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).

[7] 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.

[b] 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".

[26][9][3][27][28] Funded by SmithKline Beecham, the acute phase of study 329 was an eight-week, double-blind, randomized clinical trial conducted in 12 university or hospital psychiatric departments in the United States and Canada between 1994 and 1997.

[6] Martin Keller, then professor of psychiatry at Brown University, had proposed the trial to the company in 1992 as the largest study until then to examine the efficacy of SSRIs in children.

[15] After a screening phase from April 1994, 275 male and female patients were randomly assigned paroxetine, imipramine or placebo (an inert pill).

According to Melanie Newman, writing for the BMJ, "[t]he drug only produced a positive result when four new secondary outcome measures, which were introduced following the initial data analysis, were used instead.

"[f][33] Eleven subjects on paroxetine, compared to five on imipramine and two on placebo, experienced serious adverse events (SAE), including behavioral problems and emotional lability.

[15] An attached memo noted that the results were disappointing and would not support a label claim that paroxetine could be used to treat adolescents: "The best that could have been achieved was a statement that, although safety data was reassuring, efficacy had not been demonstrated.

SmithKline Beecham decided to publish study 329 but not 377, and not to submit either trial to the regulators, because they were "insufficiently robust to support a regulatory submission and label change for this patient population".

[41] SmithKline Beecham documents show that Laden and STI coordinated the entire publication process, including writing the cover letter to the journal that published the article, JAACAP, which she sent to Keller with the instruction that he transfer it to his own letterhead.

According to Melanie Newman in the BMJ, JAACAP's reviewers wrote that the results did not "clearly demonstrate efficacy for paroxetine", and asked whether, because of the high placebo response rate, SSRIs should be regarded as first-line therapy.

[35][45] The article continued: "Because these serious adverse events were judged by the investigator to be related to treatment in only 4 patients (paroxetine, 1; imipramine, 2; placebo, 1), causality cannot be determined conclusively."

[16] The memo continued that paroxetine was "significantly more effective than placebo" on certain outcomes: "Paxil was generally well tolerated in this adolescent population and most adverse events were not serious.

"[16]Scottish reporter Shelley Jofre presented four investigative programmes on paroxetine for BBC Panorama between 2002 and 2007, including one devoted to study 329, "Secrets of the Drug Trials", in January 2007.

[55][56] The first of Jofre's programmes, "The Secrets of Seroxat", aired on 13 October 2002, and covered the Schell case, study 329, and GSK's efforts to market the drug for use in children.

[i] To examine the issues that Panorama had raised, Britain's Medicines and Healthcare products Regulatory Agency (MHRA) set up an ad hoc group of experts, which held a meeting with GSK on 14 November 2002.

According to the MHRA, "GSK did not raise any concern about lack of efficacy or adverse reactions in the clinical trials in the paediatric population at that meeting.

[63][58] The paper included data from nine clinical trials GSK had conducted on paroxetine and children between April 1994 and September 2002:[64] The briefing paper concluded that "analysis of the safety data demonstrates that paroxetine is generally well tolerated by paediatric patients ...," but suggested a label change to the effect that efficacy had not been established in children with major depressive disorder, and that adverse reactions could include hyperkinesia, hostility, emotional lability and agitation.

Of 20 reports of adverse events in the paroxetine groups, 12 had been suidical thoughts or suicide attempts (none successful), three self-mutilation and five general emotional lability.

[65] Alasdair Breckenridge, then-chair of the MHRA, told Panorama that the GSK briefing document caused "a very dramatic change in our thinking about Seroxat and children".

Importantly, the trials conducted in a range of conditions in children and adolescents failed to demonstrate that Seroxat was effective in the treatment of depressive illness.

[78] In November 1995 Alison Bass of The Boston Globe began investigating Brown University's psychiatry department, chaired by Martin Keller, who led Study 329.

[81] Bass's work developed into a book about GlaxoSmithKline, paroxetine, and Study 329, Side Effects: A Prosecutor, a Whistleblower, and a Bestselling Antidepressant on Trial (2008).

[1][91][k] In 2005 the philosopher Leemon McHenry complained to JAACAP's editor, Mina Dulcan, that Keller and some of the other researchers named as authors had worked for GSK but had not declared their conflict of interest and had violated the journal's policy regarding authorship.

[2][95] In July 2013 Jureidini announced his intention to produce a new write-up of study 329 in accordance with the RIAT initiative (restoring invisible and abandoned trials).

[96][95] The RIAT researchers—Joanna Le Noury, John M. Nardo, David Healy, Jon Jureidini, Melissa Raven, Catalin Tufanaru, and Elia Abi-Jaoude—published their re-analysis in the BMJ in September 2015.

"[26] In 2007 the FDA required that all anti-depressants include a boxed warning of an increased risk of suicidal thoughts and behaviour in young adults (18–24 years) during the first one to two months of treatment.

An internal GSK management document (which subsequently came into the public domain) dated October 1998 says that 'it would be commercially unacceptable to include a statement that efficacy had not been demonstrated, as this would undermine the profile of paroxetine'.

"GlaxoSmithKline to Plead Guilty and Pay $3 Billion to Resolve Fraud Allegations and Failure to Report Safety Data", United States Department of Justice, 2 July 2012.