1 Boring Old Man

In the last two decades, the Pharmaceutical Industry has been able to opportunize on the reputations of our academic institutions and literature at levels we would never have imagined. The academic brand comes not only from being the repository for knowledge, but also from our collective sense that universities not only teach ethics to our children, but embody ethical principles in the institution itself. Academic integrity is the force that binds the various departments into a respected whole, an integer. In practice, the professional schools like Law and Medicine are often more self-contained than other elements in a University system, operate under their own professional ethical standards, and are connected to the academy at the upper levels of administration rather than throughout the faculty. To further complicate matters, the psychiatric research in question has been done as a collaboration of investigators from many different university faculties, adding yet another warp to the integer-like quality of a given academic institution.

While I have no sense that either the semi-independence of medical schools or the collaborative nature of some research enterprise is meant to create a loophole in the unity of the Uni·versity, that is exactly what happened. As the unprecedented corruption of academic psychiatrists colluding with the pharmaceutical industry has been exposed, we’ve watched with dismay as the university administrations have responded awkwardly, meekly, or sometimes not at all. We all know that if the Chairman of an Department in the college  behaved like the Chairmen of some of our Departments of Psychiatry, they would find themselves on the sidewalk sitting on cardboard boxes contemplating downwardly mobile career changes. The paradigm for "sometimes not at all" has been Brown University, one of our finest stars. The controversy hinges on the article published in 2001 with the Brown Chairman of Psychiatry, Dr. Martin Keller, as lead author. It’s known simply as Study 329, though the paper has a much longer title and list of authors:

Efficacy of Paroxetine in the Treatment of Adolescent Major Depression:

A Randomized, Controlled Trial
^{by MARTIN B. KELLER, M.D., NEAL D. RYAN, M.D., MICHAEL STROBER, PH.D., RACHEL G. KLEIN, PH.D., STAN P. KUTCHER, M.D., BORIS BIRMAHER, M.D., OWEN R. HAGINO, M.D., HAROLD KOPLEWICZ, M.D., GABRIELLE A. CARLSON, M.D., GREGORY N. CLARKE, PH.D., GRAHAM J. EMSLIE, M.D., DAVID FEINBERG, M.D., BARBARA GELLER, M.D., VIVEK KUSUMAKAR, M.D., GEORGE PAPATHEODOROU, M.D., WILLIAM H. SACK, M.D., MICHAEL SWEENEY, PH.D., KAREN DINEEN WAGNER, M.D., PH.D., ELIZABETH B. WELLER, M.D., NANCY C. WINTERS, M.D., ROSEMARY OAKES, M.S., AND JAMES P. MCCAFFERTY, B.S.}
Journal of the American Academy of Child and Adolescent Psychiatry, 2001, 40(7):762–772.

Abstract

^{Objective: To compare paroxetine with placebo and imipramine with placebo for the treatment of adolescent depression.}

^{Method: After a 7 to 14-day screening period, 275 adolescents with major depression began 8 weeks of double-blind paroxetine [20–40 mg], imipramine [gradual upward titration to 200–300 mg], or placebo. The two primary outcome measures were endpoint response [Hamilton Rating Scale for Depression [HAM-D] score <8 or >50% reduction in baseline HAM-D] and change from baseline HAM-D score. Other depression-related variables were [1] HAM-D depressed mood item; [2] depression item of the Schedule for Affective Disorders and Schizophrenia for Adolescents-Lifetime version [K-SADS-L]; [3] Clinical Global Impression [CGI] improvement scores of 1 or 2; [4] nine-item depression subscale of K-SADS-L; and [5] mean CGI improvement scores.}

^{Results: Paroxetine demonstrated significantly greater improvement compared with placebo in HAM-D total score <8, HAM-D depressed mood item, K-SADS-L depressed mood item, and CGI score of 1 or 2. The response to imipramine was not significantly different from placebo for any measure. Neither paroxetine nor imipramine differed significantly from placebo on parent- or self-rating measures. Withdrawal rates for adverse effects were 9.7% and 6.9% for paroxetine and placebo, respectively. Of 31.5% of subjects stopping imipramine therapy because of adverse effects, nearly one third did so because of adverse cardiovascular effects.}

^{Conclusions: Paroxetine is generally well tolerated and effective for major depression in adolescents.}

Impact of Publicity Concerning Pediatric Suicidality Data on Physician Practice Patterns in the United States
^{by Charles B. Nemeroff, Amir Kalali, Martin B. Keller, Dennis S. Charney, Susan E. Lenderts, Elisa F. Cascade, Hugo Stephenson, and Alan F. Schatzberg}
Archives of General Psychiatry. 2007 64(4):466-472.

^{US psychiatrists, as represented by the American Psychiatric Association and the American Academy of Child and Adolescent Psychiatry, have expressed concern that "the FDA action may limit access to necessary, appropriate, and effective treatment for children and adolescents with depression, anxiety, and other psychiatric disorders…}

^{In the current media environment in which safety concerns may be intensified because of several recent product recalls…, physician organizations [eg, the American Medical Association, the American Psychiatric Association, and the American Academy of Child and Adolescent Psychiatry] are concerned that the proved benefits of SSRI antidepressants may be underemphasized in discussions of potential risks and, as a result, there will be a decrease in access to appropriate treatment for children and adolescents. The FDA recently released results from an analysis that evaluated adult suicide and ideation data. The findings were mostly positive, and suggested that antidepressant drugs do not exacerbate suicidal thoughts in patients 30 years and older, but that the suicide thoughts/ideation seen in the pediatric data extends in young adults up to age 25 years. To date, these data results[ both positive and negative] have received considerably less media attention in comparison with the release of the pediatric suicidality data. Recognizing that the results of the adult analysis were only public as of December 13, 2006, it remains to be seen if and how these findings will impact prescribing in both the 18 to 25 years population and the 26 years and older population. It is evident, however, that there is need for additional exploration into the relationship between FDA action, media reaction, and physician behavior change to ensure that dissemination of drug safety information does not interfere with appropriate access to care.}

