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Low serum cholesterol has been linked in numerous scientific papers to suicide, accidents, and violence (1)(2)(3)(4)(5)(6)(7)... there are a bunch more, but I'm a bit weary of linking! This is why I write a blog, and not a peer-reviewed journal. Anyway, no one knows to this day whether depression, violence, and suicidal risk have a metabolic byproduct of low cholesterol, or whether having low cholesterol will predispose you to suicide out of hand (here's a rather snarky editorial pointing out that fact (8)). Some trials of statins (with the resultant crackerjack drop in cholesterol) will show no effect on suicide (9). A statin skeptic's favorite study, the J-LIT trial, showed deaths by accidents/suicides increased threefold in the group with total cholesterol less than 160 (yes, the p was .09, but that means there is only a 91% chance that finding didn't happen by random happenstance (10)).

Now, why could serum cholesterol have anything to do with the brain and depression? Good question - and the first question to ask in any theory of the brain is do the peripheral levels of something have anything at all to do with the central nervous system amounts of the same thing - so do serum cholesterol levels match up to relative amounts of cholesterol in the brain? They do (11). And cholesterol is important in the brain. Synapses, where brain function goes live, have to have cholesterol to form. Brain signaling is all about membranes, and cell membranes are constructed from fat. Cholesterol and the omega 3 and 6 fatty acids are the most important molecules in the synapse. If your brain fat is significantly different from so-called "normal" fat (which I'll go back to the hunter gatherer paradigm and say an HG's brain is going to have the approximate fat constituents for which we are evolved), the signaling in your brain could be very different too (12). Scientific papers will call this "alterations of membrane fluidity." (13).

So we know that low serum cholesterol is associated with suicide, violence, and accidents. (Another wrench in the works - low serum cholesterol is also associated with low CSF serotonin - which is of course associated with increased violence and suicide! These association studies are enough to make anyone give up and go boar hunting.) But does dietary fat intake have anything to do with depression and suicide? (Remember, serum cholesterol is often a chancy thing to connect to diet, after all.) Well, of 3400 some-odd people in Finland, the omega-3 rich fish consumers (14) had significantly less depression than abstainers, but the finding was more robust among women (no one knows why). In this round-up of 408 suicide attempters and an equal number of controls, there was no difference in saturated fat intake between attempters and controls, but the attempters did report lower fiber and polyunsaturated fat intake.

And, finally, do statins cause depression? I've seen statins cause or exacerbate depression several times in my clinical practice, especially in women. (I've also seen them cause paranoid psychosis a couple of times - twice in women and once a long time ago in a man. The psychosis remitted with withdrawal of the statin). Very striking! But anecdotes aren't clinical trials. This brand new study shows no link, and statins actually seemed to decrease depression in elderly women. This study also shows no link. This study shows that chronic cholesterol depletion via statin use decreases the functioning of the serotonin 1A receptors in humans, by decreasing the ability of the receptor to bind to its friendly neighborhood G proteins and other binding proteins. (The serotonin 1A receptor is more highly associated with anxiety-type symptoms than depression).

Clear as mud! But stepping back to whole health, I never like the idea of "the lower the better, no matter what," which seems to be the prevailing winds of cholesterol treatment right now. Usually, chemicals in the body are important for something, or else they wouldn't be there, and typically, a U-shaped curve emerges, where too little or too much (cholesterol, vitamin D, omega 3s, immunoglobulins, you name it!) is bad for human health. Here's an example of the U-shaped curve from the J-Lit trial (via Hyperlipid), showing increased cardiac death at low and high serum cholesterol levels.

Statins may have their role, but please don't put them in the water. In my opinion, adopt a whole foods, paleo-style diet. Keep yourself in the middle of that U-shaped curve for what our human systems were evolved for. It may help your mood, too, especially if you are a woman who eats fish!"

Continuation of Low Cholesterol and Suicide, part 2.

In my last post on the link between low cholesterol and suicide, I made note of some general trends between low cholesterol, suicide (particularly violent suicide), accidents, and violence, and raised some questions about the safety of cholesterol-lowering drugs. I didn't find any researched link between statin therapy and suicide, though one study showed that a statin reduced the ability of a certain serotonin receptor to do its job (linked below). My takeaway point from the post was that, hey, cholesterol is important and needed in the brain. Obliterating the ability of our liver to make cholesterol may have some untoward mental health side effects.

Since then, I've kept an eye out for more information, and a few interesting snippets have come up. Current Psychiatry has a decent article this month, "Cholesterol, mood, and vascular health. Untangling the relationship."

Some interesting facts from the article:
  1. 1/4 of the body's free cholesterol is found in the central nervous system.
  2. Depleting cholesterol impairs the function of the serotonin 1A receptor and the serotonin 7 receptor, and reduces the ability of the membrane serotonin transporter to do its thing. (Serotonin is made within nerve cells and needs to be transported outside into the synapse between the nerve cells to work. If the transporter isn't functioning, we have a Big Problem).
  3. Cholesterol is also needed for forming a nerve synapse (also Important) and making myelin.
  4. Cholesterol may be involved in GABA and NMDA receptor signaling, opioid signaling, and the transport of excitatory amino acids.
Just to be crystal clear - low serotonin is associated with violent suicide, impulsive acts, hostility, and aggression. We need plenty of cholesterol in the brain to have all our serotonin machinery work properly. Low cholesterol is also associated with suicide and violence. If you have low cholesterol, of course it does not mean you will be suicidal. Suicide is, fortunately, rare, and will have multiple predisposing causes.

So the paragraph above, with its caveat, brings up an interesting and actionable hypothetical question - does lowering cholesterol with medication predispose you to suicide or violence? The first cholesterol-lowering drugs were not statins. And an early analysis of the primary prevention trials of the non-statins showed a doubling of the risk of violent death or suicide. Oops. (I also linked the J-LIT trial in my previous post, which showed a 3-fold increase in suicide or accidents with statin therapy, though the increase was not statistically significant).

A later case-controlled study showed that statin users had a lower risk of depression than patients on non-statin lipid-lowering drugs. The LIPID study followed 1130 patients on pravastatin for 4 years, and found no changes in (self-reported) anger, impulsivity, anxiety, or depression. Pravastatin doesn't cross the blood-brain barrier very well. Simvastatin, a very commonly used statin, crosses it quite readily - but why this would be important may be interesting. HMG Co-A reductase inhibitors (statins) do most of their work in the liver, after all. But it turns out we have HMG Co-A reductase all sorts of places. These researchers found it in Chinese hamster ovary cells. And in these cells, administration of a statin reduced the ability of the serotonin IA receptor to work. Getting rid of the statin restored the serotonin IA receptor function.

But there's another complication in examining the literature for statin side effects. Some studies excluded patients with psychiatric problems (1). And due to the ability of statins to cause birth defects, many trials have excluded any women of childbearing age. Just something to keep in mind.

We are left with... well, a clinical trial is apparently underway to study the effects if pravastatin, simvastatin, or placebo on mood, sleep and aggression. We still don't know if low cholesterol causes suicide and aggression, or if it is a biomarker of depression. I'm convinced high cholesterol is just a biomarker for heart disease, after all, rather than a cause. Thus the whole question of why treat high cholesterol at all (though the magical anti-inflammatory statin effect may help younger men. With known heart disease.)

My brain needs cholesterol! So does yours.