Efficacy of Paroxetine in the Treatment of Adolescent Major Depression: A Randomized, Controlled Trial
by MARTIN B. KELLER, NEAL D. RYAN, MICHAEL STROBER, RACHEL G. KLEIN, STAN P. KUTCHER, BORIS BIRMAHER, OWEN R. HAGINO, HAROLD KOPLEWICZ, GABRIELLE A. CARLSON, GREGORY N. CLARKE, GRAHAM J. EMSLIE, DAVID FEINBERG, BARBARA GELLER, VIVEK KUSUMAKAR, GEORGE PAPATHEODOROU, WILLIAM H. SACK, MICHAEL SWEENEY, KAREN DINEEN WAGNER, ELIZABETH B. WELLER, NANCY C. WINTERS, ROSEMARY OAKES, AND JAMES P. MCCAFFERTY
Journal of the American Academy of Child and Adolescent Psychiatry, 2001, 40(7):762–772.…Conclusions: Paroxetine is generally well tolerated and effective for major depression in adolescents.
By the time it was published, GSK had funded two further completed Clinical Trials of Paxil in Children and Adolescents:
- Study 329 Dates: 20 April 1994 to 07 May 1997
- Study 377 Dates: 26 April 1995 to 15 May 1998
- Study 701 Dates: 20 March 2000 to 24 January 2001
Neither Study 377 nor Study 701 were published:
SKB [GSK] didn’t submit Study 329 to the FDA for a pediatric approval, but Studies 329 and 377 were submitted in 2002 as part of a package for a pediatric extension of exclusivity. The FDA said of Study 329:
Drs. Juriedini and Tonkin wrote their letter to the JAACAP criticizing the paper, it was published in 2003 [the lesson of Study 329: naked Emperors, fractious Queens… ] along with the author’s response. They said:We believe that the Keller et al. study shows evidence of distorted and unbalanced reporting that seems to have evaded the scrutiny of your editorial process… Thus a study that did not show significant improvement on either of two primary outcome measures is reported as demonstrating efficacy. Given that the research was paid for by Glaxo-Smith-Klein, the makers of paroxetine, it is tempting to explain the mode of reporting as an attempt to show the drug in the most favorable light…
Added to that, Attorney General Elliot Spitzer had successfully prosecuted GSK in 2004 in New York, focusing on Study 329. As part of that settlement, GSK was required to publish the results of their Clinical Trials on-line. They did publish summaries [but did not put up any raw data - a movement… ].
But most damaging of all, in 2004 after a meta-analysis and hearings, the FDA issued its black box warning on SSRIs, particularly for youth.
Evaluation of suicidal thoughts and behaviors in children and adolescents taking paroxetine.
by Apter A, Lipschitz A, Fong R, Carpenter DJ, Krulewicz S, Davies JT, Wilkinson C, Perera P, and Metz A.
Journal of Child and Adolescent Psychopharmacology. 2006 16[1-2]:77-90....Conclusions: Adolescents treated with paroxetine showed an increased risk of suicide-related events. Suicidality rating scales did not show this risk difference. The presence of uncontrolled suicide risk factors, the relatively low incidence of these events, and their predominance in adolescents with MDD make it difficult to identify a single cause for suicidality in these pediatric patients.
And GSK followed the review by quickly publishing Studies 377 and 701, though they were 5 and 8 years old by the publication time:
An International, Multicenter, Placebo-Controlled Trial of Paroxetine in Adolescents with Major Depressive Disorder
by Ray Berard, Regan Fong, David J. Carpenter, Christine Thomason, and Christel Wilkinson
Journal of Child and Adolescent Psychopharmacology. 2006 16[1-2]:59–75....Conclusions: No statistically significant differences were observed for paroxetine compared with placebo on the two prospectively defined primary efficacy variables. Paroxetine at 20–40 mg/day administered over a period of up to 12 weeks was generally well tolerated.
Paroxetine Treatment in Children and Adolescents With Major Depressive Disorder: A Randomized, Multicenter, Double-Blind, Placebo-Controlled Trial
by GRAHAM J. EMSLIE, KAREN DINEEN WAGNER, STAN KUTCHER, STAN KRULEWICZ, REGAN FONG, DAVID J. CARPENTER, ALAN LIPSCHITZ, ANDREA MACHIN, AND CHRISTEL WILKINSON
Journal of the American Academy of Child and Adolescent Psychiatry. 2006 45:709-719.…
Conclusions: Paroxetine was not shown to be more efficacious than placebo for treating pediatric major depressive disorder.
