Friday, January 28, 2011

I Hate Homocysteine (Also It Is Elevated in Schizophrenia and Bipolar Disorder)

There are some biochemical reactions that are just gorgeous. Poetry. Glycolysis and the citric acid cycle, for example. I used to be able to draw out the whole process, and there was always something very pleasing about doing so. Enter glucose and oxygen and a few other things, and exit energy in the form of ATP, flying off the citric acid cycle like sparkling droplets of water off a spinning wheel.

The folate cycle, on the other hand, is ugly. It plays a starring role in Evolutionary Psychiatry, however, and I have to come to terms with it. There are a zillion components, an army of vitamins, and end-products going every which way - amino acids, neurotransmitters, membrane lipids, and whatever the heck homocysteine is. (seriously - my anchor article for this post calls homocysteine a "non-protein amino acid". What does that even mean?)

Image from Wikipedia

Homocysteine is a by-product of the folate cycle. It is supposed to be recycled back into methionine, but if you are low in certain B vitamins (or, like 10% of people, genetically deficient in certain enzymes that work to recycle homocysteine), you end up with too much of it hanging around. And when that happens, you happen to have a higher risk of all sorts of nasty things, such as heart disease, stroke, hip fractures, and dementia. Turns out that homocysteine likes to cleave the disulfide bridges in cysteine molecules. That doesn't sound so bad, but it affects things you might need, like collagen, for example, which plays a major part in holding bones together and keeping your arteries nice and elastic. High homocysteine *sometimes* goes hand in hand with high triglycerides, high blood pressure (from those stiff, inelastic arteries, one would presume), low HDL, high fasting glucose, and abdominal obesity. All those signs together (or three of them at least, anyway) make up the so-called metabolic syndrome which plagues our Western populations.

The good news is that abnormally high blood levels of homocysteine can rather easily be lowered by B vitamin supplementation. Almost any B vitamin will do the trick - B6, B12, folate, even betaine. That's rather exciting, one would think. Plausible biologic mechanism for a big, big problem. Cheap and simple fix. The bad news is that lowering homocysteine with B vitamin supplementation doesn't seem to make one whit of difference in cardiovascular disease, or at least it didn't in the 3700 Norwegian heart attack survivors who were followed for two years in the last decade (3) or seem help 5500 folks with known vascular disease or diabetes (4).

I don't really care about your hearts or bones. That's not true. I care. But your brains interest me a lot more. A new paper came out this month in Psychiatry Research from researchers in Croatia about high blood levels of homocysteine in patients with bipolar disorder and schizophrenia. And you will not be surprised to know that metabolic syndrome and obesity (and diabetes and heart disease) are more common in these patients than in the general population. While some of the medications used to treat these conditions cause obesity and impaired glucose tolerance, when you really parse the data, there appears to be an increased risk of metabolic syndrome just from having the illnesses, apart from any medication contribution.

(A rather unrelated aside - antipsychotic medications are well known for some pretty disturbing side effects. One of the scariest ones is called "neuroleptic malignant syndrome" where you get a high fever, stiffness, blood pressure spikes, and it can lead to kidney failure and death from muscle injury. One of the fastest treatments for NMS is electroshock therapy, believe it or not. What many people don't know is that schizophrenics institutionalized in the years prior to the invention of medication would suffer high fevers, stiffness, and death (it was called "malignant catatonia"). Now there is no question that the medicines cause NMS, but there is also an additional issue with the dopamine regulation in schizophrenia that could lead to autonomic dysfunction in a serious and fatal way. Just some food for thought.)

Right. Homocysteine. Not only does it degrade important things like bones and arteries, but it also might be able to antagonize the NMDA receptor in the brain (1), which could be a mechanism by which homocysteine itself could cause psychosis directly. It has been suggested that high homocysteine and low folate and B12 are independent risk factors for the development of schizophrenia and bipolar disorder (2).

