The report from Karen Dineen Wagner, M.D., Ph.D., a professor of psychiatry and behavioral sciences and director of the division of child and adolescent psychiatry at the University of Texas Medical Branch in Galveston, and from the multinational Sertraline Pediatric Depression Study Group, represents the largest positive medication treatment trial in pediatric depression published to date. Only three other similar clinical trials have been published in peer-reviewed journals, two showing efficacy of fluoxetine (Prozac and generics) and one showing efficacy of paroxetine (Paxil).

Prozac remains the only antidepressant to carry a pediatric indication approved by the Food and Drug Administration (FDA).

Use of antidepressants in pediatric depression has been controversial for some time, but became more so in June when the FDA, along with the British Medicines Control Agency, issued formal warnings to physicians advising against the use of paroxetine in children and adolescents.

The agencies cited a large data set (pooled from nine clinical trials) submitted by GlaxoSmithKline that revealed not only a lack of efficacy—in the opinion of both agencies— but also a potentially significant increase in harmful behaviors, including suicidal ideations and actions (Psychiatric News, July 18).

More recently, on August 22, Wyeth sent out a "dear health care professional" letter, reminding physicians that its brands of venlafaxine (Effexor and Effexor XR) are not approved for use in children and adolescents. In addition, the company advised it is voluntarily revising labeling for both medications to include a statement that "safety and effectiveness in pediatric patients have not been established" as well as a warning that clinical trials have noted increased reports of "hostility" and "suicidal ideations and self-harm."

The report by Wagner includes data from two randomized controlled trials in 376 children and adolescents (aged 6 to 17) with DSM-IV-defined major depressive disorder of at least moderate severity.

Funded by Pfizer, the trials were undertaken at the request of the FDA under the provisions of pediatric exclusivity and the Best Pharmaceuticals for Children Act (see related article on page 16). Pfizer acknowledged it has received a letter from the FDA saying the company will "likely be able to add the pediatric safety data" to the Zoloft label; however, it was not clear that the company would receive a pediatric indication for the SSRI.

Study patients were randomly assigned to receive either sertraline (50 mg to 200 mg per day) or placebo for 10 weeks. The main outcome measures were the change from baseline on the Children’s Depression Rating Scale—Revised (CDRS—R) Best Description of Child total score and any reported adverse events.

Patients who received sertraline saw significantly more improvement in their CDRS—R scores than patients taking placebo (30.24 points vs. 25.83 points, respectively, at week 10). With "response" prospectively defined as a 40 percent reduction in the adjusted CDRS—R score by the end of the studies, 69 percent of those taking sertraline were classified as responders, compared with 59 percent of patients taking placebo.

Seventeen patients taking sertraline (9 percent) dropped out of the studies because of adverse events, compared with five patients taking placebo (3 percent). Within the overall study population, adverse events were defined as those that occurred in at least 5 percent of patients taking sertraline and with a rate at least twice that of patients taking placebo. In children (aged 6 to 11), reported events included insomnia (19.8 percent), diarrhea (15.1 percent), anorexia (10.5 percent), vomiting (9.3 percent), agitation (8.1 percent), and urinary incontinence (5.8 percent). Among adolescents (aged 12 to 18) events included vomiting (7.8 percent) and diarrhea (6.8 percent).

Seven patients taking sertraline experienced a serious adverse event (as defined by the FDA) compared with six patients taking placebo. Serious events included suicide attempt (two patients taking sertraline and two taking placebo), suicidal ideation (three sertraline, no placebo), and aggressive reaction (one sertraline, no placebo).

Patients taking sertraline lost an average of 0.8 pounds through the 10-week studies, compared with a gain of 1.7 pounds for patients taking placebo.

Wagner and her colleagues note that "the significance of the results is clinically as well as statistically relevant."

With only three previous studies showing any benefit of SSRIs for pediatric depression, and no studies showing a benefit for tricyclic antidepressants, the current study’s treatment effect is "modest in comparison with that typically observed in adult studies," according to the authors.

But in pediatrics, only one study—with fluoxetine—has shown a more robust effect with an antidepressant. That study, however, involved a significantly smaller group of children and adolescents.

Wagner and colleagues believe that one problem is the large placebo effect often seen in children. "Data suggest that the placebo response rate is at least as high in [the pediatric] age population [as it is in adults]," the authors noted. "Increased visit frequency and the attention associated with these visits may have an intrinsic component of therapy and is different from a ‘waiting period’ control, in which there is no interaction."

The authors noted that while this study suggested that sertraline was slightly more effective, as well as more tolerable, in adolescents than in children, further studies need to be completed to determine whether that is true in the general population. They also noted that discontinuation of sertraline was not associated in these studies with a "withdrawal syndrome" like that often observed in patients taking paroxetine and venlafaxine.

"Nonetheless," the authors concluded, "the results reported here support the conclusion that sertraline is an effective, safe, and well-tolerated short-term treatment."

An abstract of the article is posted on the Web at http://jama.ama-assn.org/cgi/content/full/290/8/1033. ▪

JAMA  20032901033