When heart drugs cloud the brain

This month I have an article in Scientific American MIND about the controversial link between statin drugs and memory loss. Hundreds of statins users have registered cognitive complaints with Medwatch, the FDA’s adverse drug reaction database. But drug companies don’t yet recognize memory loss as a side effect, and to be fair, at first consideration, it seems like a strange association—why in the world would a heart medication affect your brain?

Dig a little deeper, though, and it makes a lot of sense. A study published in the Archives of Neurology in 2002 reported that after taking high-doses (80mg) of the statin Zocor for 24 weeks, subjects had half as much circulating brain-derived cholesterol as they did before they started taking the drugs. A good 70 percent of the brain is comprised of cholesterol; it makes up the myelin sheaths that surround nerves, allowing them to transmit electrical impulses quickly. It is also required for the production of new synapses, or connections between neurons, an as a result is likely to play a crucial role in memory formation and brain plasticity.

But statins could also affect memory for reasons that have little to do with cholesterol. Statins block an early step along a biochemical pathway called the mevalonate pathway, which controls the production of many compounds, not just cholesterol. According to Beatrice Golomb, an associate professor of medicine at the University of California, San Diego, statins inhibit the production of Co-enzyme Q10, an antioxidant that plays an important role in the mitochondria, the cellular organelles responsible for energy production. Co-enzyme Q10 mops up damage-causing free radicals produced during energy-production processes, so when there’s less of it circulating as a result of statin use, more free radicals are around to cause mitochondrial DNA damage. This damage could ultimately impair and kill cells throughout the body, Golomb says—especially brain and muscle cells, which have extremely high energy requirements.

Golomb’s theory may also explain why only a subset of people seem to suffer from statin-related side-effects. When Georgirene Vladutiu, a professor of pediatrics, neurology and pathology at the State University of New York at Buffalo, analyzed blood samples from people suffering from statin-related muscle pain (a recognized statin side-effect) in 2006, she discovered that they were more likely to have genetic defects related to mitochondrial function than statin users who did not complain of muscle pain. In other words, the people who may suffer the most from statin side-effects may be people who have a genetic predisposition to mitochondrial problems.

I’m curious to know if any of you have experienced cognitive problems on statins and, if so, what you have done about it. If you have told your doctors, how have they reacted?  In 2007, Golomb and her colleagues interviewed 87 statin users who had talked to their physicians about their cognitive side-effects and found that more than half of the doctors had dismissed the possibility outright. I’m wondering if this is still happening, or if doctors are coming around to the possibility that statins might elicit real memory problems. These may not be common side-effects, but their being rare does not make them any less real.

Citations:

Locatelli S, Lütjohann D, Schmidt HH, Otto C, Beisiegel U, & von Bergmann K (2002). Reduction of plasma 24S-hydroxycholesterol (cerebrosterol) levels using high-dosage simvastatin in patients with hypercholesterolemia: evidence that simvastatin affects cholesterol metabolism in the human brain. Archives of neurology, 59 (2), 213-6 PMID: 11843691

Barres BA, & Smith SJ (2001). Neurobiology. Cholesterol–making or breaking the synapse. Science (New York, N.Y.), 294 (5545), 1296-7 PMID: 11701918

Buhaescu I, & Izzedine H (2007). Mevalonate pathway: a review of clinical and therapeutical implications. Clinical biochemistry, 40 (9-10), 575-84 PMID: 17467679

Golomb BA, & Evans MA (2008). Statin adverse effects : a review of the literature and evidence for a mitochondrial mechanism. American journal of cardiovascular drugs : drugs, devices, and other interventions, 8 (6), 373-418 PMID: 19159124

Vladutiu GD, Simmons Z, Isackson PJ, Tarnopolsky M, Peltier WL, Barboi AC, Sripathi N, Wortmann RL, & Phillips PS (2006). Genetic risk factors associated with lipid-lowering drug-induced myopathies. Muscle & nerve, 34 (2), 153-62 PMID: 16671104

Golomb BA, McGraw JJ, Evans MA, & Dimsdale JE (2007). Physician response to patient reports of adverse drug effects: implications for patient-targeted adverse effect surveillance. Drug safety : an international journal of medical toxicology and drug experience, 30 (8), 669-75 PMID: 17696579

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7 Responses to When heart drugs cloud the brain

  1. Michele says:

    Yes, it happened to me. After a couple of months on Lipitor I was so befogged that thought I had early Alzheimer’s; I only connected it to the drug after I developed muscle cramps and stopped taking it.

    Later, my spinal surgeon told me a women’s health practice run by doctors at a very prestigious NYC hospital started to hear so many complaints about statins and cognitive problems that they were contemplating writing a paper.

