Tuesday, August 3, 2010

Depression and the B Vitamins

I mentioned before that in psychiatry, we don't have many lab tests. In a standard work-up I might check none, or just a few. If a new patient has seen his primary care doctor within a reasonable amount of time, I might check the thyroid, B12, and folate and be done with it. I used to check vitamin D on everyone, but everyone was low, so now I tell patients to supplement with 2000 IU a day and then I check it (plus calcium) after 3 months.

Why B12 (available from animal foods) and folate? Both are B vitamins involved in nerve health and the formation of the all-important neurotransmitters. B12 deficiency can definitely cause depression along with other nerve damage over time (1)(2). In many years of doing this testing, I've caught several underactive thyroids, a few B12 deficiencies, but no folate deficiencies. Not one. In America, all grain-based food is supplemented with folate. Maybe that's why.

I've never tested for B6. It just wasn't a test we were taught to do, or to look out for. B12 deficiency is pretty common (6% of adults) - we have variable abilities to absorb it from our guts, and some people will need shots in order to keep from being low. B6 deficiency - hadn't even thought about it, really. But it stands to reason that we might need it to keep from being depressed. Recall that the all-important serotonin is made from the amino acid tryptophan. Along the way, we need B6 (and zinc) to help the process. B6 is also required to make other neurotransmitters, dopamine and norepinephrine (see this diagram from the archives of EvMedForum).

Which brings me to this study from June's American Journal of Clinical Nutrition - "Longitudinal association of vitamin B6, folate, and vitamin B12 with depressive symptoms among older adults over time."

Basically, a group in Chicago followed a mixed-race group of older adults for an average of 7 years. Food questionnaires and a 10-item Center for Epidemiologic Studies Depression Scale were administered every three years in about 3500 people aged 65 or older.

Let's stop and take a deep breath for a moment. Because, come on. A food questionnaire every three years? A 10 item scale for depression I've never even heard of, and I'm a psychiatrist? Compare the methods in this study to the Heart and Soul study, another large observational trial. In Heart and Soul, they did a real clinical research diagnostic interview - the gold standard, and they drew blood to get actual lab measures. This study is 3 times as big and maybe that's why they used cheap, crappy measures, but you hardly even know what the data is worth at the end. Two pages of this study describe how they managed to squeeze some so-called information out of it - they used "logistic regression with the generalized estimating equation to model the likelihood over time of a participant becoming depressed," plus some logit link functions, and binomial error structure. I'm sure those are all very sensible things for a statistician to do, but wouldn't it have been better to use a bigger, better scale in the first place? Sigh.

We don't have that many nutritional studies in psychiatry. I feel like I need to look at all of them, even the lousy ones. And this one was published in the premier nutrition journal! (Along with that crazy meat makes you fat study).

Anyway! Somehow, from those once-every-three-year food questionnaires, they figured out which older adults were deficient in B6, folate, and B12. They controlled for things like age, smoking, alcohol, sex, race, education, etc. In the end, high total (food + supplement) intake of B12 and B6 were associated with a decreased likelihood of the development of depression over the study period of 7.2 years. Folate intake didn't seem to have any impact, and the B6 difference was primarily made in the supplementing group. Meaning people with the education and wherewithal to take a multivitamin. Which could be a huge confounder. At least the editorial in the same issue admits that more studies need to be done. And done well.


  1. Wow! I got linked!! :)

    Do you (or have you ever) looked for MTHFR polymorphisms in those with normal folates Emily? On the odd occasion that I can convince a primary care physician to screen for the methylating vitamins, I try to push for mean red cell folate. And in one instance I was able to get a screen for MTHFR - 60y.o. female, vegetarian, 5y post-op double mastectomy, depression & anxiety... family history suggested a few dots could connect to folate. Serum folate & mean red cell folate normal, B12 low normal, homocysteine elevated... C677T MTHFR polymorphism - positive. Folate was trapped.

    This from: http://lpi.oregonstate.edu/infocenter/vitamins/fa/

    Genetic variation in folate requirements

    A common polymorphism or variation in the gene for the enzyme methylene tetrahydrofolate reductase (MTHFR), known as the C677T MTHFR polymorphism, results in a less stable enzyme (7). Depending on the population, 50% of individuals may have inherited one copy (C/T), and 5% to 25% of individuals may have inherited two copies (T/T) of the abnormal MTHFR gene. MTHFR plays an important role in maintaining the specific folate coenzyme required to form methionine from homocysteine (see diagram). When folate intake is low, individuals who are homozygous (T/T) for the abnormal gene have lower levels of the MTHFR enzyme and thus higher levels of homocysteine in their blood (8). Improved folate nutritional status appears to stabilize the MTHFR enzyme, resulting in improved enzyme levels and lower homocysteine levels. An important unanswered question about folate is whether the present RDA is enough to normalize MTHFR enzyme levels in individuals who are homozygous for the C677T polymorphism, or whether those individuals have a higher folate requirement than the RDA (9).