The Croatians did a pretty simple study. They measured the fasting homocysteine and other signs of metabolic syndrome in patients admitted to their hospital ward with schizophrenia and bipolar disorder. They did not measure serum folate and B12, which is unfortunate, because that would be interesting to know. Oh well. The results? 34.2% of the sample of 60-odd patients had metabolic syndrome. And 67% of those with metabolic syndrome had high homocysteine. Only 23% of participants without high homocysteine had metabolic syndrome. In addition, high blood pressure also independently correlated with high homocysteine, which at least makes biologic sense.

One more little interesting tidbit from the paper - high homocysteine has also been found to be correlated with high omega 6 fatty acid levels in patients with major depression.

The take home? As I said in the Zombieland 2 post, I tend to connect high homocysteine levels with poor nutrition in general. Also, high homocysteine can be caused by a number of drugs and supplements, including niacin, metformin, insulin, corticosteroids, NSAIDs, and some anticonvulsants cause high homocysteine levels too. Chronic high intensity exercise and smoking are also related to high homocysteine. What do we do about it? Having all the B vitamin players on the team can help, so it can be properly recycled. The Norwegians were heart attack survivors - the damage had already been done. Maybe (comparable to omega 3s for mild cognitive impairment = possibly useful vs omega 3s and Alzheimers = a disappointment) homocysteine is something to keep low in the long term as a preventative strategy. Lowering homocysteine did seem to reduce stroke incidence by 25% in the HOPE2 trial. But who knows? We'll have to wait for more studies.

The brain is on the front lines, and metabolic syndrome (or the inflammation behind it) has psychiatric components as well. It is all linked in ways that we only barely understand.


  1. You will not believe how many times I have requested homocysteine tests with my patients as a functional marker, only to have the Dr refuse as they deemed it a useless test that showed nothing at all (they care about hearts only, not brains, arteries, etc...).

  2. Hey Emily.
    How is the snow?

    Can you please refer in the future to the role of human growth hormone and depression ?

    If in the past I didn't sleep well for 3 nights and got hypomanic episode it means that I am b polar?

    Can adding lamictal help bring remission ? I am already on cipralex and it only mildly help. I feel still depressed

    I live in Israel so I don't have brilliant psychiatrist like you):-

  3. Hi Emily.

    What concerns me is the routine use of PPIs in old people with acid reflux (probably originally caused by straining on the toilet).

    See PubMed Search for "Vitamin B12" AND "Proton Pump Inhibitor".

    My mum's been on 20mg/day Omeprazole for years. I've asked mum's GP to monitor mum's serum B12 more regularly.


  4. Emily, when I read you I sometimes get the sense that you are on the verge of discovering a nutrition-brain connection that will have wide-ranging, life-improving clinical implications.

    Serendipity favors the prepared mind. Your mind is fertile ground. Stay the course, please.

  5. The urea cycle was always my nemesis- it’s not particularly ugly, but my introduction to it was from an atrocious lecturer and I think that killed it. The folate cycle is definitely a bear- always thought it was apropos that it involved the (abbreviated) enzyme MTHFR. I’ve tended to think that Homocysteine has been maligned much like cholesterol- we associate high levels with disease, though the correlation does not seem (for many things) to mean causation. I wonder how much a choline deficiency (which would decrease betaine thus increasing homocysteine) might be a factor in some cases of hyperhomocysteinemia, and what other effects those low choline levels may cause.

  6. Jamie - the authors of the paper suggested checking homocysteine in patients with bipolar d/o and schizophrenia to assess for overall metabolic risk.

    Shay - snow is mountainous. Up to my waist in the back yard. I'm not licensed in Israel and I can't diagnose you over the internet. Having insomnia + hypomania for three nights could mean you have bipolar disorder. It could also mean you were doing tons of cocaine. Or maybe you were on steroids for an asthma attack. There are lots of factors to consider which is why a full evaluation is needed to sort all those questions out. Lamictal looks crappy in clinical trials, but I find it to be a very helpful medicine for people with diagnosed bipolar in certain circumstances.

