The widely used antidepressant paroxetine is neither safe nor effective for adolescents with depression, concludes a re-analysis of an influential study originally published in 2001. The new results, contradict the original research findings that portrayed paroxetine as an effective and safe treatment for children and adolescents with major depression.
It is the first trial to be re-analysed and published under an initiative called RIAT (Restoring Invisible and Abandoned Trials), which encourages abandoned or misreported studies to be published or formally corrected to ensure doctors and patients have complete and accurate information to make treatment decisions.
In 2001 SmithKline Beecham, now GlaxoSmithKline (GSK), funded a study (known as Study 329) to compare the effectiveness and safety of the antidepressant drugs paroxetine and imipramine with placebo for adolescents diagnosed with major depression. It reported that paroxetine was safe and effective for adolescents and was published in the Journal of the American Academy of Child and Adolescent Psychiatry (JAACAP) in 2001. The study was criticised by the US Food and Drug Administration (FDA) in 2002. Yet, that year, over 2m prescriptions were written for children and adolescents in the US. In 2012 GSK was fined a record $3bn in part for fraudulently promoting paroxetine.
The RIAT team, led by Professor Jon Jureidini at the University of Adelaide, identified this study as an example of a misreported trial in need of restoration. Using previously confidential trial documents, they re-analysed the original data and found that neither paroxetine nor high dose imipramine was more effective than placebo in the treatment of major depression in adolescents. The authors considered the increase in harms with both drugs to be clinically significant. They conclude that “paroxetine was ineffective and unsafe in this study.”
The re-analysis of Study 329 “illustrates the necessity of making primary trial data and protocols available to increase the rigour of the evidence base,” say the authors.
In an accompanying article, Peter Doshi, sssociate editor for The BMJ says the new paper “has reignited calls for retraction of the original study and put additional pressure on academic and professional institutions to publicly address the many allegations of wrongdoing.” He points out that the original manuscript was not written by any of the 22 named authors but by an outside medical writer hired by GSK. And that the paper’s lead author – Brown University’s chief of psychiatry, Martin Keller – has been the focus of a front page investigation in the Boston Globe in 1999 that documented his under-reporting of financial ties to drug companies.
Doshi also details the refusal of the American Academy of Child and Adolescent Psychiatry to intervene and retract the paper, and Brown University’s silence over its faculty’s involvement in Study 329. “It is often said that science self corrects. But for those who have been calling for a retraction of the Keller paper for many years, the system has failed,” argues Doshi.
Dr Fiona Godlee, The BMJ editor-in-chief says publication of the re-analysed data from Study 329 “sets the record straight” and “shows the extent to which drug regulation is failing us.” It also shows that the public and clinicians do not have the unbiased information they need to make informed decisions. She calls for independent clinical trials rather than trials funded and managed by industry, as well as legislation “to ensure that the results of all clinical trials are made fully available and the individual patient data are available for legitimate independent third party scrutiny.”
Liberating the data from clinical trials has the potential to benefit patients, prevent harm, and correct misleading research, writes Professor David Henry at the University of Toronto, in an accompanying editorial. Data sharing is not without its risks, he says, but the pay-off from a systematic effort to reactivate important clinical trials will be high and will further justify the original huge investments of time and money, he concludes.
Dr David Healey, writing on the Mad In America website, notes that Study 329’s problems started to surface right after it was published. Several doctors wrote letters to the JAACAP Editor with probing questions, mostly centred on the psychiatric side effects of paroxetine, and the measures used to claim its efficacy in treating adolescents. The authors responded and the questioners did not pursue their concerns further. Except one. Child Psychiatrist Jon Jureidini, M.D. from the University of Adelaide remained convinced that there were serious methodological problems hiding real harms, and he never stopped pushing to expose the truth.
After Study 329 was accepted but before it was published, a Wyoming jury awarded $6.4 million to the relatives of retired oilman Don Schell (Tobin v.SmithKline Beecham). Forty-eight hours after Mr. Schell had been prescribed paroxetine (Paxil), he put bullets through the heads of his wife, Rita, his daughter, Deborah, and his granddaughter, Alyssa. Then he shot and killed himself. The jury decided that Paxil was responsible for the tragedy.
Scottish journalist Shelley Jofre, having learned about the Schell case, did some research on the drug and arranged to do a program on paroxetine, known as Seroxat in the U.K., for BBC’s Panorama. The segment, Secrets of Seroxat, aired in October 2002. It revealed that the drug can cause suicidal and violent thoughts and behaviours, and that many people experience serious withdrawal problems. The show received such a huge public response that a second episode was developed, Emails from the Edge.
