Anti-inflammatories and Schizophrenia

Short little post on a paper from a few weeks ago from the Journal of Clinical Psychiatry:  Nonsteroidal Anti-Inflammatory Drugs in Schizophrenia: Ready for Practice or a Good Start?  A Meta-Analysis.

Nothing spectacular here, just some interesting arguments and correlations to add to the literature that major mental illness has an inflammatory pathology, and that searching for anti-inflammatory solutions (and I consider an anti-inflammatory (nutrient-rich, low toxin) diet, proper sleep, proper coping, appropriate exercise and stress reduction as some of these non-prescription solutions to be examined further) is a reasonable course of action, and not woo-ville.

My usual radio haunts have been disappointing recently for brand new music.  But The Heavy came out with a new single this week, and I'm liking it:  What Makes A Good Man.  It sounds really good in the car, but I hope you're not driving right now.

All right, some suspicious correlations suggesting the immune system and inflammation may be involved:

1) People with schizophrenia and their close family members have higher risk of autoimmune disorders.
2) Men who have used steroids and NSAIDS (such as naproxen or ibuprofen) have a decreased prevalence of schizophrenia.
3) PET scans of folks with schizophrenia show increased numbers of active microglia in the brains (microglia are immune cells in the central nervous system, activated to fight infection or in autoimmune conditions or inflammation).
4) With brute force hacks of genomes of folks with schizophrenia, one of the gene areas that keeps popping up are markers in the major histocompatibility complex (MHC) region on chromosome 6.  MHC genes code for the markers we put up on our cells to label them as ME so our own immune army doesn't take us out.
5) There are abnormal levels of inflammatory cytokines, immune markers, and autoimmune antibodies in the serum and spinal fluid of folks with schizophrenia.

So something in the immune system is amiss.  Maybe gut-punching inflammation could help the symptoms.  Enter the NSAIDS (non-steroidal anti-inflammatory drugs).  They work by inhibiting the conversion of our old frenemy arachidonic acid (AA, made from the omega 6 linoleic acid, but also available as is from various animal foods) into the class of molecules called prostaglandins.  Prostaglandins help mediate pain, inflammation, and thermal regulation, which is why you might pop an Advil when you have a fever or a muscle ache (or both).

Now, NSAIDS are known to trash the gut and the kidneys if you aren't careful, and various versions may kill you dead with a heart attack (Vioxx) in the long term, and pregnant women and those with ulcers and ulcerative colitis and some others should avoid them�but as I am not currently afflicted with any of the previous conditions I would still take it in lieu of acetaminophen, personally, when I am not toughing it out. Like last Monday, when my children gave me a little virus that toasted me all the way up to 103.3. Personally I'm cool with 102s but the 103s start to make me worry about brain fry-age, particularly in adults.

(An oldie but a goodie:  Neil Finn: She Will Have Her Way   Definitely worth the ad�)

More specifically:  AA + the enzymes COX1 and COX2 make prostaglandins, which mediate pieces of the inflammatory response.  NSAIDS like ibuprofen, naproxen, diclofenac and acetylsalicylic acid (otherwise known as aspirin) will block COX1 and COX2, reducing the ability of the body to make prostaglandins.

So will doing that not only help a fever or an aching muscle, but also the symptoms of schizophrenia?  What does the literature say?

All the randomized controlled trials of antipsychotic medication augmentation with an NSAID were analyzed in this meta-analysis.  (No one official is just using Advil for psychosis.)  In the literature there were 5 (small) RCTs, for a total of 264 patients.  The trials all used celecoxib (a selective COX2 inhibitor) or aspirin, and lasted from 5 weeks to 3 months.  4 of the 5 studies all had similar results, modestly but significantly helpful in both "positive" symptoms such as hearing voices and "negative" symptoms such as social withdrawal.  One study showed the NSAIDs not to be helpful, compared to placebo.   Apparently two other unpublished studies also showed celecoxib to be unhelpful, so we have to be cautious about these findings.

