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The US Food and Drug Administration ordered yesterday the manufacturers of all 32 antidepressant drugs sold in America to add a stern ''black box" warning to their packaging that says the drugs put children and adolescents at greater risk for suicidal thinking and behavior.
Doctors can still prescribe antidepressants to children, but the box is the most severe warning that the agency can apply to a drug without banning it. The box tells doctors they must consider the risk of suicide when prescribing the drugs and should monitor patients for ''clinical worsening, suicidality, or unusual changes in behavior." Doctors must also advise families and patients of the need for close observation.
The FDA's decision was triggered by clinical trials that showed 4 percent of children on antidepressants had suicidal behavior as compared with 2 percent of children taking a placebo.
The move follows a hearing last month when two FDA scientific advisory committees reported on the dangers of nine of the newest-generation antidepressants, including frequently prescribed drugs such as Prozac and Zoloft. The advisers recommended that the entire class of drugs carry the agency's strongest warning.
The FDA sent a letter to drug manufacturers yesterday with the text of the new warnings to be added to the labels of all antidepressants. Companies have 30 days to consider the recommended labels and submit any proposed changes in the wording of the warning to the FDA for consideration.
''These conclusions are based on the latest and best science and reflect what we heard from our advisory committee last month," said Dr. Lester Crawford, acting FDA commissioner, at a news conference yesterday.
Psychiatrists warned that no one taking the medications should abruptly stop, because of the risk of withdrawal symptoms.
Along with the label warning, which is directed primarily to doctors, the agency is requiring new packaging, which will include a separate pamphlet written in everyday language, alerting patients and families to symptoms that could indicate the drug may be harming them. It would become one of fewer than 20 such pamphlets produced by the FDA, according to the advocacy group Public Citizen.
''I'm very satisfied and very pleased at how quickly they've moved to implement these recommendations," said Dr. P. Joan Chesney, who is chair of the committee that advises the FDA on drugs for children and who voted on the warnings in September. ''I think one of the most important things they've done is to provide very specific information for patients and caregivers regarding what to watch for."
Although only nine drugs have been studied enough to show a danger to children, FDA officials decided to require the warning on all 32 antidepressants, because the agency did not have enough safety data to show that the drugs were not potentially harmful.
The FDA thought it would be ''imprudent to leave [the others] unlabeled," said Dr. Russell Katz, director of the FDA's division of neuropharmacological products.
The information on the warning is intended to help doctors and families make a difficult choice, balancing the small but documented risk of suicide against the damage that depression can cause in the lives of young people. The patients' pamphlet is intended to make sure caregivers and patients know how to monitor their health while on the drugs. Yesterday's decision will also change advertising for antidepressants: Pharmaceutical companies are required to add the warning information to print or television ads.
Beyond the black box, the new warnings offer specific monitoring guidelines for doctors -- weekly visits with patients or families during the first four weeks of treatment, biweekly visits in the next four weeks, and then another visit at 12 weeks, at which time the clinician can determine how often to see the patient.
The FDA approved the antidepressants on the US market after testing for effectiveness and safety in adults, not in children. After tests showed Prozac could help depression in children as well, the FDA in 2003 made it the only antidepressant specifically approved to treat depression in patients under 18. The few studies that exist on the other 31 drugs in children have not yet demonstrated that they are safe or beneficial.
Doctors remain free to prescribe any legal antidepressant to children.
Critics say the proposed warning is insufficient, because it does not make clear that only Prozac has been found effective on children in clinical trials.
''There's little or no evidence that the drugs work for children and very powerful evidence" they may be harmed, said Dr. Joseph Glenmullen, an outspoken critic of the pharmaceutical industry, who said the FDA should have banned the prescription of the drugs for any use that had not been approved.
The warning will explain that the drugs, except Prozac, have not been specifically approved for treating depression in children.
The FDA has approved Prozac, Luvox, Anafranil, and Zoloft for treating obsessive-compulsive disorder in adolescents.
''No drug is free of risk, and you always have to balance the risks versus the benefit," said Larry Sasich, a pharmacist and research analyst at Public Citizen, a government watchdog. But if there is no benefit, then the risk is not worth it, no matter how small, he said.
Spokesmen from the companies that sell antidepressants supported the decision yesterday, despite studies that have shown a decrease in sales for youth antidepressant use since British authorities banned drugs other than Prozac for use in children last December. Medco Health Inc., a pharmacy benefits manager, reported last month that the number of children and teenagers taking antidepressants fell more than 20 percent this year.
Douglas Petkus, a spokesman for Wyeth Pharmaceuticals, which makes the
antidepressant Effexor, said the company supported the FDA decision. So did
Mary Ann Rhyne, a spokeswoman for
''We're supportive of providing the additional information, because we believe that could be one of the most positive steps in treating children," Rhyne said.
In contrast, the response in the medical community has been guarded. Many doctors say they fear a ''chilling effect" in patients and primary-care doctors, who lack the time and training to diagnose and care for children with depression, causing them to shun the medications.
''The child psychiatrists, who are comfortable using these medications, think that patients will become fearful of using them," said Dr. Walter Harrison, chairman of the Children's Mental Health Task force for the Massachusetts Chapter of the American Academy of Pediatrics.
Many psychiatrists point to the fact that suicide rates in the United States began to decline at the same time the newest generation of antidepressants was introduced. The suicide rate of those ages 15 to 24 has fallen from 13 to 10 per 100,000 since the early 1990s, after the first new-generation antidepressant, Prozac, appeared on the market.
Many specialists say the FDA's broad warning about an entire class of drugs reveals how little researchers know about how any antidepressant affects the young brain, and how and whether those drugs work.
''We need to have more studies on both the efficacy of these medications, the efficacy of the combined treatments of these medications and psychotherapy," said Dr. Steven Sharfstein, president-elect of the American Psychiatric Association.
''And we need to be sure that every time there is a trial that clinicians have access to results."