"Paroxetine has been studied in three randomized, double-blind, placebo-controlled trials in depressed children and/or adolescents. The results of the first two trials, which enrolled adolescents only, produced equivocal results overall (Berard et al., 2006; Keller et al., 2001). The first, a study comparing paroxetine, imipramine, and placebo in adolescents with major depressive disorder (MDD), failed to show a difference between paroxetine and placebo on the primary outcome (Hamilton Depression Rating Scale score <8 or 50% decrease on it). However, several secondary outcome measures did show differences between paroxetine and placebo, but not between imipramine and placebo (Keller et al., 2001). Thus, there was some evidence of positive benefit for adolescents taking paroxetine in the first RCT. The second study, which was an international study of both inpatients and outpatients, did not show a difference between paroxetine and placebo on any outcome measures. The third study, described here, was the only one to include patients younger than 12 years."
By any criteria, the conclusion to the 2001 Keller et al article is wrong ["Paroxetine is generally well tolerated and effective for major depression in adolescents"]. That’s not the reason that some of us have been so persistent in pushing for retraction. The reason is that it was wrong at the time the article was published, and they knew it was wrong, but published it anyway. We want to make a statement about the integrity of the scientific literature. Now, eleven years later, the process of getting that article into print and using it for false advertising is known in precise detail. The offending pharmaceutical company has settled the case and paid a $3 B fine. So the question on the table now is "Why doesn’t the Journal of the American Academy of Child and Adolescent Psychiatry retract the article?" I don’t know the answer, but I expect it has to do with things lawyers say – like this:
Journal Article Didn’t Mislead, Drug Company Asserts
Chronicle of Higher Education
October 1, 2012
[full text available on-line]
To the Editor:
As counsel for GlaxoSmithKline LLC in its recently concluded settlement with the United States government, I write to correct some significant factual inaccuracies in "Academic Researchers Escape Scrutiny in Glaxo Fraud Settlement" [The Chronicle, August 6]. The piece focuses on a peer-reviewed journal article published in 2001 in the Journal of the American Academy of Child and Adolescent Psychiatry reporting the results of a clinical trial sponsored by GlaxoSmithKline [Study 329] of Paxil® [paroxetine hydrochloride] for the treatment of major depressive disorder in adolescents [the article was "Efficacy of Paroxetine in the Treatment of Adolescent Major Depression: A Randomized, Controlled Trial," by M.B. Keller et al., in the July 2001 issue]. Unfortunately, your piece incorrectly states that, as part of its government settlement, GlaxoSmithKline admitted that the journal article "was part of the fraud" and "constituted scientific fraud." In fact, GlaxoSmithKline made no such admission and vigorously disputes that the journal article was false, misleading, or fraudulent.
As part of its settlement with the government, GlaxoSmithKline pleaded guilty to a misdemeanor violation of federal law related to the marketing of Paxil for use by patients under 18, an unapproved, "off label" use for Paxil. While the law permits physicians to prescribe medications for such off-label uses, manufacturers are not permitted to market them for such purposes. The charging document filed by the United States, known as an information, contains many allegations that are either inaccurate or incomplete, that tell only part of the story, and that draw unwarranted conclusions from disputed facts. Throughout the investigation, the settlement process, and the guilty-plea proceeding, GlaxoSmithKline made clear to the government and to the court that it did not agree with all of the factual allegations made in the information. In particular, GlaxoSmithKline has consistently denied and disputed the allegations that the journal article was false or misleading. Nothing in the settlement or the guilty plea has changed GlaxoSmithKline’s position on the journal article. Most important, GlaxoSmithKline did not admit and has not admitted that the journal article was part of any fraud or that it was false or misleading.
Your piece also incorrectly states that the journal article "was actually written by Glaxo-hired authors to overstate the benefits and understate the risks of a highly profitable Glaxo drug." While GlaxoSmithKline did hire a medical writer to provide editorial assistance to the clinical investigators, a fact that the journal article itself acknowledged, control over the contents of the manuscript remained at all times with the clinical-investigator authors who provided substantial comments on and input into the manuscript. GlaxoSmithKline believed then and continues to believe that the journal article reflects the honestly held views of the clinical-investigator authors.
Thomas H. Lee II
Editor’s note: The federal "criminal information" document in the Paxil case repeatedly describes the journal article as "false and misleading." It also notes that GlaxoSmithKline distributed the article to its marketing department and its sales representatives, who used it to promote the use of the drug for children and adolescents. In addition, the criminal information says that a contractor hired by GlaxoSmithKline wrote the first draft of the article and incorporated changes made in the article by researchers and another GlaxoSmithKline employee. The plea agreement between GlaxoSmithKline and the U.S. Department of Justice states that GlaxoSmithKline "expressly and unequivocally admits that it committed the crimes charged in the information, and is in fact guilty of those offenses."