Daily Mail and Its Frame of a Recent Homocysteine and Depression Study

Daily Mail regularly displays a remarkable similarity to the public writings of Visiting Professor Patrick Holford. It has taken time out from its usual project of dividing substances into things that will give you cancer or cure it, or similarly for diabetes to digress into the Holford obsession with over-claiming for the significance of homocysteine levels and the outcome of manipulating them. In a recent round-up, Daily Mail declared Vitamin B can beat ‘old age blues’. A little confusingly, the accompanying photograph is that of an attractive, well-turned out woman in her late 20s/early 30s or so. It’s distracting because the study was carried out in men over the age of 70.

Popping a vitamin pill could significantly reduce the risk of depression in the elderly, according to research. Scientists at the University of Western Australia found adults who took a regular dose of vitamin B12 were less likely to suffer mental-health problems in old age. The supplements lower the amount of homocysteine in the blood, high levels of which have been linked to heart disease and mood swings, among other disorders. This can be quickly reduced by taking B12 supplements, or eating food rich in the vitamin, such as red meat, oily fish, eggs, yoghurt and cheese.

Researchers questioned 3,752 men aged 70 and above on past or present symptoms of depression, and found those with the highest readings of homocysteine were 70 per cent more likely to suffer from it.

The researchers said: ‘Lowering homocysteine can reduce the odds of depression by about 20 per cent.’

Now, it so happens that I shall be in a national library today so I shall have an opportunity to check the full paper but a scan of the abstract raises some questions about the Daily Mail version: Homocysteine and depression in later life.[1] The abstract does not explicitly mention B12. This was not a trial of supplements, it was a population study: it is plausible that the men who were taking supplements were also more likely to have other lifestyle factors that mitigated the likelihood of depression (such as marriage, strong family relationships, friends, exercise habit).

Oddly, Daily Mail is unusual in making the B12 claim; even the press release from the authors’ institution doesn’t mention it. Not only that, they are less gungho about the claim for lowering depression.

“We’ve now found that the MTHFR gene, which we knew contributed to increasing the basal concentration of homocysteine by 20 percent, also increases the risk of depression by about 20 percent in older people.”

“These results suggest that if we are able to reduce the plasma concentration of homocysteine by one fifth, we can reduce the number of elderly Australians who are affected by depression by the same amount.”

It is a slightly odd suggestion to make and one that is not well-founded in the clinical literature to date where several trials have reported that vitamin supplementation can reduce Hcy levels but for no clinical gain. It bears repeating that this study did not involve a trial of supplements and the authors even conclude the abstract with the declaration of a need for an adequately-powered trial of Hcy lowering interventions:

Confirmatory data from sufficiently powered randomized trials of homocysteine-lowering therapy are now required to test if the relationship between tHcy and depression is truly causal.

Hcy research this year has repeatedly indicated that there are, as yet, no demonstrable clinical benefits for reductions in Hcy levels. Vasan gave some excellent advice about biomarkers that continues to be ignored.[2]

Regardless of the purpose for its use, a new biomarker will be of clinical value only if it is accurate, it is reproducibly obtained in a standardized fashion, it is acceptable to the patient, it is easy to interpret by clinicians, it has high sensitivity and high specificity for the outcome it is expected to identify, it explains a reasonable proportion of the outcome independent of established predictors consistently in multiple studies, and there are data to suggest that knowledge of biomarker levels changes management.

No media coverage of this study has mentioned that its findings are at odds with others reported earlier this year in which high levels of Hcy were not related to depression in elderly men.[3] The Zutphen study has a substantially smaller sample size but has the added virtue of being a longitudinal study.

There is also the recent suggestion that tHcy is a marker for renal impairment and may not necessarily be an independent risk factor.[4]

It would be tremendously exciting and useful to have a simple biomarker like Hcy levels: something than can be readily manipulated by changing the diet or supplementing particular vitamins and that will reliably produce clinical benefit. However, Hcy research to date does not indicate that Hcy is adequate to the role as useful biomarker, far less a “chemical crystal ball” for predicting diseases. Unsurprisingly, it seems Daily Mail has misunderstood the nature of this study and this has lead them to over-claim for it. A poor show.


[1] Almeida OP, McCaul K, Hankey GJ, Norman P, Jamrozik K, Flicker L. Homocysteine and depression in later life. Arch Gen Psychiatry. 2008 Nov;65(11):1286-94.
[2] Vasan RS. (2006) Biomarkers of cardiovascular disease: molecular basis and practical considerations. Circulation 113: 2335-2362.
[3] Kamphuis MH, Geerlings MI, Grobbee DE, Kromhout D. Dietary intake of B(6-9-12) vitamins, serum homocysteine levels and their association with depressive symptoms: the Zutphen Elderly Study.

