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.
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Contributed by Jake Van Der Borne of Anxiety and Depression Solutions.