Sometimes this blog writes itself. Today I was sitting around minding my business, spreading happiness and serenity, when I got an email from the Amazing Jamie Scott, who sent me a link to this paper: Diabetes and Insulin in Regulation of Brain Cholesterol Metabolism. And then my receptionist handed me my mail, and the top story of this month's Psychiatric Times is "Statins, Cholesterol Depletion, and Mood Disorders: What's the Link?"
I'm beginning to feel less small and alone in the world.
Let's start with the Psychiatric Times article. Statins, as most biochem nerds will know, are pharmacologic inhibitors of HMG-CoA reductase, which is the key rate-limiting enzyme in the biosynthesis of cholesterol. So our livers, doing their best to kill us off with heart disease, make cholesterol like mad fiends, while a statin will slow that pesky liver down, lowering serum cholesterol, and allowing us to live forever.* Or something like that.
But throwing a monkey wrench into the cholesterol machinery has some... issues. For one thing, it seems to ruin the binding and G-protein coupling (total random aside - at my medical school we had several professors of biochemistry who had Nobel Prizes to their name - among them Brown and Goldstein for their elucidation of the metabolism of cholesterol, and Gilman who discovered the G-protein. And here they are, together at last on my heretical blog) to the serotonin IA receptors (1). That's probably not the best thing to do - decreasing the ability of the serotonin IA receptors to work can lead to anxiety and irritability. At the same time, there seem to be other changes in the actions of receptors in the context of "chronic cholesterol depletion" (I bet you would never find that phrase in 'Cardiology Times.'). As we know, low serum cholesterol is associated with violence, accidents, and suicide.
Now it is my pleasure to introduce Dr. James Lake, a psychiatrist and chair of the APA's Caucus on Complementary and Integrative Medicine (that's mainstream medicine talk for "woo." I emailed one of my residency mentors about my blog a few months ago as I had some questions for him - he wrote back after reading some of the entries and said I was the "alternative Harvard Mental Health Letter" - I'm still not sure if that was a positive or negative comment). Anyway, Dr. Lake seems to have drunk some of the same kool-aid that I have, as he recommends that depressed patients with elevated cholesterol aim not to go lower than a total cholesterol of 160. How very reasonable!
He's also been hanging out with Dr. Beatrice Golomb, who has studied data from a few websites and run some surveys of her own. In an analysis of 324 emails of people taking statins who were bothered enough to go out of their way to email "https://www.statineffects.com/" or "http://www.askapatient.com/," 30% reported mood changes such as depression, irritability, and anxiety. When patients who complained about statin side effects were asked survey questions, 65% of 843 endorsed increased anxiety or irritability and 32% reported an increase in depressive symptoms. Golomb published a case series of 6 patients who self-referred with irritability or short temper on statins (including "homicidal impulses, threats to others, and road rage") - in 100% of cases, stopping the statin cured the symptoms, and 4 of the 6 had renewal of the symptoms with a statin rechallenge.
Granted, these are all people who complained of symptoms in the first place, so it is hardly a random sampling, and the case series could represent the nocebo effect. But when I looked at the PDR for Crestor a few months ago (I can't seem to find it again on the internet, but if I do I will link it), I didn't find anything on irritability or anxiety, and depression was only mentioned briefly as an "aftermarket" side effect - meaning the crestor folks didn't find those to be side effects in their carefully controlled studies, but there are now some reports of depressed mood in the general public after release of the medicine. To me that just doesn't quite add up to my own experience. I've had several situations clinically where withdrawing the statin resulted in immediate improvement of anxiety, depression, and/or irritability for some treatment resistant patients. Of course that could be nocebo too, but nocebo and placebo effects tend to wear off after about 3 months, and I've seen patients improve after 2 years, and the biological mechanisms seem plausible. Well, definitive answers will wait for another day.
Statins improve mortality for middle-aged men who have known heart disease, have had a stroke, or have high levels of inflammatory markers. If you don't meet those particular criteria, statins will give you no mortality benefit.
But let's not be so negative - a literature review involving statins and mental health "found no statistically significant effect" of low cholesterol on psychological well-being. However, there may be a difference among the different statins. Simvastatin can readily cross the blood brain barrier, whereas pravastatin really can't. Golomb tested 1016 healthy men and women for 6 months with simvastatin, pravastatin, or placebo. Those on simvastatin reported significantly worse sleep, and, if sleep was impaired, worsening aggression. It was felt that statins that cross the blood brain barrier inhibited serotonin production. Interesting.
Now onto Jamie's paper - which is a study of diabetic mice. The researchers found that insulin-deficient diabetic mice had a reduction of a major regulator of cholesterol metabolism, leading to a reduction in brain cholesterol synthesis and lower synaptic cholesterol content (that's bad). The decline in brain cholesterol production happened in cases of insulin depletion OR hyperglycemia in various mouse models of diabetes type I and II, but not in obese (but normoglycemic) or insulin resistant (but normoglycemic, meaning high levels of circulating insulin were needed to keep the blood sugars normal) mice. Diabetes type I and II can both lead to CNS complications, including delirium and faster than "normal" decline in cognitive functioning. Diabetics, as we know, have higher rates of depression and Alzheimers. The brain contains 25% of the cholesterol in the body, and much of it is made right in the brain. Therefore diabetes produces a "global suppression of the enzymes of cholesterol synthesis and their master transcriptional regulator, SREB-2 in the brain... [which alters] neuronal and physiological function." A lot of this action occurs in the hypothalamus, which is a major point of control of the endocrine system, appetite, and energy balance.
Sometimes it all comes together. The bottom line? Eat whole real food, not tons of sugar and linoleic acid or wheat. Don't get diabetes if you can help it. Don't let anyone or anything suck the cholesterol out of your brain. Once things get out of whack, they can continue to be out of whack in all sorts of disastrous ways for quite a while.
* not really
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