There have been multiple attempts to get the American Academy of Child and Adolescent Psychiatry to retract the Keller et al Study 329 from their journal with responses ranging from editor Dr. Mina Dulcan’s signature nastiness to the politeness of later editor, Dr. Andrés Martin [retract study 329…, retract study 329 – further thoughts…], but nothing has happened other than an improvement in the tone of their refusal to engage the issue. Last month, Healthy Skepticism, a well established watchdog group of health professional wrote Dr. Ruth Simmons directly asking her the intervene and request the Journal retract the article:

The Brown student paper had this to say, following this story as it has throughout the decade:

Prof’s study linked to child suicide
^{U. remains silent in face of accusations}
The Brown Daily Herald
by Sahil Luthra
November 17, 2011

^{Ten years after its publication, a study by Professor of Psychiatry and Human Behavior Martin Keller continues to generate concern in the medical community due to its alleged link to child suicide. Last month, the global nonprofit Healthy Skepticism wrote to the University requesting support for its efforts to retract Keller’s article — commonly known as Study 329 — from the Journal of the American Academy of Child and Adolescent Psychiatry. Healthy Skepticism expressed concern that the study, which identified the drug Paxil as an effective combatant of depression in children, "seriously misrepresented both the effectiveness and the safety" of the drug. The authors added that the study’s continued citation was harmful to children, since some children committed suicide after being prescribed Paxil.}

^{The letter follows several ethical examinations of Study 329, including a BBC documentary, the book "Side Effects" by former Boston Globe reporter Alison Bass and an investigation by the Senate Finance Committee. Those inquiries led to allegations that the authors of the study — who had received funds from Paxil’s parent company GlaxoSmithKline — suppressed the findings on the drug’s connection to suicidal tendencies because they would adversely affect profits. Keller, the lead author, was also accused of allowing the study to be ghostwritten by a GlaxoSmithKline affiliate. In June 2009, he stepped down as chair of the psychiatry department, citing personal reasons, but he retained his professorship. Keller did not respond to multiple requests for comment for this story. Citing confidentiality reasons, Dean of Medicine and Biological Sciences Edward Wing also declined to comment. But the University is harming itself by staying silent in the face of the accusations, said Clinical Associate Professor of Medicine Roy Poses ’73 MD’78. "There ought to be a public response. If these allegations are false or wrong, that ought to be made clear. If they’re true, then there ought to be some action."}

^{Following the October letter, President Ruth Simmons wrote to Healthy Skepticism that Wing would be in touch soon, said Jon Jureidini, one of the co-authors of the letter and a clinical professor at the University of Adelaide in Australia. Wing has not yet responded. Though Jureidini said he is waiting for a response before he plans any future actions, he "won’t necessarily give up" if the University refuses to support retracting the study. "I can’t imagine how you could review this case and not find misconduct," Jureidini said. He added that the arrival of a new president at Brown could provide an opportunity to ask the University again.}

^{University research policies state that when charges are brought against a researcher, the University must decide whether to pursue a formal investigation. If the investigation reveals misconduct, the researcher can face suspended privileges, and their papers may be withdrawn. If misconduct is not found, the University takes steps to restore the researcher’s reputation. But even if University officials found evidence of misconduct, they would likely ignore them, since Keller’s research has provided a steady source of University funding, according to Paul Thacker, an investigator at the Project On Government Oversight. Thacker, who also participated in the Senate inquiry, said he does not think the University should continue to receive any federal funding if it does not publicly address the Keller case. Thacker added that the University has prioritized discussion of less important issues over the years, citing the Steering Committee on Slavery and Justice formed in 2003. The University "spent all this time tearing themselves up about some sort of peripheral involvement in slavery," he said. "Nobody is walking around today who is being harmed by slavery. There are people who are walking around today who are harmed by this study."}

^{Bass, who has continued to report on Study 329 following the publication of "Side Effects," said though pinpointing specific examples would be difficult, "there’s no question there were adolescents and children who became suicidal and tried to kill themselves — and in some cases, succeeded in killing themselves — because the doctors were misled." Pointing to the accusations of ghostwriting, Bass added that there is a double standard in the University not taking action against Keller, because students who plagiarize face expulsion. When she was working for the Boston Globe, Bass also authored an article about conflicts of interest in Keller’s research, examining payments Keller received from pharmaceutical companies.}

^{Though the University revised its conflict of interest policies in 2009, those changes were simply "window dressing," wrote Leemon McHenry, a co-author of Healthy Skepticism’s letter, in an email to The Herald. McHenry, a researcher at California State University, Northridge, speculated that in practice, the University would likely prioritize the wishes of companies like GlaxoSmithKline over its ethical standards. The University held a forum Tuesday to hear faculty perspectives on its current conflict of interest policy.}

^{Following the October letter, President Ruth Simmons wrote to Healthy Skepticism that Wing would be in touch soon, said Jon Jureidini, one of the co-authors of the letter and a clinical professor at the University of Adelaide in Australia. Wing has not yet responded.}

It’s conceivable that she’s delegated the responsibility for doing the right thing to the Dean of the Medical School, Dr. Edward Wing. But it’s equally possible that she’s passed it down for another refusal. Study 329  is too toxic to endure and will ultimately be retracted. Dr. Simmons is making a big mistake to end her presidency without taking a stand on the side of academic integrity. Continuing to do nothing is a walk on the wrong side of the street, and negates her otherwise impressive legacy…