Low B-vitamin status and high levels of serum homocysteine are found in depressed inpatients, but results of population-based studies of this association are inconclusive. We investigated whether a low dietary intake of B(6-9-12) vitamins and high levels of serum homocysteine are associated with depressive symptoms in elderly men…
Our results do not support the hypothesis that a low dietary intake of B(6-9-12) vitamins and high levels of serum homocysteine are related to depression in healthy elderly men.

[4] Potter K, Hankey GJ, Green DJ, Eikelboom JW, Arnolda LF. Homocysteine or renal impairment: which is the real cardiovascular risk factor? Arterioscler Thromb Vasc Biol. 2008 Jun;28(6):1158-64.
The authors evaluated whether adjustment for renal function eliminates the relationship between total plasma homocysteine (tHcy) and vascular risk, assessed by carotid intima medial thickness (CIMT) and flow-mediated dilation (FMD) of the brachial artery. They assessed the cross-sectional data from 173 stroke patients who were treated with B-vitamins (folic acid 2 mg, vitamin B(6) 25 mg, and vitamin B(12) 0.5 mg) or placebo in a randomized double-blinded trial to test the relationships between posttreatment tHcy, cystatin C (a marker of glomerular filtration rate), estimated glomerular filtration rate (eGFR, Modification of Diet in Renal Disease equation) creatinine, CIMT, and FMD. The authors concluded:

Adjusting for renal function eliminates the relationship between tHcy and CIMT and FMD, supporting the hypothesis that elevated tHcy is a marker for renal impairment rather than an independent cardiovascular risk factor. [Emphasis added.]



Filed under depression, patrick holford, supplements, vitamins

3 responses to “Daily Mail and Its Frame of a Recent Homocysteine and Depression Study

  1. Reading the whole paper now – it’s a bit odd.

    They had a nice big sample of 3752 men. They measured depression using an old-age depression scale, they measured tHcy, and they genotyped for MTHFR C/T which is a polymorphism which affects tHcy levels.

    They found a correlation between depression and tHcy, and they found a correlation between MTHFR and tHcy, but they found no hint of an association between the gene and depression.

    “There was no association between
    TT homozygosity and ever receiving a diagnosis
    of depression (OR, 1.01; 95% CI, 0.75-1.37). The Cuzick
    test for trend showed a dose-effect response of the
    MTHFR C677T genotype on tHcy (z=3.84, P.001) but
    not on GDS-15 scores (z=0.03, P=.98)”

    However they then do a meta-analysis of previous studies (including their own) and find that, even if you include their negative data, there is an association between MTHFR and depression.

    This is bizarre because their own finding is that there is no such association. they’re essentially saying that their own results are wrong (about the genetic association), but in that case why should we trust them to be right about anything else?

    So when in the abstract they say “The triangular association between the
    MTHFRgenotype, tHcy, and depression implies that higher
    concentrations of tHcy increase the risk of depression and
    that lowering tHcy by 0.19 mg/L could reduce the odds
    of depression by about 20%” – there is no such triangular relationship according to the data presented in the paper which follows!

    Presumably they did the study (which seems excellent in itself), didn’t get the results they wanted, and decided to throw in some meta-analysis until they did. Nice trick.

    Also, needless to say, there is nothing about B12 in the prevention of depression. They do mention some studies of folate & tetrahydrofolate in depression but there are only 5, 1 one of them had no placebo, and in another 1 the patients weren’t even depressed; in others the benefits of vitamins were only significant in subgroups etc. etc.

  2. “Vasan gave some excellent advice about biomarkers that continues to be ignored”
    Excellent – a follow-up to the part of my Bad Science 101 Course that dealt with surrogate markers (I say “course”, I actually just read the Greenhalgh “How to Read a Paper” series you link to from your sidebar).

  3. Neuroskeptic – thank you. Life and the train service intervened to prevent the visit to the national library so I have still not seen the full paper so am grateful for your informed comments. How very odd, even for the Daily Mail. Even odder about the MTHFR and depression as I had wondered where the authors were going with that and had expected the paper to deliver a coherent account – plainly, I would have been disappointed.

    jdc – Greenhalgh is excellent and deserves much praise. I hope that she knows that this much affection for her work is out there in the blogosphere.

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