fructosey form of carb) causes everything from ADHD to delinquency to psychosis to bipolar disorder.

(Music selection - Serenade in E Major (right click to open in new tab) by Dvorak, who happened to write what is widely accepted as the most exalted piece of American classical music, though he is in fact from ~~Czechoslovakia~~ Bohemia.)

I think pretty much everyone has heard of these ideas - most recently I saw them in an article I linked a little while ago, "How I Overcame Bipolar II (and Saved My Own Life)" by Michael Ellsberg. Here is a quote from the article:

Dr. Hoffman told me there is mounting clinical evidence linking mood swings to blood sugar issues, and that in his experience bipolar patients respond well to cutting out refined sugar, and coffee and alcohol (which affect blood sugar) from their diets. “You should stop eating refined sugar altogether, and stop drinking alcohol and coffee,” he told me.

Apparently, Mr. Ellsberg went to a psychiatrist also:

I asked the psychiatrist I was seeing at the time whether he thought there was any link between nutrition and mental health. He looked at me as though I had just asked whether there was any link between mental health and UFO rectal probes. “There is absolutely no evidence of any link whatsoever between dietary choices and mental health,” he said curtly, and changed the subject.

Besides my wacky UFO rectal probe blog, on the paleo mental health side of things we have Nora Gedgaudas, who has just released an updated version of Primal Body, Primal Mind. I have read her book, and though I did not attend her talk at AHS, from my memory of her book and the coverage of that talk, it seems to me she advocates a very low carbohydrate approach, that in effect we are either fat burners or sugar burners, and fat burners are steady and serene, while sugar burners are moody and cranky. (Nora herself! clarifies her very reasonable position in the comments below - in short, her clinical experience has shown her that limiting sugars and starches for most people has been very helpful.)

Then we have the opposite side of the argument, personified by rodent and women's health researcher Judith Wurtman at MIT, and paleo blogger Don Matesz - carbs improve and are essential for good mood, particularly in the case of PMS, atypical depression, and seasonal affective disorder.

What did I learn in psychiatry residency? Well, that the ideas about sugar causing ADHD were unfounded, and that carbohydrates in general wouldn't be an issue plus or minus unless one had uncontrolled diabetes, in which case, of course, uncontrolled glucose swings could cause all sorts of craziness. Diabetes is one of those conditions we are supposed to rule out before spending 20 hours talking to someone about his or her mother, or prescribing Prozac.

So whom do we believe? Orthomolecular Dr. Hoffman? The Harvard Longwood Psychiatry Residency Training Program? Nora Gedgaudas? Parents who have observed their kids after a party with CAKE and ICE CREAM and FACE-PAINTING FAIRY PRINCESSES? (I'm going to tell you right now that the kids totally spaz out for several hours and then collapse in a twitching exhausted heap of sugar/princess withdrawal. The confounders are many, I must admit).

What have I learned from Gary Taubes and Peter and Kurt? Don't believe anyone. Look it up your own self, and see if it makes sense in the context of physiology and evolution. But y'all know me at this point - let's put aside the issue of metabolic syndrome for a second. Most hunter gatherer societies that I'm aware of ate starch when they could get their hands on it, so it doesn't make sense to me that carbohydrates alone would cause craziness. (We will also leave out alcohol and caffeine which Dr. Hoffman wisely recommends bipolar folks to avoid - both of which will affect SLEEP as well as sugar levels, an obvious confounder in bipolar disorder).

And yet, here on my blog and twitter and elsewhere I've seen reports of folks who feel so much better on VLC diets, and others who feel so much better with zone-ish ratios, and others who do better with more carbohydrates. My own experience (now documented in several podcasts) is that I had hypoglycemia in my late teens and early twenties. Of course, I never got an official diagnosis of hypoglycemia, because that doesn't exist outside the context of diabetes or an insulin overdose or insulin-secreting tumor. If I ate super low fat and high carb, I would get shaky, weak, and cranky about 90 minutes after my last meal. When I called the doctor about it, I was checked for diabetes (negative), and then I was told not to eat like a jerk. (Okay, some days I would eat raspberry fig newtons for lunch and dinner, and I was known to eat an entire package of Peeps from time to time - hey, I was 18.) Eat nuts and avoid sugar, sodas, alcohol, and honey, they told me. Eat snacks. And I was careful from then on out to not be such a jerk about eating and to have snacks - packages of peanuts, apples and string cheese, graham crackers stuffed in my bag - and woe befell anyone in my presence who found me snackless two or three hours after a meal… I don't know how I made it through 7-8 hours of sleep… I personally happen to do better eating a bit more fat, though I'm rarely VLC outside fasting days. I do eat bananas, rice, and potatoes. Yes, it's true.

But what does the literature say? Well, let me begin with a very pleasantly retro article from the halcyon days of 1966, when they believed in hypoglycemia outside of insulin tumors and diabetes - tweeted to me by @ambimorph: Relative Hypoglycemia as a Cause of Neuropsychiatric Illness.