More specifically, with a few of the celecoxib studies, the NSAID didn't appear to be particularly active in the central nervous system, as expression of COX2 wasn't altered in the hippocampus and there were no changes in the cytokine profiles in immune cells called mononuclear cells.  In the aspirin study, however, they were able to detect a treatment effect with differences in cytokine profiles due to the drug.  Since COX1 prostaglandins cause platelet aggregation, inhibiting COX1 leads to the supposed cardioprotective effects (but also the increased risk of ulcers) of the nonselective NSAIDS.  It's a bit irritating that all these studies were done with the selective COX2 inhibitor, celecoxib, but since it was the one on patent, I'm guessing that's why the money was spent there.  It would be interesting to see larger studies done with ibuprofen or aspirin, frankly.

Well!  More wait and see.

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You're a Vegetarian. Have You Lost Your Mind?

Hey, I'm back!  Looks like when I don't blog new stuff, the archives get more reads, though, which is good.  They ought to be useful for something, anyway.  Lots of action on the Evolutionary Psychiatry front behind the scenes, some of it still super secret and all very exciting.  AHS12 is coming up and with it reunions with a bunch of my best evo med-loving buddies, along with some new folks from far and wide.  I've also been invited to talk to some more of my colleagues about the notion of "Evolutionary Psychiatry" and what it means.  I'll let you know when I have that figured out.

Heard this song again� never could get enough of it:  Song Beneath the Song by Maria Taylor.

Just when I thought I was bored to death with observational studies, a new one (free full text!) came along, tweeted first by the lovely Denise Minger, and also sent along to me by none other than the Primal Blueprint himself, Mark Sisson:  Vegetarian diet and mental disorders: results from a representative community survey.

It's a German study, and for a large population-based retrospective observational design, it's actually fairly thorough and sensible.  And if you are a vegetarian, it certainly doesn't say that vegetarianism causes mental health problems.  But in every single study except for two done in the past, vegetarianism has been linked with higher rates of depression, anxiety, and particularly eating disorders (bingeing, restricting, and purging behaviors).  But to be perfectly honest, all those studies were pretty crappy (small, using special populations, and often based on just a few answers to general survey questions).  I've reviewed a few of them.  (My favorite has to be the one where they calculated arachidonic acid ingested to the hundredth of a gram based on data from a food frequency questionnaire.  Hahah!)  I don't think it is a coincidence that the two positive studies were done by the same group of researchers.

The interesting thing about the general trend that vegetarians aren't quite as mentally healthy as omnivores (in observational studies) is that vegetarians tend to do better in other measures of health.  They are better educated, as a population they are generally younger, less likely to smoke or drink, more likely to exercise, and they tend to care about ethics and the quality of their food.  However, vegetarians are also more likely to be female (which is more likely to be associated with anxiety, depression, and eating disorders by a long shot).

So this new study has some things to recommend it.  For one thing, the mental health diagnoses were determined not by answers to typical questionnaires, but by a full clinical interview using psychologists or physicians, lasting an average of 65 minutes each.  (Pretty impressive, considering there were over 4,000 participants in the population-based study).  In addition, the researchers matched omnivores to vegetarians based on age, education, sex, and whether they were urban or rural and crunched those numbers as well, so we got a good sample that took out some of the major confounders that dogged the previous studies.  Finally, this cohort was a purposeful random sampling of the German adult population (excluding people over 65, however), rather than the Seventh Day Adventists or adolescents and college students sampled in previous studies.

And when the researchers went down the line of depressive disorders, anxiety disorders, somatoform disorders (things like body dysmorphic disorder, health anxiety and hypochondriasis), and eating disorders, the mostly vegetarian were more likely to be afflicted, and the strict vegetarian even more likely.* The full blown eating disorder diagnoses were rare enough, however, that the researchers didn't compute the odds ratios, as they felt the dataset was not robust enough to be fair.  Compared to the general population, the vegetarians were more likely to have mental disorders, and compared to the sex and education and population and age matched controls, the risk of mental disorders in vegetarians really shot up, with odds ratios hovering around 2, some as high as 3.  (ORs around 2 is when you ought to start taking notice).

When the data was taken apart from another direction, it was found that participants in the study with depressive, anxiety, somatoform, and anxiety disorders consumed less meat than people without a mental disorder.  The amount of vegetables, fruits, fish, and fast food did not have a consistent pattern separating those with and without mental disorders (except fish consumption was linked with reduced anxiety.  Hmmm).   In fact, unlike the 2010 Australian study, those with mental disorders in this German population were less likely to consume fast food than the mentally healthy population.