    I did tell my then-doctor but she focused on the muscle cramps and sort of dismissed the cognitive issues. She wanted me to take Zocor instead, but I refused. No more statins for me. (I say this even though my cholesterol is over 300 and uncontrollable by diet and exercise.)

  2. Jean Hewlett says:

    I tried 3 different statins. Two I could not tolerate at all because of nausea and muscle pain, so I stopped taking these almost immediately. Zocor didn’t cause physical unpleasant effects, so I took it for several months. During that time I began having episodes where I would be unable to remember what had happened during a specific block of time. For example, I would drive to work (about 1 hour) and when I arrived I’d be unable to remember anything about the trip. Or I’d be sure I needed to mail a DVD back to Netflix, spend days searching for it, then receive an email from them saying it had been returned. I stopped taking Zocor and have refused to take any statins since, and I’m no longer troubled by memory problems.

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  4. William Kitchens says:

    Congratulations on the blog, Melinda–I have enjoyed reading it immensely! It is wonderful to see a high school classmate gain such recognition for your contributions to the popular scientific literature. As a doctor, though, I have to take issue with the premise of this post and the rather shoddy Scientific American article on which it was based. This article is almost completely underpinned by anecdotal evidence and self-reported side effect profiles, both notoriously unreliable. It is not at all shocking that many people have reported cognitive side effects of statin agents to MedWatch. After all, most people only go on statins in their 50s and 60s when the first symptoms of dementia and cognitive decline would begin to manifest themselves. . .it is a lot easier to blame the drugs rather than age!

    What the Scientific American article was woefully lacking was any sort of rigorous medical studies examining the effects of statin usage on cognitive function. In fact, many of these have been performed, mainly because it was hypothesized that statin use might actually *improve* cognitive function by limiting the insidious development of vascular dementia (which is second only to Alzheimer’s in causing cognitive decline). A massive meta-analysis was just published in August by the Cochrane Database of Systemic Reviews (probably the pre-eminent source of medical meta-analyses, as you know). This meta-analysis sifted through data of many medical studies that actually put research subjects through a battery of validated tests of cognitive function. Although the final meta-analysis did not find that statins conferred a statistically significant protection against the development of dementia (there was only a trend towards a protective effect), there was definitely no evidence whatsoever that statins resulted in worsening cognitive function, even when taken over a long time. If you do a Pubmed search for statins and dementia, you’ll find a host of studies on this issue, almost all of which either find no difference in cognitive function between age-matched patients on statins vs. those not taking statins, or else finding a slight protective effect of statins. These are much more reassuring than self-reported side-effect databases like MedWatch or rather tenuous hypotheses about the vital importance of neural cholesterol in cognitive function (totally unsupported by the data) as proposed by Golomb.

    While statins seem to have a minimal effect on cognitive function, it is almost universally accepted that there is an enormous benefit to taking statins to protect against strokes, which are probably even more disabling than dementia. Lancet Neurology in May 2009 again performed a meta-analysis on over 160,000 patients, and found that taking statins was associated with a 21% drop in stroke rates (the lead author is Pierre Amarenco, a French neurologist). In short, statins really have revolutionized the treatment of stroke, coronary atherosclerosis and peripheral vascular disease, all with a remarkably mild side effect profile (besides the well known risks of liver disease and myopathy in some patients). The data does not support a link between statin use and cognitive decline, and should not be invoked as a reason to stop taking statins.

  5. Thanks for your comment, William. So nice to know you’re following the blog.

    I’m familiar with the long-standing interest in whether statins might protect against dementia; in fact, the first iteration of my Scientific American MIND piece focused a lot on that body of research. You’re right, too, that memory loss might be expected in statin users because of their age, but I think this has to be considered from both sides: yes, some statin users may simply be suffering from age-related dementia, but some of them might also be suffering from statin-related dementia that they (or their doctors) are attributing to age.

    I did not realize Cochrane published another review on statins and dementia this year, and I can’t seem to find it on their website. I am, however, familiar with the Cochrane review published in April 2009, and it’s pretty inaccurate to say that the researchers found “definitely no evidence whatsoever” that statins can have negative cognitive effects; the review mentions the two Muldoon studies I cited and concludes that “the slightly negative effect on cognition should perhaps be borne in mind for future trials.” (Also, in my understanding, Golomb’s theory has nothing to do with neural cholesterol; her proposed mechanism involves the effects of statins on the mevalonate pathway.)

