As 2004 gets underway, antidepressant medications are on the pharmacologic equivalent of orange alert. Safety concerns raised anew in mid-2003 shadow the skyrocketing use of selective serotonin reuptake inhibitors in children and adolescents.

Last June, the Food and Drug Administration advised U.S. physicians that America’s most prescribed antidepressant, the SSRI Paxil, should not be used in children and adolescents under age 18 due to a possible increased risk of suicidal thoughts and attempts. The agency recommendation followed close on the heels of a similar action in Britain.

By late October, however, the FDA, had, in its own words, “backed off a little bit.” It issued a public health advisory stating that the agency had grown “increasingly skeptical” that there was any link between antidepressant use and the risk of suicide in children and teenagers.

The danger may be officially downgraded in February, when the agency is set to hold a public discussion with outside experts who are reviewing data from controlled studies of SSRIs in children and case reports of suicide attempts. A preliminary review of 20 placebo-controlled trials of the drugs in over 4,000 children found no completed suicides, although case reports of suicide attempts have appeared in medical journals and the press. The FDA finds such reports “difficult to interpret in the absence of a control group, as these events also occur in untreated patients with depression.”

Specialists around the country believe that in contrast to a ban imposed by British regulators, the FDA is already charting a nuanced approach to medication availability, one that grapples with the difficult realities of depression and its treatment at a stage in life when impulsive behavior is at its height.

Suicide is the eleventh leading cause of death for all Americans. It is the third leading cause of death for those aged 15 to 24. “And the number one cause of suicide in young adults is untreated depression,” emphasizes John Greden, M.D., chairman of psychiatry at the University of Michigan and head of its depression center, the nation’s first. According to the National Institute of Mental Health, depression affects up to 2.5% of children and about 8% of adolescents in the U.S.

In the year ending September 2003, some $10.6 billion worth of prescriptions were written for the SSRI antidepressants. An unknown but growing number of those were for youngsters between the ages of 12 and 18.

In January 2003, Prozac became the only SSRI approved by the FDA for use in children 8 to 18 with major depression; psychopharmacologists believe, however, that all the serotonin reuptake inhibitors act similarly enough that safety and effectiveness proved for one can be presumed of all. Many of the SSRIs have been studied and approved for use in children with obsessive-compulsive disorder and other anxiety conditions.

The latest concerns with SSRIs stem less from clear evidence of risk than a paucity of placebo-controlled studies proving benefit against depression in children. In strong contrast to the situation with adult depression, the number of studies of antidepressants in children can be counted on one’s fingers. It took an act of Congress in 1997, with the provision of financial incentives to pharmaceutical manufacturers, to encourage them to study their own drugs in children.

The current alarm was tripped when three unpublished studies failed to demonstrate any benefit of Paxil versus placebo in depressed children. Child psychiatrists are quick to put that in perspective. “Ten years ago, we were still debating whether kids could be depressed,” says Robert Kowatch, M.D., professor of psychiatry and pediatrics at Cincinnati Children’s Hospital and Medical Center. “The early studies we did were not well designed.”

Timothy Wilens, M.D., associate professor of pediatric psychiatry at Harvard, elaborates. “Only recently have psychiatrists become familiar with ways to assess childhood depression.”

What’s more, many observers believe that a variety of responses “got lumped into the ‘adverse reaction’ category.” According to Wilens, the primary problem is the emergence of “fleeting suicidal ideation.” He emphasizes that no actual suicide “events” have been tied to such reactions.

What is clear is that a number of people have transient reaction to medications. It could be manic activation. It could be activation of some psychotic features. In his own study, Wilens says, “we didn’t find any de novo suicidal ideation. The drugs are probably triggering panic and other reactions interpreted as suicidal ideation.”

Clinically, Kowatch says, there a 2% risk of any adverse effect. “Most of the time a kid who shows up in a psychiatrist’s office with depression has been through psychotherapy. He or she is failing in school and is suicidal. We’re willing to take that risk. Nine out of ten will do well with an antidepressant, though not necessarily the initial one tried. I may have to switch to find the right one.”

Kowatch contends that American psychiatrists are more comfortable with SSRIs and medications in general than are their British counterparts. “There is a cultural difference; they are still debating whether depression appears in children.”

For Michigan’s Greden, the most persuasive argument for the drug’s continued availability is the nature of depression. “Suicidal thinking and occasional attempts are to depression as fever is to untreated pneumonia. Untreated depression leads to suicidal thinking and attempts.”

Psychiatrists say they are always cautious about treating young people with drugs. They emphasize the need for complete evaluation. “Are they really depressed?” says Kowatch, explaining his chain of thinking. “Is anything else going on, in school or in the family? Does the child have a learning disability?”

Who gets treated with antidepressants in childhood? Says Greden: “It’s the most severely depressed, the ones who struggle most with impulsivity and suicide.”

Evidence now demonstrates that depression is most likely to begin in the young, those between ages 15 and 24. “If you can’t treat it, then the syndrome gets a running start,” says Greden. “Not making drugs available dooms young people to more severe disease that is harder to treat. That’s a heavy burden when we have treatments that work.”

The solution, many psychiatrists agree, is to start drugs slowly and watch patients carefully. The most dangerous time for suicide is just after treatment is started. “We don’t fully understand this yet,” Greden confides. “If you treat moderate to severe depression it’s like shaking a glass of water. You see a flare-up of suicidal ideation. No one is sure why.” The SSRIs raise serotonin levels; impulsivity is associated with low serotonin levels, not increased levels.

His best guess is that the drugs increase fear conditioning in the acute phase. The issue is not whether, but how, to use the drugs. “Clinicians should start with low doses and closely monitor children. The families should monitor them, too.”

In the long run, treatment lowers the rates of suicide. Columbia University psychiatrist John Mann, M.D., an expert on suicide, is one of many specialists to call attention to suicide statistics. As the use of SSRIs has increased four-fold, there has been a decline in suicides in the U.S. Although the correlational data do not establish a direct cause-and-effect relationship, they so suggest that the drugs aid suicide prevention.

If clinicians have a beef with Paxil, the drug that stimulated suicide concern, it is that it poses a problem of withdrawal reactions. “People have difficulty when they stop the medicine abruptly,” says Richard Kadison, M.D., director of student health services at Harvard University. This is a concern because “adolescents are, in general, not the most reliable folks when it comes to taking medications.”

Still, schools and colleges are generally reaping a “Prozac payoff.” Taking SSRIs to reverse depression has enabled many young people to stay in the academic system who in earlier times might have been forced by illness to drop out of school.

Whether in the longest run drugs are the best way to deal with depression in young people is a legitimate question now getting serious attention. At least two studies funded by the National Institute of Mental Health are exploring whether developmental approaches, alone or in combination with medication, can combat depression. One is a study of cognitive therapy versus drugs, the other looks at whether instruction in specific coping skills, can head off depression in stressed teens with a family history of the disorder. It’s too soon to know.

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