Temporally, the adoption of a vegetarian diet, on average, tended to follow the mental health diagnosis, suggesting that the vegetarian diet was not in fact causal.  A retrospective study isn't the most robust way to determine this issue, but I would tend to believe this timing to be true, particularly for anxiety disorders, which often begin before the age of 10.  The main exception to the temporal findings in this study were the eating disorders, which tended to start right around the same time as adoption of a vegetarian diet.  As I've reported before, several of my eating disordered patients have told me they adopted vegetarianism so they would have an excuse to restrict food and not have to eat in public.

So what is going on?  In Germany, are the neurotic perfectionists who are more likely to be choosey about food (and thus select vegetarianism and eschew fast food) also more vulnerable to depression and anxiety?  Sure, could be.  Or maybe those with mental troubles try to avoid what is thought to be bad food (meat and fast food).  It is also possible that the nutrient deficiencies common  in vegetarian diets (the most robustly studied being long chain omega 3 fatty acids and B12, though I think zinc and creatine and even too low a cholesterol could also be issues) could accelerate or worsen pre-existing mental conditions.

A large study comparing choosey, neurotic, perfectionistic omnivores (ahem) with strict vegetarians would be interesting, I think.

* the German word for "meat" excludes poultry.

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It Starts With Food and Two Years of Evolutionary Psychiatry

I first met Dallas and Melissa Hartwig at AHS11 at UCLA. They are formidable, friendly, bubbly, beautiful, and very tall. I first heard of them several months earlier from Jamie Scott, and then remembered a spat back and forth between Kurt Harris and someone named Dallas over dairy in the comments of Kurt's blog (then named PaNu). Shortly after that, I received a comment or email from Dallas writing he was adding me to the "resources" list of the Whole9 website ("if you care" he said, which I thought was funny.)

I poked around the website and decided to do a Whole30 leading into the inaugural Ancestral Health Symposium. I didn't achieve a "perfect" 30 days due to a vacation to Santa Fe, but I did have some very positive effects which I wrote about in this post. In the mean time, Dallas and Melissa had become part of a group of paleo journal club buddies who pass around interesting papers and whatnot, and they supplied me with a copy of their Whole30 Success Guide. Since then I've also ordered a couple of their T-shirts (one for my sister-in-law who is a big fan), and while they let me buy the gift, they always gave me my shirts with the admonishment that I was not to buy them (I have a feeling they are fond of me, and maybe one day I can leverage that so they can teach me to snowboard or something :-).  We met again at PaleoFx and bonded over our shared relative certainty that the consumption of starch (GASP) was not going to lead us to an early grave (don't even get me started on that one).

All this exposition is my way of giving you full disclosure. And it is a bit fun to walk down memory lane. I started this blog almost two years ago exactly, the readership blooming within a few months thanks to links from Nephropal, Mark Sisson, and Kurt Harris, and later Stephan Guyenet. In the intervening years, I've had the opportunity to meet or correspond (sometimes at great length) with most of the major ancestral health figures, and Dallas and Melissa are among my favorites. It is no secret that Kurt Harris is another great favorite, but I have to say that in his N=1 exchange with Dallas above, I tend to side with Dallas, though a bias comes from me and my family having some issues with dairy. Kurt's arguments (as always) are extremely solid and reasonable. It's also funny how much has changed these past two years, how much online drama we've endured, and how my internet friendships have expanded to include so many people from all over the world. I haven't looked at my oldest blog posts in quite a long time, and I wonder how much I will cringe at my certainty, my style, and ignorance displayed in those first months.

I'm not yet marinated enough in this evolutionary medicine adventure to write a book.  Dallas and Melissa, however, have been working with their paleo-style food and lifestyle both personally and professionally since about 2006 or so, experimenting with their first Whole30 in 2009. I've known they were working a book for quite a while, and was honored when they asked me to review one of their final drafts and perhaps write a quote for the jacket. I was very pleased with It Starts With Food and ended up at the top of the back cover.

I loved the practicality and writing style of the Whole30 Success Guide, so it was no surprise to me that It Starts With Food is an easy and solid read with good narrative drive that takes you right through. It is not the slog of some nutrition books, comparable to the fun read of The Primal Blueprint.

