Posted on Tuesday 26 April 2011

This is another loose end that came up as I was trying to navigate the long and winding road to personalized medicine. I was aware of two stories, but I didn’t realize they were connected until I read this comment from Dr. Bernard Carroll about a 2004 study that I’ve looked at twice [how’s your life…, personalized medicine: a conclusion in search of an argument…]. I focused on it because it was one of the early attempts to find a genetic determinant of drug response. I disagreed with the author’s conclusions, seeing them as a specific distortion of the scientific facts, twisted to support a predetermined conclusion. I noted the absence of any conflict of interest disclosures in this American Journal of Psychiatry article, but didn’t know the back story until Dr. Carroll’s comment.

Although we’re coming in in the middle of a story, this episode starts with a review article in Nature Neuroscience about the treatment of the mood disorders published in November of 2002. In the article, Dr. Nemeroff mentioned an SNRI, Milnacipran, favorably among other new medications on the horizon:
  • Treatment of mood disorders
    by Nemeroff CB and Owens MJ
    Nature Neuroscience 2002 Nov;5 Suppl:1068-70.
      "Milnacipran, a dual 5-HT reuptake inhibitor approved for the treatment of depression in France, Japan, and other countries, is being developed in the U.S. Market for the treatment of fibromyalgia as a collaboration between Pierre Fabre and Cypress Biosciences."
In the fall of the following year, Drs. Carrol and Rubin wrote a letter to the editor of pointing out three future treatments that Drs. Nemeroff had favorably reviewed that he had a direct financial interest in and had not disclosed – Mifepristone as a treatment for Psychotic Depression [Nemeroff was on the board and a stockholder in the company developing the drug], Lithium Patches [Dr. Nemeroff held the patent for Lithium Patches], and Milnacipran [see below]. They saw this as a serious failure of disclosure and requested that Nature Neuroscience change its policy to require any such conflicts of interest be declared in all published reviews.:
  • Editorial policies on financial disclosure
    by Carroll BJ and Rubin RT
    Nature Neuroscience 2003 Oct;6(10):999-1000.
      "What Dr. Nemeroff … did not reveal is that he is both director and chairman of the Psychopharmacology Advisory Board of Cypress Bioscience, for which he is paid $48,000 per year, plus stock options. He is the beneficial owner of over 18,000 company shares. He also has a performance incentive of $100,000 for materially contributing to the achievement of certain milestones in the development of milnacipran in the United States…"

