Researchers Fight to Undo a Depression Drug's Dark History

Last August, 16 doctors, researchers and academics sent a letter to the president of the American Psychiatric Association (APA) pressing her to retract a published study promoting the benefits of citalopram (CELEXA) for the treatment of depression in children and teens.[1]

The letter’s authors alleged that the study was actually ghostwritten by agents of the drug’s then manufacturer, Forest Laboratories (now Allergan[2],[3]), and seriously misrepresented the effectiveness and safety of the drug.

The story of alleged misconduct surrounding this publication, fully revealed only recently in unsealed court documents, offers a rare window into the tools pharmaceutical companies use to influence the scientific literature — and the lasting impact this can have on patient care.

Initial impact

The original citalopram study was published in 2004 in the American Journal of Psychiatry, the official journal of the APA.[4] The lead author, Dr. Karen Wagner, was influential in her field and now serves as president-elect of the American Academy of Child and Adolescent Psychiatry.[5]

The Wagner paper described what appeared to be an objective double-blind, randomized controlled trial, the gold standard for drug research. It was one of the first published studies documenting an effective treatment for childhood and adolescent depression, and it reported only mild adverse effects with use of citalopram.

Although citalopram was not then (and has never been) approved by the Food and Drug Administration (FDA) for use in children or adolescents,[6] Wagner and her colleagues concluded that their eight-week study “further support[ed] the use of citalopram in children and adolescents suffering from major depression.”[7]

Eager to promote the use of citalopram for treatment of these younger patients, Forest aggressively publicized the Wagner paper, presenting it to professional societies, pitching it to various media outlets and arranging for Dr. Wagner to chair a continuing medical education program to educate doctors about the study.[8]

The paper and accompanying marketing effort seemed to have an impact. One UK study showed that prescriptions for children and adolescents were declining in the year before the Wagner paper was published but saw a steep jump in the year afterwards, rising quickly to outpace fluoxetine (PROZAC, SELFEMRA) as the most popular antidepressant for children over the next six years.[9]

Secret documents disclosed

Pharmaceutical manufacturers have historically maintained tight control over data from their drug studies. Yet this tight hold is broken when an injured patient sues a manufacturer, which then must hand over confidential documents under court order. Unfortunately, documents obtained in this way often remain under seal by the court, preventing public access.

Only in rare cases are these secret documents revealed to the public. This happened in a lawsuit against Forest that was settled in part in 2014, when patients’ attorneys fought successfully to have some of the confidential corporate documents related to the Wagner paper unsealed and placed in a public online archive.[10]

Company control

The unsealed documents describe how Dr. Karen Wagner and the other authors listed on the citalopram publication did not draft the original manuscript.[11]

Instead, the paper was ghostwritten by Natasha Mitchner, a contractor hired by Forest’s marketing department. This allowed the company to maintain control over content, as one of Mitchner’s colleagues wrote:

… I’ve heard through the grapevine that not all the data look as great as the primary outcome data. For these reasons (speed and greater control) I think it makes sense to prepare a draft in-house that can then be provided to Karen Wagner (or whomever) for review and comments.[12]

Ghostwriting was a common practice for Forest at the time when the citalopram paper was written. The company’s 2004 marketing plan for escitalopram (LEXAPRO), a drug that is virtually identical to citalopram,[13] stated that Forest would “fold Lexapro messages into articles on depression, anxiety and co-morbidity developed by (or ghostwritten for) thought leaders.”[14]

Spinning the science

Maintaining control of the trial data and manuscript drafting allowed Forest to selectively spin the results presented in the Wagner paper to favor citalopram. Had they reported only the results based on the protocol that had been developed before the study began, the drug would not have appeared more effective than placebo.[15]

The ghostwriting team modified these results by including data from eight subjects who became aware that they were taking citalopram due to a packaging error during the study.[16] These subjects may have responded more positively to treatment once they knew they were taking an active drug and not a placebo, and including them in the results made the drug appear to be more effective than it otherwise would have. Indeed, when these subjects were removed from the results, citalopram no longer appeared to be more effective than placebo. The inclusion of these eight “unblinded” subjects, a violation of the study protocol, was not reported in the Wagner paper.[17]

And although the Wagner paper described only mild side effects, such as nausea and fatigue, troubling signs of agitation went unreported. In fact, eight subjects taking citalopram displayed signs of agitation, hypomania (unusual gaiety, excitement or irritability), anxiety or other states of emotional arousal, whereas only one subject taking placebo experienced such psychiatric symptoms.[18]

Worst of all, while Forest swiftly published and aggressively publicized the Wagner paper, the company sat on the results of a second study in adolescents that had provided much more negative results. In that second study, which was not published until 2006, citalopram had not even come close to proving more effective than placebo. Moreover, twice as many subjects taking citalopram displayed suicidal thoughts or behavior than those taking placebo (although the number of these occurrences was small enough that the difference may have been due to random chance).[19]

Irreversible damage

The APA is unlikely to retract the ghostwritten Wagner article in response to the letter sent last August, as the American Journal of Psychiatry’s editor-in-chief had already curtly rejected a similar request for a retraction earlier in 2016.[20]

The journal’s editors had also stood by the paper in 2009 when the Celexa lawsuit first made the news, stating that the authors’ failure to disclose the ghostwriter and the negative 2006 study results was inappropriate but issuing no retraction.[21] (The editors were apparently still unaware at the time that the inclusion of unblinded subjects had influenced the study results.)

