A heavily criticized drug study that promoted the use of an antidepressant to treat youth suffering from depression is back in the spotlight after the journal that published it was sued, and a child psychiatrist says he’s hopeful it may lead to the study finally being retracted. Study 329, originally published in the Journal of the American Academy of Child & Adolescent Psychiatry (JAACAP), was a randomized trial that concluded the antidepressant paroxetine, marketed as Paxil in North America, was safe and effective in those between the ages of 12 and 18. But soon after it was published, the study was criticized for allegedly downplaying certain side effects that some trial participants experienced, including suicidal thoughts. A 2015 reanalysis of the trial’s raw data concluded that not only was Paxil ineffective in treating adolescent depression, but it was also unsafe. Despite those findings, the study has not been retracted, though it was recently flagged with an “expression of concern” by the JAACAP. That came after legal action was launched against the American Academy of Child and Adolescent Psychiatry (AACAP) and its publisher Elsevier by a U.S. attorney who alleges the academy and Elsevier are engaging in a “deceptive trade practice” by continuing to sell access to the study. Dr. Jon Jureidini, a child psychiatrist with the University of Adelaide in Australia, has been one of Study 329’s most outspoken critics for more than a decade. He says he was skeptical of the study’s findings when they were first published. “I was kind of concerned, and I guess open to the possibility that perhaps there might be something not quite right about the study, which indeed it turned out that there was,” Jureidini told CTVNews.ca in an interview. “What became apparent after reading the paper carefully a couple of times, and then consulting with my pharmacologist colleague Anne Tonkin, was that they’d done a sleight of hand and misreported the primary outcome.” Jureidini was among a group of experts who conducted the 2015 reanalysis. Also on that team was Dr. Elia Abi-Jaoude, a psychiatrist at The Hospital for Sick Children, also known as SickKids, in Toronto. “It was a very nice team of experts from all around the world, and we collaborated … it was not easy work, even just to get the raw data, but we eventually were able to access the data, and from the raw data, we were able to reanalyze the study as it should have been done,” Abi-Jaoude told CTVNews.ca. “We came to the very opposite conclusions of what the original study (showed). The original study concluded that the drug was generally safe and effective, and we concluded that the study, the drug, was ineffective and unsafe.” ‘Failed to demonstrate efficacy’ The reanalysis, published in British medical journal The BMJ, came three years after Paxil’s maker, now called GlaxoSmithKline (GSK), agreed to pay US$3 billion in court settlements. It was the largest health-care fraud settlement in U.S. history at the time. The U.S. government alleged that between 1998 and 2003, GSK “unlawfully promoted Paxil for treating depression in patients under age 18,” according to a 2012 press release from the U.S. Department of Justice. “GSK participated in 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,” the release read. Despite GSK’s guilty plea, the company has never publicly acknowledged any wrongdoing specific to Study 329, Jureidini said, and the study’s original authors, as well as the JAACAP, have maintained that the study did not violate any standards or practices at the time of publication. In an emailed statement to CTVNews.ca, Elsevier said the publisher “cannot comment on any pending or ongoing legal activity.” The AACAP did not respond to a request for comment. CTVNews.ca also reached out to the original study’s lead author, Dr. Martin B. Keller of Brown University in Rhode Island, as well as Dr. Stan Kutcher, one of three Canadian authors to contribute to Study 329, but did not receive responses. Kutcher, professor emeritus in the department of psychiatry at Dalhousie University, was appointed to the Canadian Senate in 2019. He was one of a number of Study 329 authors who Abi-Jaoude said “dug their heels and insisted that they stand by the original study” after the reanalysis was published. Paxil use in Canada Although Paxil was never approved for people under the age of 18 by Health Canada, it was sometimes prescribed to adolescents anyway, Abi-Jaoude said. “Thankfully, I would say it’s not a drug that is commonly used anymore, at least not for adolescents, so I would say I rarely see it, but I wouldn’t say I never see it,” he explained. “So even to this day, I still see sometimes a young person who is prescribed paroxetine, but certainly it was the case before as well. I mean, this was the purpose of the study.” Jureidini said that “up until as recently as last year, the paper was cited as evidence for the effectiveness of antidepressants,” which is one of the reasons why he’s lobbied for its retraction for nearly 25 years. And even though his efforts have been unsuccessful so far, he says he remains hopeful. “I think there’s a chance that there will be a retraction, and the fact that it’s taken 20 years to achieve that might become a story,” said Jureidini. “And if it does become a story, it might have an impact on other decisions about retraction, so I’ve got a little bit of optimism that some good might come out of it now, but who knows?” Abi-Jaoude said whether Study 329 or other studies like it get revisited, analyzed and possibly retracted comes down to how much public attention they get. “If this does get attention, then I think it behooves us to question what’s going on in our field,” he said. “I think the retraction of the study is important because of what it represents.”
