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After determining that antidepressants can pose a risk to young people, the Food and Drug Administration is turning its attention to the drugs' effects in adults.
The FDA says it will do a study of risks to adults in light of the evidence of a tie between the widely prescribed drugs and suicidal tendencies in children and adolescents.
That finding - after an exhaustive re-examination of clinical-trial data on young people - led the agency to say it will require a strong label warning about antidepressants' risks for young people. Now FDA officials will comb through the existing data on adult clinical trials in the same detailed fashion.
“We learned from that,” says Janet Woodcock, a deputy commissioner of the FDA. “It's a different way of analyzing the data.” British regulators also are studying adult data for evidence of suicide risk.
The FDA has examined the issue in adults before, and found no increased risk of suicide.
It's unclear why some drugs could increase suicidal tendencies only in a small subset of young people, and not in adults. One theory is that younger people may have less control over their impulses, or less ability to cope with or understand an unexpected drug effect. “One hypothesis is that in some patients, [these drugs] have a disinhibiting effect,” says Wayne Goodman, chairman of the FDA panel that examined the issue in young people. “Children are already a bit disinhibited” because their brains aren't fully developed.
Many doctors believe “there is something different in depression in children and adolescents versus adults,” says John Mann, a professor of psychiatry at Columbia University.
Doctors say it's well-established that children and adults don't always respond to medications in the same way. For example, the antidepressants in wide use today - mostly selective serotonin reuptake inhibitors, or SSRIs - are effective in adults, but most haven't been proven to work in young people. Similarly, older antidepressants known as tricyclics, which aren't widely used, are considered effective for adults but not children. Moreover, tranquilizing medicines such as Ambien and Valium are far more likely to cause side effects such as hallucination and agitation in children than adults.
WEIGHING DIFFERENCES
Why risk of suicidal behavior with antidepressants may be different in adults than young people . Young people may have less impulse control, or less ability to cope with an unexpected drug effect.
. Depression in adolescents may be fundamentally different from depression in adults.
. Developmental differences between the pediatric and adult brains may play a role.
SSRIs, including Prozac, Paxil and Zoloft, act to increase the amount of serotonin, a chemical in the brain that affects mood. Children's serotonin systems are more active than those in older people, says Dr. Mann, though it isn't clear why or whether this would make the SSRIs ineffective or create side effects. “There may be other developmental differences” between adult and pediatric brains, he says.
The FDA has much more information available to study about adults and antidepressants than it had about young people. It has a database of 234 randomized trials for 20 drugs that it plans to use in its new study, Dr. Woodcock says. For pediatric patients, the FDA analyzed 23 pediatric drug-industry trials, and one result from a National Institutes of Health study.
Dr. Woodcock says the agency had gone through the adult database, in an analysis that still is being finalized, for trends based on the number of actual suicides.
As it did with the pediatric clinical trials, the agency will examine closely the adult data in an effort to find and characterize individual incidents that could indicate suicidal tendencies. The agency is trying to decide on its exact approach, such as whether the data should be sent to outside researchers to examine.
Concern among regulators and the public over the possible downsides of antidepressants emerged in 1990, when Martin Teicher, chief of a laboratory at McLean Hospital in Massachusetts, wrote a paper describing six patients who experienced “intense, violent suicidal thoughts” after taking Eli Lilly & Co.'s Prozac.
RATING BEHAVIOR
The FDA had outside experts come up with classifications to sort potentially suicide-related events that occurred in antidepressant trials with young people. Here are some of the categories, along with actual examples:
Suicide attempt: A girl lit herself on fire. A 15-year-old impulsively slit her wrists following a fight with her mother; the wounds were superficial and weren't stitched.
Preparatory actions toward imminent suicidal behavior: A 16-year-old tried to hang herself and was prevented by her family. An 11-year-old held a knife to his wrist and threatened to harm himself. Self-injurious behavior with no suicidal intent: A girl cut herself but denied that she was suicidal and said it gave her a “good, weird” feeling.
Suicidal thoughts: A patient had thoughts for three days of killing himself, but didn't take any action.
Source: Kelly Posner of Columbia University, the principal investigator
The finding in young people “makes the association in adults seem more credible,” Dr. Teicher says today. But in 1991, an FDA advisory committee - after examining the Teicher paper as well as evidence from Eli Lilly - concluded there was “no credible evidence” that Prozac caused suicides.
Why medications that are supposed to alleviate depression could, in rare cases, actually have the opposite effect remains a mystery. Dr. Teicher wrote a summary that included several theories. One was that the drugs could give patients more energy before lifting their depression, enabling them to act on a suicidal impulse. Another was that the drugs could somehow worsen depression in a small subset of patients. A third theory was that the antidepressants could cause a state of agitation and restlessness.
The questions about the adult risk of Prozac and similar drugs never completely disappeared, in part because of litigation against the medicines' makers brought by people charging that they or their relatives were hurt by the drugs. David Healy, a professor at the University of Wales in the United Kingdom and a controversial critic of the drugs, argued in a paper in 2003 that, analyzed in a certain way, clinical-trial results could show a greater risk of suicidal acts tied to antidepressants.
Drug makers have questioned Dr. Healy's methodology and said repeated studies of their clinical trials show no evidence to back his point. Lilly's analysis of Prozac clinical-trial results found no statistically significant connection between the drug and suicide. Rather, it showed a correlation between use of the drug and fewer suicidal thoughts, when compared with placebo pills. Separately, a 1995 paper in the Journal of European Neuropsychopharmacology reported “significantly fewer” new suicidal thoughts, and fewer suicides, among patients taking Paxil compared with those on placebos.
“Each time it has been looked at, there is no suggestion of an association” with suicidal tendencies in adults, with relation to SSRIs, says Alan Metz, North American medical director for GlaxoSmithKline PLC, Paxil's maker.
Further support for that camp came from researchers who authored an April 2003 report in the American Journal of Psychiatry based on their analysis of FDA clinical-trial data. They found there was no statistical difference in the suicide rate between patients taking antidepressants and those taking placebo pills.
Still, the FDA's findings about young people and antidepressants puts a new spotlight on the old questions. The agency's analysis of a series of pediatric clinical trials - endorsed by its committee of outside advisers - found that in perhaps 2% to 3% of the time, the antidepressants appeared to raise the risk of suicidal thoughts or actions. None of the patients actually committed suicide.
Write to Anna Wilde Mathews at anna.mathews@wsj.com1
URL for this article: http://online.wsj.com/article/0,,SB109632629148029432,00.html
Hyperlinks in this Article: (1) anna.mathews@wsj.com
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