The Corpus Callosum

There is a thought-provoking editorial in the openly-accessible Journal of Psychiatry of Neuroscience (JPN): Has the time come for clinical trials on the antidepressant effect of vitamin D?
(45 KB PDF). In it, the editor of the the Journal, Simon N.
Young, PhD, argues that there is enough evidence to justify increased
research efforts.

He points to a recent article in the Archives of General Psychiatry to support this view:

Depression Is Associated With Decreased 25-Hydroxyvitamin D and Increased Parathyroid Hormone Levels in Older Adults
Witte J. G. Hoogendijk, MD, PhD; Paul Lips, MD, PhD; Miranda
G. Dik, PhD; Dorly J. H. Deeg, PhD; Aartjan T. F. Beekman, MD, PhD;
Brenda W. J. H. Penninx, PhD
Arch Gen Psychiatry. 2008;65(5):508-512.

Context Depression has incidentally been
related to altered levels of 25-hydroxyvitamin D [25(OH)D] and
parathyroid hormone (PTH), but this relation has never been studied
systematically.

Objective To determine in a large population-based
cohort whether there is an association between depression and altered
25(OH)D and PTH levels…

Main Outcome Measure Depression was measured using
self-reports (Center for Epidemiologic Studies-Depression scale) and
diagnostic interviews (Diagnostic Interview Schedule). Levels of
25(OH)D and PTH were assessed. Potentially confounding factors (ie,
age, sex, smoking status, body mass index, number of chronic
conditions, and serum creatinine concentration) and explanatory factors
(ie, season of data acquisition, level of urbanization, and physical
activity) were also measured.

Results Levels of 25(OH)D were 14% lower in 169 persons
with minor depression and 14% lower in 26 persons with major depressive
disorder compared with levels in 1087 control individuals (P <
.001). Levels of PTH were 5% and 33% higher, respectively (P = .003).
Depression severity (Center for Epidemiologic Studies Depression Scale)
was significantly associated with decreased serum 25(OH)D levels (P =
.03) and increased serum PTH levels (P = .008).

Conclusion The results of this large population-based
study show an association of depression status and severity with
decreased serum 25(OH)D levels and increased serum PTH levels in older
individuals.

Of course finding a correlation does not say anything about
causation. Even if it did say something about causation, it would
not necessarily imply anything about treatment. Young points out
that most research on the potential antidepressant effect of Vitamin D
supplementation is not very helpful. He cites two studies that
had adequate design, but both used subjective feelings of positive
affect or well-being as outcome measures. That is nice, but not
informative with regard to treatment of clinically significant
depression.

He mentions a few other theoretical considerations, then concludes:

Treatment of depression with vitamin D is an idea worth
testing in carefully selected populations. This includes those with low
vitamin D levels, especially the elderly, who have an increased
incidence of low vitamin D, and patients with seasonal affective
disorder who do not respond to light therapy. If there are patients in
whom vitamin D is an effective antidepressant, this is likely to be one
of the most costeffective treatments in psychiatry, and one with
negligible side effects.

Note that he specifically is not arguing that vitamin D supplementation
should be considered as anywhere near clinically validated for
treatment. Rather, he is suggesting that it might be worth
pursuing in limited settings.

Also note that JPN is a Canadian journal. As Razib pointed out
a while ago, vitamin D deficiency is common among non-white persons in
Canada. Perhaps that is where some of the interest comes
from. The authors of the Arch Gen Psychiatry article are from the
Netherlands, another high-latitude country.

Dr. Young points out that the best evidence regarding mood
effects of vitamin D shows only that it perks some people up a
bit. So how does he use that as a basis to say that he ought to
study it more?

Well, I can’t speak for him, but since this is my blog, I happily will
speak for myself. First, I would be skeptical of the notion that
vitamin D will be found to be an “effective antidepressant” in the
usual sense. That is, if it were given as a sole treatment in a
randomized double-blind clinical trial, compared with placebo and and
active comparator, I doubt it would be very impressive. You never
know until you try, but I still doubt it.

However, that does not mean we should forget it. Not at
all. Even if all it does is to perk people up a little bit, it
still could be a useful part of our armamentarium. The reason is
this: in the treatment of depression, with antidepressants, it is
common for people to show significant improvement, while not attaining
full remission. For example, let’s say you have a moderately
severe depression, with a BDI score
of 28. You start of sertraline, get up to a dose of 200mg for six
weeks. You get 50% better. Your BDI is now 14. You
can function OK, but there are problems. For one, you are not at
your best, probably still fairly unhappy, fairly often. Two, you
are running a higher risk of relapse back into a full episode.