    Nigel - yeah, PPIs might also interfere with oral vitamin D absorption (I'm just coming up with that from memory . Maybe it's statins? Well, maybe I'll look it up.) I've never heard of the toilet straining connection but there is that intriguing element of the lifelong lack of "squat" while toileting. I check a lot of B12s and folates and never find low folate, but often find low or marginal B12s (latest American Journal of Psychiatry practice guidelines for depression suggest that anyone on antidepressants should have levels of B12 higher than 400, as the antidepressants work much better - in general, 200 or so is considered the low end of normal.) Most epidemiology studies of the elderly suggest they are at high risk for b vitamin deficiency - and the elderly also have higher levels of homocysteine.

    Steve - the reason I do so much reading and searching is that I'm sure that connection is out there. Reading "Food and Western Disease" and the anthropology and Whole Health Source blew me away with respect to the connections between nutrition and modern "physical" diseases of civilization. Knowing a bit about the history of psychiatry and the recent escalation of certain diseases (especially depression and anxiety), and knowing that our ancestors would not have survived well if so stricken, I have to think there is a connection. Environment, sleep - all those play a big role, but if nutrition problems cause met syn (which they probably do), and met syn is linked to psychiatric illness, then nutrition may have something to do with psychiatric illness too. I know some high-powered folks (like Maurizio Fava at Mass General) are interested in the nutrition angle - I doubt they have the same "evolutionary" perspective which helps me keep focused, but may add bias to my search. Anyway, I keep looking.

  7. I suspect that niacin would normally reduce homocysteine, not increase it. At least the IR form, in 1-3 g/d doses.

    1. I have read that since B3 is a methyl acceptor (from SAMe) that it drives the SAMe down the metabolic pathway to homocysteine. If you don't have the proper nutrients to convert that back into methionine I think you would end up with higher homocysteine, granted everything I have said is true. I could be wrong.

  8. Noticed that in the Norwegian trial, B6 alone did not reduce homocysteine level, but B12 in combination with B6 or folic acid did. Also these people just had heart attacks and were on a million drugs. No surprise some B-vitamins didn't help much. Interesting stuff though, and another link between the metabolism and the mind.

  9. Ned - the reference is here (shoot - there is a bug with the iPad and comments so I can't copy/paste but pubmed ID is 16047265 ). I'm working on getting access to the full text but the abstract mentions fibrates and niacin specifically.

    The reason I conceptualize the B vitamins as a football team (and keep using that reference in my posts) is because you really need all the players. Ordinary amiantus of niacin would be no problem - megadoses used for cholesterol lowering is the issue. If you have too many running backs, you won't have enough offensive lineman, and your quarterback will be sacked every time. I could have the conceptualization wrong, but it is really best in my mind to take the b vitamins as a team, unless you know you are specifically deficient in one.

  10. Pal - I'm not really a conspiracy theorist (believing the powers at be to be generally to incompetent and unorganized to succeed in vast endeavors), but it is funny how all the studies of nutritionals seemed designed to fail. But in my mind, you need a huge holistic change in food pattern (or all the B vitamins at once, for example, for perhaps much longer than two years) and that makes for messy and uncertain studies.

  11. Too incompetent, I mean of course. My husband gave me a keyboard for the iPad and I need to make more use of it ( used it for my post last night, though)

  12. Vlprince - your comment got lost in my email for half a day (sorry), but yes, the whole folate cycle and homocysteine is definitely a MTHFR

  13. Hello again.

    I don't think that PPIs affect anything to do with fat absorption e.g. Vitamin D.

    Some statins increase Vitamin D levels in the body. See Increased levels of 25 hydroxyvitamin D and 1,25-dihydroxyvitamin D after rosuvastatin treatment: a novel pleiotropic effect of statins?
    Atorvastatin increases 25-hydroxy vitamin D concentrations in patients with polycystic ovary syndrome. Mum's not on a statin.

    RE Straining causing hiatus hernias: I found that in What causes hiatus hernia?

    Mum's on folate and her last serum B12 result was around 250 a year ago after being on 1,000ug/day sub-lingual methyl B12 for a month (which was then stopped as I had no authority to give it to her).


