Teenagers, Mood, Psychosis, and Omega 3s

AHS12 is next week!  In New England all the short-sleeved outdoor fun has to be squeezed into about 8 weeks of decent weather, so I'm taking it one day at a time at this point.  But I did manage to put together my presentation (which is on Friday at 4:15) over the weekend.  I swear when I looked at the schedule the first time I was directly opposite Mat LaLonde, but it turns out I'm just after Mat but in another room, so I'll stop grousing (though Maelen Fontes' antinutrients looks really interesting too.)

I don't have a lot of time, so I'll be looking at trans fats and carbohydrates and how they affect mental health.  It should be fun, and even if you follow my blog religiously you won't have seen all the stuff that will be covered.

But back to other interesting papers I've come across recently.  The first one is from the Archives in Feb 2010 (1).  These researchers randomized 81 people at ultra-high risk for psychosis aged 13-25 years to two groups.  The individuals had to have experienced a brief and mild psychotic symptoms already or have high genetic risk (typically a first degree relative with a psychotic disorder) and loss of social functioning.  Young people with these sorts of symptoms have about a 40% chance of developing a full blown psychotic disorder within the next 12 months when followed in previous research. 

Identifying and treating these ultra-high risk individuals is a hot topic in research today, since preventing schizophrenia, if possible, would obviously be a lot better than having someone suffer devastating psychotic episodes, hospitalizations, or having to drop out of college.  Defining the group of individuals to study has led to some misperception about the diagnostic category "psychosis risk syndrome" which to many seems like psychiatrists are trying to pathologize eccentricity among youth.  The category was developed to have consistent criteria for these preventative-style research projects, not to try to change every teen-ager with black-eyeliner and an interest in ESP into a polo-wearing business school student.

These caveats are not to say the research isn't controversial.  Sometimes it involves putting ultra-high risk kids on antipsychotics to see if it will prevent conversion to schizophrenia or other full-blown psychotic disorder later on.  Any time one treats generally healthy young people with drugs with lots of side effects, one had better be trepidatious.  However, the study I'm referring to took a much less aggressive approach.  The 81 young people either took an omega 3 fatty acid (700 mg EPA, 480 mg DHA, and some vitamin E as mixed tocopherols) supplement for 12 weeks or placebo (1.2g coconut oil and the same vitamin E).  Adherence was calculated by measuring RBC (red blood cell) membrane fatty acid content and by self-report.  No use of antipsychotics were permitted (or if full blown psychotic symptoms were present for more than a week, standard treatment was started and the individuals left the study), and both treatment and placebo groups had some standard psychosocial counseling sessions (helping cope with stress, learning life skills, etc.).

After the 12 week treatment period, the groups were followed closely for the next 9 months.  Among the placebo group, 11 of 40 (27.5%) developed full-blown psychosis during the 12 month study.   Only 2 of 41 (4.9%) in the treatment group developed psychosis.   The difference was statistically significant and comparable to similar studies using the far more toxic atypical antipsychotics.  That's an impressive result for a relatively simple intervention and it would be nice to see it repeated at different medical centers.

The next study (2) was published earlier this year and measured RBC membrane fatty acid content in 150 adolescents admitted to the hospital for treatment of depression vs. 161 controls.  Long chain omega 3 fatty acids play all sorts of important roles in the brain in membrane signalling, synapse formation, dendritic growth, and seem to help facilitiate communication and repair.  Low omega 3 levels in the red blood cell membranes correlate with sudden cardiac death and depression in adults, though supplement trials with omega 3 have had mixed results.  There were two major problems with the study--cases and controls were significantly different with respect to ethnic groups which might affect genetic differences in metabolism and conversion of dietary fatty acids to those incorporated into the membrane.  Also, no attempt at dietary measures were taken, so it is unclear whether differences are from metabolism or dietary differences.  

However, in the end, the lower the DHA in the cell membrane, the more likely a subject was to be in the depressed hospitalized group.  More to look into!   

 

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Eat Fat, Be Happy

Just a little study from way back when (1997!  When I thought low fat raspberry fig newtons were healthy) sent to me by almost double doctor Victoria Prince.

One of my favorite radio stations (Sirius XM Pops) is on a Grieg kick, and I suppose I am too.

