Draw the curtain, the fraud is over. – François Rabelais
The antidepressant paroxetine is approved to treat depression, obsessive-compulsive disorder, post-traumatic stress disorder, and social anxiety in adults, but the drug’s use in teenagers has long been controversial.
Now, a major reanalysis of tens of thousands of original research documents has revealed that paroxetine is not only ineffective for teens with depression – the drug is not safe for adolescents.
For the new analysis, published in The BMJ, an international group of scientists conducted a thorough review of a study titled Efficacy of Paroxetine in the Treatment of Adolescent Major Depression, A Randomized Controlled Trial. The research, more commonly known as Study 329, was originally published in the Journal of the American Academy of Child and Adolescent Psychiatry in 2001.
Study 329 was a clinical trial conducted in North America from 1994 to 1998 to study the efficacy of paroxetine, an SSRI antidepressant marketed as Paxil and Seroxat, in treating depressed teenagers.
The study concluded that paroxetine is “generally well tolerated and effective for major depression in adolescents.” It became controversial because the article that reported the results was ghostwritten by a PR firm hired by the drug’s manufacturer, GlaxoSmithKline (GSK) and downplayed the trial’s negative findings.
The company relied on that public relations article to promote the use of Paxil in teenagers. Drug companies are prohibited from promoting drugs for uses that have not been approved, but doctors are allowed to prescribe drugs for what is known as off-label use.
In the UK 32,000 prescriptions for paroxetine were written for children and adolescents in 1999, and in the U.S. that figure rose to 2.1 million in 2002, earning GSK $55 million. Between 1997 and 2006, the drug brought in $11.6 billion.
By 2007, it was the fifth-most prescribed antidepressant drug in the U.S., with more than 18 million yearly prescriptions.
Suicide, Suits, and Settlements
In the years after Study 329’s publication, reports of suicidal thoughts and behavior in teens taking the drug raised questions about paroxetine’s effectiveness and safety. In 2002, the U.S. Food and Drug Administration began investigating the drug’s potential dangers among adolescents. The following year, the agency advised doctors not to prescribe it to teens suffering from depression.
In 2004, an FDA panel voted to require manufacturers of antidepressants to include a black box warning – the most serious warning for prescription medications – on their product labels. That requirement mandated that the labels on Paxil and other SSRIs state clearly that taking the drugs “increased the risk compared to placebo of suicidal thinking and behavior in children, adolescents and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders.” The warning also stated that anyone who takes the medication for depression should be watched closely for signs of suicidal behavior and other significant behavioral changes.
Also in 2004, New York Attorney General Elliot Spitzer filed a consumer fraud action against GSK for mismatches between its marketing claims and the data. The lawsuit was settled for $2.5 million, and the terms included requiring GSK to post study results on its website, including those for Study 329. Access to original trial data was still difficult for researchers, however, due to different interpretations of what should be included in “data” and what constitutes “access.”
In 2011, the U.S. Department of Justice filed a lawsuit under the False Claims Act accusing GSK of promoting drugs for unapproved uses, failing to report safety data, reporting false prices to Medicaid, and paying kickbacks to physicians in the form of gifts, trips, and sham consultancy fees. The complaint included preparing the JAACAP article about Study 329, exaggerating paroxetine’s efficacy while downplaying the risks, and using the article to promote the drug for adolescent use, which was not approved by the FDA.
In 2012, GSK pleaded guilty and paid $3 billion in fines – the largest health care fraud settlement in U.S. history – which included a criminal fine of $1 billion. The fine also included an amount for “preparing, publishing and distributing a misleading medical journal article that misreported that a clinical trial of Paxil demonstrated efficacy in the treatment of depression in patients under age 18, when the study failed to demonstrate efficacy.”
Approximately 5,000 people in the U.S. have filed paroxetine-related lawsuits against GlaxoSmithKline. By 2009, GSK had paid almost $1 billion to settle lawsuits related to 450 suicides, withholding data, as well as addiction, antitrust, and other claims. By July 2010, the drug company had paid $1.14 billion in settlements of approximately 800 Paxil birth defects lawsuits.
But Study 329 was never retracted or edited, despite the lawsuits and settlements, and despite requests from doctors and researchers who questioned the drug’s effectiveness and safety.
Reanalysis Uncovers Disturbing Information
In 2014, after many years of challenges, a group of researchers was finally able to gain access to GSK’s paroxetine study data, including 77,000 pages of redacted patient information.
