A controversial clinical trial of the antidepressant Paxil came to the wrong conclusion when it declared the drug safe and effective for treating troubled teenagers, according to a reanalysis of the original data more than a decade later.
This new look finds Paxil (paroxetine) can make some teenagers suicidal and likely to harm themselves, claims a report published Sept. 17 in the BMJ.
"The original study says paroxetine is safe and effective for the treatment of depressed adolescents," said co-author Dr. John Nardo, a psychiatrist with the Emory University Psychoanalytic Institute in Atlanta.
"Ours says paroxetine is neither safe nor effective in the treatment of adolescents," Nardo added. "And I don't know of any example where two studies in the literature with the same data ever reached opposite conclusions."
This reassessment was prompted by the RIAT (restoring invisible and abandoned trials) initiative, launched by an international group of researchers, Nardo said. RIAT calls for the public release of data behind unpublished or questionable clinical trials so that outside experts can check the findings, he explained.
The original trial, known as Study 329, has been controversial ever since its 2001 publication, Nardo said.
That trial was funded by the drug's marketer, SmithKline Beecham, which is now GlaxoSmithKline (GSK). The medication is currently marketed in the United States by the drug company Apotex, GSK officials said.
A year after Study 329's release, the U.S. Food and Drug Administration declared it should be considered "a failed trial," according to an editorial by BMJ Associate Editor Peter Doshi that accompanies the new analysis.
Despite this, more than 2 million prescriptions were written for U.S. children and teenagers in 2002, spurred by a marketing campaign that said Study 329 had demonstrated Paxil's "remarkable efficacy and safety," Doshi wrote.
In 2003, the FDA mandated a "black box" warning -- the most serious type of warning in prescription drug labeling -- for Paxil and other selective serotonin reuptake inhibitor (SSRI) antidepressants. The warning signaled a possible risk of suicidal thoughts among children and teens.
GlaxoSmithKline agreed to make the data behind Study 329 publicly available as part of a 2004 court settlement in New York, Nardo said.
The drug manufacturer has since come out in favor of transparency in clinical trials, and provided electronic access to the data for the new analysis, the company said in a statement.
The original trial involved 275 kids, between 12 and 18 years old, diagnosed with major depression. They were split into three groups and received either Paxil, the antidepressant drug imipramine (Tofranil), or an inactive placebo.
The new reanalysis revealed that neither Paxil nor high-dose imipramine was more effective than a placebo in the treatment of major depression in adolescents. The researchers also considered the increase in harms with both drugs to be clinically significant.
The original results appear to have been skewed by several decisions researchers made during data analysis, Nardo said.
For example, the way the researchers classified teenagers' behavior caused them to undercount the number of suicidal ideas or self-injurious actions, such as cutting or jumping from heights. Some were categorized as "emotional lability" -- the tendency to laugh or cry unexpectedly -- and this masked differences in suicidal behavior between Paxil and placebo, the reanalysis found.
The new paper also pointed out that the trial researchers ignored unfavorable data about potential harms on the grounds that the differences between Paxil and placebo were not statistically significant.
Based on the reanalysis, people can conclude that the original report "was misleading," said Dr. David Henry, a professor at the University of Toronto Dalla Lana School of Public Health and co-author of a second editorial accompanying the BMJ paper.
"It's not clear whether it was deliberate or accidental, but it wrongly gave the impression that an antidepressant drug was effective and safe in children and adolescents," Henry said. "Where trials are going to determine treatment for very large numbers of people, we need to know they are effective and safe, and sometimes the results are wrong."
Henry said that people concerned about the credibility of future studies should stick with established medical journals.
"The high-quality, high-impact peer-reviewed journals didn't get there by chance," he said. "They have really done their work, and they're realizing now that these problems occur so they're taking more care."
GlaxoSmithKline said the new results reaffirm concerns that have become widely known since Study 329's initial release.
"Importantly, the findings from this team's analysis appear to be in line with the longstanding view that there is an increased risk of suicidality in pediatric and adolescent patients given antidepressants like paroxetine," the company said in its statement. "This is widely known and clear warnings have been in place on the product label for more than a decade. As such we don't believe this reanalysis affects patient safety."
This particular trial, conducted in the 1990s, "was included in detailed reviews carried out many years ago by regulators and by GSK, which identified the increased risk. It's something the medical community and regulators are aware of," the statement concludes.