There are two things about this book, however, that take it beyond the previous Paleo bestsellers. One is the terrific attention to the psychology of change and how modern food affects the way we think and crave. Another is the attention to science and how Dallas and Melissa are careful not to overreach. I know they vetted the manuscript with a number of folks, including the Kracken, hoping not to make the mistakes of Paleo past (such as strict prescriptions for carbohydrate grams or saying that legumes will kill you via the power of phytates and lectins.) Their Rx is orthodox Paleo (plus a helping of healthy fat) but they have good solid reasons why every step of the way. Their idea, like Robb Wolf's (and borrowed and attributed to Robb Wolf) is a "perfect" elimination diet, from which you learn a lot about yourself and add back in other likely healthy foods to figure out the balance of your best nutrition with your life.

The psychology piece is incredibly important. It is not easy to do a Whole30, even if you don't have many emotional issues with food, or even if you have weight to lose or are fighting a live threatening condition such as an autoimmune disease to give you plenty of motivation. Mark Sisson breezes past the psychology with his 80/20 rule (not a bad rule for many, though I find I need more like 95/5 to stay lean and sharp), and Robb Wolf in The Paleo Solution had a tough love approach "buck up buttercup" or something to that effect, which I found a bit cringe-worthy (sorry, Robb).  His blog is never like that.

It Starts With Food gives us tough love with extensive handholding, which I know through plenty of clinical experience with addiction and eating disorders is the most effective non-pharmacologic and non-locking-people-up-for-a-spell way to get people through the first rocky part of a major life change.  In addition, with the science and unknowns fully acknowledged, I can recommend this book to my patients and relatives without caveats, which is why I said in my quote:  "Here is the nutrition book we've been waiting for."

I also love how Dallas and Melissa address the so-called radical nature of the fad "Paleo diet" (bizarrely downtrodden by the conventional nutritionists, dieticians, and doctors in so many mainstream publications compared to such champions of processed food as SlimFast and WeightWatchers).

 "It's really not that radical--unless you consider eating nutrient-dense, unprocessed food radical.  Which, in today's microwave-dinner-fast-food-low-fat era, might very well be the case."

This book is Dallas' side of the argument with Kurt Harris.  It says, look, there may be some people who are perfectly healthy eating dairy, but it is worth eliminating it from your diet for a spell to see how you do. Some people, like me, will find fat mass, complexion, and GI tract all the better for it.  Others will not. Some will do very well with a bit of black beans (I do) whereas others will find it disturbs the intestines. And, again, there is nothing radical about a 30 day prescription of elimination. The real question is, what do you do for the rest of your life, and the transition to beyond the Whole30. Dallas and Melissa have plenty of answers for that as well, as does everyone else�let the debates begin.

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Glutathione: We Loves It (NAC and Autism)

I love twitter.  And I'm nearing 10,000 tweets, which is probably diagnostic of something.  But twitter is a great way to find articles and studies and things of interest tweeted by others with similar interests.  And twitter is how I found this new study from Biological Psychiatry, A Randomized Controlled Pilot Trial of Oral N-Acetylcysteine in Children with Autism.  Everyone go follow Cognitie.  He's obviously intelligent and good-looking to boot, with lots of cool links and whatnot.

N-acetylcysteine is a supplement I've covered before, in Problems?  I Have a NAC for That.

(Phoenix:  Armistice.  Right click to open in new tab)

A healthy brain is all about balance.  One one side we have glutamate, which is the major excitatory neurotransmitter in the central nervous system.  Think of glutamate as a charioteer with a whip forcing the horses in your noggin to GO GO GO.  We're glad we have glutamate.  Without glutamate we'd be dead.  But the problem is, glutamate doesn't always know when to stop.  That's why we have GABA, the major inhibitory neurotransmitter in the central nervous system.  GABA is the groom who takes those horses out to pasture to munch on the green grass and rubs the horses down with a nice brush.  In the right balance, you have a winning horse.  With too much excitatory action you get a worn-out old nag.

