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FDA warning on one drug spurs concern over others

FDA action on the use of paroxetine by those younger than 18 brings to light a range of cracks in mental health infrastructure.

By Victoria Stagg Elliott, AMNews staff. Sept. 8, 2003.

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The repercussions of a recent announcement by U.S. and British pharmaceutical regulatory agencies are playing out in a new level of debate regarding a range of issues that plague the practice of medicine.

The two government regulators, the Food and Drug Administration and the British Committee on Safety of Medicines, recommended against using one specific antidepressant for patients who are children and adolescents. Since then, the upshot has been a domino effect including renewed calls for all drug research to be made public, especially when funded by a pharmaceutical company, and for more pediatric drug studies.

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The actions also have focused on the weaknesses of U.S. mental health care and reopened decades-old questions about the possible link between antidepressants and suicide. Finally, these developments have highlighted the ongoing challenge of studying depression and suicide.

"You can use this case to point out all the total inadequacies of the health care system," said Michael Grodin, MD, a health law professor at the Boston University School of Public Health.

Specifically, the FDA and its British counterpart issued directives in June that paroxetine, an antidepressant marketed here under the brand name Paxil and in Britain under the name Seroxat, no longer should be prescribed to those younger than 18. Both agencies reviewed several studies that showed no efficacy for this age group and an associated increased incidence of self-harm and suicidal thoughts. Both agencies also are analyzing the data to determine if there are any implications for adults.

"The benefits of taking Seroxat are well-established, and patients over 18 years and those who are benefiting from Seroxat should not be frightened into stopping their medication," said Dr. Ian Weller, chair of the expert group looking at SSRIs for the British Committee.

Initially, doctors expressed concern that adult patients would abruptly discontinue the drug in response. But this scenario has not been borne out.

To be fair, the impact of the drug's withdrawal for the treatment of childhood and adolescent depression has been minor. Doctors say they rarely use it in this age group. According to data from Britain, only 8,000 of the 4 million prescriptions written for the drug are for those younger than 18. U.S. use patterns suggest that only about 5% of prescriptions for the drug are for young patients.

But the controversy surrounding this drug has called attention to some important issues that have long dogged medicine.

Many doctors are frustrated by the fact that they haven't been able to review the evidence that indicates links between the drug and suicidal thoughts or behavior in patients younger than 18.

"Why aren't these studies published?" said Michael Greene, MD, a Macon, Ga., family physician. "Good lord, we get articles about left-handed toenail removal in lower New Guinea. It makes it hard to believe that [this information] couldn't get published in something."

GlaxoSmithKline, the maker of Paxil, doesn't dispute the findings and has no intention of seeking approval for this drug's use in this age group. The findings are fairly new and publication takes time, said Philip Perera, MD, GlaxoSmithKline medical director of psychiatric drug development. Some of it already is out there, although not necessarily in the top journals. And journals often have their own bias that makes it difficult to get less-than-positive studies published, he added.

"The data about Paxil has been published and presented at conferences, but this data is less than a year old," Dr. Perera said. "But often, when you submit data from failed or negative trials to journals, they don't get published."

Doctors who treat children also say this situation underscores the urgent need for more drug studies in youngsters and reinforces the message that children are not just small adults. The adverse events of suicidal thoughts and behavior that are currently bringing the drug under scrutiny have not surfaced in adult drug studies.

Meanwhile, the medication never has been officially approved for pediatric use. The FDA's pediatric rule requiring that drugs be tested in young patients was suspended by the courts last year, and physicians say this circumstance demonstrates that it is needed more than ever.

"I don't want Paxil pens, Paxil coffee mugs and Paxil balloons," said Joseph F. Hagan, MD, a pediatrician in Burlington, Vt. "What I want is studies in kids."

Triggering broader questions

For primary care physicians who treat both adults and children, the situation has reignited discussions about deficiencies in access to mental health services.

Those who prescribe antidepressants feel that their patients need those services, particularly during the first few weeks on medication when adverse events are most likely. But patients often do not have access to mental health care.

Some live in areas where such services are miles away. There are not enough specialists to go around, particularly for children and adolescents. And even if there were, insurance won't always pay for them.

Primary care physicians feel comfortable treating depression that is not complicated by other conditions, and specialists feel this is the best venue for that care. Still, the limited access to mental health services also means that those who have more complicated problems may be misdiagnosed and not treated appropriately.

"We do an extremely poor job with mental health in this country even for the insured patient, much less for the uninsured patient, and even less for adolescents than there is for adults," Dr. Greene said.

And as always, there is the age-old question of the link between antidepressants and suicide. Specifically, experts say, it is very difficult to separate the impact of the drug from the effect of the disease.

"Sometimes people who are very depressed are too depressed to kill themselves. Then as they get a little better, often times, that's when they have enough energy to actually go ahead and do the act. That's why you have to monitor people very carefully," Dr. Grodin said.

"But you wouldn't not treat people even if there was a suicide risk because they were starting to get better. Because ultimately the idea is that people should not be seriously, deeply depressed."

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