Vagus Nerve Stimulation and Depression: Conflict of Interest's "Perfect Storm"?

A controversial treatment, an industry-funded article with no financial disclosures, a ghostwriter, a lead author who is editor-in-chief of the journal and who is later hired by the company funding the article, and a lucrative order of 10,000 reprints-these were the potent ingredients of what the New York Times recently termed an "egregious set of events" that involved the journal Neuropsychopharmacology.¹

In July 2005, the FDA approved a new type of therapy for treatment-resistant depression: vagus nerve stimulation (VNS). However, the approval process incited controversy because the scientific team that was assigned to review the device rejected its approval unanimously 3 separate times. The reviewers were unimpressed with the efficacy research underlying the device, since the only reported placebo-controlled trial showed no significant difference between active and sham VNS. In each case, however, the director of devices for the FDA overruled the review teams' decision. The ultimate approval of VNS became so controversial within the FDA that the Senate Finance Committee investigated the process and published a highly critical report in February 2006.²

Given the already controversial background, one might have thought that Neuropsychopharmacology would have been particularly cautious about reporting industry disclosures in a recent review article on VNS.³ The article, which listed 9 coauthors, reviewed the evidence regarding VNS and concluded that it was "a promising and well-tolerated intervention" for treatment-resistant depression; the review made no mention of the FDA controversy.³

After the article was published, The Wall Street Journal broke the story that 8 of the 9 contributing authors were paid consultants for Cyberonics, the maker of VNS.⁴ This story and other media reports^5,6 revealed a series of other embarrassing pieces of information:

• The lead author, Dr Charles Nemer-off, was also the editor-in-chief of Neuropsychopharmacology.
• Shortly after the article was published, Nemeroff was hired by Cyberonics to chair its new VNS Therapy Mechanism of Action Advisory Board, the purpose of which is to seek FDA approval for new indications for VNS.⁷
• Cyberonics purchased 10,000 reprints of the article from Neuropsychopharmacology.
• The first draft of the article was not written by any of the authors listed, but was ghostwritten by a medical writer hired by Cyberonics.

When interviewed by newspaper reporters about the lack of disclosure, the journal's publisher (Nature Publishing Group) said that those relationships had, in fact, been disclosed to the journal and that it was the editors who were at fault, rather than the authors. However, since the lead author was also the editor-in-chief, it appeared that the authors could not be fully absolved of responsibility for the error.

Dr Nemeroff responded to reporters' questions by saying that he had "recused" himself from the review process; however, he acknowledged having read the final draft before publication. About a month later, he resigned as editor-in-chief of Neuropsychopharmacology.⁸

Lessons learned?
This unfortunate controversy drives home the point that the relationship between academic psychiatry and industry has become alarmingly incestuous. When an influential psychiatrist is simultaneously a journal editor, an industry advisory board chairman, and the first author of an industry-funded article published in his own journal, there must be something wrong with the system.

But what about the specific issue of disclosure? How could disclosures have been improved in this case so that readers would not have felt that they were being hoodwinked? If the journal had published the authors' financial relationships with Cyberonics, as well as with any other company involved in the antidepressant market, would this have been enough?

Remember, the purpose of disclosure is to give readers the information they require in order to make their own decision about the potential for bias. Typical disclosure statements such as "Dr X discloses that he has consulted with Companies A, B, and C" are a good start, but in many cases they do not tell the whole story. The whole story, in fact, is that different companies pay experts different amounts of money to do different things. Further, in many cases, the identified authors of journal articles are not the actual authors; they merely review and edit the work of an industry-paid professional writer, as was the case in the review article on VNS.

Thus, an argument can be made for 2 new disclosure requirements: authorship disclosures and compensation disclosures.

The problem of ghostwriting
It is clear that a significant proportion of major journal articles-both original research and review articles-are ghostwritten by writers who are funded by the pharmaceutical industry.⁹ The most well-documented example of this in psychiatry surfaced in the context of a lawsuit against Pfizer. Researchers identified all articles published on the topic of Zoloft (sertraline) from 1998 to 2000. Of the 96 published papers, 55 (57%) were ghostwritten by a medical information company, and 41 (43%) were not. Among the ghostwritten articles, 100% reported clinical results favorable for Zoloft, but only 44% of nonghostwritten articles reported similar findings.¹⁰

This study implies that approximately half of all major journal articles published in the field of psychiatry are ghostwritten and that these articles are more likely to present information that is favorable to the sponsoring company, bringing up the possibility of prosponsor bias. Thus, it seems crucial for readers to be fully informed about the authorship of all articles in addition to author affiliations.

Ghostwriting is not necessarily a corrupt practice. Busy researchers would find their productivity hobbled if they had to personally write the first draft of an article for every study they conducted. Experienced medical writers are experts at synthesizing scientific data and communicating it to a wider medical community.

The issue, as always, comes down to the need for full disclosure. In the VNS review, the medical writer who wrote the first draft was mentioned at the end of the paper in an acknowledgment section sandwiched between the article and the references. It stated: "We thank Sally Laden for editorial support in developing early drafts of this manuscript. We maintained complete control over the direction and content of the paper. Preparation of this report was supported by an unrestricted educational grant from Cyberonics Inc."³

To the uninformed, this acknowledgment implies that Laden had an unspecified and presumably minor editorial role, but that the identified authors actually wrote the paper. An "unrestricted educational grant" connotes a process in which authors are paid to write anything they want to write, without any content requirements from the funding company.

