A lot of clinical trials for antidepressants fail," added Hyman, now provost at Harvard University. "Partly that's the difficulty of trials in a waxing and waning disease, but we also need drugs of greater intrinsic efficacy."
Prozac remains the only antidepressant the FDA has approved for children's depression. The agency accepted two studies that demonstrated the drug worked better than a placebo.
Benchmark missed
But an FDA internal analysis of the trials found Prozac failed on the statistical measure that researchers had originally chosen as their primary benchmark. Senior FDA officials, however, concluded the improvement on another measure justified approval.
Australian researchers, writing this month in the British Medical Journal, reviewed the published studies of Prozac and other drugs and concluded they were consistently weak. The review charged that researchers doing the studies had selectively dramatized successes and glossed over problems.
Another analysis this month in the journal Psychiatric Services said the drugs had only modest benefits, with "many treated patients continuing to experience symptoms." The report tracked antidepressant-prescription increases among children with private health insurance.
"When a patient takes a medicine, or a family physician or a pediatrician prescribes medicine, their understanding when they hear this medicine works is they believe, 'My child will recover from depression,' " said Jane Garland, head of the mood- and anxiety-disorders clinic at the British Columbia Children's Hospital in Vancouver.
"But the data says they are not going to get any better than on a placebo," she said. "They will have some improvement in symptoms, which is a good thing, but it means there is clearly more than medication needed for treatment."
Warning heightens concerns
Concerns over the quality of the data have been heightened by a recent warning by British health authorities that urged caution in using the drugs, citing indications they may cause suicidal behavior.
"The risk-benefit ratio starts to look dodgy," said Dr. Jon Jureidini, a child psychiatrist at the Women's and Children's Hospital in Adelaide, Australia. "But if you look at the published literature, you can be forgiven for not reaching that conclusion."
Most psychiatrists say the fears about suicide risk are overreactions, although patients who suddenly stop taking medicine without consulting their doctors could put themselves at risk.
The review in Psychiatric Services said that growing awareness about depression, better diagnosis and incentives by insurance companies in favor of medication rather than talk therapy may have fueled the rise in drug treatment.
The report also cited doctors' belief that positive data from adult studies can be extrapolated to children. In a 1999 letter to Prozac's manufacturer, however, the FDA expressed "substantial concern about the ability to extrapolate positive antidepressant findings from adult to pediatric patients."
"I'm not anti-drug, but I don't know what to believe," said Dr. Wayne Blackmon, a Washington, D.C., psychiatrist who worries that clinicians have been fed misleading data. "Once you start delving into it, you start going, 'Oh no, no, no — this is not valid.' "
Placebo effect
Across the board in clinical trials, about half of all depressed children improve whether they are on a drug or a placebo. New evidence suggests the placebo effect — the tendency to get better when patients believe a treatment will help — may be even greater in the real world, because patients deemed susceptible to placebos are screened out of clinical trials.
While supporters and critics present the issue in black-and-white terms, the data from clinical trials paint a complicated picture.
In one of the two trials of Prozac used to win FDA approval, for example, the original benchmark was recovery: how many depressed children recovered on Prozac versus a placebo. The difference was not statistically significant.
But Prozac's manufacturer, Eli Lilly, then evaluated how many children improved by 30 percent on a commonly used scale to measure depression. Among children taking Prozac, 58.3 percent had a 30 percent improvement, whereas only 31.9 percent of those on a placebo improved that much.
By this new measure, the difference was statistically significant, and the company claimed success.
The internal FDA statistical analysis, however, found the difference vanished when officials looked at how many children improved by 10 percent. And there was again no difference when they evaluated how many children had a 50 percent improvement.
"The largest treatment effects was found when 20 percent or 30 percent cut-off points were chosen," an FDA statistician wrote.
In the end, however, senior FDA officials concluded the drug had succeeded on yet another measure, which they said was the best way to evaluate antidepressants: the average improvement on the children's depression scale.
Dueling statistics
Part of the problem for doctors and parents is that experts starkly disagree on the statistics.
Dr. Graham Emslie, for example, a professor of psychiatry at the University of Texas Southwestern Medical Center, who conducted the two positive trials for Prozac, said six antidepressant studies in children showed benefits. The FDA counted three.
Emslie co-chaired a panel of the American College of Neuropsychopharmacology that declared in January the drugs are safe and effective for depressed children.
But at least one manufacturer, Wyeth, has told doctors not to prescribe its drug Effexor for children.
Dr. Philip Perera, medical director at Glaxo SmithKline, which makes Paxil, said, "Our point of view with respect to pediatrics is that it is still up in the air."
Jureidini's analysis in the British Medical Journal, which examined six published trials for Prozac, Paxil, Zoloft and Effexor, found that of 42 measures used to evaluate patients in these studies, only 14 showed a statistical advantage for the medicine over a placebo.
The psychiatrist said the moderate benefits of the drugs have been oversold. He blamed marketing and the alliances the industry has made with top psychiatrists.
Once prominent doctors supported the drugs, general practitioners and the public accepted the conclusion, Jureidini said.
The researcher said doctors had a subtle but powerful bias: "There's this kind of view that we all know antidepressants work, and if the research doesn't support that, there must be something wrong with the research." |