Even if the Wagner paper is retracted, it may be impossible to fully reverse the impact the study has had on prescribing practices. The study has now been cited in multiple systematic reviews and its impact is magnified by the fact that only two randomized controlled trials have tested the effectiveness of citalopram for depression in children or adolescents.[22]

Sales of citalopram may have declined somewhat after the FDA issued a safety announcement in 2011 warning of potential heart-related risks. Yet the drug remains popular,[23] and the current FDA-approved label misleadingly suggests ways to use the drug safely in children[24] even though it remains unapproved for this population.

UpToDate, a comprehensive web-based resource used by doctors across numerous medical fields, currently recommends fluoxetine and sertraline (ZOLOFT) as first and second choices, respectively, for treatment of childhood depression.

Yet it also states that “escitalopram or citalopram are reasonable choices based upon their efficacy in randomized trials.” To support this recommendation, UpToDate cites a review that relies on the Wagner study without any reference to the lawsuit or criticisms.[25]

What You Can Do

Do not use citalopram or its nearly identical sister drug, escitalopram, to treat depression in children or adolescents, because these drugs have not shown consistent effectiveness in clinical studies and may increase the risk of suicide for younger patients. Never stop taking a prescription medication without first talking to the prescribing health care professional.
 

References


[1]Letter to Maria A. Oquendo, M.D. President, American Psychiatric Association. August 1, 2016. http://freepdfhosting.com/227f65241d.pdf. Accessed March 8, 2017.
[2]Humer C, Dey E. Actavis to buy Forest for $25 billion; windfall for investor Icahn. Reuters. February 18, 2014. https://www.reuters.com/article/us-actavis-forestlabs-idUSBREA1H0TI20140219. Accessed March 8, 2017.
[3]Allergan. Actavis plc is now Allergan plc. June 15, 2015. https://www.allergan.com/news/news/thomson-reuters/actavis-plc-is-now-allergan-plc. Accessed March 8, 2017.
[4]Wagner KD, Robb AS, Findling RL, et al. A randomized, placebo-controlled trial of citalopram for the treatment of major depression in children and adolescents. Am J Psychiatry. 2004;161(6):1079-1083.
[5]Jureidini JN, Amsterdam JD, McHenry LB. The citalopram CIT-MD-18 pediatric depression trial: Deconstruction of medical ghostwriting, data mischaracterization and academic malfeasance. Int J Risk Saf Med. 2016;28(1):33-43.
[6]Allergan USA, Inc. Label: citalopram [CELEXA]). January 2017. https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=4259d9b1-de34-43a4-85a8-41dd214e9177&type=pdf&name=4259d9b1-de34-43a4-85a8-41dd214e9177. Accessed March 8, 2017.
[7]Wagner KD, Robb AS, Findling RL, et al. A randomized, placebo-controlled trial of citalopram for the treatment of major depression in children and adolescents. Am J Psychiatry. 2004;161(6):1079-1083.
[8]United States of America ex rel. Christopher R. Gobble, et al. v. Forest Laboratories Inc., and Forest Pharmaceuticals, Inc. Civil Action No. 03-10395-NMG. February 13, 2009.
[9]John A, Marchant AL, Fone DL, et al. Recent trends in primary-care antidepressant prescribing to children and young people: an e-cohort study. Psychol Med. 2016;46(16):3315-3327.
[10]Jureidini JN, Amsterdam JD, McHenry LB. The citalopram CIT-MD-18 pediatric depression trial: Deconstruction of medical ghostwriting, data mischaracterization and academic malfeasance. Int J Risk Saf Med. 2016;28(1):33-43.
[11]Ibid.
[12]Ibid.
[13]Allergan USA, Inc. Label: escitalopram (LEXAPRO). January 2017. https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=13bb8267-1cab-43e5-acae-55a4d957630a&type=pdf&name=13bb8267-1cab-43e5-acae-55a4d957630a. Accessed March 8, 2017.
[14]Jureidini JN, Amsterdam JD, McHenry LB. The citalopram CIT-MD-18 pediatric depression trial: Deconstruction of medical ghostwriting, data mischaracterization and academic malfeasance. Int J Risk Saf Med. 2016;28(1):33-43.
[15]Ibid.
[16]Ibid.
[17]Ibid.
[18]Ibid.
[19]Von Knorring AL, Olsson GI, Thomsen PH, et al. A randomized, double-blind, placebo-controlled study of citalopram in adolescents with major depressive disorder. J Clin Psychopharmacol. 2006;26(3):311-315.
[20]Letter to Maria A. Oquendo, M.D. President, American Psychiatric Association. August 1, 2016. http://freepdfhosting.com/227f65241d.pdf. Accessed March 8, 2017.
[21]Freeman R, Roy M, Editor’s Note. Am J Psychiatry 166(8):942-943.
[22]Hetrick SE, McKenzie JE, Cox GR, Simmons MB, Merry SN. Newer generation antidepressants for depressive disorders in children and adolescents. Cochrane Database Syst Rev. 2012, 11: CD004851.
[23]John A, Marchant AL, Fone DL, et al. Recent trends in primary-care antidepressant prescribing to children and young people: an e-cohort study. Psychol Med. 2016;46(16):3315-3327.
[24]Allergan USA, Inc. Label: citalopram [CELEXA]). January 2017. https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=4259d9b1-de34-43a4-85a8-41dd214e9177&type=pdf&name=4259d9b1-de34-43a4-85a8-41dd214e9177. Accessed March 8, 2017.
[25]Moreland CS, Bonin L. Pediatric unipolar depression and pharmacotherapy: Choosing a medication. December 8, 2016. https://www.uptodate.com. Accessed March 8, 2017.