However, nothing could be further from the truth. In fact, according to The Wall Street Journal,⁴ Cyberonics began the process of writing the article by hiring Laden and providing her with the materials on which to base the first draft. These materials were derived from Cyberonics-funded advisory board meetings, which presumably consisted of clinical data and background literature endorsing the value of VNS for depression. Ms Laden wrote the first draft and then circulated it to the authors; according to her, this draft then went through "many revisions" before publication.⁴

The crucial question, of course, is who actually wrote the article? Was it Laden, who synthesized the literature and wrote the first draft? Was it the Cyberonics marketing team, who decided on what materials to base the article? Or was it the identified authors, who reviewed and commented on drafts written by Laden?

Listing academic psychiatrists as the sole authors lends the article an aura of legitimacy that is crucial for successful promotion. But one could easily argue that the article should have listed Sally Laden as the first author and Cyberonics as the second author and relegated the 9 identified authors to the acknowledgment section. This would have more accurately reflected the editorial process that led to its publication and would have fully disclosed the extent of industry influence over the content of the final manuscript.

Money talks
It is clear that the amount paid by companies to physicians for promotional work varies widely, depending on the type of work and the qualifications of the physician.

Many psychiatrists give occasional promotional talks, or know colleagues who do, and are familiar with the going rate of $1000 to $1500 to speak at a local dinner program. However, at higher levels of academia, payments may be much larger. Precise figures are hard to come by, but an indication of the scale of such payments was reported by The Boston Globe in 1999, when court documents revealed that the chairman of Brown University's psychiatry department earned $444,000 in industry consultant fees in 1997 and $556,000 in 1998.¹¹ This was all personal income to the recipient, not money passed on to the department for academic use.

Of course, just because a physician is well paid for industry work does not necessarily mean that his or her articles and talks are commercially biased. However, common sense dictates that as the financial stakes grow higher, the risk that a researcher's opinions may be altered-even if unconsciously-by the prospect of financial windfall becomes greater.

Therefore, some type of disclosure regarding compensation seems reasonable. In the VNS review, it would have been informative to know how much Cyberonics had paid each of the members of the advisory board. Such information helps the reader judge the likelihood of the opinions expressed in the review article being biased, both by the authors' past financial gain and the promise of future gain.

Conclusion
Conflicts of interest, financial and otherwise, are a fact of professional and personal life and will never go away. It is up to journal editors and professional associations to decide how best to minimize any potential damage to scientific communication that conflicts of interest can create.

Adequate disclosure is a good way to minimize the negative effects of conflict of interest, but--as we have seen in this review--there is much disagreement about what constitutes adequate disclosure. My own perspective is informed by my responsibilities as editor of a newsletter that eschews pharmaceutical funding, and thus my opinions are oriented to more, rather than less, disclosure. A proposal of what I feel editors should request from authors can be found in the Table.

Clearly, psychiatry is in crisis. Many of our top academic leaders appear willing to sell themselves to the highest corporate bidder. However, since this is a crisis of ethics, it will not be resolved easily. A good start is to require meaningful disclosures so that readers can begin to regain their trust in the integrity of psychiatric opinions.

This is part 2 of a 2-part article on conflict of interest in psychiatry. Part 1, "Conflict of Interest in Psychiatry: How Much Disclosure is Necessary?" was published in the November issue of Psychiatric Times.

Dr Carlat is assistant clinical professor of psychiatry at Tufts University School of Medicine in Boston and is editor-in-chief of The Carlat Psychiatry Report. He reports no conflicts of interest concerning the subject matter of this article.

References:

References1. Our conflicted medical journals. Editorial. The New York Times. July 23, 2006; sect 4:11.
2. US Senate Committee on Finance. Review of the FDA's approval process for the vagus nerve stimulation therapy system for treatment resistant depression. February 2006. Available at: http://finance.senate.gov/press/Gpress/02_2006 report.pdf. Accessed October 12, 2006.
3. Nemeroff CB, Mayberg HS, Krahl SE, et al. VNS therapy in treatment-resistant depression: clinical evidence and putative neurobiologic mechanisms. Neuropsychopharmacology. 2006;31:1345-1355.
4. Armstrong D. Medical reviews face criticism over lapses. Wall Street Journal. July 19, 2006;B1.
5. Waters R. Medical journal to correct Cyberonics device article. Bloomberg News. July 18, 2006.
6. Is this the perfect storm of corruption? ACNP journal. Alliance for Human Research Protection Web site. Available at: http://www.ahrp.org/cms/content/view/295/55/. Accessed October 13, 2006.
7. Leading research institutions initiate mechanism of action studies on vagus nerve stimulation (VNS) therapy for treatment-resistant depression. Cyberonics press release. May 23, 2006. Available at: http://www.cyberonics.com/PressRelease_detail.asp?ID=32A90EDE-A8C6-4AAB-A709-C0C432DFF3CA. Accessed October 13, 2006.
8. Armstrong D. Medical journal editor Nemeroff steps down over undisclosed ties. Wall Street Journal. August 28, 2006;B7.
9. Mathews AW. At medical journals, writers paid by industry play big role. Wall Street Journal. December 13, 2005;A1.
10. Healy D, Cattell D. Interface between authorship, industry and science in the domain of therapeutics. Br J Psychiatry 2003;183:22-27.
11. Bass A. Drug companies enrich Brown professor. Boston Globe; October 4, 1999:A1.