As U.S. regulators debate whether a popular class of antidepressant drugs causes suicidal behavior in children, their review is also raising questions about whether the drugs are effective.
The use of antidepressants to treat depression or other conditions, such as attention-deficit disorder, in children is growing rapidly even though there are few credible studies showing that they work.
The drugs under review by the Food and Drug Administration include such blockbusters as Prozac, Paxil and Zoloft as well as other antidepressants. The drugs are generally approved for treating depression and many other conditions in adults.
The FDA-approved uses in children, however, are far more limited. Only Prozac is approved for major childhood depression and obsessive-compulsive disorder, and Zoloft and Luvox are approved for obsessive-compulsive disorder in children.
Doctors, however, are free to prescribe a drug approved for one condition say, depression in adults to any patient, of any age, for any condition.
Such off-label prescribing is common. In the treatment of depression, it’s fueled by doctors’ belief that if the drugs help adults they should also help children. Further, insurers often won’t pay for psychotherapy for depressed children but will pay for drug therapy.
The FDA said that in 2002 nearly 11 million prescriptions for the antidepressants were written for children, spread among several different diagnoses including depression, attention-deficit disorder, anxiety and obsessive-compulsive disorder.
According to a January FDA memo, drug makers have submitted 15 studies designed to test the effectiveness of these drugs in treating depression in children. Three came back positive, two were statistically inconclusive, and 10 were negative.
“These are sobering findings and certainly raise a question about the benefits of these drugs in pediatric depression,” the FDA’s Dr. Thomas Laughren wrote in the memo. “The overall success rate for positive studies is clearly a concern.”
Laughren cautioned in the memo that the failure of the trials doesn’t necessarily mean antidepressants are ineffective in children. Trials could have failed due to poor design, and the FDA does “not view negative studies as proof of no benefit,” he wrote.
The public seldom learns that there have been so many negative studies. Pharmaceutical companies perform multiple studies on their drugs and have a great deal of control over when – or if – the results are made public.
This year, however, the FDA has plunged into a thorny debate about whether antidepressants can cause suicidal thoughts or behaviors in children after British regulators kick-started the issue in June.
British officials issued the first in a series of alerts to doctors in the United Kingdom, advising them not to use the British version of Paxil and similar drugs to treat depressed children because of an increased risk of suicide and suicidal thinking. They also found higher rates of self-harm and agitation.
“Having looked at the evidence – and it’s the most comprehensive body of evidence available – the balance of risks and benefits for taking these drugs for treating depressive illness was not favorable” for children, Steve Ryan, a spokesman for the Medicines and Healthcare products Regulatory Agency in London, said this week.
The one exception that British regulators made was for Prozac, which they concluded had evidence of effectiveness in treating childhood depression.
Health Canada, the Canadian regulatory agency, following up on earlier alerts, this month urged families there to consult with their doctors to confirm that the benefits of these drugs for children outweigh their potential risks.
It’s unclear why these drugs may increase the risk of suicide, although some experts theorize that the first few weeks on an antidepressant may give a patient enough energy to act on preexisting suicidal thoughts. But the FDA’s efforts to determine the risk is confounded by data from studies that weren’t designed to answer the suicide question.
“There is some concern there might be a risk, but it has not been clearly shown,” said Dr. James McGough, a member of the FDA’s expert panel and an associate professor of clinical psychiatry at the University of California, Los Angeles Neuropsychiatric Institute. “Carefully monitoring patients is the watchword at this time.”
Drug makers have long said that their products prevent suicide, and that any suicidal thoughts during treatment are a result of depression, not the drugs. But some companies have recently issued warnings.
GlaxoSmithKline, the maker of Paxil, in July sent a letter to Canadian doctors advising them that the drug shouldn’t be used to treat children because of a possible increased risk of suicide-related adverse events. A letter to U.S. doctors informed them of the FDA’s ongoing suicide review, but it didn’t advise them not to prescribe the drug to children.
Wyeth, the maker of Effexor, in August warned doctors of a similar risk of increased hostility and suicidal thoughts in children, especially among those taking the drug for depression.
The possibility that the drugs may cause suicidal behaviors in children has prompted greater scrutiny of their effectiveness.
If the drugs don’t work, there’s little reason to take even a small risk in prescribing them.
“People shouldn’t jump to the immediate conclusion that these medications are not for kids,” said Dr. Boris Birmaher, a professor of psychiatry at the University of Pittsburgh School of Medicine. “But people should be careful with their use.”
In the meantime, he said, doctors need to take great care in properly diagnosing children, taking the time to ensure that the child doesn’t have bipolar disorder, a condition involving bouts of depression and mania. Antidepressants can aggravate the condition.
It’s not only the drugs’ use for depression that’s caused concern.
An FDA review of prescribing data for children younger than 12 indicates that 18 percent of the antidepressant prescriptions were for patients who had attention-deficit disorder, or the related attention-deficit/hyperactivity disorder (ADHD). None of the drugs are approved to treat attention-deficit disorders. Dr. Josephine Elia of the University of Pennsylvania School of Medicine and the Children’s Hospital of Philadelphia, a key researcher on the issue, said the main class of drugs under review is “not effective in treating ADHD.”
In a separate review of prescribing data, George Washington University researcher Thomas J. Moore also found a high percentage of use for what he defined as “attention deficit and conduct disorders” among boys ages six to 12. Moore concluded that the use of antidepressants in children has expanded rapidly – “primarily for off-label use for which little or no scientific evidence exists.”
“To expose so many boys to a medical treatment without clinical trials evidence of safety or efficacy represents an uncontrolled experiment in hundreds of thousands of youths where the risks are unknown and benefits may not exist,” Moore wrote.
Treating children poses unique challenges for doctors. Most drugs have never been thoroughly tested on children, which routinely forces doctors to prescribe medications that have only been tested on adults for safety and effectiveness. Yet children, whose bodies are smaller and still developing, may absorb and metabolize drugs at different rates than adults.
Prescribing drugs that haven’t been approved for use on children is just one area of a larger and growing medical practice called off-label prescribing, where doctors take a medication that’s FDA-approved for one illness and use it to treat another. When doctors lack good data, the practice can subject patients to additional risks of side effects without assurance of a cure.
The number of these unapproved prescriptions has doubled in the past five years, according to a recent Knight Ridder analysis of prescription data. Much of that growth has been fueled by aggressive drug-company marketing, marginal research and doctors who don’t adequately research the treatments.
The idea that antidepressants aren’t always effective in treating depression smacks many doctors and patients as heresy, since so many patients do get better while on the drugs. Many of the drugs increase the activity of a brain chemical called serotonin, which is known to be lacking in depressed patients.
But researchers point out that many of those people would have gotten better on their own. In multiple industry-funded studies, the drugs have performed only slightly better than a placebo, or sugar pill, and many studies have been unable to show any statistically significant drug effect at all.
“Basically, treatment helps people get better, regardless of what the treatment is,” said Irving Kirsch, a researcher from the University of Connecticut who calls the proven benefits of antidepressants “therapeutically negligible.”
Michael E. Thase, a professor of psychiatry at the University of Pittsburgh Medical Center, disagrees that the drugs’ effects are marginal, saying that many of the trials were poorly designed to measure the drugs’ effectiveness. He said drugs produce meaningful benefits greater than what placebos deliver; roughly 30 percent of patients improve on placebo, while 40 percent to 50 percent improve on drugs, he said.