Depression and a Leaky Gut

First off, please go by and read That Paleo Guy's account of being in the middle of the latest Christchurch earthquake.  Fortunately he and his loved ones and cat are all okay.  You can also follow his twitter feed here.  I've never been at the epicenter of disaster, and I don't know that I would have acquitted myself quite so well.  I mean, once when I was in college our power was taken out by a storm, and since we lived in a crappy part of town (cheap apartment for college), it took about two weeks to get it fixed, and we congratulated ourselves on the campfire we improvised on the back porch to roast marshmallows by.  But no ground shifted.  I don't think anyone died, though quite a few trees were taken out, and there was some flooding.  Other than that, well, I've seen plenty of death and destruction in the ER and ICU, but those are more or less controlled settings.  Anyway, I hope Jamie's life is back to some sort of normalcy soon.

But for a bit of literary grounding, let's visit John Steinbeck's greatest work, East of Eden.

"But the Hebrew word, the word timshel��Thou mayest�� that gives a choice. It might be the most important word in the world. That says the way is open. That throws it right back on a man. For if �Thou mayest��it is also true that �Thou mayest not."

I need a song.  Something quiet.  How about Satie's Gymnopedies No. 1? (right click in new tab)

Back to Evolutionary Psychiatry.  During the research for the Wheat and Serious Mental Illness post, I came across this intriguing paper by none other than Michael Maes, the cranky Belgian researcher who has churned out so many fascinating papers on depression and inflammation. 

Maes and crew took 51 subjects, 23 controls and 28 outpatients with Major Depressive Disorder from the outpatient clinic.  Everyone with substance abuse, anyone on medication, and anyone with chronic fatigue or other autoimmune diseases were excluded.

The basic premise of the experiment was that activation of the inflammatory response system plays a role in the pathology of major depressive disorder.  Our guts are chock full of gram negative bacteria, who have lots of a lipopolysaccharide (LPS) on their little bacterial cell membranes.  If one finds LPS in the bloodstream, that means those naughty bacteria are somehow squeezing through the so-called tight junctions of our intestinal tract - a leaky gut.  That would be bad.  And, not surprisingly, LPS found in the bloodstream ("systemic LPS") results in rapid increases in TNFalpha levels, which might remain elevated for as long as 10 months.  Brain microglia (immune cells in the brain) launch into action to fight the invasion and send out more inflammatory cytokines.  LPS in the system results in elevations of all those cytokines associated with major depressive disorder - TNFalpha, IL-6, IL1beta.  In animal studies, LPS administration results in an appearance of symptoms of poor appetite, psychomotor retardation (meaning lack of normal fidgeting movement, characteristic of depression), malaise, and loss of interest.  These symptoms are very similar to the clinical symptoms of depressive disorders. Increased LPS also seems to induce the catabolism of tryptophan (meaning more tryptophan, the amino acid precursor of serotonin, is chewed up and not used to make serotonin.)

So Maes checked antibodies (IgA and IgM - basically, gut antibodies and freshly minted antibodies) to LPS of 6 different enterobacteria.  Turns out that IgM and/or IgA were significantly elevated against most of the enterobacteria in the subjects with major depressive disorder.

In short, people with major depressive disorders were busy mounting an immune response to bacteria which never should be in the inner sanctum of the body in the first place - bacteria that live in the gut, and ought to stay in the gut.  Symptoms of irritable bowel, fatigue, and "a subjective feeling of infection" were most likely to be associated with a large immune response. 

Maes goes on to describe some interesting characteristics of the leaky gut - he contends that an inflammatory response itself actually worsens the leaky gut, that the activation of interferon gamma and IL-6 help the gram negative bacteria use the lipid rafts to get through the gut lining into the bloodstream.  That is interesting, as inflammatory response is increased in response to stress.  So stressful life events might in themselves increase the permeability of the gut.  (Jamie, do some yoga!).  Other things that induce lipopolysaccharide translocation - alcoholism, infections such as AIDS, inflammatory bowel disease (like ulcerative colitis or crohn's), and autoimmune disorders.

Maes ends his paper by optimistically suggesting that people with major depressive disorder be checked for the presence of leaky guts via measurements of IgM and IgA against LPS, and that those with leaky guts should be treated with a "leaky gut diet." (1) (the reference indicates one can write the Maes researchers to get the details of the diet - which I have done this evening!).

So - once again - don't have a leaky gut!  As Robb Wolf would say, keep your poo where it belongs.

