Study 329 was an infamous clinical trial that took place between 1994 and 1998 in the United States of America and Canada. The trial studied the efficacy of the antidepressant drug ‘Paroxetine’ in adolescents who had been diagnosed with depression. Paroxetine is one of the most widely-used antidepressants among adults. The study proved controversial for a number of reasons – most noticeably that the results were intentionally misreported to give an unfair depiction of its implications – while downplaying safety concerns. Since then, several lawsuits were launched, and the medical world has been widely affected by the outcome of this regrettable study. In this article we look at this case in detail.
During the 1980s and 1990s, several new antidepressants were brought to the market. These antidepressants, named SSRIs, replaced many older antidepressants due to their safer profile. SSRIs have enabled many people to recover from their mental health conditions, and are still used hugely to this day. Among the new antidepressants was Paroxetine – known as Paxil or Seroxat. The drug was launched by SmithKline Beecham (later GSK) in 1991, and proved to be a popular medication – securing enormous sales.
Yet one problem with antidepressants is that they have never been considered to be safe in treating adolescents. There was a huge financial incentive for any drug company that could come up with an antidepressant that would work for children. SmithKline Beecham decided to test Paroxetine on adolescents – to see if it would herald a new era of treating adolescent depression – an issue which has grown significantly in recent times. In the contemporary era, Fluoxetine (Prozac) is generally the only SSRI which is prescribed to adolescents.
The study lasted eight weeks. 275 male and female adolescents who had been diagnosed with depression were randomly selected to participate. The 275 participants were split into three groups. One group of 93 were given Paroxetine. Another group of 95 were given Imipramine (Tofranil) – an older antidepressant. Finally, a third group of 89 were given a placebo drug – an inert pill. All three groups were randomly assigned, and no participant knew which drug they were taking. The researchers would administer the drugs for two months – and view the impact they had on the participants’ depression.
Of course, SmithKline Beecham were hoping Paroxetine would lead to an improvement in symptoms. The result however, was anything but. Unbelievably, Paroxetine was no more effective than the placebo pill in improving symptoms of depression. 11 people in the Paroxetine group experienced serious adverse events (such as suicidal gestures or emotional lability) – with only 5 in the Imipramine group and 2 in the placebo group experiencing such events. Withdrawing from Paroxetine was also a considerable problem for participants.
When the study reached its climax, SmithKline Beecham realised that the study failed to show efficacy for Paroxetine in adolescent depression – and really was a complete failure. Yet the trial data wasn’t submitted to regulators. Over the forthcoming years, a journal article was prepared. In 2001, the article was published in the Journal of the American Academy of Child and Adolescent Psychiatry. Yet the claims made in the article didn’t truly reflect the results of the study, and caused considerable controversy.
The study concluded that Paroxetine was ‘generally well tolerated and effective for major depression in adolescents’. Certain paragraphs talking about the dangers of Paroxetine had been removed from a draft copy. The article failed to mention the threat of suicidal thinking and made false claims regarding the effectiveness of the drug. Another controversy arose when it was revealed that the article had also been ghostwritten, despite 22 researchers being listed as co-authors. This means a PR firm had actually written the article for SmithKline Beecham (GSK henceforth), and that researchers had been paid to have their name added to the author list.
GSK used the article to promote Paroxetine as a treatment for adolescent depression, and regulators agreed with the claims the article made. Over 2m prescriptions were written for adolescents in 2002 in the US – amounting to a $50m windfall for GSK. However, a slew of criminal cases cast doubt over the notion that Paroxetine was helpful for adolescent depression. Murders, suicides and general acts of violence were attributed to the drug – before a landmark TV show opened the floodgates for this case.
The BBC’s Panorama show investigated the study in detail. They received tens of thousands of calls from people who claimed to have suffered from taking Paroxetine as an adolescent – including suicidal thinking, self-harm, violence and withdrawal symptoms. Mass hysteria emanated from the show, and this notified medicine regulators. It was eventually demanded that GSK disclosed the entire trial data. They subsequently did, and the UK’s Medicines and Healthcare Products Regulatory Agency (MHRA) studied them in detail.
The MHRA found ‘robust evidence’ that there was a link between Paroxetine and suicidality. Moreover, there was no evidence in the trial data that Paroxetine was effective in treating adolescent depression. They reached the ultimate conclusion that the risks outweighed the benefits in terms of adolescents taking Paroxetine. Both the US and the UK made the recommendation for Doctors not to prescribe Paroxetine to adolescents. The revelation of Study 329’s true results would prove to be a huge issue for GSK, with severe financial implications.
A criminal inquiry into the conduct of GSK was launched. A lawsuit in June 2004 by the State of New York ruled on the accusation that GSK had purposely withheld data from clinical trials about Paroxetine. GSK denied wrongdoing, but paid $2.5m after settling. By 2009, GSK had paid around $1bn to settle various Paroxetine-related lawsuits – which were related to suicides, addiction, birth defects and the withholding of data. In 2011, the United States Department of Justice started proceedings against GSK, who settled for $3bn in damages in 2012.
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Paroxetine is still a widely used antidepressant to this day – yet only in adults. Paroxetine is notorious though for being one of the most difficult antidepressants to withdraw from. This study really didn’t result well for anyone – many adolescents were wrongly prescribed a drug that did more harm than good, and GSK ended up having to pay significant damages. Study 329 has left behind a legacy of both good and bad. The good is that now drug companies are much more transparent in the results of clinical trials. However, for the millions of people wrongly prescribed Paroxetine due to exuberant claims, the impact will surely last forever.