In such a situation, there are many things you could do, and it is
likely that you eventually would find some intervention to get that
score down to 7 or so, which would be a remission.

But, there are some people who go through a lengthy course of
interventions, often two or three at a time, but never quite get
there. The way I see it, you might get a 50% improvement with the
medication. Then maybe you have the energy to start regular
exercise, and you get another 5%. You start eating better, and
get another 5%. You join a volunteer group, get another 5%.
And so forth. Some people need a lot of those 5% increments of
improvement. I suspect that our medical-industrial complex
discards a lot of things that are like that: a little bit helpful, but
with no potential to be a blockbuster.

The FDA will never approve something that results in only a 5%
improvement. Especially if it can’t be patented. But those
little things can be important. In selected populations, perhaps
vitamin D would give a boost of a lot more than 5%. I’m
particularly curious about the people who don’t respond to bright light
treatment. The lights used for this treatment are filtered so the
patient is not exposed to ultraviolet light. We think that is
good, but maybe it reduces the effect for some people.

Comments

#1 chezjake
January 15, 2009

In reference only to treatment of SAD, why not also experiment with supplementation of light therapy with Vitamin D? It certainly wouldn’t be expensive and it might yield better results.
#2 Becca
January 15, 2009

The clinical trial I want to see is:
traditional SSRI alone vs.
atypical SNRI alone vs.
SSRI + vitamin D vs.
atypical SNRI + vitamin D

in a stratified patient population with groups of A) those that have had episodes of SAD who do respond to light therapy B) those who have SAD who did not respond to light therapy and C)those with relatively constant depression
I’d like like to measure a primary outcome of depressive index scores, but also keep an eye on physical activity level changes (call it a hunch) and rates of physical illness (vitamin D does cool things to the innate immmune system). These things might be “confounders” if you look at them one way, “mechanisms” if you look at them another.
#3 Daniel Newby
January 15, 2009

It would be cheap to measure the converse effect: changes in vitamin D levels in antidepressant responders versus non-responders.
#4 stumpy
January 15, 2009

I’m not so sure this is news. I remember seeing a patient, back in my residency days, on consultation. The patient had depression, and the Wise Attending on the Consult Service suggested checking her PTH. I don’t remember the rest of the story, but anyway, the point is that, even back in the early 90′s, some people (Wise Attendings) were aware of some association between depression symptoms and parathyroid function.
#5 Becca
January 15, 2009

Anyone who’s watched a hypothyrodic loved one go through a personality makeover once they get treated knows that doctors should be checking thyroid function first, and going to antidepressants only if the thyroid is normal. Does anyone know if PTH levels are like vitamin D in terms of natural variability in levels?
I think for vitamin D you obviously need a minimal level (what with being an ‘essential nutrient’ and all) and then there’s a fairly large range of concentrations that would be considered normal. Supplementation to very high (supra-physiologic?) is certainly something to consider (of minimal risk, albeit of as-yet dubious benefit).
#6 Rob
January 16, 2009

I’m a neuroscientist and have bi-polar in my family (two generations) and I’ve often experienced symptoms associated with SAD every year with the onset of winter. At the suggestion of a family-member nutritionist (for non-mood reasons), I had my Vitamin D checked in October and found that my levels were half of what they should be. So I started taking Vitamin D3 supplements (4,000 mg/day). After a few days, I not only felt more energetic but also happier and less irritable. For various reasons, I got out of my daily routine and stopped taking the supplements for about two weeks in December. Not only did the symptoms subtly return, but when I re-started they again subsided.

There is definitely something to this hypothesis, at least from my experience. That said, I know the SCID questions for bi-polar and depression and I’ve never been close to meeting the clinical definitions. But the theory makes a lot of sense, especially with respect to the role of the sunlight in metabolizing Vitamin D.
#7 Anne
January 21, 2009

A strictly anecdotal comment: At about age 55 I began having SAD symptoms, increasing a little more each year. Adding light therapy did not seem to provide relief. In December 2007 my PCP suggested i start Vit D supplementation. My symptoms seemed improved in about a month. This year for the first time in 15 years I have not experienced SAD symptoms, despite having several difficult losses that might commonly contribute to depression. I am amazed at the difference. It does make sense, as I live in the Pacific Northwest, with not a lot of winter sun.

BTW, I am an RN and do not believe in alternative medicine–or miracles.
#8 Tod
June 15, 2009

Vitamin D insufficiency is defined as a 25OHD concentration of 20 to 30 ng/mL (50 to 75 nmol/L)(ng/mL times 2.5 gives nmol/L),

Mad dogs and ….

