Study 329

rdf:langString Study 329

rdf:langString Study 329

rdf:langString Eight-week, placebo-controlled, double-blind, randomized clinical trial comparing paroxetine with imipramine in adolescents with major depressive disorder

rdf:langString Paroxetine, sold as Paxil and Seroxat

rdf:langString SmithKline Beecham, now GlaxoSmithKline

rdf:langString Study 329 was a clinical trial which was conducted in North America from 1994 to 1998 to study the efficacy of paroxetine, an SSRI anti-depressant, in treating 12- to 18-year-olds diagnosed with major depressive disorder. Led by Martin Keller, then professor of psychiatry at Brown University, and funded by the British pharmaceutical company SmithKline Beecham—known since 2000 as GlaxoSmithKline (GSK)—the study compared paroxetine with imipramine, a tricyclic antidepressant, and placebo (an inert pill). SmithKline Beecham had released paroxetine in 1991, marketing it as Paxil in North America and Seroxat in the UK. The drug attracted sales of $11.7 billion in the United States alone from 1997 to 2006, including $2.12 billion in 2002, the year before it lost its patent. Published in July 2001 in the Journal of the American Academy of Child and Adolescent Psychiatry (JAACAP), which listed Keller and 21 other researchers as co-authors, study 329 became controversial when it was discovered that the article had been ghostwritten by a PR firm hired by SmithKline Beecham, had made inappropriate claims about the drug's efficacy, and had downplayed safety concerns. The controversy led to several lawsuits and strengthened calls for drug companies to disclose all their clinical research data. New Scientist wrote in 2015: "You may never have heard of it, but Study 329 changed medicine." SmithKline Beecham acknowledged internally in 1998 that the study had failed to show efficacy for paroxetine in adolescent depression. In addition, more patients in the group taking paroxetine had experienced suicidal thinking and behaviour. Although the JAACAP article included these negative results, it did not account for them in its conclusion; on the contrary, it concluded that paroxetine was "generally well tolerated and effective for major depression in adolescents". The company relied on the JAACAP article to promote paroxetine for off-label use in teenagers. In 2003 Britain's Medicines and Healthcare products Regulatory Agency (MHRA) analysed study 329 and other GSK studies of paroxetine, concluding that, while there was no evidence of paroxetine's efficacy in children and adolescents, there was "robust evidence" of a causal link between the drug and suicidal behaviour. The following month the MHRA and US Food and Drug Administration (FDA) advised doctors not to prescribe paroxetine to the under-18s. The MHRA launched a criminal inquiry into GSK's conduct, but announced in 2008 that there would be no charges. In 2004 New York State Attorney Eliot Spitzer sued GSK for having withheld data, and in 2012 the United States Department of Justice fined the company $3 billion, including a sum for withholding data on paroxetine, unlawfully promoting it for the under-18s, and preparing a misleading article on study 329. The company denied that it had withheld data, and said it was only when data from its nine paediatric trials on paroxetine were analysed together that "an increased rate of suicidal thinking or attempted suicide [was] revealed". The JAACAP article on study 329 was never retracted. The journal's editors say the negative findings are included in a table, and that therefore there are no grounds to withdraw the article. In September 2015 the BMJ published a re-analysis of the study. This concluded that neither paroxetine nor imipramine had differed in efficacy from placebo in treating depression, that the paroxetine group had experienced more suicidal ideation and behaviour, and that the imipramine group had experienced more cardiovascular problems.

rdf:langString Martin Keller, then professor of psychiatry, Brown University