by Jureidini, Jon, Amsterdam, Jay, McHenry, LeemonInternational Journal of Risk & Safety in Medicine. 2016 28[1]:33-43.
OBJECTIVE:Deconstruction of a ghostwritten report of a randomized, double-blind, placebo-controlled efficacy and safety trial of citalopram in depressed children and adolescents conducted in the United States.METHODS:Approximately 750 documents from the Celexa and Lexapro Marketing and Sales Practices Litigation: Master Docket 09-MD-2067-[NMG] were deconstructed.CONCLUSION:Deconstruction of court documents revealed that protocol-specified outcome measures showed no statistically significant difference between citalopram and placebo. However, the published article concluded that citalopram was safe and significantly more efficacious than placebo for children and adolescents, with possible adverse effects on patient safety.
Background for Reference:
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2001: Efficacy of Paroxetine in the Treatment of Adolescent Major Depression: A Randomized, Controlled Trial. "Paroxetine is generally well tolerated and effective for major depression in adolescents."by Keller MB, Ryan ND, Strober M, Klein RG, Kutcher SP, Birmaher B, Hagino OR, Koplewicz H, Carlson GA, Clarke GN, Emslie GJ, Feinberg D, Geller B, Kusumakar V, Papatheodorou G, Sack WH, Sweeney M, Wagner KD, Weller EB, Winters NC, Oakes R, and McCafferty JP
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2002: Fluoxetine for Acute Treatment of Depression in Children and Adolescents: A Placebo-Controlled, Randomized Clinical Trial. "Fluoxetine was superior to placebo in the acute phase treatment of major depressive disorder in child and adolescent outpatients with severe, persistent depression."by Emslie GJ, Heiligenstein JH, Wagner KD, Hoog SL, Ernest DE, Brown E, Nilsson M, and Jacobson JG
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2003: Efficacy of sertraline in the treatment of children and adolescents with major depressive disorder: two randomized controlled trials. "…sertraline is an effective and well-tolerated short-term treatment for children and adolescents with MDD."by Wagner KD, Ambrosini P, Rynn M, Wohlberg C, Yang R, Greenbaum MS, Childress A, Donnelly C, Deas D; and the Sertraline Pediatric Depression Study Group
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2004: A randomized, placebo-controlled trial of citalopram for the treatment of major depression in children and adolescents. "…treatment with citalopram reduced depressive symptoms to a significantly greater extent than placebo treatment and was well tolerated."by Wagner KD, Robb AS, Findling RL, Jin J, Gutierrez MM, and Heydorn WE
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by Mann JJ, Emslie G, Baldessarini RJ, Beardslee W, Fawcett JA, Goodwin FK, Leon AC, Meltzer HY, Ryan ND, Shaffer D, and Wagner KD
by Karen Dineen Wagner, Adelaide S. Robb, Robert L. Findling, Jianqing Jin, Marcelo M. Gutierrez, and William E. HeydornAmerican Journal of Psychiatry. 2004 161:1079-1083.
Objective: Open-label trials with the selective serotonin reuptake inhibitor citalopram suggest that this agent is effective and safe for the treatment of depressive symptoms in children and adolescents. The current study investigated the efficacy and safety of citalopram compared with placebo in the treatment of pediatric pa- tients with major depression.Method: An 8-week, randomized, double- blind, placebo-controlled study compared the safety and efficacy of citalopram with placebo in the treatment of children [ages 7–11] and adolescents [ages 12–17] with major depressive disorder. Diagnosis was established with the Schedule for Affective Disorders and Schizophrenia for School- Age Children—Present and Lifetime Version. Patients [N=174] were treated initially with placebo or 20 mg/day of citalopram, with an option to increase the dose to 40 mg/day at week 4 if clinically indicated. The primary outcome measure was score on the Children’s Depression Rating Scale— Revised; the response criterion was defined as a score of ≤ 28.Results: The overall mean citalopram dose was approximately 24 mg/day. Mean Children’s Depression Rating Scale—Revised scores decreased significantly more from baseline in the citalopram treatment group than in the placebo treatment group, beginning at week 1 and continuing at every observation point to the end of the study [effect size=2.9]. The difference in response rate at week 8 between placebo [24%] and citalopram [36%] also was statistically significant. Citalopram treatment was well tolerated. Rates of discontinua- tion due to adverse events were comparable in the placebo and citalopram groups [5.9% versus 5.6%, respectively]. Rhinitis, nausea, and abdominal pain were the only adverse events to occur with a frequency exceeding 10% in either treatment group.Conclusions: In this population of children and adolescents, treatment with citalopram reduced depressive symptoms to a significantly greater extent than placebo treatment and was well tolerated.