There's a lot to like about the study, which tracked mood for folks on a 41% fat diet (controls on the average fat consumption in the UK at the time) and a 25% fat diet for several months.  They were given three meals and two snacks with enough calories to keep them at a steady weight.  Though it is small (20 people), all food was provided and detailed food diaries were kept for every morsal consumed.  All 20 finished the program, but one was excluded from the results because she had a very serious personal tragedy which would have affected her mood.  The twenty subjects had no previous psychiatric history and at the beginning of the study had no major stressful life events going on.

Hostility and anger increased significantly among the low fat dieters, and depressed mood decreased among the 41% fat dieters while it increased among the low fat dieters. Tension and anxiety also increased among the low fat dieters.  All in all, things did not look rosy for reducing fat to, well, unnaturally low levels.

Editorial comment:  As most of you will know, I am fairly macronutrient agnostic, and I've read reports of people who are plenty happy eating low low fat, and others who are content eating very low carb.  My main beef with the "official" low-fat and counting-happy guidelines is that they encourage the consumption of processed food.  It's a lot easier to calculate points and calories when you are eating SmartOnes 6 times a day.  Not so easy with pastured eggs of different sizes and cooking all your own food.  Of course I haven't tried to calculate calories since the advent of all sorts of helpful apps for that purpose, but it is not something I'm particularly interested in pursuing.  I'd far rather control portion size and eat from a long list of healthy "real food" options than track every bite.  There are others who find restricting food groups leads to anxiety.  I would say, don't fix what ain't broke.  If it works for you, keep doing it.  If it doesn't�look for another solution.

I also don't see much benefit to chasing very low carb to the extreme unless you have dementia, seizures, brain cancer, or another neurological condition that may benefit.  I don't believe VLC is the fountain of youth, an evolutionary precedent, or particularly advantageous to whole body health compared to a whole foods diet comprised of mixed macronutrients (and "cellular" carbohydrates).  A really good paper has been circulating recently, which I saw first via the one and only Robb Wolf.  It is free full text!  Google the name or download from the link.  Well worth the time.

The discussion and introduction to the paper I linked from 1997 was illuminating.  The authors noted that folks with low cholesterol have a higher tendency to die from suicide, violent death, and accidents.  (I review much of the literature in this classic post).  We also see a statistically significant increase in depression and hostility with any non-statin cholesterol-lowering medicine (for whatever reason, docs in my area are starting to prescribe fibrates to lower triglyceride numbers, and I'm not too thrilled).  The statins seem to be a wash for most, though I've certainly seen a few clinical cases where they seem to worsen depression and even psychosis.  (In monkeys, diet promoting low cholesterol significantly increased "contact aggression" compared to a typical diet.)

In the small pilot study, mood and irritability and such seemed independent of cholesterol levels, suggesting that maybe the links between low cholesterol and violence/suicide in the general population might be a general sign of low-fat diets rather than a straight-up link between cholesterol levels and behavior per se.  But who knows.  As expected, the low-fat diet decreased HDL, but not LDL or triglycerides too much.

The take home?  Conservatives, go Mediterranean and glop on the olive oil.  Rebels, eat your chicken skin and the fat that is left on your steak.  It's all right.   Your brain might even thank you.

Image credit

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Genetic Findings Key to New Alzheimer's Drug*

*probably not, but that is the media portrayal,

Rachmaninoff, Prelude in C# Minor (Right click to open in new window.  My mother used to play this one all the time, and, being really one of his most famous pieces, Rachmaninoff was asked to play it in an encore at nearly every performance, and apparently got very sick of it.)

A new paper came out in Nature earlier this week.  A genetic study from Iceland.  Iceland is a pretty cool place for genetic studies, because everyone knows everyone else, I've been told, and everyone is someone's third cousin or whatever.  It reminds me of my family from North Carolina and the smallish towns where you will meet someone and one of the first questions will be (in a cheerful Southern accent):  "So who are your people?"

I've covered interesting genetic findings in Iceland before, quite some time ago, where I also made a case for evolutionary medicine being useful even for those pesky diseases of old age, such as dementia or cardiovascular disease.  I simultaneously mocked Dr. T. Colin Campbell.  Hey, I was young and perky back then.  And shout out to Dr. Aaron Blaisdell, Professor of Psychology and Strict Grammarian for setting me straight on the Octopuses v Octopi situation (it's Greek, not Latin, or something).

