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FDA Study Confirms Antidepressant Risks

Mosholder found that children getting antidepressants had 1.9 times the risk of "serious suicide-related events."

Multiple congressional investigations are underway into the controversy. In a statement yesterday, the chairman of the Senate Finance Committee, Charles E. Grassley (R-Iowa) said: "It's been almost nine months since British regulators issued new recommendations, and it's been six months since Dr. Mosholder made his determinations. Now, given this new information, it's fair to ask if the Food and Drug Administration is taking too much time to draw a conclusion."

In April, the FDA's associate director for medical policy, Robert Temple, said in an interview that officials believed that a second analysis might provide a different answer than the one reached by Mosholder: "Andy thinks the results are unlikely to change from this analysis, and we are not so sure of that."

Temple said the agency decided to withhold Mosholder's findings because "we didn't think it was time to present a conclusion about a study because we as an agency didn't want to present it . . . in the absence of all the data; you want to be careful about reaching premature conclusions."

Agency officials said at the time that they were concerned about whether the companies had classified suicidal cases properly, and referred the question to Columbia University scientists. But in a memo dated Feb. 18, Mosholder warned the new analysis would waste time: "In my view, it is unlikely that the new information will alter the basic finding of an association of . . . serious suicide-related events with active treatment."

Given the risks, he urged the agency to take the interim step of officially discouraging the use of antidepressants other than Prozac for children. The FDA declined to do so but called for stronger warning labels to remind doctors to be vigilant about suicide -- for more than a decade, the agency has said that depression, not antidepressants, causes suicidal behavior.

"The whole thing is plain worrisome," said Hyman, who is currently provost of Harvard University. He said his reading of the two internal FDA documents suggested clinicians ought to use Prozac as first-line treatment for children's depression. If it failed to help, Hyman said, he would still cautiously use other medications, because the alternative -- leaving depression untreated -- could itself lead to suicidal behavior.

Jane Garland, a professor of psychiatry at the University of British Columbia, said she still thinks British regulators went too far. But after reviewing the two FDA analyses, she said the risk of suicide could not be dismissed: "I think the [FDA] assumption was if they looked at it more carefully it may disappear, and it hasn't disappeared." Garland recommended better tracking of side effects in clinical practice.

Glenmullen pointed out that no antidepressant apart from Prozac had demonstrated superiority to placebos in treating children's depression. If final FDA reviews confirmed the safety problems that Hammad and Mosholder found, he said, the lack of proven efficacy ought to discourage use of several drugs.

Both the FDA staff analyses calculated the risk of suicidal behavior for individual drugs as well as for all the drugs combined. Both were fraught with difficulties because the different studies used different measures of suicidal behavior.

Hammad and Mosholder found the risk of suicidal behavior varied widely among the drugs and between different trials of the same drug.

Hyman said more government-sponsored research is needed to objectively evaluate the issue. All the company-sponsored trials, for instance, excluded children who were suicidal to begin with. Including such patients might have showed the medicines lowered the risk of suicide, Hyman said. But just as easily, they might also have heightened concerns about the impact of the drugs on suicidal children.

"Maybe they are at the highest risk for these adverse events," Hyman said. "We just don't know."

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