April 17, 2007 — Antidepressants may slightly increase children’s risk of suicide, but the drugs’ benefits far outweigh this risk, a new look at the evidence suggests.

To give prescription antidepressants to your child or teen, you have to get past the FDA’s scary black-box warning on the label.

“In clinical studies, antidepressants increased the risk of suicidal thinking and behavior in children and adolescents with depression and other psychiatric disorders,” the label states.

Pediatric antidepressant use has dropped since the labels appeared in 2004. But the child and teen suicide rate has gone up, not down. Why?

A new analysis of clinical-trial data suggests an answer: The FDA may have overestimated the risks — and underestimated the benefits — of antidepressant drugs for children. The study comes from University of Pittsburgh researcher David A. Brent, MD, and colleagues.

“These medications appear to be safe and effective for anxiety, obsessive-compulsive disorder (OCD), and depression,” Brent tells WebMD. “The number of people likely to be helped is much larger than the number likely to develop some suicidal response to treatment. In our opinion, the risk/benefit ratio is favorable.”

The findings appear in the April 18 issue of The Journal of the American Medical Association.

Antidepressant Benefit vs. Suicide Risk

Brent, Ohio State University researcher Jeffrey A. Bridge, PhD, and colleagues analyzed all available data from pediatric clinical trials of so-called “second-generation” antidepressants. These include Effexor, Remeron, and selective serotonin reuptake inhibitors (SSRIs) such as Prozac.

All children and teens in the studies suffered from major depression, OCD, or a non-OCD anxiety disorder.

“In all of the three indications, more people benefit from the medication than benefit from placebo,” Brent says. “We saw the strongest effect in anxiety, about a 37% difference in response rate. In OCD, we saw about a 20% difference, in the moderate range. For depression the effect was more modest, about 11%.”

Brent stresses that the trials were designed only to see whether the drugs had an effect. They were not designed to see what it takes to return children or teens to mental health.

“Response in these trials meant ‘improved or very much improved.’ But that is not the same as being completely better,” Brent says. “Part of the issue is that these are short trials, eight to 12 weeks, and treatment takes longer. Often people need psychotherapy in addition to medication to recover. So the medication may be necessary rather than sufficient.”

In 2004, the FDA presented to its expert advisory panel an analysis of much the same data. Using a different statistical approach, that analysis came to a much different conclusion. It found little evidence that antidepressants helped kids but found a small but significant risk of suicidal thinking. It led to the panel’s eventual 18-5 vote to put the black-box warning on the drugs’ labels.

Robert Gibbons, PhD, professor of psychiatry and director of the Center for Health Statistics at the University of Illinois at Chicago, was one of the five panel members who voted against the black-box warning.

“The FDA presentation showed very little benefit — so most panel members said, ‘Why tolerate even the slightest risk?'” Gibbons tells WebMD.

“The Brent study is showing that the FDA overestimated the effect of antidepressant medications on suicidality and dramatically underestimated the efficacy of antidepressants in the treatment of childhood depression,” Gibbons says.

Weighing Antidepressants’ Suicide Risk

None of the kids or teens in antidepressant clinical trials actually tried to kill themselves. But some said they thought about suicide or even made preparations for suicide. Even the Brent study found some link between this “suicidality” and antidepressant use.

“Did the drugs make people more disinhibited and more likely to report suicidal thoughts?” Brent asks. “Almost all of these events were suicidal thoughts that increased. There were no suicide attempts and no suicide completions. So while this is a concern, it is not clear what the importance of these events really is.”

The real question, Brent says, is whether the possible benefits of antidepressant treatment outweigh the possible risks. One way of looking at this is to compare the “number needed to treat” — that is, the number of kids who must be treated to ensure that one kid gets a benefit — to the “number needed to harm,” in this case the number of kids who must take antidepressants before one has a suicidal thought.

Brent and colleagues found that for every three to 10 children and teens treated with the drugs, one got a significant benefit. Out of every 112 to 200 children and teens treated, one had suicidal thoughts.

“Our goal was to try to make the decision-making more transparent by presenting the risk/benefit ratios,” Brent says. “We leave it up to families and their doctors to choose whether the possible benefits are worth the possible risks. We are trying to take some of the emotion out of it, and put the risks and benefits side by side.”

“Brent and colleagues have very accurately characterized the real risks and the real benefits of pediatric antidepressants,” Gibbons says.

Both Gibbons and Brent would like to see the black-box warning taken off antidepressant labels.

“We need to consider the risk of doing nothing. Especially with the diagnosis of depression, these are potentially fatal illnesses,” Brent says. “The stakes are high. That is why looking at the risks in context of benefits is so important.”

This doesn’t mean that putting a child on antidepressants is an easy decision. Brent says families must be carefully educated about three things:

• Antidepressant risks and benefits
• Assessment for response to the drugs. If a child or teen doesn’t respond to the medication, there’s no way to compare benefit to risk.
• The need for careful patient monitoring

And Brent warns that successful treatment of depression, OCD, or anxiety isn’t a simple matter of giving children or teens a few months of pills.

“These conditions tend to be chronic and recurrent,” he says. “There is no way an eight- to 12-week study will answer questions about a several-year treatment plan, which is what it takes to get people better and keep them better.”