An amazing letter was sent to the president of the American Psychiatric Association (APA) on August 1, 2016 by no less than sixteen well known medical and psychological professionals from around the globe. They are attempting to have an article published in a 2004 issue of the American Journal of Psychiatry retracted. Their concern was that a recent analysis of that study found “gross misrepresentations” made in the article with regard to use of citalopram (Celexa) in treating child and adolescent depression. As of the beginning of December of 2016, the original journal article is still available; nor does there seem to have been any response to the letter requesting the retraction. Perhaps the APA hopes that if they simply ignore the issue, it will just go away.
The article was ghostwritten by agents of the manufacturer and seriously misrepresented both the effectiveness and the safety of citalopram in treating child and adolescent depression.
The letter was addressed to Dr. Maria Oquendo, the 2016 President of the APA. The coauthors of the letter expressed concerns with the “gross misrepresentations” made within the 2004 article, “A Randomized, Placebo-Controlled Trial of Citalopram for the Treatment of Major Depression in Children and Adolescents.”
Since the publication of the analysis alleging the problems with the 2004 Celexa article, there were three different attempts to have it retracted. In response to a May 9, 2016 letter, the current editor for the American Journal of Psychiatry refused to retract the original study. Two other attempts, one to the former editor of the American Journal of Psychiatry who accepted the article, received no response. Given the failure of the American Journal of Psychiatry to retract the article, the letter’s authors are concerned that children and adolescents are put at risk of unnecessary harm because well-intentioned physicians who continue to prescribe citalopram to children and adolescents are being misled.
The 2004 citalopram study said it provided evidence that “citalopram produces a statistically and clinically significant reduction in depressive symptoms in children and adolescents.” It was said to be superior to placebo and the adverse events were mild.
In conclusion, citalopram treatment significantly improved depressive symptoms compared with placebo within 1 week in this population of children and adolescents. No serious adverse events were reported, and the rate of discontinuation due to adverse events among citalopram-treated patients was comparable to that of placebo. These findings further support the use of citalopram in children and adolescents suffering from major depression.
Yet there have been a series of lawsuits against Forest Laboratories, the manufacturer of Celexa, because of its serious side effects; and for Forrest’s failure to warn about the risks when using Celexa and other SSRIs. Drugwatch noted that Celexa is the best-selling antidepressant in 13 countries. Yet it has been linked to several congenital birth defects as well as autism. FindLaw noted evidence that Celexa and other antidepressants have been linked to an increased risk of suicidal behavior in patients under the age of 25.
Forest Laboratories also pleaded guilty in a 2010 criminal case for misbranding Celexa for a use not approved by the FDA. “According to the Department of Justice, Forest Pharmaceuticals had illegally promoted Celexa for the treatment of depression in children and adolescents. The company also pleaded guilty to obstructing justice and distributing an unapproved drug.” Forest Pharmaceuticals was fined $150 million.
A class action law suit, Celexa and Lexapro Marketing and Sales Practice Litigation, was brought by plaintiffs who alleged that Forest Laboratories misrepresented the safety and efficacy of Celexa and Lexapro when marketing the drugs for off-label pediatric use. Over 63,000 documents from Forest were deposited in a database maintained by the plaintiff’s attorneys. Jureidini, Amsterdam and McHenry reviewed 750 internal documents from this database in their 2016 article for the International Journal of Risk & Safety in Medicine.
They found that the published article, “A Randomized, Placebo-Controlled Trial of Citalopram for the Treatment of Major Depression in Children and Adolescents,” contained efficacy and safety data that was inconsistent with the protocol criteria. Although the published article concluded citalopram was safe and significantly more efficacious than placebo for children and adolescents, the outcome measures “showed no statistically significant differences between citalopram and placebo.”
Unreported procedural deviations contributed to the claimed statistical significance of the primary outcome and negative secondary outcomes were not reported. Moreover, post hoc measures were introduced; and adverse events were misleadingly analyzed. The Wagner et al. citalopram study failed to mention five citalopram-treated subjects who discontinued treatment due to hypomania, agitation, or akathisia. “None of these potentially dangerous states of over-arousal occurred with placebo.” There were also many more adverse gastrointestinal events for citalopram than placebo. Yet the final report grouped the data in a way that masked the evidence for potential gastrointestinal intolerance.
In conclusion, corporate mischaracterisation of clinical trial results is of concern in psychiatry where outcome measures are more subjective and easily manipulated. Because few industry-sponsored studies gain public scrutiny and even fewer are ever formally retracted, it is important to make these articles transparent to correct the scientific record. It is furthermore imperative to inform the medical community of mischaracterized data that could lead to potential harm to children and adolescents who are vulnerable to the effects of medication on the growing brain and may increase suicidal thinking and behaviour.
STAT News reported the retraction request comes after years of controversy over the extent to which some drug makers massaged clinical studies to broaden their medicines’ market. Four years ago, GlaxoSmithKline paid $3 billion to settle civil and criminal charges of “preparing, publishing, and distributing a misleading journal article” about the use Paxil with children and adolescents. “The pill had not been approved for that use and the study cited by federal authorities had been ghostwritten.” David Healy, John Nardo, and Jon Jureidini, three of the sixteen individuals who submitted the letter to the APA requesting that the 2004 citalopram study be retracted, have been actively involved in critiquing the misrepresentation of Study 329 and attempting to get it retracted as well. See a series of articles Healy has written on this issue here, in the Mad in America archives.
After a running a gauntlet of reviews, Le Noury et al. were able to successfully publish a reanalysis of Study 329 in the British Medical Journal. But getting there wasn’t easy, see: “Restoring Study 329: Letter to BMJ” and “The Troubled Life of Study 329: Consequences of Failure to Retract.” However, the original article, “Efficacy of Paroxetine in the Treatment of Adolescent Major Depression, A Randomized Controlled Trial,” was never retracted by Journal of the American Academy of Child and Adolescent Psychiatry (JAACAP).
Hmmm. Perhaps my opening comment that the APA is hoping the request to withdraw the 2004 citlopram article, “A Randomized, Placebo-Controlled Trial of Citalopram for the Treatment of Major Depression in Children and Adolescents,” wasn’t all that smarmy. They could be hoping that it will just fade away like footprints in the sand.