Cognitive Behavioral Therapy Reduces Risks of Teen Antidepressant Use

DURHAM, N.C., Oct. 1 -- The combination of fluoxetine (Prozac) and cognitive behavior therapy for depressed teens may accelerate treatment response and protect against suicidality.

In a randomized trial, combination therapy was not superior to fluoxetine or cognitive behavior therapy after 36 weeks, reported John S. March, M.D., M.P.H., of Duke here, and colleagues in the October issue of Archives of General Psychiatry.

But a previously published analysis of the same patients, which showed an early advantage in response rate at 12 weeks with combination therapy (73% versus 62% and 48%), suggests that it may be a superior strategy, they said.

"Because accelerating symptom reduction by using medication is an important clinical outcome in psychiatry, as it is in other areas of medicine, use of fluoxetine should be made widely available, not discouraged," they wrote.

Since 2004, antidepressants have carried a black box warning of increased risk of suicidal thoughts or behaviors for children and adolescents, a warning which some researchers say has discouraged prescription.

(See: AACAP: Black Box Warnings Decreased Pediatric Antidepressant Use)

Dr. March's group affirmed that suicidal ideation and attempts were about twice as common with fluoxetine than with other treatments through 36 weeks in the Treatment for Adolescents With Depression Study (TADS).

However, adding cognitive behavior therapy to fluoxetine reduced suicidality rates compared with even cognitive therapy alone.

This potentially protective effect suggests cognitive behavior therapy "should be made readily available as part of comprehensive treatment for depressed adolescents," they wrote, although this would require "a significant shift in current practice."

"Until this occurs," the investigators said, "fluoxetine monotherapy, delivered in the context of regular clinical management and careful clinical monitoring, will remain an important stop-gap measure in patients for whom the earliest possible response is deemed clinically meaningful."

Their 36-week analysis included 327 teens ages 12 to 17 with typically moderate to severe major depressive disorder and randomized to treatment with fluoxetine, cognitive behavior therapy, or the combination. Another group of 112 patients was randomized to placebo pills for 12 weeks then active treatment, but this un unblinded group was excluded from the final analysis.

Fluoxetine was initially prescribed at 10 mg/day with subsequent changes depending on treatment response or adverse events. Cognitive behavioral therapy consisted of 15 one-hour psychotherapy sessions during the first 12 weeks, after which frequency depended on treatment response.

In the long-term analysis, response to treatment-"much" or "very much" improved Clinical Global Impressions-Improvement scores-remained significantly better with combination therapy than with fluoxetine or cognitive behavior therapy at week 18 (85%, 69%, and 65%, P=0.002 versus cognitive behavior therapy, P=0.01 versus fluoxetine).

By week 30, response rates converged. At week 36, response rates were 86% for combination therapy, 81% for fluoxetine therapy, and 81% for cognitive behavior therapy with no significant differences between any of the groups.

Suicidal ideation decreased with treatment from 39.6% on combination therapy, 26.2% on fluoxetine, and 25.2% on cognitive behavior therapy at baseline to 8.9%, 18.6%, and 5.5% at week 12.

At week 36, the rate of suicidality remained significantly higher with fluoxetine than with combination (13.7% versus 2.5%, P=0.01) or cognitive behavior therapy (13.7% versus 3.9%, P=0.04).

Although no completed suicides were observed in the trial, 9.8% of patients overall attempted suicide through 36 weeks. Attempts were more common in patients on fluoxetine (14.7%) than among those receiving combination therapy (8.4%, odds ratio 1.9 versus fluoxetine, P=0.15) or cognitive behavior therapy (6.3%, OR 2.6 versus fluoxetine, P=0.04).

The reason for the advantage of combination therapy is unclear, the researchers said. Although the study was underpowered to detect a difference in early suicidality risk, the benefit could be of "considerable public health relevance," they added.

"After taking benefit and risk into account, we conclude that the combination of fluoxetine and cognitive behavior therapy appears superior to either monotherapy as a long-term treatment strategy for major depressive disorder in adolescents," they concluded.

Some of the researchers reported conflicts of interest for Eli Lilly and a range of other pharmaceutical companies. One of the researchers reported funding from the FDA to develop the suicidality classification system used in their antidepressant safety analysis.