Saturday, June 23, 2012

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)


  1. I am intrigued with the meaning, or significance, of cholesterol levels. A year or two ago I was at 245. At first I was mildly distressed, because I had been on a Paleo-type diet for about a year. But then I did some research: the hdl-ldl ratios were perfect, and triglycerides were at about 60.

    Meanwhile, as you say, the ideal turns out to be about 220, and drugs to reduce cholesterol, particularly to the extent they succeed in doing that, are not helpful in terms of over-all health. In short, cholesterol is necessary and beneficial.

    But we do not seem to know what an ideal level really is, or why. What is the cholesterol level in middle aged primitive folks on a proper stone-age diet? (It is somewhat of a rhetorical question...) Simply reducing cholesterol seems like a bad idea.

    But then comes the concept that cholesterol is necessary for proper use of Vitamin D, and the possibility that cholesterol is somehow related to that, and sun exposure, or lack thereof, and the concept that lack of Vitamin K2 (from certain fermented foods) in the diet relates to calcium plaque in arteries which causes problems related to cholesterol in the arteries. Not to mention osteoporosis.

    Could proper levels of sun exposure and proper levels of K2 be more effective than statins (not in reducing cholesterol, but in preventing heart and arterial issues)? Clearly statins are a very bad idea for most people taking them. At some point we can only wonder when the malpractice attorneys will get a complete understanding the data. That should be an interesting time.

    1. I think that for preventative purposes, a clean diet, enough sunshine (but not burning), stress reduction, responsible exercise, and good sleep are always preferable to pharmaceuticals. Things change on an individual level when something is amiss, however.

  2. This was a nice post Dr. Deans. Very informative. Did you happen to see the article that suggests that cognitive impairment with the use of statins is minimal?

    Misconceptions regarding cholesterol are so engrained into our culture that its really hard to get people thinking clearly about it.

    1. Thanks. Yes, I read a recent review and the literature for cognitive impairment is pretty much limited to case reports. I think it is obvious that the "bad" cholesterol ratios are markers for inefficient recycling of cholesterol and inflammation. Big fluffy happy fresh LDL is a sign of health, IMO. I'm not surprised that the CETP inhibitors are failures though they do a gangbuster job of lowering LDL and raising HDL. But another kicker is that Kitavans have relatively low HDL, but no heart disease, and raising HDL with crap like tons of niacin hasn't been helpful… it's as if everyone's head got stuck in the wrong place.

  3. What is impact of low HDL on Brain? How does it affect brain function?

  4. Dr. Deans mentioned:

    > poweful liver, muscle, and brain irritating cholesterol-killing drug

    Here you are talking about statins. Do fibrates possibly have the same drawbacks?

  5. In 2008 my depression was so severe that I could not get out of bed. It was impossible to concentrate, feel pleasure, or even live. I went from high functioning to severely disabled. Easily 30-40 points off of I.Q. Even my vision became altered to where all repetitive geometry like tiles or window blinds vibrated and moved much like heat waves on the horizon of a hot day. I'm a 200 lb man and my total cholesterol was 115. My doctors thought that was great! No antidepressants helped at all. I also had severe tinnitus, tingling in the extremities, IBS, and orthostatic hypotension. I lost all mental connection to reality. It took me 4 years but I finally solved it. Ready?

    Chronic subclinical dehydration from drinking too much coffee over too many years.

    * Chronic dehydration = chronic inflamation = gradual glutathione depletion.
    * Glutathione depletion = cysteine depletion = coenzymeA depletion.
    * CoenzymeA depletion = cholesterol depletion.

    The solution is high dose sulfur and water. Daily doses of 6 grams MSM, 2 grams n-acetylcysteine, 2 grams Vit C, and 1 gallon of water w/ electrolyte salts added. This gives the body the chance to recover both detox and neurotransmitter pathways. Rebuilding both BH4 and the antioxidants needed to preserve BH4 so it accumulates again.

    Sam-e would be helpful in the early stages but the dosing is to small to make advanced recoveries in chronic severe sulfur depletion. Mega doses of Sam-e are WAY too intense because it stimulates norepinephrine/adrenaline conversion. The muscular pain with depression is best treated with MSM because lack of sulfur is causing the problem. Glutathione and Cysteine are best replenished with n-acetylcysteine.

    For very low cholesterol suffers. (Cysteine + B5) -> CoA -> Cholesterol.

    Early lab clues for me were:

    Very low Cholesterol
    Very Low urine Sulfate
    Low serum Histidine w/ high Histamine
    Low serum Glutamine
    High serum Taurine
    Low serum Fatty Acids Omega 3 AND 6
    Low serum Zinc

    All CBC and metabolic panel values were within normal range. Sorry for the long post but I'll share this info with any doctor who will listen. It's very real and doctors don't know how to identify it and suicide is the inevitable outcome because the sulfur never gets adequately replenished through diet alone. Without cholesterol you fail as an organism. Divided dosing throughout the day is necessary. Good luck to anyone suffering from this.

  6. Since reading Stephaine Seneff's articles about the importance of sulfer (and sunlight to provide sulfated Vit D and cholesterol), I've been wondering if supplementing with sulpher would help depression; interesting that this matches your experience.

    William Walsh wrote Nutrient Power and has treated thousands of depressed patients, using interviews and blood tests to determine proper treatment. For high histamine patients, he uses SAMe and/or methione, and says that folate/B12 are extremely counter-productive because of their effect on brain epigentic methylation. (For low histamine, he uses folate/B12/zinc/etc)

    So it looks like you found a treatment course that matches his for your blood tests, but provides extra sulfer directly.

    My guess is that sunlight around solar noon would also help, because it provides sulfated Vit D and cholesterol.

    Re the original cause of the problem, it could be the mycotoxin contamination of typical coffee, instead of dehydration. When my wife and I drink even very-high-quality "normal" coffee every day, we start to run elevated fasting blood glucose (low 90s) after a couple of weeks, which is a marker for inflammation. When we stop the coffee, our fasting blood glucose drops back down to 83 within a week.

    So, when we drink Dave Asprey's Bulletproof coffee, which is supposed to have minimal mycotoxin contamination, we don't have any issues...

    Fascinating reply, thanks!


