Mainstreaming

For all that I have a jabbery twitter account and like putting filters over my crap pictures for posting on instagram, I'm not exactly the kind of person that when you meet me for the first time, I'll say, "HEY, HAVE YOU SEEN MY BLOG??"

In fact, many of my friends and patients don't even know I have a blog.  It's sort of a niche audience.  But as the years go by and the archives build, more and more I will talk to a colleague or therapist who might refer to me, or even someone at the gym, and they will say, "Oh, by the way, I saw your blog…"  

The colleagues are especially exciting.  In the past few months I've been invited to a few more journal clubs and Grand Rounds to speak to more psychiatrists, neurologists, and other head-interested professionals.  Some of these folks might even have a research budget.  I really love these opportunities, because when it comes down to it, Evolutionary Psychiatry is not about the paleo diet.  It's about the pathology of mental illness and conceiving our brains as connected to our bodies and guts and environment.  It's about how physical and mental health are derived from our genes and the protoplasm of the world around us.  It's about simple interventions and the complex ways in which they influence our nerves and hormones and flesh.

It's a niche audience, but I feel Evolutionary Psychiatry deserves to be mainstream medicine.  It's about asking questions in a common sense fashion, and approaching disease with multi-pronged, inflammation-reducing and neurotransmitter-savvy and sensible solutions.  It's about acknowledging the wisdom of the past generations and translating the therapies and traditions into real results.  Mostly it is about asking the questions in a way that will generate the answers we need for the science to be useful.

My daughter asked me if the iPhone knew everything.  I said, a vast amount, no doubt, if you ask the question just the right way.  She will never remember an early life without Siri.

I didn't plan on blogging today, but in my mailbox arrived the brand spanking new fresh edition of the Green Journal, and two of the articles just SING evolutionary psychiatry.  So here I am again.

A Silent Film: Danny Dakota and the Wishing Well (reminds me of those angsty John Hughes movies from the 80s, before he started doing movies about John Travolta and babies)

The first article is a double-blind placebo controlled trial of NAC in cannabis-dependent adolescents (1).  I know there is a bit of a link between paleophiles, libertarians, real food hippies, and weed, but I've never been a big fan.  Mostly because I'm often confronted with parents and older adolescents who struggle with psychosis and/or lack of motivation and crippling anxiety who smoke pot ALL THE TIME.  Not to mention the older folks who come in after decades of daily heavy use and can barely finish a sentence.  I've covered it before here and here.  Weed has some interesting properties, no doubt, but I've seen it to be more the fountain of rotten brain, agoraphobia, and dementia than the fountain of creativity and youth.  My sample is not randomized, and I have no doubt of that.  But roll the dice and take your chances, as they say.

ERGO, I think finding ways to get adolescents to smoke less pot might be a good thing.  And in the linked paper, it is noted that 25% of high school students use pot, 7% on a daily basis.  Besides standard psychosocial therapies, there's not much out there to help adolescents quit the dependency.  Could a pill help?

NAC, as we know, is particularly exciting in psychiatric disorders because it targets glutamate and antioxidants in a novel way.  There's no prescription pharmaceudical with the research data or similar mechanism.  In animal models, self-administering addictive drugs down-regulates the cysteine-glutamate exchanger in the nucleus accumbens.  NAC upregulates this exchanger, reducing the reinforcement of drug-seeking.

The authors of the study did a promising open-label pilot trial and then organized a larger randomized controlled trial.  Cannabid-dependent adolescents (13-21) who desired some help and met other exclusionary criteria were randomized to placebo or 1200mg NAC daily for 8 weeks.  All participants received cessation counseling at every research visit.  Cannabis use was determined by urine sample (which will be positive for about a month with moderate cannabis use, depending on body habitus).

In the NAC group, 40.9% of the cannabis tests were negative (assuming all missed urine tests were positive).  In the placebo group, 27.2% were negative, a statistically signficant difference.   Participants who had made the decision to quit and were negative at baseline were six times more likely to be abstinent through the rest of the study, those with fewer years of use were more likely to be negative, and those with major depressive disorder were more likely to continue using.  There were no significant differences in adverse events between NAC and placebo users (like most studies, NAC users had fewer side effects than placebo, 38 in the NAC group and 46 in the placebo group).

These results should be repeated and consolidated at multi-treatment center groups, but all in all it adds to the NAC family of interesting psychiatric results.

The Ting Tings Hit Me Down Sonny

The second interesting article is about poor nutrition at age 3 and schizotypal personality at age 23.  Studies of populations in China and the Netherlands have shown that periods of famine during pregnancy results in the birth of children who are twice as likely to have schizophrenia or schizoid personality, and the risks can be worse when malnutrition extends to the postnatal period.  Thinness in childhood from malnutrition is associated with later schizophrenia as well.

Is it the malnutrition or some other variable that increases the risk?  Malnutrition is associated with low IQ, and low IQ is also associated with the development of schizophrenia.  Iron deficiency is associated with malnutriton, stunting, and schizophrenia.  Let's try to sort it all out…

In Mauritius, all children (1795) from two towns born in 1969 to 1970 were followed from the age of three.  Height (in developing countries, a measure of nutitional status) and hemoglobin (which is an indirect measure of iron) were collected and normalized for the different ethnic groups.  An "adversity index" was also measured from a home visit for each child, counting points for uneducated parents, semiskilled parents, single parents, separation from parents, large family size, poor health of mother, teenage mother, or overcrowded home.  IQ was measured at age 11.  Schizotypal personality was measured with a questionnaire at age 23.

The researchers found that poor nutrition in early childhood resulted in poor cognitive performance (IQ at age 11) and a higher risk of schizotypal personality at age 23.  The adversity index at age 3 was also significantly related to IQ at age 11.  Individuals with higher performance (vs. verbal) IQs were less likey to have schizotypal features.  It is thought that malnutrition leads to hippocampal and frontal brain impairments, leading to difficulty with emotional regulation, maintaining relationships, and the all important executive function.

How do these finding play in the first world?  I suppose it depends on how many pregnant young women live off of vending machine food.  Still, more evidence that nutrition is important.  As if we didn't know.

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!   

 

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

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.

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.

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?

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)