1 Boring Old Man

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.

• 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."}

• 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…"}

• Authors reply
  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…"}

^{"…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…"}

• Financial disclosure for review authors
  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…"}

• Prediction of Antidepressant Response to Milnacipran by Norepinephrine Transporter Gene Polymorphisms
  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.}