1 Boring Old Man

The citalopram CIT-MD-18 pediatric depression trial: Deconstruction of medical ghostwriting, data mischaracterisation and academic malfeasance

by Jureidini, Jon, Amsterdam, Jay, McHenry, Leemon

International 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:

• 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
• 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
• 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
• 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

• 2006: ACNP Task Force Report on SSRIs and Suicidal Behavior in Youth.
  by Mann JJ, Emslie G, Baldessarini RJ, Beardslee W, Fawcett JA, Goodwin FK, Leon AC, Meltzer HY, Ryan ND, Shaffer D, and Wagner KD

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. The 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."

A Randomized, Placebo-Controlled Trial of Citalopram for the Treatment of Major Depression in Children and Adolescents

by Karen Dineen Wagner, Adelaide S. Robb, Robert L. Findling, Jianqing Jin, Marcelo M. Gutierrez, and William E. Heydorn

American Journal of Psychiatry. 2004 161:1079-1083.

[full text online]

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’ Note

by Robert Freedman and Michael D. Roy

American 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 …