July, 2002The Guardian reveals that Seroxat tops the league table for complaints of side-effects made by doctors to the U.K. government's committee on the safety of medicines under the yellow card scheme. A total of 1,281 complaints have been filed; more than the combined total for the rest of the top 20 most cited drugs.

August 3, 2002News item: "United States Professional football sensation Ricky Williams last week sparked a blaze of publicity when he revealed that he had social anxiety disorder and was benefiting from therapy and Paxil (Seroxat/paroxetine), the drug that earned GlaxoSmithKline global sales last year of US $2.7 billion (£1.7 billion, €2.7 billion)… Celebrity selling is just one more way in which pharmaceutical companies are indirectly shaping public perception…"(BMJ Celebrity Selling Article Part 1)

Two years later, this Heisman trophy winner whose dream had been to join the NFL, quit football after becoming involved with illegal drugs and apparently losing interest in playing.

Sept 16, 2002The last of 9 clinical trials conducted by GSK and its predecessor SKB, attempting to find evidence of efficacy of paroxetine in the treatment of MDD in paediatric populations, concludes. None of the trials was ever able to demonstrate a positive outcome. Many of the trials avoided noting safety concerns by attributing suicidality and other adverse events experienced by subjects to factors other than being in the active drug group.

October, 2002Article: Fluoxetine for acute treatment of depression in children and adolescents: a placebo-controlled, randomized clinical trial.

122 children and 97 adolescents with MDD are randomly assigned to placebo or fluoxetine. The authors report that significantly more fluoxetine-treated patients (41%) meet the prospectively defined criteria for remission than placebo-treated patients (20%). They also note that there are no significant differences between treatment groups in discontinuations due to adverse events ( =.408).

Emslie et al conclude that Fluoxetine 20 mg daily appears to be well tolerated and effective for acute treatment of MDD in child and adolescent outpatients.

October 10, 2002 — Russell Katz, Director of Neuropharmacological Drug Products at the FDA, sends an approvable letter to GSK for Paxil in children requesting additional information about Paxil.

Dr David Healy describes this letter as follows: "the letter notes that GSK had already told the FDA that Study 329 showed that Paxil doesn't work for depressed children. FDA were happy to go along with GSK's suggestion that this should not be mentioned in the labeling of the drug. Given that the Study 329 publication majored on how effective Paxil was, it would have been inconvenient if the label said otherwise."

There are many notable things in this approvable letter. Perhaps the most interesting is FDA asking GSK to clarify just what emotional lability meant.

FDA have later spun this into a story that their reviewers detected there was an increase of emotional lability events in Study 329 that needed looking at. In fact this idea came on their radar after plaintiff's lawyers visited the FDA on August 28th and suggested that the FDA explore the issue of emotional lability.

FDA at the time had a few weeks to respond to GSK's request to market Paxil for children. Neither Jofre nor the lawyers knew at the time that GSK were seeking pediatric approval for Paxil."

October 13, 2002 — BBC Panorama broadcast "Secrets of Seroxat" —Scottish journalist Shelley Jofre, after learning of the Schell/Tobin lawsuit, does a show on Seroxat (Paxil) revealing that the drug can cause suicidal and violent thoughts, and serious withdrawal problems. In response to this broadcast, the BBC receives 67,000 phone calls and nearly 1,400 e-mails.

November 2002Review: Treatment of mood disorders, by Nemeroff CB and Owens MJ is published in Nature Neuroscience. It notes that "available antidepressant drugs are safe and effective" and "highlights" specific mechanisms that will lead to better treatment. They conclude that both mifepristone and a transdermal lithium patch are promising treatments for mood disorders, without disclosing that Dr Nemeroff has a significant financial interest in both.

November 14, 2002 — In response to public concerns about Seroxat following the Panorama broadcast, the Committee on Safety of Medicines (CSM) in the U.K. decides to convene a panel of experts. On Nov 14, in preparation for the first meeting of this ad hoc committee, CSM officials meet with GSK. At the meeting, GSK does not raise any concern about lack of efficacy or adverse reactions in the clinical trials in the paediatric population.

November 21, 2002 —The U.K. CSM ad hoc group meet with MHRA representatives and independent experts to discuss issues relating to SSRIs. The meeting is focused mainly on withdrawal reactions although suicidality is also discussed.

At this meeting Dr David Healy presents research relating to suicidal behaviour, including reanalysis of studies on fluoxetine, to a group of CSM and external experts who conclude that no change in regulatory position in relation to suicide is necessary, but advise changes to UK Seroxat PIL to clarify withdrawal reactions.

December 20, 2002Letter: Child Psychiatrist Jon Jueidini, M.D. and Prof Anne Tonkin, from the University of Adelaide, alarmed by what they see as potentially serious issues with Study 329, write a letter to the Editor of JAACAP suggesting that it might be a good idea to sort out their differences immediately, and "off-line":

"We write to request that you reconsider your decision not to give us access to Keller et al's reply to our letter prior to its publication in the middle of 2003. Our letter raises significant concerns and impact on the standing of the journal and profession that we believe cannot wait 6 months for our further attention.

We would not wish to pursue these concerns if Keller et al have sucessfully refuted our criticisms. We think it is important and urgent to know whether we are correct in raising concerns about journal standards. We therefore request that you forward us a copy of Keller et al's response as soon as possible."

December 26, 2002Reply: Editor Mina Dulcan sends a response with a very negative tone to the Dec 20 Jureidini and Tonkin request:

"Dear Dr. Jureidini,

It is not the policy of the Journal to share responses to letters before publication. We do not have a backlog, and your letter and the Keller response will be published as soon as our production process allows. This is not a debate. We are under no obligation to publish whatever rejoinders you wish to make (or your original letter, either, which was quite rude and accusatory). Your approach to this process leads me to believe that whatever Dr. Keller says, you will disagree. Our readers will see both letters and make their own judgments. Frankly, your haste seems odd, since the article was originally published in July of 2001. I find your adversarial tone and urgency tedious.

You have not been appointed as the guardian of the Journal, or of the profession of child and adolescent psychiatry. Many highly expert child and adolescent psychiatrists were participants in that study, and others that were similar, and others equally contributed to the review process. In addition, the prescription of SSRIs for youth, not only in this country but around the world, far predated any research data on their effects with youth, so this article could hardly be blamed or praised for that trend.

I noticed that you are members of Healthy Skepticism. Is this organization backed by anyone we should know about, for potential conflict of interest?"

Interesting context to Dr Dulcan's remark about Jureidini and Tonkin's "tedious sense of urgency" is provided by Graham Aldred's data chart (see April 27, 2004). He calculates that in 2002, Paxil was causing up to 52* suicides per day in the USA alone (all ages).