Meta-Analysis: Efficacy & Safety of Antidepressants for Children – Brit Medical Journal

Meta-Analysis: Efficacy & Safety of Antidepressants for Children – Brit Medical Journal

Sat, 10 Apr 2004

As news of skyrocketing prescribing of antidepressants for children–especially in preschool children–hit the news waves around the world, a major meta-analysis of the 5 published pediatric antidepressant studies was published in the British Medical Journal, April 9.

This independent analysis–by authors who have no financial ties to the drug companies that manufacture the drugs–essentially overturns the inflated claims for the efficacy of the drugs by industry financed psychiatrists who trivialized the evidence of these drugs’ hazards.

The analysis by a team of Australian and UK experts led by Dr. Jon Jureidini, head of the Department of Psychological Medicine, Women’s and Children’s Hospital, North Adelaide, notes that rather than lacking evidence against prescribing antidepressants for children, the evidence of increased risks of harm is compelling. Their analysis confirms the following:

  1. In all 5 published studies children taking the drugs suffered higher incidence of adverse effects compared to those on placebo;
  2. In some cases, the adverse effects were so severe as to require hospitalization;
  3. There was a high drop out rate due to adverse effects during the short duration (6-8 weeks) of the trials;
  4. The investigators failed to include the children who dropped out in the outcome analysis;
  5. Failure to include the outcome of all children who participated in the trial undermines the validity of the claimed “positive” conclusions.

Therefore, Jureidini et al, conclude that the published SSRI reports of the pediatric trials are biased and have been manipulated to inflate clinically inconsequential effects, while concealing the serious risks of potential harm. Furthermore, inasmuch as psychotherapy has been shown to work for children, the authors conclude that Antidepressant drugs cannot confidently be recommended as a treatment option for childhood depression.

In their analysis of the Emslie (Prozac) report that won Lilly FDA approval of Prozac for depressed children, the BMJ report points out that FDA’s statistical analysis of the Emslie study found the study had failed to meet its own stated primary criteria for recovery. Emslie et al, switched the criteria in the middle of the study when the evidence failed to produce a statistically significant benefit. This mid-trial switch reveals a fundamental flaw undermining the scientific integrity of antidepressant studies.

See: Efficacy and safety of antidepressants for children and Adolescents by Jon N Jureidini, Christopher J Doecke, Peter R Mansfield, Michelle M Haby, David B Menkes, Anne L Tonkin, BMJ, online at: http://bmj.bmjjournals.com/cgi/content/full/328/7444/879?

In sharp contrast to the BMJ analysis is a letter by investigators with , Brent and Birmaher, in the J of Child & Adolescent Psychiatry. The letter criticizes the action of the British medicine authority to protect children from the hazards of antidepressants by trivializing the evidence of a two-fold increased suicide risk, claiming the risk is “statistically insignificant.”

Brent and Birmaher–who is a co-author of the discredited Keller et al paroxetine study (329) that omitted mention of existing negative data from the trial, reporting only about the company selected positive data–continue to argue on behalf of SSRI “safety and efficacy.” Implausibly, they continue to defend the drugs even after the manufacturers of the drugs have acknowledged the absence of evidence of their benefit, and have issued warnings about a two- fold suicidal risk. See: Brent, David A M.D.; Birmaher, Boris M.D, BRITISH WARNINGS ON SSRIs QUESTIONED, Journal of the American Academy of Child & Adolescent Psychiatry : Volume 43(4) April 2004 pp 379-380

The BMJ analysis validates and strengthens the call for safeguards and unambiguous black box warnings on SSRI drug labels. The analysis also vindicates the critics who had been marginalized and maligned by and prevented from publishing their critiques in the major, most read, American scientific journals whose editors / publishers are beholden to industry.

It is becoming ever clearer that the market success of SSRIs rests on junk science and the endorsement by the medical profession and government oversight agencies–all of whom have grown dependent upon funding from the pharmaceutical industry.

The complicity of the psychiatric / medical establishment–including leading academic psychiatrists, major research institutions, major medical journals–in suspending their professional integrity to promote unsubstantiated claims about the drugs’ benefits and safety based on partial selected data, while disregarding the evidence of serious risks of harm, will be viewed in the future as a major source of embarrassment for the medical profession.

Below are 2 news reports about the BMJ analysis from The Sydney Morning Herald and The New York Times. (We note the Times disclosure to readers that Dr. Emslie, “like many psychiatric researchers, is a consultant to pharmaceutical companies.”)

Contact: Vera Hassner Sharav
Tel: 212-595-8974

http://www.smh.com.au/articles/2004/04/09/1081326929815.html
The Sydney Morning Herald
Drug firms accused of preying on children By Julie Robotham, Medical Editor
April 10, 2004

Doctors are prescribing antidepressants to children and adolescents based on exaggerated claims of their benefits from studies tainted by drug company funding, says a leading psychiatrist.

Jon Jureidini analysed the results of several published surveys comparing children prescribed drugs like Prozac, Aropax and Zoloft with those who took a placebo, and concluded severe side-effects – including the possibility of triggering suicidal behaviour – had been downplayed by scientists.

Dr Jureidini found one study of Aropax, of which its authors claimed “most adverse events were not serious,” included seven patients who had to be put in hospital. A study of Zoloft described it as “an effective, safe and well tolerated short-term treatment for children and adolescents”, despite dangerous side-effects that occurred twice as often as in children taking the placebo.

