Recently, a federal advisory panel urged regulators to warn parents that not only do antidepressant drugs increase the risk of suicide in some children, but most have a poor track record in curing their disease. The recommendation came after a yearlong debate over whether the drugs are as safe and effective as advertised. It was based on evidence that a small minority of children show increased signs of suicidal behaviour when taking the drugs. Through it all, one of the drugs seemed somehow above the fray: Prozac.
Although the warning is recommended for Prozac as well as other drugs, Prozac is still the only one approved by the Food and Drug Administration (FDA) for the treatment of depression in children and adolescents. A large government-financed trial recently found that it worked better than talk therapy in helping teenagers overcome depression. And when British health officials announced a sweeping ban of antidepressant use in children, which touched off the debate last year, they specifically exempted Prozac.
But is it really so different' The short answer is no, experts say. Although chemically distinct from other drugs in the same class, Prozac works on precisely the same principle, they say, and there's no evidence that it is significantly safer or more effective than the others in treating childhood depression. Prozac has shown in several trials that it can relieve depression in youngsters and adolescents significantly better than dummy pills do. Such convincing evidence is not available for the other drugs. But, research psychiatrists say, that does not mean the other drugs in the same family do not work in young people, only that they have not been properly tested.
'It makes no scientific sense that you would find any significant difference in the effects' of these drugs, said Dr Steven Hyman, a Harvard psychiatrist and former director of the National Institute of Mental Health, who is not a consultant for antidepressant makers. 'All target and bind to the same molecule in the brain.'
Dr John M. Plewes, a medical adviser at Eli Lilly, which makes Prozac, did not agree that the differences were minimal. 'We've got very good data that the drug is safe and effective in children, and no other drug has this kind of data,' he said.
The molecule these drugs bind to is the one the body uses to dampen the activity of a mood-altering brain chemical called serotonin, Hyman said. When this molecule is tied up by a drug, serotonin surges last longer and, over time, improving mood in some people who are depressed. Prozac was the first antidepressant drug on the market to work primarily on serotonin, and the others that came later ' including Paxil, from GlaxoSmithKline; Zoloft, from Pfizer; and Celexa, from Forest Laboratories ' are what some researchers consider copycat or me-too drugs.
Prozac does linger in the body longer than the others do, once people stop taking it, psychiatrists say. This makes withdrawal more gradual than from other antidepressants, and keeps levels of the drug steady if people miss doses. Teenagers in particular often forget or skip doses, child psychiatrists say, and many of these psychiatrists believe that the potential for suicide is highest in people being treated when their dosage is changing, up or down.
One recent analysis of records of patients who had taken antidepressants, including some 160,000 adults and children, found that the suicide risk was highest in the first three to four weeks of treatment. But no one has shown convincingly that there are significant differences among the drugs, or determined exactly what the withdrawal risks are.
'You really need to watch young patients on these drugs closely at all times,' said Dr John March, chief of the division of child and adolescent psychiatry at Duke University Medical School, the lead author of the recent study comparing Prozac to talk therapy. March has been a consultant to Pfizer and other drug makers but currently receives almost all his research financing from the government, he said.
More so than effects and chemistry, experts say, what distinguishes Prozac is the methodology of the studies that have been done to test it. Depression is a subjective experience for which doctors have no blood test, no hard and fast measure. Especially in children and teenagers, depression is fleeting.
This is one reason that in antidepressant trials the placebo effect is so large and unpredictable. In a study lasting six or eight weeks, many participants get better on their own, drug or no drug. In childhood depression studies the placebo effect can range from 30 percent up to 59 percent, which is difficult for any antidepressant to beat.
"The wonderful thing about the FDA panel's findings is that it's going to force people to talk about these things and look at the studies very carefully," said Dr. Jane Garland, chief of the Mood and Anxiety Clinic at British Columbia Children's Hospital in Vancouver, who has argued that company-sponsored trials have presented data to make the drugs look more effective than they are.
For example, some researchers questioned the findings of two studies reported last year, testing Zoloft for depression in children and adolescents. The placebo response was very high, 59 percent, and some doctors were not convinced that the drug proved much better, as the study's authors had concluded. The studies were large, conducted at multiple sites in five countries, and the criteria for test subjects was not controlled well enough to give a clear picture of what the drugs were doing, if anything, some experts said. Other studies of antidepressants have met similar criticism.
The exception is Prozac, for which there have been three rigorous trials. In 1997 and again in 2002, Dr. Graham J. Emslie of the University of Texas Southwestern Medical Center at Dallas screened children and adolescents to make sure they had persistent depression. He found that those on Prozac reported feeling significantly better than those taking dummy pills after eight weeks, and in one of the trials, were more likely to meet one criterion for recovery.
The first trial was government financed, the second was paid for by Eli Lilly. Emslie has consulted widely for antidepressant makers. "If you tested the other drugs in the same way, tightly controlled, I believe you would get similar results," he said.
The third trial, led by March, appeared in the Aug. 18 issue of The Journal of the American Medical Association. The researchers made sure to include only teenagers who had persistent depression, for more then 40 weeks on average, with a diagnosis in the moderate to serious range. The placebo effect was on the lower end, and after 12 weeks those on Prozac were doing significantly better on ratings of depression. When combined with a brand of counselling called cognitive behaviour therapy, the drug treatment did even better.
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But careful experiments are usually better at picking up risk, too. Although previous studies had not found noticeable association between Prozac and increased risk of suicidal or self-harmful behaviour, March's trial did. Six teenagers taking the drug attempted suicide during the trial, compared with one who was in therapy but not on the drug.
Considering all the data on self-harmful behaviour, March said, Prozac has about the same profile as others in the same family - it is associated with an increased risk of suicidal behaviour in about one in 50 teenagers who take it. "But you have to keep in mind that you can't distinguish that one from the eight or nine in 50 depressed teenagers who also would be at risk for suicide because of the underlying depression," he said.
Individual responses to antidepressants are hardly uniform. Some children who react badly to Zoloft thrive on Prozac, or another antidepressant, and vice versa.
Even doctors who are highly sceptical of drug company claims say that the drugs do help some children overcome a sometimes deadly condition. That is why many psychiatrists are relieved that the FDA panel did not follow British regulators and recommend a ban on use of all but one of the drugs in young people. Although Prozac is approved for treatment of childhood depression and is off patent - meaning it costs a fraction of what the others do - it is good to have options, they say.
"If the recommendations are too derogatory, the use of drugs that I believe are saving hundreds of lives a year could be diminished or withdrawn," said Dr. David Shaffer, a professor of psychiatry and pediatrics at Columbia University. "Then you've got another kind of tragedy." Shaffer said he does not receive any money from drug makers.
Doctors and researchers agree that more work on treatment and diagnosis will be required to sort out the role of drugs. But given the publicity about suicide risk, some doubt that it will happen soon.
Emslie said that when he first proposed studying Prozac in children in the 1990s, Eli Lilly was not interested. "They wouldn't even give us the pills," he said. "They said it was all risk, no benefit. Now, I think it's going to much more difficult to do any of this kind of research."