Professor Patrick Holford has a remarkably agile PR team with helpful lacunae in their collective memories. 27.02.2007, Holford’s email subscribers received an email, What’s the alternative to ineffective anti-depressants?
A recent study published in the Public Library of Science Medicine, and reported widely in the press this week, showed that a number of anti- depressant drugs including Prozac, Seroxat and Efexor were little more effective than a placebo for treating depression. Yet with more people than ever seeking help for depression – and current prescriptions for anti-depressants at record levels – is there any alternative?
In fact, there is much that can be done nutritionally to tackle depression. The conventional approach is to give a drug that alters the body’s biochemistry – typically to increase levels of neurotransmitters such as serotonin, that helps keep us happy, or adrenalin/noradrenlin, that helps us stay motivated. But brain health and neurotransmitter production can also be improved with nutrition… [Full text of email available at Uncommon.]
Regular readers can probably make an informed guess as to the bulk of the standard Holford advice.
- Balance your blood sugar
- Consider supplementing chromium
- Ensure optimum levels of omega-3 fish oils
- Check your homocysteine level and get enough B vitamins
- Boost your serotonin with amino acids and consider supplementing 5-HTP
So, there was nothing for you if you were looking for an informed commentary on the PLoS study or information about what you GP might have to offer you, social support, exercise, talking therapies and their impact on categories of depression. If you want to read some decent commentary on the study, Dr Ben Goldacre offers an overview: A quick fix would stops drug firms bending the truth.
- It was not a study of SSRI antidepressant drugs: neither nefazodone nor venlafaxine are SSRI drugs.
- It did not look at all the trials ever done on these drugs: it looked only at the trials done before the drugs were licensed (none of them more than six weeks long), and specifically excluded all the trials done after they were licensed. It is common for quacks and journalists to think that the moment of licensing is some kind of definitive “it works” stamp of approval. It’s not, it’s just the beginning of the story of a drugs’ evidence, usually.
- It did not show that these drugs have no benefit over placebo: it showed that they do have a statistically significant (”measurable”) benefit over placebo, but for mild and moderate depression that benefit was not big enough for most people to consider it clinically significant, ie there was an improvement, but not enough points improvement on a depression rating scale for anyone to get too excited over it.
We’ve reproduced part of Goldacre’s commentary for several reasons. Goldacre has read the full paper and he pulls out some points that were mis-reported both in the Editor’s Summary for the study and (seemingly) in the press releases. E.g., venlaflaxine is an SNRI, not an SSRI. There is an interesting Bad Science Forum thread about the study with some useful reinterpretations of the data graphs. Several bloggers have also re-analysed the data and report that the different drugs have effect sizes that indicate, for some groups of people, that some of them are more powerful than others. PJ was quick to spot that the mainstream media are mostly Misrepresenting Science in their coverage of this story, albeit aided by some oddities in the paper. PJ offers useful observations about effect sizes and presents an argument that the final scores for the depression rating instrument may be more useful than the change score:
overall the effect size is 2.93 (95% CI 1.99-3.87) but if we look at paroxetine and venlafaxine weighted mean differences in HRSD scores are 3.67 and 3.93 points respectively – both above NICE’s criteria of:
“a between group difference of at least 3 points (2 points for treatment-resistant depression) was considered clinically significant for both BDI and HRSD [Hamilton Rating Scale for Depression]”
Make of that what you will.
Hawk/Handsaw has also expressed his disappointment that: Antidepressant manufacturers sound a bit like homeopaths as some of their spokespeople made what sounded suspiciously like appeals to anecdote rather than addressing the issues of the science. End of Phil argues for a more nuanced interpretation of the efficacy of anti-depressants than is being offered in the MSM.
So, a number of bloggers have spotted widespread misinterpretations of the study and have re-analysed and re-presented the data to show valuable nuances. PJ in particular has responded by re-analysing data following online responses to the PLoS study. Holford does not seem to have noticed these nuances. This would be unremarkable except that Holford regularly accuses scientists and researchers of hiding or misinterpreting research. Similarly, he claims that there are times when the MSM fail to read and understand a full paper before reporting it. Holford wrote about a glucosamine study:
This study, however, was widely reported as disproving the power of glucosamine because overall the supplements didn’t reduce pain significantly more than the drug-except in those with higher levels of pain. The abstract (the summary at the beginning) and the press release failed to point out this last, extremely important positive result. [pg. 247; Food Is Better Medicine Than Drugs FIBMTD]
Which sounds rather like the nuanced argument that Goldacre and some bloggers are making albeit those writers are also highlighting some errors.
It almost goes without saying that Holfordwatch disagrees with Holford’s characterisation of the abstract of Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis which concludes:
Glucosamine and chondroitin sulfate alone or in combination did not reduce pain effectively in the overall group of patients with osteoarthritis of the knee. Exploratory analyses suggest that the combination of glucosamine and chondroitin sulfate may be effective in the subgroup of patients with moderate-to-severe knee pain. [Emphasis added.]