“How can vitamin-D deficiency exist despite lengthy sun exposure? This apparent paradox was raised in my last post. The medical community now recommends bloodstream vitamin D levels of at least 75-150 nmol/L, yet these levels are not reached by many tanned, outdoorsy people.[...]

Only mega-doses can overcome what seems to be a homeostatic mechanism that keeps bloodstream vitamin D within a certain range. Indeed, this range falls below the one that is now recommended. Curious isn’t it? Why would natural selection design us the wrong way? [...]

In a wide range of traditional societies, people avoided the sun as much as possible, especially during the hours of peak UV (Frost, 2005, pp. 60-62). Midday was a time for staying in the shade, having the main meal, and taking a nap. Nor is there reason to believe that sun avoidance and clothing were absent among early modern humans. Upper Paleolithic sites have yielded plenty of eyed needles, awls, and other tools for making tight-fitting, tailored clothes.”
#9 sandy
March 25, 2010

I have been on antidepressants for years and do have a long and ugly story about them but I will spare you the details. I am no longer taking any medications and have been in protracted withdrawal from effexor a long time. I broke my foot this winter and had a bone scan as my foot broke with very little strain. The scan showed osteopenia and I was advised to take 1500 mg of calcium and 1000 mg of Vit D. The first day I took 1000 vit D with 500 calcium as they come in 500 doses. I went to bed an hour after taking this and did not wake till dinner I had just woke in the morning when I took it. I have had kidney stones in the past and was advised by an emerg doc to stop taking calcium supplement and so have a bad feeling about taking calcium not sure the bone health is worth another kidney stone. ouch…
So the next day I thought I would just take the Vit D as I drink milk cheese ect After taking 1000mg of vit D only I had a reaction – there were two fire balls around my eyes like a migraine aura but not really- my bp went to 179/93 I was dizzy and heart was pounding. I told this to the doc and had pth and vit blood work done. At this point the only thing that looks off is the Vit D I am going to see an endocrinologist eventually it could take six months to get in. I was wondering if anyone has any ideas what is going on here. It has crossed my mind that maybe the reaction was because I am low in Vit D and I should start taking it now. It has been three months and my foot is healing extremely slowly. Any ideas?
#10 sandy
September 25, 2010

I am here today to update my previous post. I did see the endo doc she did a 24hr urine collection to see if my kidneys were dumping calcium- she did this test before and after her advised treatment.
Treatment was 400mg of Vit D3 daily.
This was horrid for me. After three days I of this treatment I had anxiety and horrid insomnia. I kept thinking ok you have to suck it up and maybe you will feel better in a few days it did not happen. I had to give up the vit D3 for a few days in order to get some rest and calm my system down. Then I would start again. The treatment was to last a month and then a recheck of my vit D levels. The last wk of treatment about drove me mad as I held firm and took the vit D3 daily for 7 days. At the end of all this guess what- my vit D blood tests at the end were lower than they were when I first seen this doc.
What did she say? She has no idea what is going on is she doing any follow up nope only comment is the 400mg is not that high a dose and she guesses it was not high enough. I could not believe her reluctance to follow up or her lack of interest in this issue. There is nothing I can do she said I can get another bone scan in a couple of years as that is all insurance will pay for and see what the result of that bone density scan shows.
I feel there is some thing going on here and I do not know if my long time treatment with antidepressants has changed my body but I do think it possible. Mostly because I have read that many antidepressants damage the mitochondria ( the parts of cells in your body that enable the use of energy) damage to this part of the cell is being studies as a cause of chronic fatigue.
Other things I noticed while on Vit D3 more energy increasing the longer I took it without a break ending in anxiety and sleeplessness. Constipation, fuzzy thinking bad mood which is not like depression bad mood at all but rather just a mean person more like a personality change. I would hear myself saying things that shocked me they were so mean. I really wish there was some studies done on this subject.
Since all this started I have been researching vit D3 and have found others that have had the same reactions. The other thing I have found is this site called the Marshall protocol- the guy Marshall is some kind of scientist who stumbled upon new info. – vit D is more a hormone than a vit it has a huge affect on our immune system. The vit D receptor can be shut down by many viruses and this may well be the cause of many other illnesses. He has developed a protocol to repair this and many people are reporting a cures in shut things as diabetes MS and a host of other issues.
Could he be a genius… I do not know but if I had one of these major illnesses I think I would give his protocol a try as I have learned the hard way to fear legal drugs the docs hand out. I have read some books done some research and think many drugs are worse than the illness. I would try his way first.