The federal government ordered yesterday that all antidepressant drugs carry a prominent "black box" warning to alert doctors that the medications increase the risk of suicidal thoughts and behavior among children and adolescents.
Clinical trials showed that children taking antidepressants have a 4 percent risk of suicidal thoughts and behavior, compared with a 2 percent risk among children getting placebos, said regulators at the Food and Drug Administration.
"The use of these products causes a statistically significant increase in suicidal thoughts and behavior among children," said Lester M. Crawford, acting director of the FDA. Crawford urged physicians to evaluate patients carefully before deciding whether the benefits of the drugs in treating depression and other disorders are worth the risks.
"In other words," added Sandra Kweder, acting director for the Office of New Drugs at the agency's Center for Drug Evaluation and Research, "these drugs should not be used casually."
The decision represents a major shift in the agency's long-standing position on the drugs and could significantly alter how they are marketed, prescribed and used.
Controversy has dogged antidepressants for more than a decade, but most psychiatrists have attributed patients' suicidal thoughts and behavior to illness, not medication.
Congressional investigators are looking into whether the FDA erred in not issuing warnings sooner. Yesterday's announcement came more than a year after investigators first learned of concerns over the antidepressant Paxil, 10 months after British authorities warned physicians not to use the drugs for children and eight months after an FDA scientist recommended warning the public about the drugs.
Critics have pointed out that the FDA has long had access to the studies on which today's warnings were based, which compared the risks of children taking drugs to children taking sugar pills. But the agency argued that the trials, conducted largely by pharmaceutical companies in recent years, did not clearly distinguish suicidal thoughts and behavior from other side effects. Officials defended their cautious approach as scientifically appropriate and argued that reevaluations of the data were necessary to lend certainty to their conclusions.
Psychiatrists have vigorously defended use of the drugs because untreated depression can be deadly. FDA officials had said they feared that warnings such as the one announced yesterday could scare families away from the drugs and deprive sick children of valuable treatment.
The American Psychiatric Association said it had "deep concern" over the black-box warning and its potential "chilling effect" on treatment. The association urged the FDA to track the consequences of the warning on prescribing patterns and "also track any increase in actions by patients to harm themselves as a result of reduced access to medically necessary treatment with antidepressants."
"We believe the biggest threat to a depressed child's well-being is to receive no care at all," the statement said.
Eli Lilly & Co., maker of the antidepressants Prozac and Cymbalta, echoed the association's statement and said the warning "may have a dangerous effect on appropriate prescribing for patients who urgently need proven treatment options."
But the American Academy of Pediatrics, whose members also widely prescribe the drugs, said that "pediatricians support stronger warnings, including the black box, as we now know there is definitely an increased risk of suicidal thinking and behavior in children who are on these drugs."
Doug Petkus, a spokesman for Wyeth, which makes the antidepressant Effexor, said the company also supports the FDA action.
Because the available studies on the drugs were not specifically designed to examine suicide risks, evaluating the scientific evidence has been complicated. Prozac has been shown to be effective in treating children's depression, so today's warning suggests the drug might increase suicidal thoughts and behavior among some children and adolescents while simultaneously relieving depression.
None of the other antidepressants has been specifically approved to treat depression among children, so doctors who prescribe them are extrapolating from studies that show they are effective in adults. In children with depression, the overwhelming majority of clinical trials have failed to show that widely prescribed drugs including Paxil, Zoloft and Effexor are superior to placebos; until recently, however, physicians did not have access to most of those negative results.
"To give a child a drug that can make them suicidal for conditions where there is nonexistent or inadequate proof that the drugs work is irresponsible and fails to protect our children," said Joseph Glenmullen, a Harvard University psychiatrist and the author of "Prozac Backlash," who urged the FDA to go further in limiting the use of unapproved antidepressants.
FDA officials said patients are to receive a separate warning, called a "MedGuide," written in easy-to-understand language, about the risks.
The changes will be implemented immediately, officials said, and patients and doctors should see the new warnings within weeks. All advertising for the drugs will have to mention the risks of suicidal thinking and behavior.
Physicians are not likely to be told exactly how many studies of a given drug turned out negative. The problem with describing positive and negative studies, said Robert Temple, director of the FDA's Office of Medical Policy, is that doctors may think a medication is effective because of one positive study. But the FDA requires two positive studies to approve a medication.
Kweder said the wording of the labeling will be worked out in consultation with individual companies, which have sometimes evaluated their products very differently than the agency. In the case of Zoloft, for example, Pfizer Inc. published a paper that pooled the results of two trials and concluded that the results were positive. FDA regulators, however, ruled that individually, the two trials were negative.
"It'll be our judgment" as to what goes on the label, Temple said yesterday.
Regulators also said they were examining data from trials of the drugs in adults to see if there was a similar pattern of suicidal tendencies.