Sept. 14, 2004 — Experts are urging the FDA to require strong warnings on nine popular antidepressant drugs because of evidence that they increase the risk of suicidal behavior in children.

The recommendation, issued by an FDA advisory panel Tuesday, applies to nine antidepressants that affect the brain chemical serotonin. The warning includes the most popular class of antidepressants, called SSRIs or selective serotonin reuptake inhibitors.

The FDA is also moving to require new warnings on other classes of antidepressant drugs including tricyclic drugs and MAO inhibitors.

Antidepressants included in the advisory are:

• Celexa
• Effexor
• Luvox
• Paxil
• Prozac
• Remeron
• Serzone
• Wellbutrin
• Zoloft

“We are unable to conclude that any single antidepressant agent is free of risk at this time,” the panel says.

The committee stopped short of recommending banning the use of the drugs in children but voted 23 to 8 to urge the use of stark “black-box” warnings on all package inserts and drug advertisements warning of increased suicide risk in children. A black box warning is the strongest type of warning that the FDA can require on a drug’s labeling information.

Some members opposed the black-box warning, saying it would scare families and doctors from seeking treatment for children. But others say that the warnings were appropriate given the risks and limited known effectiveness of antidepressants in children.

Analysts unveiled a pair of studies yesterday showing that these antidepressants may increase children’s risk of suicidal thoughts or behaviors by as much as 2% to 3% over what is expected in patients with major depression.

No cases of completed suicide were recorded in any of 23 drug company trials reviewed by the FDA. But many parents of children who have killed themselves while taking antidepressants have claimed a causal link.

The reviews and officials’ statements yesterday went against a years-old position by the agency and drugmakers suggesting that any increased risk of suicide was caused by children’s underlying depression and not their medications.

“The fact that they all lean the same way … that’s what makes a powerful argument,” Robert Temple, the FDA’s head of scientific investigation, said Monday.

The committee voted 25 to 1 that the trials show reliably that the drugs increase the risk of suicidal thoughts or attempts when used in children. Advisors stopped short of recommending that the FDA ban use of the drugs in children, which British regulators did last year.

The FDA issued a public warning in March cautioning about a possible increased risk of suicide with the drugs. Most reports show that the risk is greatest within a few weeks of starting the medications.

Dozens of members of the public testified before the panel urging stronger safety warnings or an outright ban of the drugs.

“If I heard nothing from the public, it’s that they want to be warned. They want to know the risks,” says Jean E. Bronstein, a consumer representative on the committee.

Public attention on the safety of antidepressants has not affected their use. Overall sales rose 7% from the first half of 2003 to the first half of 2004, a growth rate similar to that seen in earlier years, according to Michael Evans, an officer in the FDA’s Office of Drug Safety. Use in child and adolescent patients has also not changed, holding steady at 7% of the total U.S. SSRI market.

Assessing Risks and Benefits

Several physicians and organizations supporting antidepressant use warned the agency Thursday not to make moves that might curtail the public’s access to vital drug treatment. As many as 20% of the American adult population and 3% to 5% of children are thought to suffer from depression at some point, according to the American Psychiatric Association.

But many experts express concerns that doctors and parents don’t have enough information about whether the potential advantage of using antidepressants is worth their side effects.

Despite widespread use of different antidepressants in children, only Prozac has been shown in clinical studies to be effective in depression. Still, Zoloft, not Prozac, leads U.S. sales for child and adolescent patients. Meanwhile, only 3 of 15 studies have shown a clinical benefit of antidepressant use in depressed children, according to an analysis presented at the hearing.

“I think it’s an absence of a benefit, an absence of efficacy, that I’m concerned about,” says Wayne K. Goodman, MD, head of psychiatry at the University of Florida College of Medicine and the advisory panel’s chairman.

Gail Griffith, the panel’s patient representative, urged the FDA to come up with rules ensuring that parents are explicitly made aware of the antidepressants’ side effects before the drugs are prescribed to their children.

“You’ve put the parents now actually in the position of doing the risk/benefit analysis,” she said.

All Drugs Included

The committee voted unanimously for action on all nine of the antidepressants.

Prozac was not suspected of influencing greater suicidal behavior in children until recently. But a national study organized by Duke University and discussed at the hearing linked that drug to increased risk as well.

The results helped lead experts to recommend stronger warnings for all uses of these antidepressants in children. Many of the drugs are used for illnesses other than depression, including anxiety and obsessive-compulsive disorder, and are sometimes prescribed for non-mental health problems like migraine headache.

Two drugs — Serzone and Wellbutrin — did not show evidence of elevated suicidal behavior in clinical trials. But experts urged the FDA to include these two drugs because some studies are inconclusive.

Panelists also urged the FDA to apply stronger warnings to any future antidepressants of this type that hit the U.S. market.

“It would be premature to identify a single drug that should be exempt,” Goodman says.

The safety of antidepressant use in children is the subject of several congressional investigations. Both pharmaceutical companies and the FDA have been accused of acting to suppress information suggesting that these drugs increase the risk of suicide.

The agency was widely criticized for preventing one of its analysts, Andrew Mosholder, MD, from discussing such a conclusion at a public meeting in February. Mosholder’s delivered his conclusions Tuesday, which largely confirmed the results of the FDA’s review of the 23 manufacturer trials.