Low Cholesterol and Bipolar Disorder

I would say most cardiologists still believe that for cholesterol, the lower the better. In the diet, in the serum, in the liver, in the arteries. However, it is safe to say that super low cholesterol is not better in the brain. The dry weight of the brain is 60% fat and cholesterol is vital to synaptic function. Low cholesterol seems to be associated with Alzheimer's, suicide, and violent death. The association with depression is spurious. Turns out, however, that people with bipolar disorder also seem to have lower cholesterol - and that it gets lower during mixed manic episodes (a very uncomfortable combination of mania and depression that is particularly hard to treat), and also in manic episodes (1). As the mood swings remit, the cholesterol tends to get higher. And no one really knows why that is or what it means - is it some sort of biomarker of inflammation? Does the low cholesterol itself cause the problem? And yes, bipolar disorder (and depressive disorders) are associated with metabolic syndrome, but especially in bipolar disorder, the link to serum lipid alterations is much stronger to high triglycerides than high LDL or total serum cholesterol. Also interesting - depressed folks with high cholesterol are less likely to respond to antidepressants than folks with low cholesterol.


I've already discussed what low cholesterol can do to the serotonin receptors in Low Cholesterol and Suicide 2. Two different subtypes of serotonin receptor seem to be particularly affected, and as low serotonin is associated with violence and suicide (but not *necessarily* depression), it is intriguing that low cholesterol is associated with the same.

But in chasing down the original paper (2) that sparked this post (in the Journal of Clinical Psychiatry, which has the most user-unfriendly interface and I hate it when I have to find papers there), I came upon a meatier paper on mixed manic episodes, which led to a number of other neurotransmitter and brain stuff and cholesterol papers.  From here on out the neurochemistry is a bit heavy, so strap in.  Here's a nice Graffiti6 song, to make it all wash down easier (right click in new tab).

Big picture - most of the cholesterol we use in the brain is made in the brain.  However, autopsy studies show us that cholesterol levels in the brain correlate to those in the rest of the body, and statins and cholesterol-lowering medicine that cross the blood brain barrier will likely have similar effects in the brain as they do in the liver - at least the work of Golomb seems to suggest this is the case.

So we know from the previous posts that we need cholesterol for proper myelination of nerve fibers (myelin is insulating for electrical conduction and also specially designed so that nerve signals run faster. Demyelination - then you have slow and fritzy conduction, and big problems, as in multiple sclerosis), and we know we need it for proper serotonin signaling. Not only are the 5HT1A and 5HT7 receptors particularly affected (serotonin = 5HT), but cholesterol also stabilizes the serotonin transporters. Cholesterol is a critical component of the "lipid rafts" through which a lot of membrane communication transpires.

In Low Cholesterol and Suicide 2, I also made a brief note that cholesterol may be involved in GABA and NMDA receptor signaling, opioid signaling, and the transport of excitatory amino acids. All those are a rather big deal when it comes down to the totality of how the brain signals information.  So today I wanted to review that in a little more detail.

Glutamate (the excitatory amino acid in question) transport may be entirely altered by cholesterol depletion, at least in mice. It seems to affect the sodium powered transporter directly (3). I talk about glutamate a lot - in fact, last week I called it the excitatory neurotransmitter of doom. Almost every "paleo" intervention (such as ketosis, decreased inflammation, having enough nutrients like magnesium, proper sleep, meditation - which is not paleo, of course, but I feel emulates the necessary "being in the moment" that a hunter-gatherer would face hunting, gathering, collecting, building, etc.) - seems to modulate glutamate in a way that is favorable for neuron plasticity and repair. The SAD and stressful modern life promote glutamate excess, which will tend to cause neurotoxicity and eventually neuron death. Oops.  Having glutamate work for you instead of against you is all about energy and having the right machinery to send glutamate through the transporter at the right place and the right time - so skunking those transporters by depleting them of cholesterol seems like a crazy bad idea.

One of the places glutamate acts is at the NMDA receptor.  Turns out the NMDA receptor itself needs to be rich in cholesterol to do its work. (5)(6) If the NMDA receptor is depleted of cholesterol, there is a potential that it may fire differently, irregardless of the amount of glutamate out there.

And then there is GABA, who is rather like the Glenda the Good Witch compared to glutamate's Wicked Witch of the West. GABA transmission is relaxing. Literally like a nice glass of wine (which affects the GABA receptors). Yoga seems to increase GABA in key areas. Well, cholesterol depletion decreases GABA transmission too (4) (which it seems, in rats at least, that both depletion and major excess of cholesterol will do. So not too high (250% of normal) and not too low (56% of normal in this rat study) Low GABA signaling = anxiety, irritability, and sleep problems (symptoms associated with statin and cholesterol lowering drugs according to Golomb). These symptoms will also be prominent in a mixed manic episode (we did start today with bipolar disorder, after all).
 
Finally, there is opiate.  Good old opiate.  Opiate receptors (not surprisingly) along with dopamine are involved in the reward system of the brain.  There are several varieties of opiate receptors, but the delta receptor is associated with mood effects (7).  This subject is very complicated and I'd rather conquer it in a few more posts, but the short version is that cholesterol depletion seems to reduce the signaling capability of the delta opiate receptor in neuronal cells.  This could, of course, presumably affect mood.
 
That's it for now.  And perhaps it is not surprising that cholesterol, in a part of the body absolutely brimming with it, will have explicit effects on nearly every signaling pathway you ever heard of.  Which is why I get a little bit perturbed when you realize that in many statin studies, people with psychiatric illness were excluded.  People with mental illness make up a rather large percentage of the population (NIMH says 26.2% of adults in the US in any given year (8)).  What happens when you take a brain that is already firing a little off, and deplete it of cholesterol?  Gosh, it sure would be nice to know before we recommend statins for large percentages of the population.  Oh, wait, it seems we've already done that...
 
To be fair, there was a large analysis of statin trials looking for new onset mental illness perhaps caused by statins, not finding it to be the case (9) - though they acknowledge that dietary interventions lowering cholesterol and non-statin drugs did cause issues, suggesting that, yes, indeed, cholesterol is important in the brain, and perhaps the magical anti-inflammatory effect of statins is once again the only thing that saves them from just being plain old harmful to everyone.  And, again, many of those trials excluded people with previous psychiatric illness.  Questions, questions, questions.

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