Tuesday, January 31, 2012

Medicine Is Still an Art

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.)

Saturday, January 28, 2012

More Evidence for a Gut-Brain Connection

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.

Sunday, January 22, 2012

Autism and Antioxidants -- A Wee Little Explanation

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.

Saturday, January 21, 2012

Tylenol and Autism?

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 antipyreticIn 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.

Sunday, January 15, 2012

Diet and ADHD - A Literature Review

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.)

Thursday, January 12, 2012

Just Eat Fish

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?

Yes, it's complicated.  

Sometimes the best generalized advice is to keep things simple.

Saturday, January 7, 2012

New Study on Vitamin D and Depression

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

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

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

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

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

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

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

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

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

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

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

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

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

Friday, January 6, 2012

The Glorious Cause

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Sunday, January 1, 2012

More on Diet and Dementia

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

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

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

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

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

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

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

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

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

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