Their review of Study 329 is the first trial to be reanalyzed and published by The BMJ under a new initiative called RIAT, which stands for Restoring Invisible and Abandoned Trials. RIAT 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.
Time reports that reanalysis author Dr. Jon Jureidini, professor and research leader of critical and ethical mental health at the University of Adelaide, said the authors of the original 2001 paper “deliberately misrepresented the outcomes of the study” and changed the protocols of the study without following the proper procedures to do so:
All trials are designed with a strict protocol that defines, before the trial starts, what the researchers will measure and how they will measure it. These protocols are approved by review boards to ensure that they are scientifically sound and that they follow ethical guidelines for protecting the safety of the trial participants, who volunteer for the study. Any change in the objectives needs to be submitted to and approved by the board again.
However, that’s not what the authors appear to have done for Study 329. While they laid out two primary objectives—where the participants ended up on a depression rating scale, and the change in this measure from the start to the end of the study—these were not the outcomes they reported on.
Instead, they reported on a modified version of one of the outcomes and four additional outcomes that were listed as secondary, not primary, objectives.
Dr. Jureidini added that adverse events were not reported in the proper way, with suicide attempts severe enough to require hospitalization vaguely labeled as “emotional liability.”
Dr. David Healy, a professor of psychiatry at Bangor University in Wales, who worked with Jureidini on the reanalysis, told The New York Times that five of six adverse events labeled “emotional liability” in the original study involved suicidal thinking or behavior but were not presented as such. The patient-level files provided detail on what actually happened in those cases: One teenager was hospitalized after taking 80 Tylenol tablets. Another overdosed on Paxil and other medications after a “disagreement with her mother.” Others suffered “severe suicidal ideation,” and one was “admitted due to severe suicidal and homicidal ideation, towards his parents.”
Q. Why is paroxetine so dangerous?
A: All SSRI antidepressants increase the risk of disturbed thinking for a significant percent of users. This can include manic reactions, psychosis, hostility, violent impulses, social withdrawal, paranoia and suicidal preoccupation. Dependence is a common problem, leading to serious difficulties upon withdrawal. There is evidence that long-term use of SSRIs worsens the prognosis for recovery from depression.
Q. Are selective serotonin-reuptake inhibitors useful medications or not?
A. SSRIs can be useful for a small group of people, especially when used for a limited time. Careful assessment and monitoring are critical to ensure that only people who can truly benefit are given these drugs. Because most people who get prescriptions for them cannot benefit. Given that harms often outweigh the benefits, the current extent of prescribing SSRIs will some day be viewed as a major disaster.
Implications of the Findings
Unfortunately, Study 329 is unlikely to be an exception: drug studies have long been known to be flawed, mainly because testing is conducted by the very entities that stand to profit from sales of the medications – the drug manufacturers.
In a press release, Dr. Fiona Godlee, The BMJ Editor-in-Chief, says publication of the reanalyzed data from Study 329 “sets the record straight” and “shows the extent to which drug regulation is failing us.”
RIAT’s reanalysis also shows that the public and clinicians do not have the unbiased information they need to make informed decisions. Dr. Godlee is calling 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.”
Dr. Healy says he believes that the issues uncovered are bigger that what happened with Study 329:
This was not an anomaly, but rather what has become standard industry practice for branded medicines. It raises many questions about drug safety, the limitations of randomized controlled trials, the need for access to individual patient level data, and the question of how to reduce harms from misleading health information.
Dr. Jon Jureidini added:
Our reanalysis of Study 329 reveals that drug regulators, pharmaceutical companies, senior ‘independent’ researchers, and journal editors are all failing patients. The core problem is that the process for safety and effectiveness testing is left to drug manufacturers, who have a vested interest in seeing positive results without the medical and scientific community being able to scrutinize what they are doing.
In an article about the study, Peter Doshi, associate editor for The BMJ, says the new analysis 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.”
Over the years, thousands of people taking or withdrawing from Paxil and other psychiatric drugs have committed violent acts, including suicide, experts say, though no firm statistics are available. Because many factors could have contributed to the behavior, it is still far from clear who is at risk.
With the current reanalysis, more doctors may weigh the risks of potential increased suicide risk more heavily before prescribing the drug to teens. Experts say that at the very least, doctors who decide to prescribe paroxetine should monitor their patients more carefully for any potential signs of worsening depression or desire to harm themselves.