MANY Australian adolescents are prescribed antidepressants
, usually selective serotonin reuptake inhibitors (SSRIs), and the numbers are increasing.
We coauthored a recent article in The BMJ
challenging Study 329
— a key study used to justify the prescribing of antidepressants to adolescents.
Published in 2001 in the Journal of the American Academy of Child and Adolescent Psychiatry
and widely cited
, Study 329 was a randomised controlled trial that compared paroxetine and imipramine with placebo for the treatment of adolescent depression.
It was funded by SmithKline Beecham (SKB) — now GlaxoSmithKline (GSK) — the manufacturer of paroxetine. It has been repeatedly criticised, and there have been calls over the years since it was published for it to be retracted
Our study, Restoring Study 329, was conducted under the restoring invisible and abandoned trials (RIAT
) initiative. The aims were first, to reanalyse the evidence of effectiveness and safety, and second, to see what implications our results had for evidence-based medicine.
We used the original study protocol
and the clinical study report (CSR
) submitted by SKB to the US Food and Drug Administration (FDA), and we accessed (with difficulty
) patient-level data provided by GSK. These documents, and much more information, are available on the Study329.org
We found that paroxetine was no more effective than placebo, contrary to claims in the original paper of its “efficacy and safety”.
Further, we found there were clinically significant increases in harms, with more than twice as many severe adverse events and four times as many psychiatric adverse events, including suicidal behaviours and self-harm.
There were also significant problems with the CSR. Although it reported more adverse events than the original journal article, it omitted many problems that our reanalysis detected in the case report forms (CRFs
) for individual patients.
The implications of our RIAT reanalysis extend far beyond Study 329. Our findings make it clear that it is not possible to adequately scrutinise trial outcomes, particularly in relation to harms, simply on the basis of what is reported in CSRs, which can contain significant errors. Selective reporting
is common in psychiatric studies, but there are no grounds to believe this is restricted to psychiatry.
Access to full individual patient data, backed up by CRFs and protocols, is required to judge the validity of published reports of clinical trials. Instead of AllTrials
, we need “AllData”
Our RIAT reanalysis was demanding because we were breaking new ground and because data access was very time consuming. However, we have now established a methodology for this kind of analysis so it will be possible for researchers to undertake similar reanalyses reasonably inexpensively, if data are provided in a user-friendly format.
If other trials are found to contain similar errors, this could lead to changes in the requirements for submissions to the Therapeutic Goods Administration
, the FDA
and other regulatory agencies.
It would also challenge editors of medical journals not to publish trials unless data are available for independent scrutiny.
Peer reviewers would also need to be far more critical of the manuscripts they review.
Professor Jon Jureidini is a child psychiatrist at the Women’s and Children’s Hospital, Adelaide, and professor in the disciplines of psychiatry and paediatrics, University of Adelaide, where he leads the Robinson Research Institute’s Critical and Ethical Mental Health (CEMH) research group.
Dr Melissa Raven is a psychiatric epidemiologist and policy analyst with the CEMH research group.