The original study, published in the Journal of the American Academy of Child and Adolescent Psychiatry (JAACAP), describes an eight week, double-blind randomized control trial that compared the safety and effectiveness of paroxetine (20 mg to 40 mg) and imipramine (gradual upward titration to 200 mg to 300 mg) with placebo in 275 adolescents aged 12 to 18 with major depression.
In the paper, Martin Keller, M.D., of Brown University and colleagues reported that after eight weeks, those in the paroxetine group demonstrated significantly greater improvement compared with placebo on the Hamilton Rating Scale for Depression (HAM-D) total score, HAM-D depressed mood item, depression item of the Schedule for Affective Disorders and Schizophrenia for Adolescents-Lifetime version depressed mood item, and Clinical Global Impression score.
For the BMJ study, Jon Jureidini, M.B.B.S., of the University of Adelaide, and colleagues reanalyzed the data from the 2001 study, including a review of primary data from the original trial supplied by GlaxoSmithKline. (The reanalysis was part of an initiative called RIAT [Restoring Invisible and Abandoned Trials], which calls on “funders and investigators of abandoned [unpublished] or misreported trials to publish undisclosed outcomes or correct misleading publications,” according to the study authors.)
Based on the reanalysis, the authors reported, “The efficacy of paroxetine and imipramine was not significantly different from placebo for any prespecified primary or secondary outcome.” The authors also described “clinically significant increases in harms, including suicidal ideation and behavior and other serious adverse events in the paroxetine group and cardiovascular problems in the imipramine group.”
“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 colleagues noted in a letter in response to the BMJ article. The authors concluded, “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.
“This new reanalysis has sparked a healthy discussion over the value of open access to clinical trial data, the importance of following protocol specified analyses, and the risks of confirmation bias, which is a tendency to search for information that confirms the investigator's preconceptions,” Mark Olfson, M.D., M.P.H., a professor of psychiatry at Columbia University Medical Center who was not involved with either study, told Psychiatric News. “However, the new reanalyses does not alter the totality of clinical trial evidence that continues to support the safety and efficacy of SSRIs for adolescent depression.”
Daniel Pine, M.D., chief of NIMH's Section on Development and Affective Neuroscience, added, “We have known for some time that antidepressant medications have both significant benefits for some children as well as significant risks for other children. This new analysis really does nothing to change this knowledge, and provides no new insights into what we have known about these medications for the past few years.”
“AACAP supports transparency in clinical trial reporting and welcomes the RIAT initiative, which enables publicly available primary data to be reanalyzed and published as new, potentially revised reports,” Paramjit T. Joshi, M.D., President of the American Academy of Child and Adolescent Psychiatry, told Psychiatric News. “JAACAP is a forum for scientific reporting and scholarly discussion. The scientific process builds on itself over time through a cycle of new research, analysis, and ongoing dialog. This process stimulates debate and moves the field forward toward a better understanding of critical issues.”
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