Will Paroxetine Controversy Change Clinical Practice?
Abstract
The findings of the recent BMJ study are unlikely to lead to changes in clinical practice, but do raise questions about psychiatric research, experts say.
A 2001 study that found paroxetine to be effective for treating major depression in adolescents was back in the news last month after a group of scientists who reanalyzed the original data from the trial concluded that the medication was neither safe nor effective for this patient population.
Contrary to initial reports, paroxetine was no more effective than placebo in treating adolescents with depression, according to a recent reanalysis of data from a 2001 study.
While these findings are unlikely to result in changes to prescribing patterns—it has been more than a decade since the Food and Drug Administration first issued a warning about the risks of paroxetine for the treatment of depression in children and adolescents—several experts told Psychiatric News that the study does raise important questions about psychiatric research.
The original study, published in the Journal of the American Academy of Child and Adolescent Psychiatry (JAACAP), described an eight-week, randomized, controlled trial that compared the safety and effectiveness of daily paroxetine (20 mg to 40 mg) and imipramine (gradual upward titration to 200 mg to 300 mg) treatment with placebo in 275 adolescents aged 12 to 18 with major depression.
In the 2001 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, 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. This 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called RIAT (Restoring Invisible and Abandoned Trials), which calls on “funders and investigators of abandoned [unpublished] or misreported trials to publish undisclosed outcomes or correct misleading publications,” according to the study authors.
On the basis of 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.”
In a letter in response to the BMJ article, Keller and his colleagues wrote, “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.” They continued, “[T]o 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 reanalysis does not alter the totality of clinical trial evidence that continues to support the safety and efficacy of SSRIs for adolescent depression.”
“Hardly anyone uses paroxetine for treating children anymore,” R. Scott Benson, M.D., an APA trustee and child psychiatrist in private practice in Pensacola, Fla., told Psychiatric News. “Fortunately, there are other medications that research shows are effective for young people with depression, and these benefits have translated into clinical practice.”
Still, he noted, “The study does point out that there are flaws in the way that we do psychiatric research.” While a reliance on the findings of clinical trials involving hundreds of patients has helped to inform clinical practice to date, Benson said he is excited about the potential of psychiatric patient registries to change the way research is conducted.
“If we’re talking about a trial that examines the outcomes of 12,000 kids instead of 20, that’s going to make a big difference in clinical practice,” Benson said.
In response to the publication of the reanalysis paper in BMJ, American Academy of Child and Adolescent Psychiatry (AACAP) President Paramjit T. Joshi, M.D., told Psychiatric News, “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. 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 dialogue. This process stimulates debate and moves the field forward toward a better understanding of critical issues.” ■
