Cholesterol Levels and Depression

by Duane Graveline, MD, MPH

The ESPRIT Study published in 2010 (Ref. 1) suggests that blood lipids play a major role in clinical depression (that for which treatment is sought) and the mechanism for this difference may differ between the sexes (Ref. 2).

The ESPRIT study followed 1040 women and 762 men for a period of seven years, obtaining baseline lipid levels at the beginning and end of this study period.

Study participants were all 65 years of age or older at the start of the study. They found that depression in men was associated primarily with low LDL cholesterol whereas depression in women was associated more with low HDL cholesterol.

The relationship between  total cholesterol and brain function has been known for many years, especially when cholesterol has been lowered artificially such as with the use of a statin drug.

The mechanism for this appears to be excess lowering of serum cholesterol below that to which the body has been accustomed. In this case the brain's glial cells, which have been tasked with the job of synthesizing brain cholesterol, no longer can provide adequate amounts due to the effect of the statin drugs on the synthesis mechanism within the glial cells.

The result of this has been a spectrum of cognitive disorders such as amnesia, confusion, disorientation, forgetfulness and dementia.

The tendency of statin drugs also to provoke depression in some manner, particularly in seniors, has been recognized and reported for more than a decade. This depression is thought to be due to an entirely novel mechanism involving dolichol inhibition.

When statin drugs are used to lower cholesterol, they do so by the method of reductase inhibition, thereby blocking the mevalonate pathway of cholesterol synthesis. The result is usually prompt and substantial lowering of the serum cholesterol.

It so happens that the inevitable consequence of mevalonate blockade is also to block the synthesis of CoQ10 and dolichols, both vital in cell function. It is this dolichol blockade that exerts its effect on emotion and behavior, including depression.

The mechanism involved is that of glycoprotein synthesis, the manufacture of those billions of molecules of sugar and proteins responsible for cell identification, cell communication, immunodefense and neurohormones.

It is the neurohormones that govern our mood and when this ability is compromised, such as by insufficiency of dolichol, the emotional consequences can be extreme. This can contribute to the symptoms of aggressiveness, sensitivity, paranoia, road rage type reactions, suicidal ideation, homicidal ideation and depression — all associated with the use of statins.

The observation that depression is associated with low LDL cholesterol levels in men and low HDL cholesterol levels in women may purely be one of association only, with no contribution to causality, sort of like the subtle association of sedentary activity or moderate obesity with heart disease. Low LDL cholesterol also has been associated with mediocre intelligence, limited learning ability, antisocial behavior and criminality.
Those who strongly believe in the widespread use of statin drugs are now learning that the cardiovascular improvements with statins have come not from cholesterol lowering but from the previously unknown anti-inflammatory action of statins.

This is forcing a new look at how cardiovascular disease is treated, where cholesterol manipulation may have little to nothing to do with it, while the adverse effects associated with cholesterol manipulation may be severe.

With respect to the effects of low HDL cholesterol in women seemingly associated with depression, we should remember that HDL cholesterol has a unique anti-inflammatory component. However this knowledge falls far short of explaining possible mechanisms.

We have so much more yet to learn. This anti-inflammatory effect of HDL cholesterol would appear to be complementary to the anti-inflammatory effects of statin drug use, the process now believed by many to underlie the positive effect of statins on cardiovascular health.

The association of depression in women with low HDL cholesterol involves mechanisms that remain to be defined or, as mentioned previously, there may be no causal relationship.

At this stage in our understanding of the role of cholesterol in the human body, any attempts to manipulate LDL cholesterol down or HDL up should be viewed as a recipe for disaster.

I view our cholesterol as innate, meaning like our height and color of our eyes it is fixed and not an item to be changed unless some underlying genetic mechanism is at work as in the tendency for cholesterol deposition seen in some familial hypercholesterolemia cases.

Duane Graveline MD MPH
Former USAF Flight Surgeon
Former NASA Astronaut
Retired Family Doctor

Ref 1:
Ref 2:

Updated July 2016

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