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Lithium and Longevity

A new paper was published this week - Low-dose lithium uptake promotes longevity in humans and metazoans.  Now, as a psychiatrist, I'm a lithium fan.  Apparently, it is an essential trace micronutrient (who knew) aside from the uses for decreasing suicide and helping mood stabilization. Want a primer - look at my blog post here.  (Here is the original lithium for treating mania paper by John Cade if you are interested.)

Decreasing suicide?  Yes, well lithium is actually very good at keeping people alive.  Even those with bipolar disorder or major depression who have no real symptomatic improvement seem to have less suicidal thoughts and suicides while on lithium.  Very interesting.  But why?

Let's start with some observational studies.  Back in 1989, Schrauzer and Shrestha published a paper called "Lithium in Drinking Water and the Incidences of Crimes, Suicides, and Arrests Related to Drug Addictions."  They took information about the lithium level in the water of  27 counties in the Great State of Texas.  Seems that counties with higher lithium levels in the water had a statistically significant decrease in the incidence of homicide, suicide, arrests for opiates and cocaine, and violent criminal behavior.  Now to put things into perspective, a high lithium water content translates to about 2mg of lithium a day.  Psychiatric doses start at 300mg daily. 

From the 1989 paper:

Lithium has previously been used to control episodic outbreaks of rage among prisoners and in the management of drug abusers.  Animal experiments have demonstrated that lithium suppresses cocaine-induced super sensitivity... the kindling phenomenon following the chronic application of ... a central nervous system stimulant, and head-twitching in response to the administration of mescaline.  Furthermore, lithium has been found to [improve] distractability... and produce improvement of selective attention to stimuli... it prevents behavioral alterations owing to social isolation, lowers aggressivity owing to confinement... and causes a normalization of spontaneous motor activity.

 Wow!  That's a lot for one little trace mineral.  And observational studies from Japan seem to correlate - back in 2009, researchers there noted that suicide rates decreased with higher amounts of lithium in the water (1)(In Japan, rates of suicide have been distressingly high for the past 15 years - Japan has a suicide rate of 21 per 100,000 individuals per year vs. the US rate of 11 per 100,000 (3)).  And, with the newest paper, longevity in Japan increased with the amount of trace lithium in the water in humans, and the same trace amounts of lithium in a controlled experiment (equivalent to about 2mg of lithium daily) increased the lifespan of the C elegans worms (2)(due to the increased suicide rates in Japan, suicide was controlled for in the numbers, and lithium still seemed to increase longevity in the observational studies.).

So, all old, that is rather interesting.  Trace amounts of lithium seem to improve human behavior in general, and no one knows why. 

Basic science time - lithium looks a lot like sodium.  It has the same number of electrons in the outer shell - the molecule itself is a bit smaller, but the kidneys don't seem to be able to tell the difference.  And, perhaps, neither do the neurons.  So the addition of a bit of lithium to the matrix will decrease the overall sodium gradient in the brain, decreasing neuroxicity, and increasing the efficiency of brain energetics. From the Japanese drinking water, lithium, and suicide study:

It can be speculated that very low but very long lithium exposure can enhance neurotrophic factors, neuroprotective factors and/or neurogenesis, which may account for a reduced risk of suicide.

In addition, lithium is thought to modulate the system of second messengers in the brain, meaning they enhance certain signaling processes.

The authors of these studies get rather enthusiastic, recommending supplementation at a level of about 2mg per day for human populations with the proposed effect to control behavior, increase longevity, and reduce suicide.

On the negative side, some Swedish researchers tested thyroid effects of trace lithium in the water in some villages in the Peruvian Andes (3).  Some of these villages had some 10-20X the natural lithium in the food and water of the Japanese subjects, up to a maximum of 30mg daily (which is, of course, within an order of magnitude of the pharmacologic dose of 300mg).  They found that lithium in the water seemed to decrease active thyroid hormone levels and increase thyroid stimulating levels - lithium as a medicine will tend to cause hypothyroidism.

In another interesting tidbit, they found that natural selenium levels in the water correlated with free T4 thyroid levels.  Only, thing is, selenium is supposed to act to help T4 become active thryoid hormone, T3.  So one would expect selenium levels to correlate with T3 levels and inversely correlate with T4. 

So, all told, lithium is a natural component of drinking water, and observationally decreases suicide and general naughtiness, and increases longevity, but perhaps also decreases thyroid function. 