Editors’ Noteby Robert Freedman and Michael D. RoyAmerican Journal of Psychiatry. 2009 166[8]:942-943.The article "A Randomized, Placebo-Controlled Trial of Cilalopram for the Treatment of Major Depression in Children and Adolescents," published in the June 2004 issue of The American Journal of Psychiatry [vol. 161, pp 1079-1083] is alleged by the United States Department of Justice in an ongoing suit to have been written and submitted to the Journal by a commercial medical writer on behalf of Forest Laboratories, Inc.
We requested responses from Drs. Karen Dineen Wagner, Adelaide S. Robb, and Robert L Findling [authors in their role as investigators in the clinical trial at their respective universities], Dr. William E. Heydom [the senior Forest laboratories study director], and Forest laboratories. Drs. Wagner, Robb, and Findling reported that they had received an initial draft from Dr. Heydom to which they contributed through several drafts, This paper was submitted as a Brief Report, which the Journal’s editors requested be resubmitted as a full-length Article. Drs. Wagner, Robb, and Findling report that they contributed with Dr. Heydorn to the resubmission and that they were not aware that Dr. Heydorn was working with a commercial writer. Dr. Heydorn did not respond to our request for comment.
A Forest laboratory official in a letter of April 17, 2009, acknowledged that: "Forest retained a medical communications company to assist with preparation of the manuscript, a practice we understand to be common among pharmaceutical companies. Following discussion with the article’s named authors, the medical communications company created an initial draft of the manuscript. Over the course of time, however, from the initial draft to the final publication, the manuscript went through multiple iterations with the input of the named authors, as well as others who reviewed and commented on the manuscript; throughout this process, the medical communications company continued to provide copy editing, formatting, referencing and other editorial support. Hie manuscript was then submitted to AJP by Dr. Wagner, who, along with the other named authors, maintained control over the final content of the manuscript."
We are satisfied that the named contributors of this article satisfy the criteria for authorship as set forth in the "Uniform Requirements for Manuscripts Submitted to Biomedical Journals" from the International Committee of Medical Journal Editors. However, the Journal’s Instructions to the Authors in 2004 and our policy today do not allow contributions by unnamed writers to the preparation of a paper. Thus, the editorial contributions of Prescott Medical Communications Group should have been acknowledged in the published article as required at the time the article was published.
Furthermore, Forest Laboratories failed to disclose to the Journal that it was aware of data from a study by Lundbeck that showed increased suicidality in children and adolescents who were treated with citalopram. Authors and sponsors are expected to disclose the existence of all data that affects the interpretation of their study. This note will appear in Medline and other databases as a Comment on the paper.
The official complaint [United States and Christopher R. Gobble v. Forest Laboratories Inc. and Forest Pharmaceuticals Inc. Civil Action No. 03-10395-NMG] is posted at …
The article really NEEDS to become freely available on line.
OK, have read it. The full text article REALLY REALLY NEEDS to become freely available on line. Can we pay the publisher a fee to make that happen? I’m absolutely not kidding.
And nothing of consequence will happen to the authors. Well, not the actual authors but the KOLs who signed off on the study.
More on Leemon McHenry:
https://en.wikipedia.org/wiki/Leemon_McHenry
A latter day Paul Meehl?
“Following discussion with the article’s named authors, the medical communications company created an initial draft of the manuscript.”
Huh. I just noticed that line. It does not seem entirely clear that that is accurate?
“Drs. Wagner, Robb, and Findling reported that they had received an initial draft from Dr. Heydom to which they contributed through several drafts….”
That seems accurate. Interestingly, this is not considered an issue at all in the editor commentary. As long as the commercial writing company is referenced.
The dominos are starting to fall. I commend Dr. Jureidini and colleagues, as well as you and your Study 329 reanalysis colleagues, on these critically important and herculean efforts. Through them, we may someday learn that an entire generation of published clinical trials are not worth the paper they’re printed on.
Mickey, recall this post, and my comment: http://1boringoldman.com/index.php/2015/05/27/a-study-worth-looking-into/. Now we know that a second study included in this meta-analysis of 13 trials of antidepressants in youth is rotten. There is good reason to believe Study 329 and the aforementioned citalopram study are the rule, not exceptions to it. Data from these studies (and others that are likely just as fraudulent) have made their way into meta-analyses, clinical guidelines, and routine clinical care for millions of young people.
What do we do now? I have one small suggestion as a starting point: re-conduct meta-analytic studies of antidepressants in youth without data from these two discredited trials. Continued use of antidepressants in youth is supported by highly cited meta-analyses like this one (http://www.ncbi.nlm.nih.gov/pubmed/17440145) that report a small (d = .20) but statistically significant benefit of antidepressants. Let’s see what happens to that effect size when it’s not influenced by fraudulent data.
Brett,
That’s a good thought. I think the first order of business is to be sure this paper gets the attention is deserves and is available in full text on-line. Frankly, the next step ought to come from the FDA and the DOJ [see my next post]. I’m not holding my breath for that, but it definitely is a call for action…