UNMC was one of 13 clinical sites to participate in a study that found the most favorable way of treating teens suffering from major depressive disorder (MDD) is via a combination of antidepressant and cognitive-behavioral therapy (CBT). Findings in the study, coordinated by Duke University Medical Center, indicate that such a combination appears the best approach to alleviating depression and reducing the level of suicidal thinking in adolescents.
The findings result from stage one of the “Treatment for Adolescents with Depression Study” (TADS). The federally funded study is the first multicenter, randomized clinical trial to examine the individual and combined effectiveness of the antidepressant fluoxetine (trade name Prozac) and CBT in adolescents diagnosed with MDD. The results appeared as a lead story in the Aug. 18, 2004, issue of the Journal of the American Medical Association.
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Chris Kratochvil, M.D. |
“UNMC is really entering the national field as far as conducting clinical trials in child and adolescent psychiatry,” he said. “It’s rewarding to be part of an exceptional team of researchers here at UNMC, and be able to contribute to a study that will have such a significant impact on adolescents with depression.”
The study also is important because it shows adolescent depression can be safely and effectively treated, Dr. Kratochvil said. “It’s a tremendously common disorder,” he said. “About one in 20 teens have depression so it’s a significant public health issue and one that’s historically been understudied.”
Follow-up continues with the study participants, Dr. Kratochvil said, noting that when the study is complete, the teens will have been followed for approximately five years.
The multi-site study team found that fluoxetine plus CBT offered greater effectiveness in treatment than the drug alone. The CBT used in this study is a depression-specific psychotherapeutic treatment designed to create and reinforce positive thought patterns and behavior in the adolescents, said the researchers. Contrary to expectations, CBT alone offered no greater effectiveness than placebo, they found.
The researchers emphasized that their findings regarding the safety issues of the therapies — specifically protection against the potential danger of suicide — are complex. Their results show that suicidal thinking decreased among all treatment groups, with the greatest reduction occurring in the group receiving combination therapy. Although fluoxetine alone did not increase suicidal thoughts, it did seem to increase the risk for harm-related behaviors. This effect, however, seemed to be buffered by concomitant CBT. The complexity will add to the considerable debate about the use of antidepressants and the potential link to suicidality in adolescents, according to the lead author.
“Depression constitutes a significant public health problem among adolescents, and there has been a tremendous need for identifying effective treatments that are also deemed safe,” said John March, M.D., chief of child and adolescent psychiatry at Duke and lead investigator on the study. “Children and young adults suffer serious impairments from depression, especially if they remain undiagnosed. Depression is very common, but those affected must be identified and referred for treatment.
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“While fluoxetine proved to be an effective treatment, after weighing the risks and benefits I would strongly encourage the use of combination therapy as the best treatment for depressed teenagers.”
The randomized, controlled clinical trial enrolled 439 patients between the ages of 12 and 17 with a primary diagnosis of major depressive disorder. None of the patients were taking antidepressants before beginning study treatment and all could be cared for on an outpatient basis. To be considered for the trial, the patients must have experienced a depressive mood in at least two of three areas (home, school or among peers) for at least six weeks prior to the study. Adolescents with other severe behavioral or mental disorders, a history of endangering themselves or others, or dealing with drug abuse or addictions were excluded from the study.
The three-year enrollment took place at 13 academic and community clinics. Patients were randomized into one of four groups for a 12-week treatment period. One group received treatment with fluoxetine alone (10 to 40 milligrams per day); one group received CBT alone (15 one-hour treatment sessions); one group received a combination of fluoxetine (at the dosage above) with CBT; and the final group received placebo alone (placebo pills identical in appearance to those containing fluoxetine). Fluoxetine and placebo were both administered in a double-blind fashion; the CBT alone and CBT with fluoxetine groups were unblinded.
Compared with fluoxetine and CBT alone, the combination therapy proved superior with a 71 percent response rate. Compared to placebo, fluoxetine worked very well with a 60.6 percent response rate. However, CBT alone (43.2 percent response) proved to be not much more effective than placebo (34.8 percent response). Clinically significant suicidal “ideation,” meaning suicidal thinking or imaginings, had been present in 29 percent of the study participants at the beginning of the study. By study completion, the level of suicidal ideation improved significantly in all treatment groups. The team found that fluoxetine coupled with CBT offered the greatest reduction in suicidal thoughts. There were seven cases of attempted suicide but no completed suicides.
“Our data show that suicidal thinking gets better with all forms of treatment used in this trial,” Dr. March said. “Harm-related behaviors occurred at a very low rate among our participants. While harm-related behaviors might be slightly more likely to occur in teens taking the antidepressant, CBT reduces harm-related behaviors to such an extent that the benefits of CBT outweigh the risks associated with the medication. We think this may be one of the reasons why the combination therapy proved to be more effective.”
According to the researchers, MDD is common, with one in 20 teens affected at varying levels of severity. Like other forms of depression, MDD has been associated with increased risk of suicidal behavior and with completed suicide. It has also been linked to long-term psychosocial impairment in adulthood. In the United States, 500,000 adolescents attempt suicide every year and 2,000 die as the result of their injuries. According to 2001 statistics from the National Center for Injury Prevention and Control, suicide is the third leading cause of death in Americans aged 10 to 24.
The National Institute of Mental Health, a division of the National Institutes of Health, funded the research. Eli Lilly & Company, maker of Prozac, provided the fluoxetine and matching placebo used in TADS under an independent educational grant to Duke.