In their reply, the authors let us know up front that this is not the first time that Drs. Carroll and Rubin had questioned their being forthcoming about conflicts of interest in their work – so we have, indeed, stepped into the middle of a fight. They imply that their critics may be fighting unfairly by going public:
  • by Nemeroff CB and Owens MJ
    Nature Neuroscience 2003 Oct;6(10):1000-1001.
      "We appreciate the opportunity to respond to the issues raised by Drs. Carroll and Rubin, which were also featured in a recent New York Times article. This is not the first time Drs. Carroll and Rubin have criticized our peer-reviewed publications and citations of our work in the popular press. Two journals, Biologic Psychiatry and Neuropsychopharmacology have previously published their letters and our responses, and the interested reader may wish to refer to this scientific dialogue. These investigators have never contacted us directly regarding their concerns about our scientific publications…"
Drs. Nemeroff and Owens went on to acknowledged that all of the conflicts existed, but denied any wrong-doing [I’m focusing on Milnacipran only for obvious reasons]. Notice, however, their promise to "provide all financial disclosure information, even if it is not requested by the journal editor" in the future.
      "…it is indeed true that one of us [C.B.N.] serves on the board of directors of Cypress Biosciences, the company developing milnacipran for the treatment of fibromyalgia, and the other [M.J.O.] was a grant recipient and consultant to Cypress. However, the statement covering a ‘performance incentive of $1000,000’ is wrong…"
      "Going forward, we intend to provide all financial disclosure information, even if it is not requested by the journal editor…"
The editors agreed that Dr. Nemeroff and Owens had not violated the letter of Nature Neuroscience‘s existing policies, but also agreed with Drs. Carroll and Rubin that such conflicts should, in fact, be disclosed, and changed their policy [including all of the Nature Journals] to require those kinds of disclosures moving ahead:
  • Editorial
    Nature Neuroscience 2003 Oct;6(10):997.
      "…this episode underlines the importance of financial disclosure for maintaining public confidence in science, and we [along with the other Nature Journals] have now changed our policy on disclosure for review articles. For the past two years, we have been publishing statements of competing financial interests for all primary research papers, and henceforth we shall request similar disclosures for reviews as well…"
One might have thought that it would’ve ended here. Drs. Nemeroff and Owens were "off the hook" in a legalistic sense, but chided by the editors nonetheless. They didn’t admit to unethical behavior, but promised to be pristine in disclosure henceforth and forevermore. And so to bed? Drs. Carroll and Rubin had succeeded in getting the policy changed. But that’s not how it played out. The following January [01/06/2004], just three months later, the American Journal of Psychiatry received this next article on Milnacipran with Dr. Nemeroff as  the senior author. Dr. Nemeroff made no disclosures of conflicts of interest in spite of admitting them a few months before and promising to "provide all financial disclosure information, even if it is not requested by the journal editor." This study was published in the September 2004 issue.
  • by Keizo Yoshida, Hitoshi Takahashi, Hisashi Higuchi, Mitsuhiro Kamata, Ken-ichi Ito, Kazuhiro Sato, Shingo Naito, Tetsuo Shimizu, Kunihiko Itoh, Kazuyuki Inoue, Toshio Suzuki, Charles B. Nemeroff
    American Journal of Psychiatry 2004; 161:1575–1580.
      Objective: With a multitude of antidepressants available, predictors of response to different classes of antidepressants are of considerable interest. The purpose of the present study was to determine whether norepinephrine transporter gene (NET) and serotonin transporter gene (5-HTT) polymorphisms are associated with the antidepressant response to milnacipran, a dual serotonin/norepinephrine reuptake inhibitor.
      Method: Ninety-six Japanese patients with major depressive disorder were treated with milnacipran, 50–100 mg/day, for 6 weeks. Severity of depression was assessed with the Montgomery-Åsberg Depression Rating Scale. Assessments were carried out at baseline and at 1, 2, 4, and 6 weeks of treatment. The method of polymerase chain reaction was used to determine allelic variants.
      Results: Eighty patients completed the study. The presence of the T allele of the NET T-182C polymorphism was associated with a superior antidepressant response, whereas the A/A genotype of the NET G1287A polymorphism was associated with a slower onset of therapeutic response. In contrast, no influence of 5-HTT polymorphisms on the antidepressant response to milnacipran was detected.
      Conclusions: The results suggest that NET but not 5-HTT polymorphisms in part determine the antidepressant response to milnacipran.
I’ve said all I need to say about this study itself [how’s your life…, personalized medicine: a conclusion in search of an argument…]. What I want to mention right now is the amazing hubris involved in having been openly challenged about his conflict of interest  with this particular drug, making a pledge to  "provide all financial disclosure information," and then ignoring that promise in a matter of a few months in the most public Psychiatric Journal possible. I don’t know if he was  called to task on this one or not, and it doesn’t matter in that the behavior continued until he lost his editorship and ultimately his chairmanship over the same kind of things. The story reads more like it’s the subject of a Grand Rounds presentation on Character Disorders than about the Chairman of a Department sitting in the audience. I related this narrative for another reason which I’ll get to next time. For now, I’ll just be awed by the hubris…
    April 27, 2011 | 8:14 AM

    Yeah but have you seen how the DSM-V Task Force is about to vote character disorders out of existence? By committee roll call, PRESTO, no more character disorders! They are GONE. And just at the time that Academic Psychiatry has been taken over by psychopathic psychiatrists! Coincidence? Me thinks not.

    BTW, have you any idea on why the University of Miami decided to give Charlie Bling Bling a Chair after the Emory defrocking?

    April 28, 2011 | 5:07 PM

    I’d like to know the answer to Tom’s question about Miami, too…I already know Tom Insell got in some trouble assuring Miami that Nemeroff would still be eligible for NIMH grants (I think I”ve got that right). My husband maintains Miami is not exactly an ethical giant in terms of their sports program…just wonder what the “culture” is there. My guess is that it’s more about $$$$ than anything else. And just for the record, I’ve written to the American Foundation for Suicide Prevention more than once asking why “Charlie Bling Bling” is on their board of directors and holds other noteworthy positions there and none of my inquiries has even been given the courtesy of a reply. And, oh, yeah, psychopharmacology has just helped loads with suicide prevention, right? All these people on meds have surely driven down the suicide rate, right???

    April 28, 2011 | 9:39 PM

    Hey Mickey: Is there a NIH/NIMH registry where one can see who received grants from these agencies? I am just wondering how much money Charlie and Alan have received from these federal agencies after being exposed as Insel’s water boys (or vice versa).

    April 28, 2011 | 9:54 PM

    Yeah. It’s the NIH REPORTeR. It’s a challenge to figure out. One secret is to pick “all years” in the “FY” field, and sort the results by year by clicking the header of the “FY” column in the results table. Happy hunting!

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