Low serum cholesterol has been linked in numerous scientific papers to suicide, accidents, and violence (1)(2)(3)(4)(5)(6)(7). No one knows whether violence and suicidal risk have a metabolic byproduct of low cholesterol, or whether having low cholesterol will predispose you to suicide out of hand (8). However, the brain's dry weight is 60% fat, and cholesterol plays a vital role in neuron signaling and brain structure. In fact, one quarter of your body's free cholesterol is found in the nervous system (9). It would make sense that if your cholesterol drops too low then mood and behavior could be affected.

Synapses, where brain function goes live, must 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. Altering the composition of these membrane structures through eating novel industrial foods we never evolved to eat and depleting the ability of the brain and body to make cholesterol through aggressive cholesterol-lowering medication could cause a change in how the brain works.

More specifically, cholesterol depletion is known to impair the function of the serotonin 1A receptor (10), the serotonin 7 receptor, and reduces the ability of the serotonin transporter to move serotonin in and out of the synapse. It is interesting that low serotonin in the spinal fluid is also associated with suicide, impulsive acts, hostility, and aggression - and low serotonin in the spinal fluid is associated with low cholesterol. Cholesterol is also needed for the formation of the synapse, to make myelin, the specialized insulating covering of the nerves, and in various other neurotransmitter signalling processes associated with anxiety, depression, and aggression.

Just to be crystal clear - if you have low cholesterol, it does not mean you will be suicidal. Suicide is, fortunately, rare, and will have multiple predisposing causes. However, we don't want to encourage suicide and violence as an accidental byproduct of another intervention.

In recent decades, the drive toward lowering cholesterol more and more 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. An early analysis of the primary prevention trials of the non-statins showed a doubling of the risk of violent death or suicide (11). Oops. The J-LIT statin trial showed a 3-fold increase in suicide or accidents in the lowest cholesterol group with statin therapy, though the increase was not statistically significant (12).

Another case-controlled study (13) showed that statin users had a lower risk of depression than patients on non-statin lipid-lowering drugs. The LIPID study (14) 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. HMG Co-A reductase inhibitors (statins) do most of their work in the liver, where much of the body's cholesterol is made. As the rate-limiting enzyme in the production of cholesterol, slowing down HMG Co-A reductase will tend to decrease the liver's ability to make cholesterol. But it turns out we have HMG Co-A reductase all sorts of places, including the brain. Most of the brain's cholesterol is made by the brain, though autopsy studies have shown that serum cholesterol levels correlate with brain cholesterol levels (15).

But there's another complication in examining the literature for statin side effects. Some studies excluded patients with psychiatric problems (16). And due to the ability of statins to cause birth defects, many trials have excluded any women of childbearing age. The unknowns are such that Dr. James Lake, a psychiatrist and chair of the American Psychiatric Association's Caucus on Complementary and Integrative Medicine, recommends that depressed patients with elevated cholesterol aim to go no lower than a total serum cholesterol level of 160 (17). Below that level is where risk for violent death and suicide and accidents begins to climb in many of the association studies.

Dr. Beatrice Golomb has been studying the issue of statins and mental illness (17). 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. Dr. Golomb tested 1016 healthy men and women for 6 months with simvastatin, pravastatin, or placebo. Those on simvastatin (which can readily cross the blood-brain barrier) reported significantly worse sleep, and, if sleep was impaired, worsening aggression.

Granted, several of her samples are comprised of people who complained of symptoms in the first place, so it is hardly random, and the case series could represent the nocebo effect (a placebo effect is when you get a positive response to a "sugar pill" - a nocebo effect is when you get a side effect to a "sugar pill."). My own clinical experience has shown me several cases where withdrawal of a statin resulted in immediate improvement in paranoia, depression, cognitive issues, anxiety, and/or irritability.

A literature review of statins and mental health showed "no statistically significant effect" of low cholesterol on psychological well-being (*) - however, as stated before, many of the statin trials excluded people with mental health problems, and the different statin medications with differing abilities to get into the brain might have varying impacts, muddling the results of a broad review.

Statins seem to 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. A recent Cochrane review (18) urged caution in using statins for population-wide prevention of cardiovascular disease, as the risks may well outweigh the benefits.

My brain needs cholesterol! So does yours.  Dismantling your body's ability to make it might have some far-reaching effects.

* Pazarlis P, Katsigiannopoulos K, Bolimou S, et al. Poster presented at: International Society on Brain and Behaviour: 2nd International Congress on Brain and Behaviour; November 17-20, 2005; Thessalo-niki, Greece. Published in: Ann Gen Psychiatry. 2006;55:767-773.

Photo Credit

Copyright Emily Deans, M.D.

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