Following Secrets of Seroxat, the U.K. public was highly sensitized to the potential problems associated with paroxetine. In December of the year that Emails from the Edge was broadcast, the Medicines and Healthcare Products Regulatory Agency (MHRA) issued an advisory warning to physicians against prescribing SSRI antidepressants, including Seroxat, to people under age 18.
In June of 2004, New York State Attorney General Elliot Spitzer filed a lawsuit accusing British drug giant GlaxoSmithKline PLC of “repeated and persistent fraud” for concealing known problems with efficacy and safety of Paxil (paroxetine) for children and adolescents. Evidence was largely based on documents that had come to light in the Tobin case. The suit was settled for $2.5 million plus a promise by GSK that they would make their drug trial data accessible. Later that year, the FDA required that a “black box” warning label be added for all SSRI antidepressants, including Paxil.
In 2008, US Senator Chuck Grassley investigated serious violations of conflict of interest policies among high-profile academic psychiatrists, including Martin Keller, lead author of Study 329, and three of his coauthors. Senator Grassley’s investigation brought attention to the fact the nominal authors in many research studies are not the real authors. This was the case in Study 329. GSK hired a “ghostwriter”, Sally Laden of STI, to write the study article under GSK direction.
Over the next few years, many lawsuits involving suicidality and violence caused by paroxetine were settled. In addition, Paxil and other SSRI drugs became the target of lawsuits for causing birth defects. The FDA recognized suicidality and violence as side effects of SSRI antidepressants in all age groups and expanded the required “black box” warning.
In 2012, the U.S. Department of Justice brought an action in U.S. District Court to recover damages and civil penalties from GSK under the False Claims Act, and damages and other monetary relief under common law and equity for causing the submission of false or fraudulent claims to federal health care programs. Three drugs were implicated, including Paxil. This action was settled for $3 billion, the largest settlement of its kind.
All in all, the past decade was not an unqualified success for Paxil and its manufacturer. Still, the conclusion of Study 329, that “Paroxetine is generally well tolerated and effective for major depression in adolescents”, has stayed officially intact, since the study was never retracted, and has been widely cited.”
Objectives: To reanalyse SmithKline Beecham’s Study 329 (published by Keller and colleagues in 2001), the primary objective of which was to compare the efficacy and safety of paroxetine and imipramine with placebo in the treatment of adolescents with unipolar major depression. The reanalysis under the restoring invisible and abandoned trials (RIAT) initiative was done to see whether access to and reanalysis of a full dataset from a randomised controlled trial would have clinically relevant implications for evidence based medicine.
Design: Double blind randomised placebo controlled trial.
Setting: 12 North American academic psychiatry centres, from
20 April 1994 to 15 February 1998.
Participants: 275 adolescents with major depression of at least eight weeks in duration. Exclusion criteria included a range of comorbid psychiatric and medical disorders and suicidality.
Interventions: Participants were randomised to eight weeks double blind treatment with paroxetine (20-40 mg), imipramine (200-300 mg), or placebo.
Measures: The prespecified primary efficacy variables were change from baseline to the end of the eight week acute treatment phase in total Hamilton depression
scale (HAM-D) score and the proportion of responders (HAM-D score ≤ 8 or ≥ 50% reduction in baseline HAM-D) at acute endpoint. Prespecified secondary outcomes were changes from baseline to endpoint in depression items in K-SADS-L, clinical global impression, autonomous functioning checklist, self-perception profile, and sickness impact scale; predictors of response; and number of patients who relapse during the maintenance phase. Adverse experiences were to be compared primarily by using descriptive statistics. No coding dictionary was prespecified.
Results: The efficacy of paroxetine and imipramine was not statistically or clinically significantly different from placebo for any prespecified primary or secondary efficacy outcome. HAM-D scores decreased by 10.7 (least squares mean) (95% confidence interval 9.1 to 12.3), 9.0 (7.4 to 10.5), and 9.1 (7.5 to 10.7) points, respectively, for the paroxetine, imipramine and placebo groups (P
=0.20). There were clinically significant increases in harms, including suicidal ideation and behaviour and other serious adverse events in the paroxetine group and cardiovascular problems in the imipramine group.
Conclusions: Neither paroxetine nor high dose imipramine showed efficacy for major depression in adolescents and there was an increase in harms with both drugs. Access to primary data from trials has important implications for both clinical practice and research, including that published conclusions about efficacy and safety should not be read as authoritative. The reanalysis of Study 329 illustrates the necessity of making primary trial data and protocols available to increase the rigour of the evidence base.