{"id":8138,"date":"2011-04-26T22:36:25","date_gmt":"2011-04-27T02:36:25","guid":{"rendered":"http:\/\/1boringoldman.com\/?p=8138"},"modified":"2011-04-26T22:36:25","modified_gmt":"2011-04-27T02:36:25","slug":"hubris-4","status":"publish","type":"post","link":"https:\/\/1boringoldman.com\/index.php\/2011\/04\/26\/hubris-4\/","title":{"rendered":"hubris&#8230;"},"content":{"rendered":"\n<p align=\"justify\">This is another loose end that came up as I was trying to navigate the long and winding road to <strong><font color=\"#200020\">personalized medicine<\/font><\/strong>. I was aware of two stories, but I didn&#8217;t realize they were connected until I read <a href=\"http:\/\/1boringoldman.com\/index.php\/2011\/04\/23\/personalized-medicine-a-conclusion-in-search-of-an-argument\/#comment-200048\" target=\"_blank\"><u><strong><font color=\"#200020\">this comment from Dr. Bernard Carroll<\/font><\/strong><\/u><\/a> about a 2004 study that I&#8217;ve looked at twice [<a href=\"http:\/\/1boringoldman.com\/index.php\/2010\/07\/05\/hows-your-life\/\" target=\"_blank\"><u><strong><font color=\"#300030\">how&#8217;s your life&#8230;<\/font><\/strong><\/u><\/a>, <u><strong><a href=\"http:\/\/1boringoldman.com\/wp-admin\/..\/index.php\/2011\/04\/23\/personalized-medicine-a-conclusion-in-search-of-an-argument\/\" target=\"_blank\"><font color=\"#300030\">personalized medicine: a conclusion in search of an argument&hellip;<\/font><\/a><\/strong><\/u>]. 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&#8217;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 <strong>American Journal of Psychiatry<\/strong> article, but didn&#8217;t know the back story until Dr. Carroll&#8217;s comment.      <\/p>\n<div align=\"justify\">Although we&#8217;re coming in in the middle of a story, this episode starts with a review article in <strong>Nature Neuroscience<\/strong> about the treatment of the mood disorders published in November of 2002. In the article, Dr. Nemeroff mentioned  an SNRI, <strong>Milnacipran<\/strong>, favorably among other new medications on the horizon:     <\/div>\n<ul>\n<li>\n<div><a href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/12403988\" target=\"_blank\"><u><strong><font color=\"#200020\">Treatment of mood disorders<\/font><\/strong><\/u><\/a><br \/>                  by Nemeroff CB and Owens MJ<br \/>                  <strong><font color=\"#200020\">Nature Neuroscience<\/font><\/strong> 2002 Nov;5 Suppl:1068-70.<\/div>\n<ol>\n<div align=\"justify\">  <sup>&quot;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.&quot;<\/sup><\/div>\n<\/ol>\n<\/li>\n<\/ul>\n<div align=\"justify\">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 &#8211; <strong>Mifepristone<\/strong> as a treatment for Psychotic Depression [Nemeroff was on the board and a stockholder in the company developing the drug], <strong>Lithium Patches<\/strong> [Dr. Nemeroff held the patent for Lithium Patches], and <strong>Milnacipran<\/strong> [see below]. They saw this as a serious failure of disclosure and requested that <strong>Nature Neuroscience<\/strong> change its policy to require any such conflicts of interest be declared in all published reviews.:     <\/div>\n<ul>\n<li>\n<div><a href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/14513028\" target=\"_blank\"><u><strong><font color=\"#200020\">Editorial policies on financial disclosure<\/font><\/strong><\/u><\/a><br \/>               by Carroll BJ and Rubin RT<br \/>               <strong><font color=\"#200020\">Nature Neuroscience<\/font><\/strong> 2003 Oct;6(10):999-1000.<\/div>\n<ol>\n<div>\n<div align=\"justify\"><sup>&quot;What Dr. Nemeroff &#8230; 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&#8230;&quot;<\/sup><\/div>\n<\/p><\/div>\n<\/ol>\n<\/li>\n<\/ul>\n<div align=\"justify\">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 &#8211; so we have, indeed, stepped into the middle of a fight. They imply that their critics may be fighting unfairly by going public:     <\/div>\n<ul>\n<li>\n<div><a href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/14513028\" target=\"_blank\"><u><strong><font color=\"#200020\">Authors reply<\/font><\/strong><\/u><\/a><\/div>\n<div>by Nemeroff CB and Owens MJ<\/div>\n<div><strong><font color=\"#200020\">Nature Neuroscience<\/font><\/strong> 2003 Oct;6(10):1000-1001.<\/div>\n<ol>\n<div align=\"justify\"><sup>&quot;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&#8230;&quot;<\/sup><\/div>\n<\/ol>\n<\/li>\n<\/ul>\n<div align=\"justify\">Drs. Nemeroff and Owens went on to acknowledged that all of the conflicts existed, but denied any wrong-doing [I&#8217;m focusing on <strong>Milnacipran<\/strong> only for obvious reasons]. Notice, however, their promise to &quot;<strong>provide all financial disclosure information, even if it is not requested by the journal editor<\/strong>&quot; in the future.     <\/div>\n<ul>\n<ol>\n<div align=\"justify\"><sup>&quot;&#8230;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 &#8216;performance incentive of $1000,000&#8217; is wrong&#8230;&quot;<\/sup><\/div>\n<div><sup>&quot;Going forward, we intend to provide all financial disclosure information, even if it is not requested by the journal editor&#8230;&quot;<\/sup><\/div>\n<\/ol>\n<\/ul>\n<div align=\"justify\">The editors agreed that Dr. Nemeroff and Owens had not violated the letter of <strong>Nature Neuroscience<\/strong>&#8216;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 <strong>Nature<\/strong> Journals] to require those kinds of disclosures moving ahead:     <\/div>\n<ul>\n<li>\n<div><a href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/14513028\" target=\"_blank\"><u><strong><font color=\"#200020\">Financial disclosure for review authors<\/font><\/strong><\/u><\/a><\/div>\n<div><strong><font color=\"#200020\">Editorial <\/font><\/strong>          <\/div>\n<div><strong><font color=\"#200020\">Nature Neuroscience<\/font><\/strong> 2003 Oct;6(10):997.<\/div>\n<ol>\n<div align=\"justify\"><sup>&quot;&#8230;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&#8230;&quot;<\/sup><\/div>\n<\/ol>\n<\/li>\n<\/ul>\n<div align=\"justify\">One might have thought that it would&#8217;ve ended here. Drs. Nemeroff and Owens were &quot;off the hook&quot; in a legalistic sense, but chided by the editors nonetheless. They didn&#8217;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&#8217;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 <strong>Milnacipran<\/strong> with Dr. Nemeroff as&nbsp; the senior author. Dr. Nemeroff made no disclosures of conflicts of interest in spite of admitting them a few months before and promising to &quot;provide all financial disclosure information, even if it is not requested by the journal editor.&quot; This study was published in the September 2004 issue.<\/div>\n<ul>\n<li>\n<div align=\"justify\"><a target=\"_blank\" href=\"http:\/\/ajp.psychiatryonline.org\/cgi\/content\/full\/161\/9\/1575\"><u><strong><font color=\"#200020\">Prediction of Antidepressant Response to Milnacipran by Norepinephrine Transporter Gene Polymorphisms<\/font><\/strong><\/u><\/a><\/div>\n<div align=\"justify\">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<\/div>\n<div><strong><font color=\"#200020\">American Journal of Psychiatry<\/font><\/strong> 2004; 161:1575&ndash;1580.<\/div>\n<ol>\n<div align=\"justify\"><sup><strong><font color=\"#200020\">Objective<\/font><\/strong>:  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.<\/sup><\/div>\n<div align=\"justify\"><sup><strong><font color=\"#200020\">Method<\/font><\/strong>: Ninety-six Japanese patients with major depressive disorder were  treated with milnacipran, 50&ndash;100 mg\/day, for 6 weeks. Severity of  depression was assessed with the Montgomery-&Aring;sberg 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.<\/sup><\/div>\n<div align=\"justify\"><sup><strong><font color=\"#200020\">Results<\/font><\/strong>:  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.<\/sup><\/div>\n<div align=\"justify\"><sup><strong><font color=\"#200020\">Conclusions<\/font><\/strong>: The results suggest that NET but not 5-HTT polymorphisms in part determine the antidepressant response to milnacipran.<\/sup><\/div>\n<\/ol>\n<\/li>\n<\/ul>\n<div align=\"justify\">I&#8217;ve said all I need to say about this study itself [<a href=\"http:\/\/1boringoldman.com\/index.php\/2010\/07\/05\/hows-your-life\" target=\"_blank\"><u><strong><font color=\"#300030\">how&#8217;s your life&#8230;<\/font><\/strong><\/u><\/a>, <u><strong><a href=\"http:\/\/1boringoldman.com\/index.php\/2011\/04\/23\/personalized-medicine-a-conclusion-in-search-of-an-argument\" target=\"_blank\"><font color=\"#300030\">personalized medicine: a conclusion in search of an argument&hellip;<\/font><\/a><\/strong><\/u>]. What I want to mention right now is the amazing hubris involved in having been openly challenged about his conflict of interest&nbsp; with this particular drug, making a pledge to&nbsp; &quot;provide all financial disclosure information,&quot; and then ignoring that promise in a matter of a few months in the most public Psychiatric Journal possible. I don&#8217;t know if he was&nbsp; called to task on this one or not, and it doesn&#8217;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&#8217;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&#8217;ll get to next time. For now, I&#8217;ll just be awed by the hubris&#8230;<\/div>\n","protected":false},"excerpt":{"rendered":"<p>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&#8217;t realize they were connected until I read this comment from Dr. Bernard Carroll about a 2004 study that I&#8217;ve looked at twice [how&#8217;s your [&hellip;]<\/p>\n","protected":false},"author":2,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_bbp_topic_count":0,"_bbp_reply_count":0,"_bbp_total_topic_count":0,"_bbp_total_reply_count":0,"_bbp_voice_count":0,"_bbp_anonymous_reply_count":0,"_bbp_topic_count_hidden":0,"_bbp_reply_count_hidden":0,"_bbp_forum_subforum_count":0,"footnotes":""},"categories":[2],"tags":[],"class_list":["post-8138","post","type-post","status-publish","format-standard","hentry","category-politics"],"_links":{"self":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/8138","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/comments?post=8138"}],"version-history":[{"count":32,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/8138\/revisions"}],"predecessor-version":[{"id":8171,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/8138\/revisions\/8171"}],"wp:attachment":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/media?parent=8138"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/categories?post=8138"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/tags?post=8138"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}