Monday, March 7, 2011

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.

27 comments:

  1. Every time I read your bipolar pieces I understand a little more why I am now well having become Primal 15 months ago - it's marvellous.

    One question for you if I may, my father is still haunted by the face of his mother pleading with him (he was 12 at the time) not to let them 'put the electricity in her head again' (she was a manic depressive) this was 1957 - he seems driven now (some 50 years on) to prove that it is a totally barbaric treatment. Is there anything I can say that would help? I know electric shock treatment is still used (at least a friend's daughter elected for it in Slovakia last year not sure what her condition is) but I'm assuming it is a highly modified version - does it have it's place in modern psychiatry to your mind?

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  2. Dr. Deans, thank you for another fascinating post. I am looking forward to your posts on opiate receptors. I'm taking a break (due to the pollen season) from my scrumptious yoghurt made from heavy cream, and I find I miss something in it, which might be those opioid-like peptides.

    Would you consider writing on the need for cholesterol as women age, menopause, etc.?

    Am enjoying reading your many nice reasons to have such lovely things as beef bacon and egg yolks for breakfast.

    I appreciate your taking the time to write this blog.

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  3. Great post. I have just in the past few months began consciously eating more animal foods (and therefore cholesterol), and have found it to lessened my anxiety substantially.

    I am wondering how familiar you are with the pituitary. I know that a dopamine agonist is prescribed for elevated prolactin levels, so I am curious how that fits in the bigger picture and how diet affects it.

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  4. So, if lowering cholesterol with statins apparently do not correlate with mental illness, what about the theory of Paul Jaminet: infections? Infections can cause low cholesterol and mental illness.

    http://www.ncbi.nlm.nih.gov/pubmed/20490350
    http://www.ncbi.nlm.nih.gov/pubmed/20449978
    http://www.ncbi.nlm.nih.gov/pubmed/20608475
    http://www.ncbi.nlm.nih.gov/pubmed/20495465
    http://www.ncbi.nlm.nih.gov/pubmed/20969465
    http://www.ncbi.nlm.nih.gov/pubmed/21030090

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  5. Cavegirl - I've seen people who have literally been frozen in a doorway because they were too overcome with depression to decide whether to go in or out, people who were tortured by voices telling them they are evil and dangerous and need to die, people who feel they have no reason to live get better, lively, back to themselves within a few weeks of beginning electroshock treatment. They use anesthesia so it is much better than the old days. It can cause memory loss, sometimes permanent, but is far more effective than medicines or therapy percentage -wise for a severe depression. Is it barbaric? Far less so than cracking the chest open to perform heart surgery. Is it lifesaving? From what I have seen, yes, like the heart surgery. Kitty Dukakis wrote a book about it that is supposed to be good.

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  6. H - glad you like it, I'm not actually a metabolism or hormone expert but as stuff comes up about women and aging, I will keep an eye out.

    Ellen - one of the dopamine pathways is the tuberoinfundibular one - the hypothalamus secretes dopamine that inhibits the pituitary prolactin-making cellsmdirectly. Therefore a dopamine blocker can cause high prolactin, and a dopamine agonist can lower prolactin levels, the only dietary use for this I'm aware of is fenugreek - which is sometimes used by breastfeeding women with low supply Jack up prolactin levels and increase supply. It is supposed to smell like licorice. While I did not use it, some of my friends have and reported it did work for them.

    Mario - there is definitely something to that as it makes sense holistically, and I plan to do another post on infections and chronic fatigue. Thanks for the links.
    I still have your thyroid ones - but with thyroid I need to dive in from the textbook level and I haven't yet had the time.

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  7. Dr Deans

    Thank you very much for that response. I will duly pass it along the line to my father.

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  8. Enjoyed the post . . . but it seems to me that even though there might not be any scientific citations to prove meditation is primal, even the most cursory examination of so-called primitive religions and culture reveals deep knowledge of the subject. We don't know when these practices developed. They're just there, whenever the historical record begins.

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  9. I just found you via the Healthy Skeptic! So glad I did. I'm a social worker and am very interested in mental health and nutrition. I'm in the process of reading the China Project and am left wishing there were something on how a vegan diet affects mental health. I look forward to reading more of your posts. Take care.

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  10. I do far, far, better on a high-fat diet. I have realized sugar is a mood poison and opt for a whole fruit when I'm craving a sweet; and always eaten with fat and protein.

    I have mixed, rapid cycling episodes with psychotic features.

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  11. Not exactly pertinent, but the readers of this blog will enjoy this:
    http://www.marketingexperiments.com/blog/wp-content/uploads/ScienceComic.gif

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  12. Hi Emily,

    It's really refreshing to see a post like this from a psychiatrist, especially one in Massachusetts. I just posted it on my Facebook page. I'm a Nutritional Therapist with a practice in Northampton. I preach and practice the Paleo/Weston Price philosophy which is so much needed in the mental health fields. Let me know if you ever make it out this way. It would be good to connect. I do know some good Nutritional Therapists in the Boston area if you'd like some good people to network with and/or refer to. Here's my website with my contact info: www.pvnutritionaltherapy.com

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  13. Hello,

    I have a question about a quote in the introductory paragraph. You claimed that, "depressed folks with high cholesterol are less likely to respond to antidepressants than folks with low cholesterol." After reading the article, I was not able to locate any further synthesis regarding this phrase. It seems to me, that it goes against the main crux of the argument, i.e. lower cholesterol is, perhaps, detrimental. Thank you for your time.

