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U.S. Urges Close Watch on Antidepressant Users

Concern mounts over behavior changes, including suicidal notions

MONDAY, March 22, 2004 (HealthDayNews) -- The U.S. government is urging doctors and parents to keep a close eye on people, especially children, who are taking antidepressants because the drugs could cause serious side effects that might include suicidal thoughts.

On Monday, the U.S. Food and Drug Administration sent letters to the manufacturers of 10 popular antidepressants, asking them to incorporate more stringent and visible warnings on their labels.

The action amounts to a "just-in-case" caveat, as experts have been unable to state categorically whether the drugs or the condition they treat could cause these behavioral changes.

The changes would alert physicians, patients and parents or caregivers to look for signs depression was deepening, in particular for any suicidal behavior or thinking, as well as for the onset of other types of behavior such as agitation, anxiety, irritability and severe restlessness. The agency wants them to pay particular attention to people just starting on the drugs or when the dosing level changes.

The new labels would apply to both pediatric and adult usage of bupropion (Wellbutrin), citalopram (Celexa), fluoxetine (Prozac), fluvoxamine (Luvox), mirtazapine (Remeron), nefazodone (Serzone), paroxetine (Paxil), sertraline (Zoloft), escitalopram (Lexapro), and venlafaxine (Effexor). Prozac is the only drug approved for use in children with major depressive disorder, yet doctors are at liberty to -- and do -- prescribe many others for kids.

"There is a fair amount of off-label use of these products," Dr. Dianne Murphy, director of the FDA's Office of Pediatric Therapeutics, said at a news conference Monday. "It is thought that this information would better inform not just psychiatrists who are prescribing, but there is an increasing shift that these products are being used by family practitioners and pediatricians. So we're hoping that this kind of information will let everybody -- parents and physicians -- to make a better informed choice."

FDA officials made it clear the actions were not intended to place blame on the drugs themselves. "We do not know whether or not the treatment causes these changes," said Dr. Russell Katz, director of the Division of Neuropharmacological Drug Products at the FDA's Center for Drug Evaluation and Research (CDER). "It may be the natural course of the disease but, in any event, patients should be aware that changes may occur."

The action is the culmination of months of review and deliberation since June 2003, after concerns were raised that Paxil and other similar drugs might contribute to increased suicidal thoughts and actions, particularly in young people.

No children in any of the studies took their own lives, however, though some adults did.

In February, the FDA's Psychopharmacologic Drugs Advisory Committee and the Pediatric Subcommittee of the Anti-Infective Drugs Advisory Committees recommended that labeling should stress the need to monitor patients taking certain antidepressants.

Still, the labels will contain little new information. "Many of these warnings have already been in the labeling but, on the advice of our advisors, we are consolidating these warnings and making them more prominent in the labeling to make sure physicians get the message that they should be watching patients very closely for any behavioral changes," Katz said.

One new addition relates to bipolar disorder. Regulators are concerned that some patients presenting with depression might actually be in the beginning phases of bipolar disorder, which is marked by phases of depression alternating with periods of mania. "It's not proven, but treatment of depression may trigger a manic attack, and that's very dangerous," Katz said.

The FDA does not have the authority to require manufacturers to change their language. Nevertheless, officials are obviously hoping the cachet of the office will persuade manufacturers to see their point of view. All the manufacturers were sent changes in identical language. "We would hope that they would adopt the language intact," Katz said.

By the FDA's own admission, this action is not likely to be the final word on the subject. Existing science on the topic is imperfect, and the agency has enlisted the help of Columbia University to review existing research. "Columbia is looking at all reports and trying to classify them sensibly as to whether they are suicidal thinking or not," said Dr. Robert Temple, director of medical policy at CDER. "It's not a new study, but they're helping us interpret what the results of previous studies say."

Katz added the FDA was planning to go back to the advisory committee in September to present the final analyses. "We don't know if the analyses will settle the question, but we do believe that they will tell us as much as the data currently in hand call tell us. They will be as definitive as they can be."

This does not obviate the fact that studies in children are far fewer in number than those in adults. "There's something in particular we're very worried about but what we don't know what to do with is a child who is seriously depressed," Temple said. "Depression has its own liabilities and is, in some ways, a fatal illness. We wish we had enough data to see if the long-term benefits [of antidepressants] outweigh the risk, but most of the studies weren't able to show a clear benefit. That doesn't mean that these drugs aren't useful or important in some people."

Dr. Marvin Lipkowitz, chairman of psychiatry at Maimonides Medical Center in New York City, favors the recommendations. "The newer drugs have been a boon in the treatment of depression," he said. "However, the advertisements and the way people think about the drugs makes them sound as if they are sort of like aspirin for headache. This is an error."

Many people now go to their primary-care physicians to get antidepressants, he said. "There is the potential that there will be an increase in the suicide rate. I don't think it's going to be a great increase, but any suicide is a great tragedy."

More information

Go to the U.S. Food and Drug Administration for both the Public Health Advisory and a Q&A on antidepressant use.

SOURCES: March 22, 2004, news teleconference with Russell Katz, M.D., director, Division of Neuropharmacological Drug Products, Center for Drug Evaluation and Research (CDER), U.S. Food and Drug Administration, Rockville, Md., Robert Temple, M.D., director, Medical Policy, CDER; Dianne Murphy, M.D., director, Office of Pediatric Therapeutics, FDA; Marvin Lipkowitz, M.D., chairman, psychiatry, Maimonides Medical Center, New York City
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