All about Study 329
by Julie Wood, Children of the Cure, Author
In the early 1960’s the pharmaceutical industry began attempting to convince people that depression was an illness that could usefully be treated by drugs. For the first couple of decades, efforts were unsuccessful. People realized that when they were “down” the solutions lay in the passage of time and thoughtful attention to underlying causes.
In the 1970’s, Pharmaceutical manufacturer Eli Lilly began to experiment with a new medication, fluoxetine. By the early 1980’s this first selective serotonin reuptake inhibitor (SSRI), was the focus of a major development effort. When Lilly tried to get the drug approved in Germany in 1985, the regulators there decided the drug was ineffective and risky, and refused to approve it.
To make the drug acceptable to the FDA, Lilly executives altered the data from their studies to remove the evidence of suicidality and in 1987, the FDA gave them the go-ahead to market it in the US. Over the next few years, Prozac (fluoxetine) was hyped as a miracle drug that could make people feel better than well. Despite on-the-ground reports of serious side effects that led to the formation of “survivor” groups around the country, sales of Prozac took off. By now, the campaign to market depression was succeeding and would ultimately increase the rate of depression diagnoses one thousandfold. The NIMH and Lilly had developed a campaign to “educate” the public about depression, and the new wonder drugs that could alleviate it. The Prozac marketing message was picked up and made headlines in New York Magazine and Newsweek.
Eli Lilly was not the only one looking to cash in on the newly created market for depression-fighting medication. SmithKline Beecham (SKB) had been testing paroxetine for use as an antidepressant. In 1991, they presented a report to the FDA, accompanied by data which, if examined closely, showed rates of suicidality more than 2-and-a-half times higher on paroxetine than placebo. This problem was not mentioned in the reported results and in 1992, the FDA, whose members had serious conflicts of interest, approved paroxetine to treat adult depression. Thus, in 1991, SKB released its new drug, calling it Paxil in North America, Seroxat in the UK, and Aropax in Australia.
The next year, 1993, a proposal was developed to study the drug for use in adolescent “depression”. SKB approved it, and Study 329 was launched. Originally, Dr. Neal Ryan was named lead investigator but in the end, Dr. Martin Keller took over as lead. The study enrolled 375 subjects aged 12-18 years, in an 8-week, 2-phase comparison of the effects of imipramine, placebo and paroxetine.
In addition to Doctors Keller and Neal, the research team included Graham Emslie and Karen Wagner. All four of these physicians would be targeted in 2008 by Senator Chuck Grassley in his investigation of serious conflicts of interest in academic medicine. These doctors were taking large payments from pharmaceutical companies at the same time as they were conducting research into their drugs.
Study 329 did not show a clear benefit compared to placebo, and some study participants suffered serious side effects. The researchers played these down by coding suicidality as lability, and overlooking certain adverse events altogether. The data did not support a conclusion of either efficacy or safety.
Another study, 377, was conducted in Europe with the same objective. Completed in 1998, it showed that the children on placebo clearly fared better than the Paxil group.
A 1998 internal SmithKline memo revealed that company executives knew their drug didn’t work and wasn’t safe, and they believed they could not show it to the regulators. Instead of shelving the project, however, they decided to interpret it from a different perspective than originally planned, and to write a positive conclusion at odds with what the data showed. They hired a ghostwriter, Sally Laden, to do this.
The Journal of the American Medical Association (JAMA) declined to publish Study 329, but agreed to forward it to other journals. In July 2001 it was published in the Journal of the American Academy of Child and Adolescent Psychiatry (JAACAP). There were criticisms from the start regarding whether the study’s conclusion that “Paroxetine is generally well tolerated and effective for major depression in adolescents” was supported by the data.
Unfortunately, researchers were unable to resolve the situation by viewing the patient-level Study 329 data. As part of its settlement in a 2004 lawsuit, brought by the Attorney General of New York, GSK (GlaxoSmithKline, as SKB had become) agreed to make its data available to researchers. However, this access never materialized in any meaningful sense.
A number of physicians and researchers continued to express concern about the problems with Study 329, and called for its retraction. For years important questions were raised, and the retraction requests were dismissed and ignored.
In 2005, following a second set of hearings on the issue of SSRIs and suicidality, the FDA belatedly required that a boxed warning be added to Paxil and other SSRI’s, indicating that they can cause suicidality in people under 18. This warning was later extended to include people up to age 24.
In 2012, a team of senior researchers got together with a plan to re-interpret the original Study 329 data as a RIAT (Restoring Invisible and Abandoned Trials) initiative. The RIAT movement was formed in response to growing awareness that randomized control trials, the supposed gold standard for medical research, are routinely based on manipulated and inaccurate data. Reported results are frequently misrepresentations and the results of trials that fail to produce the desired outcomes remain unpublished.
Study 329 went a step further. It was published even though the data did not support the conclusions reached, one reason it is infamous in a business where misrepresentation is common. The other reason is that it was the main supporting evidence supporting countless Paxil prescriptions, including prescriptions to children and adolescents. The drug attracted sales of $11.7 billion in the United States alone from 1997 to 2006, including $2.12 billion in 2002, the year before it lost its patent.
The findings of Restoring Study 329, based on as much of the data as the researchers were able to glean, were opposite to those of the original study. Far from being well-tolerated, the data showed that paroxetine caused serious side effects in young people, including hostility, insomnia, and akathisia. The rate of suicidality in the Paxil group was more than 3 times that of placebo.
Study 329 exposed the ugly underside of drug research. The respected and generously compensated university medical researchers clearly did not think of themselves as murderers or fraudsters. A few minor adjustments to 77,000 pages of written information probably didn’t seem important to those who were even aware of them. Their ivory towers were light years away from the children taking Paxil who experienced serious problems, hanging themselves or otherwise ended their lives in the throes of paroxetine-induced thought disturbance. The agony created in so many households since these drugs became common is simply not on the radars of the perpetrators of the carnage, because the government and the media conspire to support a self-serving, false narrative about what is happening.
Julie Wood is an author of Children of the Cure: Missing Data, Lost Lives and Antidepressants. With her husband Peter, Wood is the driving force behind RxISK.org, SSRI Stories and Study 329.org — a website that hosts all of the documents behind the Study 329 story. Like a growing number of others, she lost a talented and beloved child to antidepressants