In autistic spectrum disorders, there are a number of lines of evidence pointing to problems with the excitatory/inhibitory balance in the brain.  There seem to be increases in expression of RNA for genes in the glutamate pathway, and there are certain genes having to do with the glutamate system that increase the risk for having autism.  Glutamate is actually the precursor for GABA, and the enzyme that catalyzes the transformation from one to the other is glutamic acid decarboxylase.  Both reduced levels of this enzyme and increased levels of glutamate have been reported in areas of the brain and spinal fluid in some children with autism.

In addition, as I noted in a previous blog post, autism symptoms may be a result of redox imbalance.  That is, throughout the body, we have oxidants and antioxidants.  We oxidize things to burn them in order to make energy, but we are left with "reactive oxygen species" as part of the burning process.  Antioxidants go around and sop up the reactive oxygen species to prevent them from damaging and destabilizing proteins and fats and whatnot.  Reactive oxygen species run amok can damage neurons and cause major brain problems.

We're used to thinking of "antioxidants" as vitamins such as C and E.  However, the major antioxidants in the body are actually superoxide dismutase, catalase, and glutathione.  The glutathione is one of the ways where NAC comes in, because as a supplement it is the best way to replenish gluathione in the liver and the rest of the body.*

(Animal Kingdom: Strange Attractor )

In the brain, the cysteine from N-acetylcysteine activates a glutamate-cysteine antiporter (a type of transporter in and out of a cell that exchanges cysteine for glutamate).  Shoving glutamate into the extracellular space in the brain leads to downregulation of glutamate transmission in the central nervous system.  So if you have too much glutamate whipping the brain, NAC seems like a mighty useful supplement to take.  Therefore, if autism spectrum disorders (and other neurologic and psychiatric disorders) are a result of an excitatory:inhibitory imbalance, with overabundant excitation, NAC will bring the players more into balance.

At the same time, if autism spectrum disorders (and other neurologic and psychiatric disorders) are a result of redox imbalance, with reactive oxygen species terrorizing the delicate neurons, NAC will help the body make plenty of glutathione to help clean up those bad boys.

There's no single cause of austim, but NAC might be a way to kill several birds with one stone, as it were.  AND, in the brain the two pathways (excitatory:inhibitory and redox) come together, as glutathione can displace glutamate at its receptor.  Another win for NAC, it would seem.**

And, as noted in the excellent editorial in the same issue of Biological Psychiatry, Translating the Rosetta Stone of N-Acetylcysteine, these multiple effects may be why NAC has been shown to be efficacious in trials of so many psychiatric disorders.  In the first paper I linked above, a small pilot trial, symptoms of irritability in autism were much improved in 5 kids, minimally improved in 6 kids, no change in 2, and one child got worse (though after the trial and on no NAC the subject had the same symptoms which were eventually found to be due to constipation).  In the placebo group, two were much improved, five were minimally improved, five had no change, one was minimally worse, and one was much worse.  Postive trials for NAC have also been reported for certain symptoms of schizophrenia, bipolar depression, cocaine craving, smoking cessation, trichotillomania, and gambling. What is also fairly remarkable is a lack of negative studies (established agents for all of these conditions have many negative studies.)

We still don't know if NAC is entirely safe (I wrote some theoretical problems with long-term use in my original blog article), and dietary supplements that aren't pharmaceutical grade might not be as reliable in dose, active ingredient, etc. as prescription medication.  On the other hand, we know that prescription medicines aren't entirely safe, and in many cases, we know they have very considerable risks.
It would be nice to have some replication of these studies.  As it stands, however, NAC has more of an evidence-base for use trichotillomania than any standard pharmaceutical.

Out of all the supplements, the ones that impress me the most are NAC and magnesium.  NAC sure isn't "evolutionary psychiatry," but in this modern world of stress, poor sleep, and inflammatory food, beefing up the glutathione and taming the glutamate seems like a reasonable approach, particularly if you are having devastating symptoms (as in severe autistic disorders).

*Glutathione itself is poorly absorbed as a supplement, and is too large a molecule to be easily absorbed into the cells.  Cysteine is the rate-limiting component of the reactions taking glutamate + cysteine to eventually make glutathione.  Cysteine itself is not easily absorbed, but the acetylated form, N-acetylcysteine, is.  Therefore, if you take n-acetylcysteine, you supply both a necessary precursor for glutathione and a nifty way to mop up excess glutamate.  Win-win on that front.

**and another eek! for acetaminophen

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