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  14. Hi PV - will definitely look into it! Thanks!

    Lucid - we are in the realm of "highly speculative" but as near as I can tell, antidepressants work (when they do) primarily via anti-inflammatory mechanisms centered in the brain - so if low cholesterol is a biomarker of a certain state of inflammation (as Mario alludes to), then people with low cholesterol ought to respond better to the antidepressants. That is probably grossly simplified compared to what is actually going on if it is even correct... but it is a thought. I think we are looking at two issues here - there's the natural history of these disorders and the links with cholesterol (poorly understood), and then there is the separate question of is it wise to muck about with the cholesterol machinery with so many far-reaching consequences we don't fully understand.

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  15. Emily the thyroid issue has to studied with this duality. The brain has full control of controling all thyroid hormone needs independent of the body numbers. Most docs, dont realize that the numbers that they get are reflections of the non brain component. The other key issue is there is comorbid leptin resistance thyroid labs will be just about worthless. We often see clinicians just ramp up synthroid and when it fails they change to cytomel. And when that fails they refer to an endocrinologist who makes the same errors. Reverse T3 is a great measure to check leptin resistance. The hormone issue is vital to helping folks get better. This is something I do all the time in my own practice. Great Blog and I may need to pick your brain soon Emily about a topic I am working on for publication.

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  16. Low cholesterol may be part of the pathophysiology of bipolar disorder (along with low leptin - leptin is a neurotropic , brain protective hormone and low leptin is a finding in all seriously mentally ill people, including those in recovery - leptin remains low compared to controls).

    However another reason for low cholesterol in mixed and manic states would be the hyper energy and low appetite. Manic people don't eat, and don't stop moving... this results in lower blood glucose, lower insulin, and lower cholesterol levels.
    If you took a normal person and asked them to mimic mania for a week their cholesterol would probably drop too.

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  17. When, around what number exactly, is cholesterol considered "low"?

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  18. Klshinny - in the French observational studies the increased risk of suicide started below total chol of 160 or so

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  19. and we have US Cardiologist telling the country to shoot for as low and LDL as possible.....and getting ready to push more CETP drugs. Crazy. But that is why we have to fight this battle.

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  20. And in the J-LIT statination study, if you drop TC to below 160mg/dl accident/suicide RR is 2.87 vs TC of 200-219mg/dl. Interestingly, cardiac death RR is 6.23 at TC <160mg/dl cf 200-220mg/dl.

    http://www.ncbi.nlm.nih.gov/pubmed/12499611

    Peter

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  21. John - I had never even heard that about the thyroid. I'm afraid here in Massachusetts if you order anything other than TSH reflex to free T4 you are considered something of a lunatic. One problem with the chains of "standard of care" and the heavy influence of managed care (which will generally not pay for interesting extra tests) is that in some respects we aren't really allowed to think.

    I would say there are 15-20 papers on pubmed linking low cholesterol to suicide. James Lake, the chair of integrative medicine for the APA, suggests that people with mental illness not drop total cholesterol below 160.

    Peter - yes, I've looked at your graph of the JLIT trial data! Remarkable, really, how that cardiac death shoots up at the low end in that trial.

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  22. I'm a psychiatric social worker who had a two year period of severe depression and some monthis of mania. After a dozen psychotropic drugs didn't seem to help, I started taking the supplement for bi-polar from Truehope.com, a Canadian company. The depression and mania disappeared and I have been over 5 years with no symptoms and no drugs. I can't say for sure it was the supplement that did it, but it sure coincided with the timing. I'm not recommending anyone stop their medication, as I know that can be horrible for many people. This is just what happened to me.

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  23. During a mixed episode that resulted in the longest hospitalization I ever had my cholesterol level was measured at 133.

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  24. Dr. Deans,

    I wanted to thank you for your blog and this site. I have a BA in psychology, an MA in teaching, and was recently getting a BS in health and wellness (funding ran out, though). I was also diagnosed as bipolar when I lived in MN (around 2001). Since I have changed my lifestyle to that of a more paleo template, I have not experienced any of the symptoms of bipolar (no anxiety, no depression, and no extreme ups). My life has changed! I have my own blog in which I have wanted to post about moods and foods, but wanted to really get some strong research behind it. Your blog really helps! I wonder if you could point me toward some great research studies which have helped you throughout your studies and career. Since I research these things a lot, and try to put them to the people I know and share with, it would really help! Thanks for your work! I hope to also do the same!

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  25. Dr. Deans,

    If one is believed to have low total cholesterol, the question is how does one raise it? There is virtually no literature on this.

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    Replies
    1. Try whole milk and eggs. It works for me.

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  26. What happens when you have high cholesterol and bipolar?
    Last year I was diagnosed with Bipolar 1, and yesterday, my doctor did some blood tests, and my cholesterol is too high. My mother says it's genetic, but I wonder if it's because I've been eating more WAPF and Primal style?

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