long overdue…

Posted on Thursday 26 January 2012

Previous posts [of sound and fury…, it’s about time…] have focused on Dr. Ian Hickie’s review article in the Lancet on Agomelatine, a Melatonin receptor agonist and Serotonin antagonist]. The notion is that the drug might correct circadian dysregulation and thereby be an antidepressant. Hickie’s review article [Novel melatonin-based therapies: potential advances in the treatment of major depression] summarized the clinical trials and reported on them positively to the surprise of anyone who actually looked at the data which was itself quite lean [of sound and fury…]. So the question becomes, why is Dr. Hickie so keen on Agomelatine in the absence of visible clinical trial data that supports his enthusiasm. His conflict of interest statement makes clear that he has been a grant recipient from and has served as an advisor to Servier, the manufacturer of Agomelatine – suggesting a clear reason for his affinity to the drug. In his response to the letters criticizing the study that mention his ties to Servier, he responds:
    Your correspondents focus rather narrowly on four issues surrounding our review of novel melatonin-based treatments: the efficacy of agomelatine, the clinical significance of agomelatine for managing depression, the comparative side-effect profile of this compound, and our professional relationships with its manufacturer [Servier Laboratories].
    Fourth, the paper was commissioned by The Lancet and developed solely by us. It was not initiated or supported financially by Servier Laboratories. The additional research assistants who assisted with the paper’s preparation are long-standing employees of our institution who have worked previously on many similar datasets via our own financial resources. After initial submission [July 31, 2009], the paper progressed through a lengthy process of external peer review, revision, and consultation with the editorial staff of The Lancet. As outlined previously, issues of fact with regard to clinical trials of agomelatine were checked against international trial registers and with representatives of the manufacturer, Servier Laboratories. The opinions expressed and the conclusions drawn are those of the authors.
That would be classified as a "non-denial, denial." Even the final comment doesn’t help much because it’s the "why" of the author’s opinions that’s in question. Below, I’ve highlighted Dr. Hickie’s comments at a November 2010 Servier Foundation Depression Masterclass [click for original] where he’s on the program recommending Atypicals and Agomelatine for depressed adolescents over SSRIs.

And when the drug was approved in Australia for private prescriptions, there he is again in Servier’s press release:


July 26, 2009:   
Lancet review article submitted for publication
"He [Ian Hickie] has led projects for health professionals and the community supported by governmental, community agency, and drug industry partners (Wyeth, Eli Lily, Servier, Pfizer, AstraZeneca) for the identification and management of depression and anxiety. He has served on advisory boards convened by the drug industry in relation to specific antidepressants, including nefazodone, duloxetine, and desvenlafaxine, and has participated in a multicentre clinical trial of agomelatine effects on sleep architecture in depression. IBH is also supported by a National Health and Medical Research Council Australian Medical Research Fellowship. He is a participant in a family-practice-based audit of sleep disturbance and major depression, supported by Servier, the manufacturers of agomelatine."
November 5, 2010:   
Hickie speaks at a Servier Masterclass recommending Agomelatine in Depression
April 11, 2011:   
Hickie quoted as part of Servier Press Release when Agomelatine is approved
May 18, 2011:   
Lancet article published online
August 13, 2011:   
Lancet article published in the journal
November 7, 2011:   
US approval effort for Agomelatine abandoned
January 21, 2012:   
Six letters published in the Lancet disputing the claims made by the article

It is simply too much to ask that we accept this level of conflict of interest and consider the opinions expressed in this article as unbiased. In this case, the conclusions also happen to be wrong on face value. If anything, this would be an example for a textbook on medical ethics – an example of an article that should never have been published – and if it were published, it should be retracted. Just because people have gotten away with this kind of thing in the psychiatric literature before is no reason to continue it. There is a time to put an end to this nonsense, a time that is already long overdue…
    January 26, 2012 | 2:35 AM

    “Valdoxan represents a paradigm shift in the treatment of depression.”

    Thomas Kuhn is turning in his grave.

    January 26, 2012 | 2:56 AM

    Great coverage sir!

    January 26, 2012 | 9:57 AM

    All these studies and the write ups are generated by the marketing divisions of pharma companies. Pharma companies usually hire med ed companies to write them. They, in turn recruit the authors. Or the pharma company already as an author “on board” who’ll pretty much go along with whatever is written (not always but usually).

    Journals used to “sell” supplements to sponsors without editorial oversight, which destroyed the credibility of supplements.

    The fact that the Lancet commissioned the Hicks article means there’s some kind of new link/twist on all this; this one appears to be between the Servier marketing department and the Lancet–as if the Lancet has taken over the role of a med ed company. The fact that the Lancet claims the article went through peer review is meaningless–it commissioned the article.

    January 26, 2012 | 10:33 AM


    Excellent point!! Requiring much contemplation.

    January 26, 2012 | 3:10 PM

    There are some other strange locutions, such as the word “commissioned.” Journals invite people to write things all the time–but the word is “invite”–not commission, which implies payment.

    Also the point about “It was not initiated or supported financially by Servier Laboratories” means it was initiated and supported financially by somebody. If it was the Lancet, that usually means some kind of promise of ad revenue. And note–Servier reviewed the ms. That is pretty odd for an independent ms.

    January 30, 2012 | 10:35 AM

    More bad news. The Australian Govt has appointed Ian Hickie to its new ‘independent’ National Mental Health Commission while the Lancet scandal unfolds. Hickie, like McGorry, can do no wrong by the Gillard government. http://t.co/HjaN5kEA #fail

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