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Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence

BMJ 2015; 351 doi: (Published 16 September 2015) Cite this as: BMJ 2015;351:h4320

Paroxetine and Study 329 – What We Already Knew and When

The authors of the re-analysis of Study 329 [1] in which the original study examined paroxetine’s safety and tolerability in children and adolescents with depression using the Restoring Invisible and Abandoned Trials (RIAT) protocol miss some critical aspects of patient drug safety.[2,3]

Perhaps their most notable omission is that it has been known since at least 1998 from the US Food and Drug Administration (US FDA) approval package, posted free of charge on agency’s web site, that paroxetine had not been shown to be safe and effective in pediatric populations.[4] This information was available to the public three years before the original publication of Study 329.[2] The professional product label for paroxetine has been required to contain a box warning, the strongest type of safety alert the US FDA can require, that the drug is not approved for use in pediatric patients since the mid-2000s.[5]

More disturbing than the results of the Study 329 re-analysis is the continued prescribing of drugs, such as paroxetine, in populations in which there is no evidence at the level of rigorous regulatory scrutiny that the drug is beneficial. This leaves patients with only the possibility of harm. Prescribers must recognize that the phrase “safe and effective” has two meanings. One is the common usage that can be used in conclusions of medical journal articles with impunity and the other is the regulatory meaning that requires rigorous review of the evidence submitted to support the approval of or use of a drug in a specific population.

Thirty-five years ago evidence emerged suggesting that prescribing decisions may be based on commercial rather than scientific sources of information.[6] Prescribers are inundated with promotional materials that can also include some peer-reviewed medical journal articles claiming drugs are “safe and effective”. Advertising is no defense for prescribing drugs that have not been shown to be beneficial when public summaries exist based on rigorous evaluations of the known evidence supports avoiding the drug in this specific population. These public summaries would include US regulatory documents and the professional product information.

Any positive impact on patient safety from the re-analysis of Study 329 trial 14 years after the original study was published is questionable. A lesson that should be learned from the Study 329 tale is that patient drug safety may be better served by promoting and placing the information from regulatory summary documents in the hands of patients and their parents.


1. Le Noury J, Nardo JM, Healy D, et al. Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence. BMJ 2015;351:h4320.

2. Keller MB, Ryan ND, Strober M, et al. Efficacy of paroxetine in the treatment of adolescent major depression: a randomized, controlled trial. J Am Acad Child Adolesc Psychiatry Jul 2001;40(7):762-772.

3 Doshi P, Dickersin K, Healy D, Vedula SS, Jefferson T: Restoring invisible and abandoned trials: a call for people to publish the findings. BMJ 2013;346:f2865.

4. Dubitsky GM. Food and Drug Administration Review and Evaluation of Paroxetine Controlled Released Tablets, July 17, 1998. At Accessed August 24, 2015.

5. Apotex Corp. Professional Product Label: Paxil CR (Paroxetine), July 12, 2015. At Accessed August 24, 2015.

6. Avorn J, Chen M, Hartley R. Scientific versus commercial sources of influence on the prescribing behavior of physicians. Am J Med. Jul 1982;73(1):4-8.

Competing interests: No competing interests

17 September 2015
Larry D. Sasich
Burlington, ON, Canada L7S 15