Something to ponder.

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More on Wheat and Serious Mental Illness

All right.  Tuesday.  Yesterday at noon local time a big earthquake hit Christchurch, and all of our good wishes are with the people there, especially as one of Evolutionary Psychiatry's best internet friends is Jamie, who lives smack dab in the middle of Christchurch.  Here's a link to the New Zealand Red Cross if you would like to lend a hand.

Before disaster struck, Jamie was kind enough to send me a link to a new paper (free full text) about Bipolar Disorder and gluten markers.  The paper doesn't give us much, but it does stir up some good ol' murk.  So let's investigate.  Bipolar disorder is an illness of mania or hypomania plus or minus depressive episodes.  Bipolar disorder does not equal "moody" or "irritable," though those can certainly be signs.  It's not the disorder unless the symptoms are bad enough to get you into serious trouble.  You spend too much, you sleep around too much, you don't sleep, you are more religious, you are grandiose - in cycles.   And, of course, it is associated with inflammation and metabolic syndrome (1), diabetes (2) and a "western" style diet. 

I have suspicions about those links.  I'd bet a monkey that a combination of sugar, trans fats and vegetable oil, and high doses of refined wheat products (as I've mentioned before, the evidence against wheat is circumstantial) are culprits behind metabolic syndrome and diabetes.  And maybe a subset of the population suffers at the brain level too and manifests bipolar disorder.  Hey, seems as good a theory as any. 

Wheat has been investigated on and off over the years as a culprit in schizophrenia.  And bipolar disorder and schizophrenia can overlap sometimes in symptoms - while depressed people can be psychotic, a frank manic psychosis will look pretty much the same in the hospital as a schizophrenic psychotic episode, and there may even be some genetic overlaps (3)(4).  The new paper that Jamie sent me is the first to study celiac and wheat-associated antibodies in bipolar disorder.  In schizophrenia, there is a definite increase in wheat-associated antibodies in the serum (5) and these antibodies aren't the same ones that are seen in celiac disease.  Well, with bipolar disorder, seems the same thing is true.  Bipolar folks had a significant IgG gliadin reaction compared to controls, but there weren't really differences with respect to tTG and IgA gliadin antibodies which are typically elevated in celiac disease. 

Ooh ooh ooh, wheat is BAD.  Well, probably, for various reasons.  But, of course, I don't necessarily believe that a positive IgG test to gliadin means one has a sensitivity to gliadin.  I griped about IgG food sensitivity tests not too terribly long ago.  I think a robustly positive IgG test to lots of things means one may have a leaky gut.  Gliadin is a pretty darn common thing to eat, so folks with leaky guts may come up positive for gliadin.  The most robust evidence in humans I've seen for leaky guts linked to wheat (or maybe casein) consumption was from this nifty study in autism (6), where the kids on the GF/CF diets had pretty tight junctions in their guts, especially compared to the autistic kids and their relatives.  Boy, I bet the researchers have really pounced on this diet and mental health link and studied leaky guts in bipolar disorder (7)(9)! Er, no.  But, links have been found between major depressive disorder and leaky guts (8 - an interesting enough paper for another day).

Like I said, murk.  Best I can consolidate from all this information - it may be that folks with bipolar disorder have gut issues, and gut issues are inflammatory issues, and a higher IgG response to gliadin occurs, and inflammation causes the body to release cytokines and general badness, and those cytokines may predispose the genetically vulnerable to psychosis.  Also, there may be particular ick associated with exorphins in wheat being neuroactive.  And is it just wheat?  There's a paper linking recent onset psychosis and schizophrenia to IgG and IgA antibodies to casein (10).  In this study, the severity of psychosis was linked to the level of antibody response to casein (actually, the alpha and kappa subunits moreso than the beta, which is interesting, though first onset psychosis had a robust immune response to the beta subunit).

And I'm not entirely off the wall here, because here is an excerpt of the discussion from paper 10 -

We can speculate that a subset of individuals with recent onset psychosis and/or schizophrenia may have cellular junction pathology that allows peptide fragments generated from the digestion of bovine milk to permeate the intestinal tract, and enter the bloodstream... Dohan... hypothesized that the aberrent proteolysis of milk and grain products may produce small neuroactive peptides that can enter into the circulation and ultimately cross the blood-brain barrier.

