Intriguing Links Between Depression and Cholesterol

Today's paper comes from the Journal of Clinical Psychiatry: Serum Lipoproteins Improve After Successful Pharmacologic Antidepressant Treatment: A Randomized Open-Label Prospective Trial.  Turns out that depression researchers are thinking about the whole body and not just the brain.  My basic premise is that it is all connected, folks.  Inflammation, heart disease, diabetes, obesity, metabolic syndrome, depression, IBS… Let's lump, shall we?

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So the truth of the matter is that people suffering from depression have lower overall cholesterol than average.  I know, crazy, right?  Here's where I really blow your mind - people with major depressive disorder, despite the lower cholesterol, have higher rates of death from heart disease, whether or not you had heart disease before or after the diagnosis of depression.

But anyone in the primal/paleo community will know that total cholesterol doesn't mean much - we want to know about HDL and the subfractions of LDL - the big fluffy new fresh LDL are not associated with increased risk, whereas the old, rancid, small dense LDL are certainly associated with increased risk of heart disease.  Here is a quote from the article (though I'm not entirely sure I agree with the pathology description):

"small dense" LDL particles, resulting from packing of LDL particles with higher amounts of triglycerides, have a higher propensity to be oxidized, to be trapped in the subendothelial space, and, subsequently, to form the seed of an atherosclerotic plaque."

In favor of further lumpage, it is known that depression is associated with insulin resistance, which is associated with more small, dense LDL, and thus higher triglycerides and higher apolipoprotein B.   Successful antidepressant treatment will just so happen to to improve insulin sensitivity and all those bad metabolic markers.

In the paper, lipoprotein composition of various folks with major depressive disorder were recorded and compared to healthy controls.  Then depressed subjects were randomized to treatment with either mirtazapine (an effective antidepressant known to cause weight gain) or venlafaxine (another antidepressant less likely to cause the same).

Results:  not surprisingly, total cholesterol was lower in depressed patients compared to healthy controls (surely the total cholesterol amount and how important robust cholesterol levels are to the brain has nothing to do with that.  I'm sure it is just a confounder.) Both HDL and LDL were significantly lower.  There was also a higher ratio of nasty, small, dense LDL particles to HDL particles  in depressed patients compared to controls.  Depressed people are much more likely to have rancid LDL lingering in their bloodstream.  To me, not surprising.

Let's add the psychotropics - predictably, folks taking mirtazapine gained some weight, and folks taking venlafaxine lost some weight (serotonergic antidepressants such as venlafaxine will tend to cause short-term weight loss, likely though increasing satiety signals to the hypothalamus, of course some folks consider the hypothalamus to be of secondary importance with respect to weight gain or loss).

So what happened with the interesting subfractions of lipoproteins among the antidepressant treated groups?  With fat-inducing mirtazapine (which causes weight gain through a central histamine or anticholinergic mechanism, most likely), total cholesterol and triglycerides increased.  Under venlafaxine treatment, total cholesterol remained stable and triglycerides decreased.  With both groups (and these are both powerful antidepressants who tend to actually work and help people feel a bit better - the study showed about 60-65% response, which is typical for these agents), the HDL levels improved, and HDL to LDL ratio and apolipoprotein B (a measure of old, dense, rancid cholesterol) decreased.  The mirtazapine group gained weight (as expected), the venlafaxine group did not.  In both groups, responders had a slight increase in total cholesterol.

What do we learn?  Depressed folks who responded to antidepressant treatment tend to increase their HDL levels and had favorable changes decreasing old small dense LDL.  Oddly enough, those on the fattening mirtazapine had similar good lipid changes (if the medicine worked) compared to the short-term slimming venlafaxine.  (Editorial note:  inflammation is inflammation, my friends, and an anticholinergic or histamine mechanism will make you fat regardless of how inflamed you are - and while most of this work has been done with antidepressant medication, I have linked studies in the past showing that therapy has also been shown to be anti-inflammatory, though to be honest it has not been looked at robustly).

Wildly enough, this study says "to the best of our knowledge, the composition of LDL particles has not been studied previously in depressed patients."  WHAT?  Small dense LDL vs large fluffy LDL was only discovered, like, 20 years ago, right?  Mental health research is always lagging! And antidepressants might actually be anti-inflammatory as suspected… dare I say like statins?  Both classes of drugs have evidence for some modest benefit in certain situations, and major drawbacks.