The Case for Evolution:  Octopuses, Grandmothers, Iceland, and Poor Dr. T Colin Campbell.

Soooo, let's review a little bit about Alzheimer's pathology.  Over a long period of time (decades), you get slow build-up of amyloid beta plaque which is pretty asymptomatic.  Then the inflammatory markers in the brain begin to build big time along with the accumulation of tau "tangles," there is massive neuronal destruction, and over the next years you get steady cognitive decline and eventually death.  There's no simple cause, no easy solution (such as a vaccine or pill) to prevent or cure it.

Part of the pathology of Alzheimer's involves a protein called Amyloid Precursor Protein (or APP).  APP can be spliced in a number of ways.  Via the beta (BACE1) and gamma secretases, APP gets split into the fragments that can lead to plaque build-up.  A deficit of omega3 in the brain may push this process along.  If you cleave APP at an alpha site, the beta subunit is broken-up and the metabolic products are harmless.  Plenty of omega3 seems to favor this cleavage.

Various human genes for APP exist, and some (at least 30 known variants) seem to make folks at risk for early Alzheimer's disease.  In Iceland, researchers found an allele of a part of the APP gene called rs63750847-A.  Carriers of this allele (also known as the A673T substitution, as there is an alanine to threonine substitution at position 673 of the APP protein)  were significantly less likely to have dementia at the age of 85 than the general population.  This mutation seems to make people resistant to Alzheimer's dementia and cognitive decline in general.  In fact, the effect is such that folks who actually reach the age of 85 are more likely to carry the gene than the general population as well.  However, in most populations, fewer than 1% of folks seem to carry the protective gene.  


BACE1 is an enzyme that cleaves APP into the beta amyloid fragment, and havign the protective gene seems to reduce this cleavage.  Interestingly (as seen on twitter), levels of BACE1 seem to depend upon your folate/methylation status, with high homocysteine, an inefficient folate cycle, and poor nutrition also favoring cleavage of APP into the amyloid beta plaque.


Why am I skeptical about this research leading to a curative drug?  Well, we already hae researched amyloid killers.  There is even a vaccine that seems to clear out amyloid, but it doesn't seem to stop the progression of Alzheimer's, and in some cases, anti-plaque drugs seem to have made the situation worse.  However, focusing on reducing BACE1 cleavage might be more fruitful.  Of course, having enough B12 and folate and SAMe and omega3 will help as well.


Interestingly, this study also seems to link Alzheimer's pathlogy with cognitive decline in non-Alzheimer's patients.  But is that a human trait, born of our crazy large brains, or a product of modern lifestyle and deficient nutrition?  I speculate about that issue in this article.


It's always interesting to learn something new about Alzheimer's and our brains.  It's also important to remember that the pathology of Alzheimer's is a complicated and constantly evolving process, and something that might be helpful at early stages might not do diddly squat at later stages (omega3 supplementation, for example), or something like a deep ketogenic diet may be very helpful at later stages but either too stringent or not preventative at earlier stages.  I also find it interesting that this protective allele is so rare.  We would not have grandmothers if the survival of the older generation were not important to the propagation of our species.  Could this protective allele leave folks more vulnerable to infection or some other issue?  


Just some pondering!  I can't promise I will be blogging with any frequency coming up.  We have AHS, a couple of other planned talks, and summertime, and it looks at this point like every weekend is bespoke between now and late August.  Since I'm one of those folks who prefers very little in the way of plans� we'll see how it goes.

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Toxo and Suicide in Women

I've talked about the interesting psychiatric correlations with infections with the parasite Toxoplasma gondii before:

Infections and schizophrenia risk

I've also discussed how a vulnerability to clinical depression may be a deal with the devil with the risk of dying from infectious disease:

Depression:  A genetic faustian bargain with infection?

Now a new paper has come out from Denmark, one of those lovely socialist medicine papers following an entire country's subjects for years and years.  Is it worth the high taxes?  I suppose we'll have to see here in America� in any event, the paper is quite extraordinary and free full text!  Go take a look at it.  Also, some media interpretation via the intrepid and lovely Melissa McEwen.