So, lesson number one.  Don't have a leaky gut.  Lesson number two.  If your gut is leaky, best to avoid creepy neuroactive peptides.  Lesson number three.  There is nothing horribly definitive here, but plenty to study.

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Basic Science - Energy is Everything

Let's review.  Some 9 months ago, an excitable young psychiatrist of reasonable pedigree launched Evolutionary Psychiatry as a means to explore how the differences between our modern lives and diets compared to traditional/evolutionary experiences may influence the generation of mental illness.  To that end she peeled back the edges of several lines of inquiry - what mental illnesses are increasing rapidly, and what are the theorized reasons as to why?  What are the correlations between mental illness and the known diseases of civilization (heart disease and type II diabetes, primarily, though acne, IBS, and autoimmune diseases of all kinds fall in that rubric)? What dietary factors are drastically different between the nutrient-rich traditional fare and our post-modern industrial food, and what is known about how those dietary factors affect neurotransmitters and brain energetics?  So I read, and read, and read, and depend upon a small cadre of loyal compatriots and commenters with a similar nose for research and a similar goal, and together we have uncovered some interesting things, and nowhere in thousands of pages of reading have I uncovered something that would absolutely refute my original hypothesis.

Part of the story of Evolutionary Psychiatry is the story of its creator and how she [I] thinks.  And when I say I have no patience for philosophy, I mean it.  I've rarely made it past the "God cannot be both benevolent and omnipotent" chapter one of most philosophy books before they are consigned to the dustiest reaches of the bookshelf.  I am left-handed, so theoretically more able to bring in the right brain (though in all likelihood I am also predominantly left-brained like most of you).  I am a woman, therefore likely more balanced between dopamine and serotonin in my ponderings.  I think in collages.  In pictures.  In stories.  My influences are literature and music, the oral and written histories of our people.  For some, the structured rationality of philosophical thought creates links and certainty.  For me, that structure is an imposing irritant and a distraction from the elusive creative links.  I hope I make up in scope for what I lack in rigor.  I rely on folks like Denise and Ned to lose themselves in numbers.  I want the story behind the numbers.

In Evolutionary Psychiatry there are only a few truths that bob to the surface again and again.  Inflammation is the mediator of most evils.   Energy should be made efficiently or there will be a cost.  Fatty meat is good.  Starch is not a dirty word, but an excess sugar certainly is. Ketosis in moderation can be a powerful tool.  Plant protein should be regarded with suspicion as an inflammatory mediator.  Stress and sugar and poor sleep damage the brain.  We should probably consume a little more dirt and get a little more sunshine. 

But let's bring it back to energy.  Energy is everything, and the brain, for all its small size, a massive consumer of energy.  Energy for eukaryotic cells is primarily made in the mitochondria. 

Image from The Science Experts

There are a few "need to knows" about mitochondria.  Like most engines, they create waste.  However, it seems that what we want is plenty of mitochondria working at full efficiency.  If we have leftover or damaged mitochondria just hanging out, they seem to create destructive reactive oxygen species and general mischief (1).  Mischief such as dementia, premature aging, cancer, and probably autism. 

Things that make mitochondria happy and promote effiency and clean energy:

1) A high-fat diet and utilization of ketones
2) A ready supply of energy and mitochondrial cofactors such as the animal flesh-derived carnitine, creatine, and carnosine, and the cholesterol buddy buddy ubiquinone (CoEnzymeQ10), vitamin A, and the football crew of B vitamins are also utilized in the respiratory chain.
3) Protein and/or calorie restriction which promotes the activation of PPAR (that is peroxisome-proliferator acttivated receptors).  See, the mitochondria have two major types of garbage containment facilities, the lysosomes and the peroxisomes.  They are the waste clean-up crew, and they become more active in states of protein restriction and ketosis.  In addition, the old and inefficient mitochondria spewing more reactive oxygen species than they ought get properly decomissioned in states of protein restriction and ketosis.  This is one part of a positive clean-up process called "autophagy." 
4) Aerobic exercise seems to stimulate the creation of new, shiny, efficient mitochondria (2).

What sorts of things promote mitochondrial ineffiency and general dirty cell-killing cancer dementia promoting badness?

