Lead author of JAMA article rethinks positive Zoloft report – Guardian

Wed, 1 Oct 2003

In August 2003, the Sertraline Pediatric Study Group reported: “Sertraline-treated patients experienced statistically significantly greater improvement than placebo.”

Their report was published in the authoritative Journal of the American Medical Association (JAMA). The authors claimed that the data they analyzed from two multicenter placebo-controlled safety and efficacy trials in children and adolescents, demonstrated that: “sertraline is an effective and well-tolerated short-term treatment for children and adolescents with [major depressive disorder] MDD.”

However, those claims about both safety and efficacy are belied by the facts: “Seventeen children who were given the drug were pulled out of the trial because of side effects, compared with five who were given a placebo.”

“Patients treated with sertraline more frequently experienced agitation, anorexia, diarrhea, nausea, purpura, urinary incontinence, and vomiting. … a higher proportion of sertraline-treated children discontinued because of adverse events.” It should be noted that drug-induced agitation is linked to violence and self-harm. Furthermore, according to their own findings: “Only 10% more children improved on the drug than improved on a placebo.”

The JAMA report was published at the time that two similar antidepressant drugs (Paxil / Seroxat and Effexor) were declared unsafe, and ineffective for children by the manufacturers. The UK banned their use in children inasmuch as children taking the drugs in controlled clinical trials were found to be at three fold risk of suicidal behavior than those on placebo.

It was published precisely when both the FDA and the British Committee on Safety in Medicines announced that the agencies were reanalyzing all SSRI clinical trial data.

One is led to wonder what the current standards of “peer review” are at JAMA? How do scientists explain their widely publicized (though erroneous) conclusion, “sertraline is an effective and well-tolerated short-term treatment for children,” when in fact they only documented a mere 10% improvement above placebo?

When challenged by the health editor of the Guardian, the principle author, Dr. Karen Wagner, of the University of Texas, said: “I think it requires further investigation and looking at the entire database of these medications.”

Scientist in rethink over drug link to suicide

Sarah Boseley, health editor
Wednesday October 1, 2003
The Guardian

The scientist who led the latest trial of an antidepressant drug given to children, which claimed that it was effective and safe, has conceded to the Guardian that the drug’s potential to cause suicidal thinking needs to be investigated.

Last month the Journal of the American Medical Association published results from two trials of children treated with Pfizer’s antidepressant drug Lustral, known in the US as Zoloft.

Seventeen children who were given the drug were pulled out of the trial because of side effects, compared with five who were given a placebo. Only 10% more children improved on the drug than improved on a placebo.

The researchers nonetheless concluded that “the results of this pooled analysis demonstrate that sertraline (Lustral) is an effective and well-tolerated short-term treatment for children and adolescents with major depressive disorder”.

The lead author of the study was Karen Wagner of the department of psychiatry at the University of Texas. She was also one of the authors of studies of a similar antidepressant, Seroxat, which was banned for use in children in June by the UK licensing body, the medicines and healthcare products regulatory agency.

The MHRA said a re-analysis of the data from the Seroxat trials showed an increase in the numbers of children who became suicidal on the drug. The studies that Dr Wagner and colleagues carried out on Seroxat in children had also concluded that Seroxat was effective and well-tolerated.

Asked whether she still believed both drugs were safe, after the MHRA ban on Seroxat and the inquiry that has now been launched by the US regulator, she replied: “I think it requires further investigation and looking at the entire database of these medications. With regards to paroxetine [Seroxat], it is being investigated.”

But Dr Wagner maintained that the numbers of children who became suicidal in the Lustral trial were small, and that in her experience, “these medications are extremely effective in children who are suffering from depression”.

Manufacturers of this class of drug, the selective Serotonin re-uptake inhibitors which includes Prozac, have always said that suicidal thinking or gestures are caused by the illness, not by the drugs.

An expert report written in 1997 for the US food and drug administration reviewed two trials of Lustral carried out on children. “The adverse events which led to discontinuation were generally psychiatric in nature,” it said, concluding that the drug “is well tolerated” by children.

Yet four out of 44 children with depression in one of the two studies became suicidal while taking Lustral – a rate of 9%. The expert report stated that only side effects that occurred in more than 10% of patients were significant.

In the second study, on children with obsessive compulsive disorder, or OCD (repetitive behaviour such as continual hand washing), two children became suicidal on Lustral and one on a placebo.

Wilma Harrison, a senior Pfizer executive, was questioned by a US lawyer about one of the two children who became suicidal while taking Lustral during that OCD study. Matt Miller, 13, killed himself, and his family are suing Pfizer, alleging that the drug was responsible for his death. Pfizer denies the charge.

After the expert report, the drug was licensed for use in children suffering from OCD in the US. David Healy, director of the North Wales department of psychological medicine says that because of this licence, and after last month’s positive report in the American Medical Association’s journal, doctors will be more inclined to prescribe it for depressed children, for whom it is not licensed.

There are around 50,000 children in the UK on antidepressants, none of which is licensed for use in children. Doctors are permitted to prescribe adult drugs for children on their own responsibility.

Both Seroxat and another drug, Effexor, have effectively been banned for use on children by the MHRA because of concerns about the drugs’ potential to cause suicide.

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