    In my piece, I point out early on that if these side-effects exist, they are not common. They may well be extremely rare, which would explain why even large trials have had a hard time identifying them. My piece is also not meant to be definitive on the matter. I pointed out that study results are inconclusive, but that experts are “starting to believe that a small percentage of the population is at risk, and they are calling for increased public awareness of the possible cognitive side effects.” I think it’s only fair for there to be public awareness if there is a chance that these risks exist.

    Finally, where did I write that statins aren’t useful? They have certainly saved many lives. I am simply presenting the possibility that the drugs may have unexpected cognitive side-effects in a small proportion of the population. I think this idea—which is not just the product of anecdotes, but an active area of scientific research—deserves a voice.

  6. William Kitchens says:

    I owe you an apology. I read your blog post too quickly, and only now saw the byline of the Scientific American article. While I still disagree with some of its conclusions, my language describing the article was unjustified and inflammatory…mea culpa. I think my chief objection to the article is not the fact that it raises the possibility of possible cognitive side effects of statin use. As you very correctly point out both in the blog post and the article itself, if there are any deleterious cognitive effects of these drugs, they may only affect a small number of people and may therefore be difficult to identify in either randomized controlled trials or subsequent meta-analyses. Giving voice to these concerns is certainly within the purview of an exceptional scientific reporter such as yourself.

    However, where the article falters slightly is in the lack of context it provides, which was my chief point in bringing up the dramatic anti-stroke effects of statins. From a perspective of overall cognitive function, I would argue that the possible negative effects of statins on cognitive function in a small number of people (which, I think you would admit, is still unproven and controversial in the least) is vastly outweighed by the definitively proven significant beneficial effects of statins in preventing disabling (and indeed, often fatal) strokes. As usual for you, the article is eminently balanced, and indeed you specifically state in your conclusion that “for many, the benefits that statins provide will overshadow their risks.” Since the whole focus of the article is on the cognitive effects of statins, though, I think omitting mention of the known neuroprotective anti-stroke benefits of statins doesn’t provide a full context to these potential cognitive risks of statin use.

    All medications have side effects–the challenge to physicians (and their patients) is balancing these side effects against the benefits of a drug. Perhaps I am overly sensitive to the way that drug side effects are reported in the popular media, because I have repeatedly seen patients refuse to take medications that they would immensely benefit from because they read sensationalist reports in the media from far less scrupulous reporters than you that don’t provide the proper context or improperly inflate the frequency of a side effect. For example, it is hard to believe, but I actually had a kidney transplant patient decide to stop taking her cyclosporine (an immunosuppresant) because she read that it can cause excessive hair growth in some patients! Sadly, she lost her kidney before it was detected.

    I would never suggest that the media neglect its duty to investigate these side effects. Even rare adverse reactions may be significant to those unlucky patients who suffer from them, and patients deserve to know the risks of the drugs prescribed by their doctors.

    I look forward to reading many more beautifully written, insightful medical investigations from you in the future (such as your excellent recent article on Yerba Mate). I would just make the plea to you and to all other medical reporters that you be extra vigilant when reporting side effects of drugs or medical therapies so that they are properly placed in context, allowing patients to understand how common or rare they are and how they may be properly weighed against the benefits of the drug/therapy. Your eloquence provides your words with enormous power to shape both public opinion and the public understanding of medicine–I’m sure you will use yours for good ;) .

  7. Dave Kraus RPh says:

    Nice reply from evidence based medicine Doc.
    And certainly the author deserves credit for bringing to light a potentially serious effect of statins.
    Causality is a difficult thing to prove – let alone find significant scientific evidence that there is even a correlation. Prime example is Zetia. Its been proven to lower absorption of cholesterol from the gut. Yet studies failed to prove any benefit in terms of an overall reduction of CAD.
    I’d say controlled trials are necessary though at this point evaluating only to find if there is a reduction in cognitive function in patients taking statins. The studies the doc cited were looking for the opposite and the result was additional information…but not proof.
    I will say however that the authors statements about statins and the formation of myelin is very important in another context – pregnancy and lactation . Statins are contraindicated in pregnancy and lactation.
    Cochrane has become just about the best thing to hit evidence based research. Meta analysis is a great tool when evaluating cause and effect. Very often studies are either small or contain flaws.
    Author….thanks for making my week a bit more difficult as many of my customers are readers and I’m sure I’ll be asked questions. My fear is that they will stop the statins (the act of suddenly stopping a statin itself has been shown to be a hazard) in a fashion similar to the estrogen-CAD disease scare a few years ago. Women read about studies that weren’t really explained well for a lay-person to comprehend and quickly stopped HRT. I had dozens of angry, sweating, sleep-deprived post-menopausal women looking for relief of their hot flashes. Studies suggested that a person who suddenly stops a statin great increases their risk of CAD and worse.
    Thanks for some good reading.