This paper defines "relative hypoglycemia" as my doctor did back in the late 90s - a drop in blood sugar that occurs after eating like a jerk - lots of caffeine or sugar. Apparently the people of the early 20th century suffered from this condition, which was misdiagnosed sometimes as a brain tumor, diabetes, or cerebrovascular problems, but when you stop eating like a jerk and consume some protein, fat, and get rid of the caffeine and alcohol, your symptoms go away.

In 1966 Dr. Salzer found that:

…patients with relative hypoglycemia have been diagnosed as having psychoneurotic anxiety, psychoneurotic depression, depressive reactions, schizophrenia, manic-depressive psychosis, psychopathic personality, chronic alcoholism, convulsive disorders, migraine, idiopathic cephalalgia, second cervical root syndrome, neurodermatitis, and even hypertensive cardiovascular disease... Major symptoms from a psychiatric standpoint are depression, insomnia, anxiety, irritability, lack of concentration, crying spells, phobias, forgetfulness, confusion… antisocial behavior, and suicidal tendencies… The major neurological symptoms are headache, dizziness, inward and external tremulousness, numbness, blurred vision, staggering, fainting or blackouts, and muscular twitching...There are also extensive somatic symptoms as follows: exhaustion, fatigue, sweating, anorexia, tachycardia, cold hands and feet, obesity, chronic indigestion, bloating, abdomnial spasm, muscle and joint pains, backache, muscle cramps, colitis, and convulsions.

Well. That sounds really bad. It sure does sound like sugar (and caffeine) can make you pretty crazy. And when I (personally) was pregnant, I did suffer from some frank neurologic symptoms related to hypoglycemia (despite the fact that I was eating like Michael Pollan told me to, not like a jerk) - true vertigo, headaches, severe nausea… the thing was, it was all pretty much instantly cured by eating some instant mashed potato flakes. Which is why I know I did not have a brain tumor (not typically responsive to mashed potato therapy). In the modern emergency room we have dextrose IV drips, ginger ale, and instant glucometer measures. I think perhaps that put the end to the mysterious hypoglycemia masking as a brain tumor era of medicine.

Next time… a discussion of carbohydrates and mood, from the literature. And a review of the relationship between blood sugar in mood in folks with diabetes, insulin resistance, and women with PCOS.

AHS 2011 Presentation - Slides and Video

2011-08-16T20:38:00.002-04:00

Just in case you missed them:

The slides

The video

Next up, I will look at carbohydrates, blood glucose, and mood connections.

Neuroregulation of Appetite

2011-08-13T15:46:00.003-04:00

The cause of obesity has been a hot topic in the paleoblogosphere lately. Let me be the first to tell you that I am no obesity researcher or expert (there, first point goes to Itsthewooo). All I know is that a few percentage of folks have been obese for thousands of years. And back in the late 1870s, here's a picture of my great great great (etc.) grandfather's funeral - you might have to click on it to enlarge and squint a bit, but I really don't see any obese people there.

Fast forward to 1919 - here's my grandmother, her mother, and her mother. Babies were chubby-cheeked as was my great great grandmother. They lived in the same area and were of the same socioeconomic class as many of the people in the first photograph.

And now 1943. My father is the baby in this next picture. As you can see, the children and young or middle-aged adults (including the middle-aged women who have had children) are lean, whereas the older folks have some extra adipose, especially around the middle (again, same area of the country):

And then 1987 - this picture is a tour of the USS Constitution in Charlestown, MA. As you can see, middle aged folks and even the kids are starting to be chubby, especially around the middle:

These pictures don't tell us much about what we don't already know. Obesity is a 20th and 21st century disease, that came upon us younger and younger as the decades rolled along, accelerating since 1980 or so.

What caused it? Video games? Captain Crunch commercials? Environmental toxins? I don't know, but my money is still on the food. Somewhere between the diets of the Kitavans and the Sioux and most of the people in the world before 1900 and our current diets is the cause of obesity.

Dr. Pendergrass of the University of Kansas had a great poster presentation up at AHS about the neuroregulation of appetite. He painstakingly cobbled together a fantastic diagram that detailed the communications between different organ systems, adipose tissue, and the brain. He highly recommended this paper if you are interested: Stress, eating, and the reward system.

Dr. Pendergrass' diagram was highly technical, inclusive, and awesome, though he warned me that he left out "about 120 known hormonal signals" between the GI tract and the brain. His also had a great deal of detail regarding the brain and different areas of it, along with specific hormonal and molecular signals and feedback there. Here is my layperson's version, which leaves out all the crushing detail. I can't promise all the arrows are leading the right direction (a graphic designer I am not):

It's complicated. Yeah, leptin, insulin, amylin, CCK, glucose, fat, etc. are all involved. Yes, once you have metabolic syndrome, dropping the carbohydrate will likely help (how low for how long? Beats me.) If you have advanced types of certain kinds of neurologic disease, there's evidence a ketogenic diet can be helpful. Make sure your micronutrient status is tip top and eliminate food toxins. Real, evolutionary medicine-inspired food is the easiest way to do that sort of thing.

But anyone who says he or she completely understands obesity is probably lying.