1) Hyperglycemia
2) Inactivity
3) Micronutrient deficiencies
4) Never dipping into ketosis

I'm guessing the mitochondrial research folks probably never heard of the paleolithic or primal style approach to diet and living.  But the common recommendations of that approach all converge to make mitochondria mighty happy.  Even the paleo conservatives with their fat phobia will be low carb and encourage intermittent fasting - which in combination should bring *some* ketones into the picture along with temporary protein restriction to promote autophagy.  Paleo/traditional foodists will be rather strident in getting plenty of micronutrients and will have the steaming plates of offal to prove it.  The special mitochondrial-loving amino acids found in meat will be, more than likely, adequately consumed by the meat-loving paleo eater.  In addition, activity is encouraged, lots of it, in realistic exertion and quantity.  The diet itself, being antinflammatory and muscle-sparing, is the perfect fuel to spur activity.

In contrast, the Standard American Diet du jour will promote inflammation ultimately resulting in hyperglycemia, weight gain, inflammation, fatigue, and sedentary living.  Micronutrient deficiencies will be the rule, unless one is exceedingly careful.  And one is told never to let 3 hours or more go by without eating lest the metabolism sputter to a halt (which I'm ashamed to admit I ever believed).  Restricting calories to the point of avoiding obesity only while eating 5-6 times a day is no picnic.  Welcome constant food with constant hunger and constant restriction.  One could hardly think of a more unnatural way to eat, or a better way to make for miserable free-radical spewing mitochondria.

Yes, more research papers, more basic science, a deeper look at a vast picture, and more of the same old answers.  If you haven't given IF a try, consider skipping breakfast every once in a while.  Or at least have some stretches of time where fat is the primary macronutrient you consume (but avoid those vegetable oils, of course).  You might be surprised how you feel - not weak, but focused, energetic, and driven.  All the better to devise a plan to bring back that large ruminant to the camp for a delicious supper.  Yum.

(Thanks once more to Jamie who sent me several of the papers and links.)

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Healthy Skepticism

Among the papers from the last post fell out this letter in Science, The Potential of Nutritional Therapy. (unfortunately, limited access).  However, the letter speaks to many of the shortcomings in investigating the science of nutritional cures, and has a number of important points.  Conventional adherents might find this odd, but these shortcomings are, in part, why I hold fast to a "paleolithic-style" approach (with forays into dairy fat, white rice, and neolithic vegetables that I believe are scientifically sound.)   I think the paleo fall-back is the safety zone.  Forays into modern industrial food requires a bit more careful study before we recommend it for the masses (sorry, USDA.  Grains and copious vegetable oil for my little ones?  I don't think so.)

The problem with the studies if nutritional therapies?  Often they have been poorly done, or investigated one nutrient at a time.  A "paleolithic" focus requires cutting out grains, balancing the omega 3/6 ratio, and drastically reducing fructose and eliminating processed food.  There are absolutely no randomized controlled trials for mental disorders with these criteria (unless you count the recent ADHD trial with the limited wheat and unlimited rice - which is why I post so much about the ketogenic diet trials, some omega 3 supplement trials, and the ADHD elimination diet trials - they are ALL I HAVE to truly hang my hat on.  Everything else is just vague supporting evidence and a flair for spinning a tale, and don't think I don't know that.)

The letter in Science mentions the issue with mitochondrial dysfunction that often accompanies mental issues (see Brain Efficiency and Brain Efficiency, Pediatric Edition), and notes that nutritional problems may induce mitochondrial inefficiency. 

And bless Science magazine - they discuss the problem of nutritional journalism, with the crappy headlines shadowing the misleading abstracts redoubling the worth of the Denise Mingers out there with every stupid headline:

"Medical journalism may be one important agent for spreading
information about legitimate research on nutrition and mental health,
especially in the face of the lack of profit-generated funding. This also
implies a special responsibility for medical journalists, since the dan-
ger of �pseudoscience� is close at hand."

Doctors cannot recommend therapies without evidence.  And I shake my head at (for the most part) perfectly reasonable skeptic alternative health practitioners who eschew traditional prescriptions for traditional herbals which have no more evidence (and more than likely less regulation of the actual content of the herbal formulation) than any prescription product.

"Show me the evidence" should be the rallying call of the health-conscious consumer these days.  Otherwise, I'll stick with eating nose-to-tail and seeking out seafood and going for the seasonal fruits, starchy vegetables, green leafy vegetables, and rendered fats and oils that my ancestors did. 

