March, 2000 —Article: "Emergence of antidepressant induced suicidality" by Dr David Healy finds that out of 20 healthy volunteers with no history of depression or suicidal ideation, two became suicidal on sertraline (Zoloft), an SSRI. This is important refutation to the contention that suicidal acts of people on SSRI medications could always be attributed to underlying depression.
April, 2000 — Study 701 on the effectiveness of paroxetine (Seroxat, Paxil) in treating children and adolescents with major depressive disorder (MDD) is completed. Study 701 involves 206 pediatric patients, 149 who complete the study. Nine Paxil patients (8.9 percent) withdraw from the study due to adverse events vs two (two percent) on the placebo, mostly due to depression, "emotional lability" (suicidality), agitation, hostility, and nervousness. In addition, three Paxil patients withdraw from the study due to "emotional lability" soon after the last dose of study medication. One Paxil patient overdoses and cuts herself, another experiences suicidal ideation, and three others experience exacerbation of their depressive symptoms. All these events are considered unrelated to Paxil by the study's investigators. Another overdose is regarded as related to the Paxil. Overall, the patients on Paxil fare worse than those on placebo on the primary measures. The study is never published.
April 26, 2000 —Letter: In a missive entitled "Revision of Paroxetine Adolescent Depression Manuscript", Sally Laden writes to Jim McCafferty noting the revisions she is making to the Study 329 manuscript, and outlining the plan for resubmission of the article to the Journal of American Psychiatry. All the revisions are "cosmetic" they relate to wording and presentation:"Dear Jim,
I attempted to make as many of the JAMA reviewer comments (sic) as practical. A summary of the more substantive points is listed below:
This letter is interesting because it clearly illustrates who is making the decisions about the content of the final manuscript, a document that will impact the lives of thousands of young people. Sally laden decided that it was not "practical" to deal with the safety issues. The significant incidence of adverse events (11 out of 93) in paroxetine group, 7 of whom had to be hospitalized, is not addressed. Subjects experiencing adverse events on paroxetine continue to be omitted from the considered data.
May, 2000 —According to the April 26, 2000 letter from Sally Laden to Jim McCafferty, the intention is to submit the "revised" Study 329 manuscript to the Journal of American Psychiatry. Apparently the decision changed at some point in May, 2000 to submit it to the Journal of the American Academy of Child and Adolescent Psychiatry (JAACAP) instead. The reason for this change is not stated. At the time, Graham Emslie, one of the Study 329 authors, is on the Board of JAACAP.
July 27, 2000 —Letter: Mina Dulcan, M.D., Editor of the Journal of the American Academy of Child and Adolescent Psychiatry (JAACAP) writes to Dr Martin Keller acknowledging submission of Study 329:
"Dear Marty,Your manuscript has come back from review, and I enclose copies of the reviewers' comments and suggestions. If you will revise your manuscript to meet their concerns, we will be happy to consider it further for publication." The reviewers' comments included the following: "Were they really persistently depressed over that entire year? In clinical settings most "depressed" youth have moods that are more labile and reactive. Is this well reflected in methods using standardized interviews? Is there possible informant bias ? There are other issues that need addressing, including:
September 14, 2000 — Medical Review: Lilly submits application to FDA to gain an additional 6-month patent exclusivity for Prozac. The application later updated to include Lilly's integrated safety data summaries (ISS) from 3 pooled Prozac pediatric trials: the NIMH-funded trial (Emslie, 1997)*, a Lilly-funded trial with depressed children (Emslie, 2002), and a trial with children diagnosed with obsessive-compulsive disorder (Geller, 2001).
In 2002, Dr Andrew Mosholder does the medical review on the efficacy of fluoxetine (Prozac), compared to placebo, for children and adolescents with major depression. He finds:
*see November, 1997 and June 22, 2004
2000 — Marketing Facts: Between 1995 and 2000 the number of marketing staff working for US pharmaceutical companies increases by 60% while research staff declines by 29% (see page 15). GlaxoSmithKline spends $91.8 million US advertising the SSRI Paxil in the US, almost $15 million more than Nike spends advertising its top brands of running shoes. (See Page 17) This level of spending is associated with a $355.6 million increase in sales between 1999 and 2000.