Treatment of Adolescents With Major Depression
Authors: Richard M. Glass
Journal: JAMA (2004)

THE PUBLICATION OF THE RESULTS OF THE TREATment for Adolescents With Depression Study (TADS) in this issue of JAMA is certainly timely in view of recent and widely publicized controversies regarding treating adolescents with depression. Beyond that, these results shed new light on some older controversies about psychiatric treatments. As is usually the case with good research, the study provides important answers but also raises several important questions. In the TADS study, a randomized controlled trial funded by the National Institute of Mental Health and conducted at 13 academic and community centers in the United States, 429 patients aged 12 to 17 years (mean age, 15 years), who had a primary diagnosis of major depressive disorder, provided written informed consent (along with consent from at least one of their parents) to participate in the study. Participants on average had moderate to severe symptom levels based on scores on the Children’s Depression Rating ScaleRevised and 27% had at least minimal suicidal ideation at baseline. The average depressive episode duration was 72 weeks, adding to the evidence that these mood disturbances were not temporary fluctuations. Potential participants were excluded if they had been hospitalized for dangerousness within the preceding 3 months, had made a suicide attempt causing medical attention within 6 months, had clear suicidal intent or an active plan for suicide, or if they had suicidal ideation with a disorganized family believed by the investigators to be unable to guarantee adequate safety monitoring. Such exclusions are reasonable and necessary for research participation, but unfortunately limit the controlled research evidence base available to clinicians treating depressed patients with the highest potential danger to themselves. Participants were randomly assigned to 1 of 4 treatments for 12 weeks: fluoxetine with clinical management (6 physician visits lasting 20-30 minutes to monitor clinical status and medication effects), pill placebo with clinical management, cognitive-behavioral therapy (CBT), or the combination of fluoxetine with CBT. Fluoxetine and equivalent placebo doses could be adjusted from a starting dose of 10 mg/d to 40 mg/d; the mean highest dose received by participants was about 30 mg/d in the fluoxetine alone, fluoxetine with CBT, and placebo groups. The CBT was planned for 15 sessions over 12 weeks and was designed to restructure the negative thought patterns typical of depression and to increase active, positively reinforcing behaviors. In an important consideration for treatment of adolescents, parent and family sessions were integrated with individual CBT. The fluoxetine alone and placebo treatment groups were double-blind, but participants and their clinicians in the fluoxetine with CBT group knew they were receiving active medication. Those receiving CBT, either alone or combined with fluoxetine, knew they were receiving an active psychotherapy because there was no placebo therapy control group receiving equivalent amounts of time and contact. Outcomes were assessed by independent evaluators who were blind to treatment assignments. After 12 weeks of treatment, total scores on the Children’s Depression Rating Scale-Revised as a measure of depression symptoms based on interviews with adolescents and their parents indicated that the combination of fluoxetine with CBT was significantly superior to placebo, fluoxetine alone, and CBT alone. Fluoxetine alone was significantly better than CBT alone, and also better than placebo, although the latter was true only based on the week 12 adjusted mean scores and not on an analysis of the changes over time across the 12 weeks. Based on a global rating of being much improved or very much improved, response rates were 71% in the fluoxetine with CBT group, 61% in the fluoxetine alone group, 43% in the CBT alone group, and 35% in the placebo group. In view of concerns about possible increases in suicidal behavior in children receiving selective serotonin reuptake inhibitors (SSRIs), including recent warnings from the US Food and Drug Administration and the British Medicines and Healthcare Products Regulatory Agency, the safety data provided by TADS are of particular interest. Suicidal ideation (measured by a self-report questionnaire ) declined in all of the treatment groups. About 6% of the patients experienced a suicide-related event defined as either worsening suicidal ideation or making a suicide attempt, with no