Suicide is a pretty rare event, affecting about 12 per 100,000 in the U.S. (though statistics are higher in some other countries, including Japan).  That said, it is still the 10th leading cause of death, higher in younger populations.  But suicide is rare enough that anything with an observational statisitical correlation can be pretty interesting.  For every suicide death, there are 10-20 people attempting suicide, and the greatest risk for death by suicide is a previous attempt.  (In this study, there were 18 completed suicides in over 45,000 women over up to 14 years, but the risk associated with Toxo infection was still statistically significant.)

Toxo infection during pregnancy is associated with birth defects, so in Denmark, babies had IgG levels for anti-Toxo antibodies measured.  Since IgG in newborns can only come from the mothers (newborn babies cannot make IgG yet), these antibodies reflect Toxo infection in the mother with the associated immune response.  Toxoplasma gondii infection is most likely obtained from cleaning up the litter box of your outdoor cat, but you can also get it from unwashed vegetables.  1/3 of the people in the world are infected, but most are relatively asymptomatic.

In Denmark, risk of later suicide attempt had a relative risk of 1.25, but greater in women with no mental health history (1.5).  Even greater was a risk of completed suicide (>2, which is when the ears prick that something very interesting is happening in these sorts of studies).  Higher seropositivity (meaning higher levels of IgG measured) is also associated with greater risk (1.9).  These results are consistent with those of smaller studies in Maryland and Turkey.

So why would Toxo infection increase the risk of suicide so much that it might be detecable in an observational study?  Well, turns out the infection increases the incidence of the serotonin precursor tryptophan turning into kynurenic acid rather than serotonin.  Also, toxo infection increases other inflammatory cytokines.

There are various reasons for mental disorders and suicidal behaviors.  Diet and infectious causes are part of the problems, and a good diet and washing your hands after cleaning the cat litter may be part of the solution.

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Neurobiology of Obesity (Again)

Between a quick 4th of July trip to Texas, kiddo piano lessons, and potty training, we are super busy here at Evolutionary Psychiatry.  And AHS12 is coming up at lighting speed!  I'm speaking (don't have the actual schedule yet, so no clue when!) and the paleo doctor crowd is coming for a visit, as well as the Antipodeans, and the be-yootiful Lindsay.  Maybe Evolvify will show up on his satphone, like those hapless reporters from the war zone on nightly news casts.

The new Temper Trap song is just lovely: Trembling Hands (right click to open in new tab)

All that business doesn't mean I'm not still neck-deep in interesting scientific papers.  There's a big problem, actually, in that my psychiatry practice is bursting full and the articles keep coming�if I've ignored your email, there are 10 more pressing emails in front of yours.  Sorry!

Papers that have been on the back burner for a while but deserve some attention:

Obesity is associated with high serotonin 4 receptor availabiity in the brain reward circuitry

Reward, dopamine and the control of food intake: implications for obesity (free full text)

I work a lot with addiction.  Alcohol, pot, nicotine, opiates, cocaine.  Not a lot of meth around here, but otherwise we have a fairly full spectrum.  And no one thinks cocaine addiction lives in the liver.  It's the brain.  You like something to excess, even if it stinks (nicotine, pot), makes you puke (opiates, alcohol), or makes you crazy (cocaine).  You take more and more, even if it isn't enjoyable, just to chase the anticipatory feeling of eating it.  What better describes eating a whole sleeve of Pringles?  "I was hungry." or "That was disgusting but I could eat another sleeve."

I don't think calories in and calories out is the whole story.  Otherwise we could all have just enough nicotine, or just enough cocaine.  But some of us can't, just like food.  Some of us face a world of twizzlers and Taco Bell and go "meh."  Others need a $20,000 gastric bypass to sever the hormonal feedback loops.