Where the studies showed some benefit, it was very slight and unlikely to make a difference in the real world, wrote Dr Jureidini, the head of the department of psychological medicine at Adelaide’s Women’s and Children’s Hospital, in the British Medical Journal. He blamed the involvement of the drugs’ manufacturers in the trials.

His analysis comes amid mounting international concern about the safety of the new generation of antidepressants known as selective serotonin reuptake inhibitors (SSRIs) in childhood and adolescence. The Federal Government issued interim advice to doctors a month ago to prescribe them very cautiously with rigorous follow-up of patients, pending the results of a US government review that is expected to outline whether they are safe. British health authorities have already ruled Prozac is the only SSRI safe enough for depressed children.

The principal medical adviser of the Health Department’s Therapeutic Goods Administration, John McEwen, said it would be months before the final advice became available. He emphasised none of the drugs were formally licensed to treat childhood depression and that the Government already recommends two brands – Aropax and Efexor – not be used on children.

Louise Newman, chairwoman of the faculty of child and adolescent psychiatry of the Royal Australian and New Zealand College of Psychiatrists (RANZCP), said Dr Jureidini was right to point out there was not enough evidence to back the use of antidepressants in children. “He makes a very valid point that non-pharmacological treatments have a very good evidence base,” Dr Newman said.

But she cautioned against “simplistic” prescribing rules, saying there would always be cases where drugs were needed.

Dr Newman said the RANZCP had recommended to the TGA that children prescribed antidepressants by a doctor “as soon as practically possible should be reviewed by a child psychiatrist or a pediatrician”.

Ian Hickie, clinical adviser to the national depression initiative, beyondblue, said early hopes SSRIs would work well in children’s depression had been largely unfulfilled, though they had an important role in treating some other conditions – such as obsessive compulsive disorder – during childhood.

But he agreed with Dr Newman that they were sometimes needed. “If you’ve got a depressed and suicidal adolescent, doing nothing is not an option either,” Professor Hickie said.

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http://www.nytimes.com/2004/04/09/health/09DRUG.html?pagewanted=print&position=
THE NEW YORK TIMES
April 9, 2004
Study Advises Against Drugs for Children in Depression By GARDINER HARRIS

ediatricians and family physicians should not prescribe antidepressants for depressed children and adolescents because the drugs barely work and their side effects are often significant, Australian researchers have concluded.

The researchers analyzed data from five published trials of three antidepressants, Prozac, Zoloft and Paxil, in depressed patients under age 18. They found that the drugs offered only a “very modest” benefit over placebos.

At the same time, the drugs carry significant risks, the researchers said in their report, published in today’s issue of the British medical journal BMJ.

“If the drugs were highly advantageous over placebo, then you’d live with the risks,” Jon Jureidini, a child psychiatrist in Adelaide and the study’s lead author, said in an interview. “If the drugs were completely safe, then you might argue that there’s nothing wrong with giving something that’s only slightly better than a placebo.”

However, Dr. Jureidini said, neither is true, so antidepressants should not be prescribed for children and adolescents except in extreme circumstances.

“We strongly want to say that non-child-psychiatrists should not be initiating the prescribing of” the antidepressants known as selective serotonin reuptake inhibitors or S.S.R.I.’s, a class that includes Eli Lilly’s Prozac, Pfizer’s Zoloft, and GlaxoSmithKline’s Paxil, Dr. Jureidini said.

The study is the latest salvo in an increasingly bitter war over whether prescribing antidepressants to children and adolescents is appropriate.

Dr. Joseph Glenmullen, author of “Prozac Backlash” and a fierce critic of the pills, said the latest study further vindicated his view that antidepressants can be dangerous. “What this shows is that, on balance, there is no good reason to prescribe these pills,” Dr. Glenmullen said.

However, Dr. Graham Emslie, a professor of psychiatry at the University of Texas Southwestern Medical Center, who was an author of some of the studies reviewed in the article, said the study was “illogical.”

“I wish the effect size of these drugs was bigger, but at least there’s some effect,” Dr. Emslie said. “Some of these kids are severely depressed and we’ve got to do something.”

Dr. Emslie, like many psychiatric researchers, is a consultant to pharmaceutical companies.

The Australian researchers suggested that psychiatrists offer children talk therapy in place of the drugs. But Dr. Emslie said that only one study had shown that talk therapy was beneficial.

“If people could offer better treatments than drugs, it’d be great,” Dr. Emslie said.

British drug regulators have cautioned doctors against using any antidepressant but Prozac to treat depressed children and adolescents because the drugs have not proved effective against depression and may increase the risk of suicidal thoughts and behavior.

The Food and Drug Administration recently issued a warning that all patients taking antidepressants should be closely monitored by doctors, especially in the first weeks. But the agency emphasized that it had not concluded that the drugs caused suicidal thinking or behavior.

Dr. Laurence Greenhill, a professor of clinical psychiatry at Columbia University, said neither side in the debate had a monopoly on truth.

“I think that these medications are neither as much of a silver bullet as the advocates would have it nor as terrible as the critics would say,” Dr. Greenhill said.

Copyright 2004 The New York Times Company

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