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Mental Health and Omega 3/6 Ratio, A New Review

Twitter is a black hole for time spitting out information like Hawking radiation. (I may have achieved the geekiest simile ever!)  I've been a bit busy, as the applications for preschool are pretty detailed, asking for medical records, descriptions of my culture, and different ways we help the little one settle down or take her nap (bribery and threats, mostly.  Oh, wait, the correct answer is "routine.") And sure, she's allergic to sunscreen.  Well, with all that going on the blogging and reading has gone by the wayside a little.  Also, most papers come out as a preview in the last week of the month, so there tends to be a rush of exciting new information all at once.  Then a dry spell.  If I'm fired up, I'll actually look into a topic in depth and do a nearly proper literature review.  But not having had the time to do that... there's always twitter (and Jamie Scott, who is sending me a slew of papers about mitochondria, histamine, and sleep because he is awesome that way.  I'm hoping to settle down and look at them sometime over the next couple of weeks).

Twitter!  The be-ripped Martin Berkhan tweeted up a paper earlier today that is a new review of Omega 3s and 6s.  The article, Evolutionary Aspects of Diet: The Omega-6/Omega-3 Ratio and the Brain, is a tidy look at omega-3 and omega -6 biochemistry detailing all the conversions and enzymes along the way for the biochem geeks.  In the end, it describes the more interesting stuff about the evidence that omega 3s, in fact, do have an important role in the brain, and that one would be a sad and foolish monkey indeed to consume the modern 25:1 6:3 ratio (just say no to corn and safflower and soybean oil...)  Another interesting fact - the review is written by Artemis P Simopoulos, who pretty much first popularized the Mediterranean diet with her book The Omega Diet: The Lifesaving Nutritional Program Based on the Diet of the Island of Crete.  Guess she knows what she's talking about with respect to the omegas.  

Let's dig in.  Hmmm... "psychologic stress in humans induces the production of pro-inflammatory cytokines such as IFN gamma, TNF alpha, IL-6, and IL-1."  Yup.  Too much omega-6 compared to omega 3 can lead to the overproduction of inflammatory cytokines, which for various reasons is Not Good.  Theoretically, changes in PUFA ratios can alter the function and structure of the serotonin receptors (for example, essential fatty acids in the plasma predict the CSF metabolites of serotonin and dopamine)(1).  Treatment with DHA and EPA can be useful in major depressive disorder and bipolar disorder.  Other researchers note that as the dietary ratio of omega-6/omega-3 increases, depression symptoms, TNF-alpha, IL-6, and the IL-6 soluble receptor increases.  Another group studied brains of people suffering from depression when they died vs. controls.  A decrease in AA/DHA ratios were negatively correlated with age in depressed people, but not in controls.  All these lines of evidence, including the randomized controlled trials of omega-3 supplementation, seem to support the idea that our brain needs omega-3s to work well and keep the mood stable.    

Now onto the studies of cognition and omega-3 PUFAs.  Turns out that when the neurons are stimulated with neurotransmitters, the PUFAs in the cell membrane can be released to become all sorts of different inflammatory and anti-inflammatory or signaling molecules.  The PUFAs also seem to influence cell migration and cell self-destruction (called apoptosis) - they even influence the length of telomeres, which are known to decrease with age, cancer, and cardiovascular disease.   A lot of neurochemistry has been elucidated in this area - the details are nicely summarized by Simopolous.  Suffice it to say that brain inflammation is part of the pathology of schizophrenia, dementia, and likely autism, and that omega 6/3 ratios could be important, and omega 3 supplementation (if done early on), can possibly be helpful.  There is some controversy as to the best ratio with which to supplement (2:1 EPA to DHA is recommended by Simopolous), and in these unknowns I prefer to fall back to the primary sources - fatty fish themselves.   

A study of prisoners showed many violent incarcerated young folks have deficiency ("0% intake") in omega 3 fatty acids from fish and selenium in the Table 5 of the paper, called "Diet of disaffection: nutrient intakes from a sample of disadvantaged young people."  Only 17% of them get adequate intake of magnesium too.  Interesting.

When one looks at studies of substance abusers, one also finds deficiencies of omega 3s.  Alcoholics, for example, are a known population rife with nutrient deficiencies (a med school professor used to call it the BBB diet - "beer, bread, and bologna.")  A group of researchers carried out a small double-blind randomized controlled trial of 3g EPA and DHA vs soybean oil control in substance abusers. After three months, the treatment arm had significantly reduced feelings of anger, anxiety, and cravings.  The increase in plasma EPA strongly correlated with the reduced anxiety, and the effects persisted for 3 months after the end of the treatment.