But I'm biased.  Some folks think the whole reward/brain/calorie thing is garbage*.  That's cool.  Everyone is entitled to an opinion.  Obese people and mice keep lighting up the reward circuitry PET scanners, with the endocannabinoids, dopamine, serotonin, opiates, GABA, cholecystokinin, neuropeptide y, and norepinephrine all playing a role, and serotonin drugs keep getting FDA approved to treat obesity.  So I suppose I am just used to thinking this way.  Leptin, insulin, orexin, ghrelin, neuropeptide y, and certain key areas of the brain (hypothalamus, hippocampus, amygdala) and regulation of endocrine systems (thyroid) and muscle systems regulating metabolism, calorie burn, fidgeting, the whole shebang.  And what I see, over and over, is neurochemistry lit up like firecrackers by highly rewarding foods.  See the definition of palatable if you are confused.

The most interesting thing about the Kitavans is that they don't exercise more than the average active American, and they have food to spare.  Piles are left for the dogs.  They are skinny, but they have easy calories available in excess.  So should we, if our brain neuroendocrine system worked properly, as it should with natural available foods and not the hyperengineered frankenfoods of the 20th and 21st centuries.  That's my opinion.

Back to the papers.  In the first, a long history of rodent papers are cited, but in this paper, actual humans were examined for the amount and receptivity of serotonin 4 receptors (5HT-4) they had in certain key reward areas of the brain.  Turns out the higher your BMI, the more active 5-HT4 receptors women had in the reward areas of the brain.  Happy and inactive 5-HT4 receptors are associated with the "fed state" and satiety.   In the reward areas, 5-HT4 transmission controls opiate and dopamine transmission.  The "neocortex" or the place of human "free conscious will" as it were is fairly light in 5-HT4 neurons.  It's the deeper areas of the brain, places of urges and impulse, that light up in PET scans of the obese.

The free full text review paper is also useful in describing the hypothalamus and how food intake is regulated (via amino acids, fats, and other signals).

(I've linked this song before, but it deserves a new listen:  Kasabian, Reason is Treason)

Based on findings from imaging studies, a model of obesity was recently proposed in which overeating reflects and imbalance between circuits that motivate behavior (because of their involvement in reward and conditioning) and circuits that control and inhibit pre-potent responses.  This model identifies four main circuits: (i) reward--saliency (ii) motivation--drive (iii) learning--conditioning and (iv) inhibitory control--emotional regulation--executive functioning.  

In folks with addictions, the consumption of high quantities of "palatable" substances (or food) will result in an enhanced reinforcing value of the food and weakening of the control circuits.

The definition of a "palatable" food is anything you could eat when you are stuffed.  Like Pringles.  Or pie.  Or kraft macaroni and cheese.  Or ramen.  Anything you can eat when you are stuffed should rarely be eaten. That may be the cardinal paleo rule.

But it's only the brain.  It has little to do with macronutrients (except super low fat, super low carb, or low protein foods are likely to be highly "palatable" in our definition).  You won't get fat on garlic, or plain baked potato, butter, or even (gasp) a banana.

My opinion.  I welcome you to read others!

*The main argument here being that the nutritional transition occured with poor and crappy foods� white flour, beer, white sugar.  Have the folks arguing against this theory never tasted ramen noodles or kraft macaroni and cheese?

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Statins and Depression

Another quickie from a recent Journal of Clinical Psychiatry article:  Statin Use and Risk of Depression: Data From the Heart and Soul Study.

(Shostakovich, Festive Overture, Op 96 in an excellent recording from the Nobel Prize awards from 2009.  We played this one in college and it was a lot of fun.)

Long-time readers will know I'm not a huge fan of statins in the water.  That is to say I don't like primary preventative treatment of the general population with a poweful liver, muscle, and brain irritating cholesterol-killing drug without knowing if it is really worth it.  The anti-platelet and anti-inflammatory effects may be worth it for a lucky few (while the unlucky few develop diabetes and muscle damage� seriously, click that link, and then go watch a Crestor commercial)... that said, if you are a middle aged man with a couple of heart attacks or unstable plaque and you eat Ho-Hos and Doritos and smoke two packs a day, hey, take the Zocor.  It may well prevent an earlier death (though even cardiologists will admit this magical effect is not due to lowering cholesterol, but through the aforementioned anti-inflammatory and anti-platelet effects).  Believe it or not, not everyone who comes to my office is excited about giving up her bag-a-day chip habit.  C'est la vie.