Again, this would not rankle quite so much if Holford were not, in this same email, misleading his readers about the quality of the evidence for his recommendations.
Just not getting enough trpytophan [sic] is likely to make you depressed so consider supplementing it if you are not getting enough in your diet. 27 studies have shown conclusively that 5-HTP is effective in treating depression. [Emphasis added.]
This last was rather a surprise because in FIBMTD Holford and Burne have a more nuanced claim:
Not getting enough tryptophan is likely to make you depressed: people fed food deficient in tryptophan become rapidly depressed within hours. [Tryptophan and 5-HTP] have been shown to have an anti-depressant effect in clinical trials, although 5-HTP is more effective. There have been 27 studies, involving 990 people to date, most of which proved positive. [Emphasis added.]
Holfordwatch notes that the supporting reference is a study involving “15 women who had suffered recurrent episodes of major depression but had recovered and were no longer on drug treatment” so should not be generalised to support Holford and Burne’s claim. However, we would draw Holford’s attention to a recent paper by his colleague, Professor Philip Cowen. Cowen and his colleagues argue that the current evidence is limited and the results for women can not necessarily be generalised to men.
The serotonin precursor L: -tryptophan (TRP) is available as a nutritional supplement and is licensed as an antidepressant in a number of countries. However, evidence of its efficacy as the primary treatment for depression is limited, and the direct action of TRP on the symptoms of depression and anxiety has not been well-characterised…
[This study of trytophan supplementation and healthy women] highlights a key role for serotonin in emotional processing and lends support to the use of TRP as a nutritional supplement in people with mild depression or for prevention in those at risk. Future studies are needed to clarify the effect of tryptophan on these measures in men.
We would also highlight that there is a substantial difference between 27 studies, most of which proved positive and claiming that they ‘conclusively’ show efficacy for depression.
Unsurprisingly, despite his frequent complaints about other researchers who misinterpret research or mis-reporting in the MSM, Holford seems to have overlooked some relevant nuances in the PLoS review. Further, Holford overstates the quality and quantity of evidence for his recommended nutritional alternatives to antidepressants.
In the meantime, please, if you have any mental health concerns or are wondering about the implications of these findings for medication usage, then discuss them with your GP or a suitably qualified individual. One especial plea, there are many classes of drugs that can not be stopped abruptly, e.g., immunosuppressants such as corticosteroids and anti-depressants; if you know someone, maybe a friend or family member, who is thinking of stopping their medication, please make sure that they continue their medication at the prescribed dosage and visit their doctor to take appropriate advice.
Update 29.02 The excellent Behind the Headlines looks at the story: Antidepressants “don’t work”. PJ has updated the data-analysis to look at the raw Hamilton scores and has calculated a larger effect size.
I made the overall effect size 2.74 (95% CI 1.90-3.58) which is a fair bit higher than the 1.80 the study authors report, and more importantly I found that the effect sizes for paroxetine and venlafaxine were 3.13 and 3.92 Hamilton depression score points respectively. These are both above that oh so important NICE ‘clinical efficacy’ threshold.
So my conclusion is that I don’t trust this study, and I certainly don’t trust their conclusions. I’m not sure exactly why my analyses are so different from the authors’ but I’m fairly sure it has something to do with their over reliance on the standardised mean difference as a measure of effect size.
Update: 31.03 The excellent PJ of Pyjamas in Bananas offers: Kirsch et al update
Update 6 May: Again, PJ of Pyjamas in Bananas offers a follow-up of Kirsch et al’s latest responses to the thoughtful criticisms of their study. This story will run but is an example of the scientific method in progress: scientists write something, others comment and we all learn more along the way.
 Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, Johnson BT. Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration. PLoS Medicine Vol. 5, No. 2, e45 doi:10.1371/journal.pmed.0050045
 Clegg DO, Reda DJ, Harris CL, Klein MA, O’Dell JR, Hooper MM, Bradley JD, Bingham CO 3rd, Weisman MH, Jackson CG, Lane NE, Cush JJ, Moreland LW, Schumacher HR Jr, Oddis CV, Wolfe F, Molitor JA, Yocum DE, Schnitzer TJ, Furst DE, Sawitzke AD, Shi H, Brandt KD, Moskowitz RW, Williams HJ. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med. 2006 Feb 23;354(8):795-808.
 Holford PJ, Burne J. 2007. Food Is Better Medicine Than Drugs. Paperback. Piatkus Books; London.
 Smith KA, Fairburn CG, Cowen PJ. Relapse of depression after rapid depletion of tryptophan. Lancet. 1997 Mar 29;349(9056):915-9.
 Turner EH, Loftis JM, Blackwell AD. Serotonin a la carte: supplementation with the serotonin precursor 5-hydroxytryptophan. Pharmacol Ther. 2006 Mar;109(3):325-38.
 Murphy SE, Longhitano C, Ayres RE, Cowen PJ, Harmer CJ. Tryptophan supplementation induces a positive bias in the processing of emotional material in healthy female volunteers. Psychopharmacology (Berl). 2006 Jul;187(1):121-30.