Putting it all together - the overall evidence suggests that if you want to be anxious, moody, depressed, violent, and craving addictive substances, by all means slurp down those omega 6 PUFAs. If you want more control over your brain and urges, maybe look into avoiding any extra 6 (the animal fats will have all that is necessary) and be sure to get the omega 3s you need via fish a few times a week or properly sourced beef or other grassfed ruminant meat.  This brain chemistry thing ain't so hard after all.

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The Neurobiology of Insomnia - How I Learned to *Start* Worrying and Love Orexin

The sleep and insomnia literature is vast enough to make one... well, overwhelmed.  New textbooks, then, can be a nice resource.  But textbooks are a bit of a gamble - some are fantastic, and others are disorganized and hideously boring.  Like the one I'm reading now.  But I spent some $$ and I'm powering through. (Today we're in chapter 7, pages 68-82) 

Insomnia.  There are various types.  Chronic, acute, secondary, primary.  And then there are the sub-varieties- difficulty getting to sleep, difficulty maintaining sleep, early awakening, and non-restorative sleep.  10-20% of the population has chronic insomnia, and the societal costs are huge (poor productivity, car accidents, mood disturbance, irritability, poor academic performance, tension, headaches, and GI problems, to name a few.)

A quarter of those with chronic insomnia have primary insomnia.  That is, these folks just don't sleep well for no particularly good reason.  EEG and neuroimaging findings seem to suggest a general case of hyperarousal.  Like being on cocaine without the cocaine (cocaine intoxication would be a cause of secondary insomnia).  High cortisol levels, high CRH response to stress.  Elevated alpha and beta wave "power" and diminished delta wave power.  Primary insomniacs are alert, and there's no two ways about it.

Serotonin, norepinephrine, dopamine, and histamine are all now thought to be wakefulness-promoting neurotransmitters.  These neurotransmitter concentrations will be highest while awake, low during slow wave sleep, and lowest during REM sleep. 

Sleep promoting neurotransmitters include GABA and adenosine.

Acetylcholine is seen in wakefulness, but also thought to promote REM sleep.  Activation of cholinergic neurons by GABA seems to initiate REM sleep in rats.

But now let's break up the activities of our new friend, orexin.  Orexin if you recall is a neurochemical responsible for promoting appetite and wakefulness made and released in areas in and around the hypothalamus.  Fibers from the orexin neurons reach out to innervate most brain regions, including the brainstem, cortex, and spinal cord.  Orexin neurons discharge regularly during wakefulness, and sputter to a stop when our EEGs start to slow and synchronize during sleep.  They begin to fire again in short bursts prior to waking up.  Orexin excites almost all the wakefulness-promoting neurons (acetylcholine, dopamine, norepinephrine, and serotonin neurons).  Narcoleptic dogs in research seem to lack some orexin receptors.   

There is quite a bit of evidence that various types of stress affect orexin.  However, the effects can differ depending upon the type of stress (cold vs. immobilization, for example), or age (old vs. young rats - presumably shivering and/or tied up in these experiments).  CRH, corticosterone and the gluococortocoids seem to increase orexin.  This will increase wakefulness and increase appetite.

Whew.  I'm exhausted already.  A bit of different music today (Pixies, Where Is My Mind).

Classical depression is often linked with insomnia.  Seems that stress steroid hormones induce orexin, which induces wakefulness.  Orexin will jack up serotonin (and the other wakeful neurotransmitters), which will then (if all is going well) induce negative feedback on orexin.  But say your serotonin machinery isn't running efficiently in the first place.  So you burn it out with too much wakefulness, then you don't have the negative feedback.  So you end up awake and grumpy.  This is one theory of depression.  I'm not sure it holds water, entirely, especially as depression promotes sleepiness OR insomnia and weight gain OR weight loss.  But between the different neurotransmitters and the different negative feedback, issues with any one of those systems could cause issues with sleep, mood, and appetite.

By the time you are depressed enough to be suicidal, your orexin levels in the CSF will drop.  Maybe at this point your hypothalamus has just plumb given out.  Who knows.

Tying it all together:

Primary chronic insomnia is thought to be mediated by hyperarousal.  Stress seems to activate CRH, which activates orexin, which will leave you watching the Home Shopping Network in the wee sma's.  Over time, your entire neural network will get exhausted, and your serotonin and dopamine depleted, leaving you without negative feedback to shut down the orexin, and thus exhausted, hungry, and depressed.  Good night!

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