I also have bizzare and outlandish views about cholesterol.  I think it might be important to have enough.  And my idea of a "normal" total cholesterol is more along the lines of 220, not "as low as possible."  Though I have no doubts that super-high cholesterol (as in familial hypercholesterolemia) in the present Western food environment comes with a greatly increased risk of heart disease as there is a crapload of oxidized LDL hanging out in the blood.

On the other hand, super low cholesterol is almost always associated with increased risk of death from various causes, including suicide and violence.  Those risks begin to climb below a serum level of 160, and start to really spike around 130.  It's a correlation, not necessarily causative, but given the importance of a nice fluffy supply of fresh free cholesterol in the brain, it is certainly plausible that low cholesterol could be problematic.  For the details, visit my blog article here.  But let's be realistic.  Mr. Smith with advanced diabetes and a history of stroke with a total cholesterol of 330 is unlikely to be plummeted to below 160 by a statin alone (though they might try to get him down there in a heroic effort to make the LDL as low as pharmacologicaly possible as current guidelines reccomend an LDL<70).

Anyway, I have suspicions of statins and the brain, but where the rubber meets the road is the data.  (Or perhaps in the interpretation of the data ;-).  But I do like the Heart and Soul study.  Lots of participants, a long time�though they do use a mere 9-item "Patient Health Questionnaire" (known in the biz as the PHQ-9*) to determine depressive symptoms and not a standardized clinical interview like those careful Germans.

All the participants in Heart and Soul were folks with prior heart disease (that means we are talking about secondary prevention of early death with statins, for which there is a better track record than for primary prevention).  1024 patients (mostly male, as two of the three recruitment sites were VA hospitals) enrolled, 59 died in the first year, but 965 were able to give at least 2 or more annual measures of depressive symptoms to be included in the analysis.  All right, blah blah, analysis, confounders, statistics, etc (you can read the full paper from the first link if you like):

Statin users at baseline (about two thirds of the sample) had a lower rate of depression, but were also less likely to develop new depressive symptoms over the next 6 years.  Non-statin users were more likely to have depression at baseline and develop more depression symptoms later on.   These correlations were preserved by removing a number of confounders (such as "nonadherence" to medication regimen, which occured in 6.1% of the statin users and 12.2% of the non-statin users**)  All told, the odds of developing "depression" (meaning a PHQ score greater than or equal to 10) were 34% less among statin users than non-statin users, and those who were depressed at baseline had a 38%  decreased odds of having depression at a later measured date.  This number is consistent with the only other prospective cohort study done and with 2 large, retrospective case-control studies.

But here's the rub:

To date, however, randomized trials have failed to demonstrate a beneficial effect of statin therapy on psychological well-being.  In 1 randomized trial of 1,230 patients with existing coronary heart disease, those assigned to pravastatin had lower subsequent depression scores (measured by the Global Health Questionnaire) during 4 years of follow-up than those assigned to placebo, but these differences were not statistically significant.  Another trial in individuals with hyperlipidemia but without known coronary artery disease found no improvement of depressive symptoms�during almost 3 years of follow up among patients assigned to simvastatin versus those assigned to placebo.

The authors guess that patients who take statins were "more likely to exhibit healthy other behaviors that would decrease their risk of depression."  They are certainly less likely to admit to nonadherence!  It's also possible that the anti-inflammatory effects of statins could help balance out (my suspicion) pummeling cholesterol metabolism when it comes to mental health states.  The authors think maybe we need larger trials of longer duration to find the beneficial effects�

One more cute quote and then I'm signing off for the day:  "in the previous observational study of patients with coronary heart disease, the beneficial effects of statins on depression appeared to be independent of lipid-lowering effects."

*From time to time I will get a letter from an insurance company.  One of my patients will go to his or her primary care doctor's office and be given the PHQ-9.  A positive score will prompt the insurance company to let me know that my patient might be depressed, and urges me to consider treating that patient.  Insurance premiums well-spent?

**I can't tell from this paper how "nonadherence" was determined.  It says "medical history" was determined by self-report.  I can tell you that both the 6.1% and 12.2% numbers for nonadherence seem incredibly low to me depending upon the definition of "nonadherence," particulary for medicines such as statins or blood pressure medicines that one doesn't notice anything right away if you miss a dose)

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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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