(Reuters Health) — According to a reanalysis of the original data from a 2001 study of paroxetine (Paxil) for teens with major depression, the drug was not effective and led to serious side effects, which is not how the results were presented 14 years ago.
“There have been warnings about paroxetine for a long time,” including a 2007 Food and Drug Administration advisory on the risk of increased suicidality when antidepressants like paroxetine or imipramine are used to treat people age 18 to 24, according to Dr. Jon Jureidini of the University of Adelaide in Australia.
The authors of the 2001 study did not report this side effect, although the evidence was there, said Jureidini, a coauthor of the reanalysis.
“A broad community of people around the world have raised concerns,” he told Reuters Health by phone.
The original trial, known as ‘Study 329,’ ran from 1994 to 1998 and included 275 teens with major depression. For eight weeks, about a third of them received 20 to 40 milligrams (mg) of paroxetine, another third received up to 300 mg of imipramine (Tofranil), and a third received placebo pills.
The researchers, supported by paroxetine’s maker GlaxoSmithKline, measured the participants’ total Hamilton depression scale score before and after treatment, as well as several other mental health assessment scales.
The original published results described paroxetine as effective and safe.
In the new analysis, Jureidini and colleagues found that neither paroxetine nor imipramine were better than placebo for any measure of depression. Furthermore, the drugs did notably increase harms, like suicidal thoughts and behavioural problems in the paroxetine group and heart problems in the imipramine group.
According to Jureidini’s team, the original analysis departed from the stated protocol for the study and included four more clinical endpoints that were not part of the original design, but were introduced after the data had been collected, which allowed the investigators to present the results as positive.
The original number of side effects seemed to be lower because the authors only included problems that affected at least five per cent of the study participants.
The reanalysis, published in the BMJ, was part of the “restoring invisible and abandoned trials” (RIAT) initiative that began in 2013 and is aimed at publishing undisclosed trial outcomes or correcting misleading publications.
The RIAT organisers identified questionable studies and contacted original study funders and authors asking them to publicize their results or correct their published results.
In the case of Study 329, the original authors and the journal where they published, the Journal of the American Academy of Child and Adolescent Psychiatry, did not agree to make corrections, so another group of researchers set out to reanalyze their now public data.
“This isn’t out and out scientific fraud,” said professor David Henry of the Institute for Clinical Evaluative Sciences in Ontario, Canada, who coauthored an editorial in the BMJ on the importance of clinical data sharing.
“This is a subtle form of manipulation of the analysis of the data and interpretation of the results that may actually happen quite often,” Henry told Reuters Health by phone.
It takes a lot of time and effort to reanalyze this type of data, and academic reviewers are not paid to do it, so it often does not happen, he said.
“Statistical analysis is not black and white, you can make a drug look better than it actually is,” Henry said.
Although paroxetine and imipramine were prescribed for kids and teens following the 2001 publication, this new paper won’t have a big effect on clinical practice, as those prescriptions are much less common now following the FDA advisory and other red flags, he said.
In 2012, GlaxoSmithKline agreed to pay three billion dollars in the largest healthcare fraud settlement in U.S. history, which resolved claims of introducing misbranded drugs and failing to report safety data for some of their products, including Paxil.
Dr. Martin Keller of Brown University and eight of the 22 authors of the original JAACAP paper wrote a letter to the industry site Retraction Watch in response to the reanalysis. Keller shared a copy of the letter with Reuters Health; in it, he and his colleagues express “strong disagreement” with many of the points raised in the BMJ paper.
“That one can do better reanalyzing adverse-event data using refinements in approach that have accrued in the 15 years since a study’s publication is unsurprising and not a valid critique of our study as performed and presented,” Keller and his coauthors write. “In summary, to describe our trial as ‘misreported’ is pejorative and wrong, both from consideration of best research practices at the time, and in terms of a retrospective from the standpoint of current best practices.”
Jureidini says open data sharing could prevent this kind of problem from happening again.
“All of the problems with the (original) paper, none would have been there if their data and protocol were publicly available at publication,” Jureidini said.
“A call has been made for drug companies to publish data, not papers,” he said.
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