    I put her on a product called Methyl Max to boost B6, B9, B12, increased omega-3, vitamin D... got her eating eggs & fish (couldn't get her to go the whole hog to eat our yummy grass-fed lamb, beef, and bacon though - she doesn't know what she is missing). Within 12 weeks, a substantial shift in her mood & outlook - enough to cease taking fluoxetine. Too many other things going on to say it was the folate. Homocysteine did drop on the follow up tests though.

  2. so what's the average D level they reach after giving them 2000IU for a few months? ;) what level do you aim for in your patients?

    also, in my experience (and according to some studies iirc) sublingual B12 is easily as effective as injected B12. i find a combo supplement of methyl- and adenosylcobolamin optimal. do you also check for ferritin if one is low in B12? those often go together because of lacking nutritional status or malabsorption bc of gluten intolerance etc.

    with regard to mood/depression, i find SAMe as a supplement can be very effective with fast and impressive results. also very helpful in my personal experience is NADH, ALC, Inositol, Ginseng Extract (a mix of the 4 major ginsengs), Green Tea Extract and several more.

    love the neurotransmitter diagram btw :)

  3. Hi Jamie - no, I don't tend to test for MTHFR. I've seen it tested in infertility work-ups quite frequently. It might be useful to test for compliance to a higher folate supplementation, but I might have trouble getting insurance to pay for the test for a psychiatric diagnosis. Overall the data for folate is exciting, but my clinical experience has been a bust, and the docs I talk to have the same experience. There's even a branded methylfolate called deplin - pharmaceudical grade, readily goes to the CNS and has a strength comparable to something like 56 regular folate pills (but has been tested in randomized controlled trials and is safe) - I've tried it many times with many patients and never found any benefit. Not even fleeting placebo benefit. Maybe I've just had bad luck? Sounds like you had a good experience with the diagnosis, though!

    Qualia - my adult population overall is pretty young, I would say, compared to say a cardiologist or a primary care doc, and they tend to do okay on lower levels of vit D. I aim for 50. There are a couple of reasons I've changing from checking up front. Again, everyone was low (usually in the 20s), so it seemed like a waste. Also, if they end up being quite low, the primary care doc will often jump in and prescribe 50,000 IU (D2 is what is available in the pharmacies here) for 8-12 weeks weekly, and I'm not sure if that is helpful or not. The 2000 IU gets them used to taking the daily supplement, and from that point we can have a more accurate idea of what we will need to add to get to a level of 50. Even Grassrootshealth recommends supplementing for a few months before the initial level, as long as the supplementation level is moderate but not miniscule. Everyone is different, though. If someone is already supplementing, obviously I will check right away. Can't imagine how many times I hear: "Oh, yeah, a couple years ago it was low, and my doctor put me on those green pills once a week." But then no one ever checked again.

    I haven't used SL B12 - I typically do the diagnosis of B12 and the primary does the prescribing and follow up. They measure ferritin also. One patient preferred the shots because it was so much cheaper than the SL.

    I'm a fan of SAM-E and there is good data. I'll do a post on it soon. Inositol also has some good studies, but I've yet to meet anyone who wants to take 12-20 capsules of it a day, or however many you need (it's been a few years since I looked at it, after getting turned down on the recommendation a few times!).

  4. thanks for your response, very interesting :)
    re. inositol: i already notice a mood improvement and anti-anxiety effect at 500mg (say, as a "booster" for certain situations). if i take 1g + 2g fish oil caps the effect is very pronounced. of course one can also add 50-100mg 5HTP to the mix, as always. also, st. johns wort is very effective, as everybody knows by now.
    what i also found to be interesting is mucuna pruriens extract, which is a natural source of L-Dopa (dihydroxyphenylalanine). excellent for temporarily (maybe 3-4h)increasing self-confidence and drive. if you take all this stuff together (incl. NADH, Ginseng etc) in the morning, and fine-tune it to your needs, it's way superior to any commercial anti-depressant IMO. but then we're talking about 10-20 capsules a day - and that's probably not everyones preference *g*

  5. Qualia - interesting in that the numero UNO antidepressant - ask anyone - will be an MAOI with the dopamine, serotonin, and norepinephine effects - just the side effects and drug interactions are horrendous. Your supplement regimen would seem to mimic that mix. No idea as to the risks of such a regimen, though - will have to rely on a naturopath for that. I'm not the biggest dietary supplement fan - I can see the use for D3, zinc, magnesium, potassium, etc, especially as I am not an offal eater (or not yet, anyway). I'm also not the biggest lab test fan - what is the point unless it will give us info that would change our approach, or increase compliance to the healthful approach. But that is my maverick side talking.


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