Paroxetine is not a safe or effective drug for adolescent major depression, according to a reanalysis of data from a prominent and controversial trial.
The findings highlight the problem of bias in published studies, including underreporting of harms, Joanna Le Noury, Ph.D., of Bangor (Wales) University and her associates wrote online Sept. 16 in The BMJ. “Regulatory authorities should mandate accessibility of data and protocols,” the investigators added (BMJ 2015;351:h4320. doi: 10.1136/bmj.h4320).
Published in 2001, Study 329 was a randomized, multicenter, double-blind, placebo-controlled trial of 275 adolescents aged 12-18 whose major depression had lasted at least 8 weeks. Patients received 20-40 mg paroxetine once daily, 200-300 mg imipramine once daily, or placebo. Dr. Martin B. Keller of Brown University, Providence, R.I., and his colleagues concluded that paroxetine “is generally well tolerated and effective for major depression in adolescents” (J Am Acad Child Adolesc Psychiatry. 2001;40:762-72).
However, that “largely ghostwritten” article drew conclusions about paroxetine that were “at odds with the data,” wrote Dr. Le Noury and her associates. They cited other researchers who previously concluded that Dr. Keller and his colleagues introduced new outcome measures, conflated primary and secondary outcomes, downplayed a nonsignificant difference for a primary outcome, and reversed their stance on whether emergent suicidal ideation and other psychiatric events were related to paroxetine use.
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Dr. Le Noury and her associates therefore obtained and reanalyzed the original Study 329 trial data as part of the restoring invisible and abandoned trials (RIAT) initiative of The BMJ. They concluded that the efficacy of paroxetine and imipramine did not statistically or clinically differ from placebo for any prespecified primary or secondary outcome measure. For example, Hamilton Depression Rating Scale scores dropped by an average of 10.7 (95% confidence interval, 9.1-12.3) for the paroxetine group, compared with 9 (7.4-10.5) for the imipramine group, and 9.1 (7.5-10.7) for placebo (P = .20), they reported.
Furthermore, the reanalysis uncovered “clinically significant” increases in psychiatric harms in the paroxetine group and cardiovascular effects in the imipramine group, said Dr. Le Noury and her associates. “The extent of the clinically significant increases in adverse events in the paroxetine and imipramine arms, including serious, severe, and suicide-related adverse events, became apparent only when the data were made available for reanalysis,” they wrote. “As with most scientific papers, Keller and colleagues convey an impression that ‘the data have spoken.’ This authoritative stance is possible only in the absence of access to the data. When the data become accessible to others, it becomes clear that scientific authorship is provisional rather than authoritative.”
In a statement, the American Academy of Child and Adolescent Psychiatry (AACAP), publisher of the Study 329 findings, said statements and opinions found in its journal “are those of the authors and not necessarily those of AACAP, the editors, or the publisher.” In addition AACAP said it has the “utmost respect for the BMJ” and thanks the journal for its “continued efforts to bring science to the forefront.”
SmithKline Beecham was the manufacturer of Paxil, the trade name for paroxetine. The company merged with Glaxo Wellcome in 2000 and became GlaxoSmithKline. Dr. Le Noury and her associates reported receiving no specific funding for the reanalysis. One coauthor reported having served as an expert witness for plaintiffs in lawsuits involving paroxetine, and as a witness for plaintiffs in lawsuits involving antidepressants with the same mechanism of action. Another coauthor reported receiving fees to provide expert analysis and opinion for a class action over Study 329 and an action over pediatric use of the antidepressant citalopram.