  14. I found this study to be rather interesting: This study, called

    Metabolic Syndrome Predisposes to Depressive Symptoms: A Population-Based 7-Year Follow-Up Study concluded this: "The higher rate of depressive symptoms in the subgroup with metabolic syndrome suggests that the metabolic syndrome may be an important predisposing factor for the development of depression. Effective prevention and treatment of metabolic syndrome could also be important for the prevention of depression."

    Simply put, I think when hormones are "off" the brain is off. In some cases, getting insulin levels in balance will heal metabolic issues and depression.

    As for Vitamin D... many many people have low levels of Vitamin D. (I don't think it's due to the use of sun block.) Doctors will be having people pumping up the volume of vit D to help metabolic issues. That is only a band-aid. Getting the fat growth hormone insulin levels regulated is key. Who knows? maybe regulating insulin levels will help with Vit D deficiency I know... I went from med dependent type II diabetic FBG 160 Ha1c 6.3 to pre-diabetic no meds, by using diet (& exercise) alone. Last labs, end of year: fasting BG- 100 Ha1c- 5.0 Although I was not depressed, my mind is more focused & clearer than ever and I feel the best I have in my adult life. I am 50 years old.

  15. What do you think of testing for and supplementing L-Methylfolate(5MTHF) ?

    Apparently something like 50% of Americans are heterozygous for the MTHFR polymorphism, and an additional 25% are actually homozygous for it.
    The polymorphism slows conversion of folic acid to l-methylfolate.

    You might expect to find lower than normal values of l-methylfolate in a sick population, but measuring only folate levels won't catch it.

  16. Lynn - I have quite a few posts on that sort of thing - "Stress is metabolic syndrome" and "chronic stress is chronic illness" come to mind. I think that poor vitamin D levels in the population has a lot to do with sunblock and sun avoidance, as it is my understanding we get about 90% of our vit D from the sun.

    Nigel - thanks for looking that up!

    Kiran - there is a lot of research into that as there are prescription vitamin forms of methylfolate used as adjunctive boosters for antidepressants - but no o e has come up with a standard protocol.

  17. Dr. Deans,

    Just wanted to say how much I enjoy reading your posts. They are just incredibly informative as well as entertaining to read. Your statement from above, "ATP, flying off the citric acid cycle like sparkling droplets of water off a spinning wheel" is sheer poetry. Now...I'm off to take a B-100 complex tab!

  18. Good point regarding Bs working as a team Emily. Here is a link supporting your point regarding pharmacological doses of niacin:

    It is interesting that niacin at 1-3 g/d doses seems to also have a number of effects on other health markers; mostly positive.

    A bit of a puzzle ...

  19. I have the AG genotype for SNP rs1801133, but am not sure if this puts me at risk for elevated homycysteine levels. According to, AG genotype is not even indicated, (though this is what has been determined for me through testing at I did read that the genotypes TT and CT are at highest risk, and the SNP is also linked to a number of other disorders:
    cancer, including
    gastric cancer
    lung cancer
    head and neck cancer
    cleft lip and cleft palate
    coronary artery disease
    neural tube defects
    pre-eclampsia (gestational hypertension)
    Since I have experienced 3 of the disorders named above, I'd be curious to know if the AG genotype is indicated with higher risk of poor folate metabolism. I do get B injections weekly, and am encouraged to see that this might help to ammeliorate elevated homocysteine levels and associated disorders.

  20. Thanks for writing this!
    I do a lot of research into nutrition and disease (both brain and body). I'm starting to think that a diet like Dr. Fuhrman's, with the addition of healthy fish and omega 3 supplements might fix half or most of these things.

  21. With low vitD; truely I think it is the obsessive showering in the US, as the naturally produced vitD on you skin has to be absorbed back in.

    I am so thrilled to find your blog, so much great information. I am so thrilled to find someone investigating these things. So many questions forming.

  22. What are the final metabolites of carbohydrates or refined sugars in diabetics? Is homocysteine involved here? Taking B Vitamins will solve problems if any?


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