Treatment of Depression in Adolescents: TADS Results and Future Directions

The Treatment for Adolescents With Depression Study (TADS) represents the single largest and potentially most informative clinical trial of adolescents with depressive illness. The overall aim of the study was to investigate the effectiveness of standard interventions for adolescent outpatients with moderate to severe depression. The rationale for the trial, the study design, the clinical characteristics of the sample recruited for the trial, the acute phase treatment results, and a series of secondary analyses of the acute treatment phase have been published in recent papers.^1-11 This article summarizes these published reports with the goal of guiding stakeholders in making informed decisions about treatment interventions for youths with depression.

Funded in 1998 by the NIMH, TADS, a multisite study, was designed to answer questions regarding the short-term and longer-term relative effectiveness and safety of the best evidence-supported interventions available for the treatment of depression in adolescents. The study consisted of 4 stages. In the 12-week acute trial phase (stage 1), 3 active treatments—cognitive-behavioral therapy (CBT), fluoxetine(Drug information on fluoxetine), and a combination of fluoxetine and CBT (COMB)—were compared with placebo.

Patients who were considered responders or partial responders to an active treatment (CBT, fluoxetine, or COMB) in the first stage could continue in their assigned treatment arm for 6 weeks of intensive (for partial responders) or maintenance treatment (for full responders) in stage 2. Treatment responders at the end of the second stage could continue in their assigned treatment arm for 18 weeks of additional maintenance level treatment in stage 3. At the end of stage 3, patients and families received appropriate treatment recommendations and exited the controlled part of the trial.

All adolescents recruited for the trial in all treatment arms, regardless of responder status, were encouraged to participate in all study assessments to track their clinical and functional outcomes. In stage 4, patients were followed naturalistically for a year after completing the initial treatment protocol.

Primary outcome measures included clinician-rated and self-reported depressive symptoms and clinician-rated global improvement in depressive illness since beginning treatment. Because of the importance of eliminating bias from the primary outcome measures, independent evaluators (IE) blinded to treatment assignment followed the adolescents and their families through the course of the trial and provided the primary effectiveness outcome data. The primary measures comparing safety and tolerance of the interventions were clinician-rated adverse-event measures.

The data analyses published to date have focused on the baseline characteristics of the recruited sample and primary and secondary analyses of the data collected through stage 1. TADS data suggest that the investigators were successful in recruiting adolescents with moderate to severe depression.³ Some of the pertinent summary statistics of the baseline characteristics of the sample are presented in Table 1. For the most part, generally comparable subsamples were randomly assigned to the 3 active (CBT, fluoxetine, or COMB) and the comparison (placebo) interventions.³

In terms of the effectiveness of the 4 interventions studied, a clear and generally consistent story emerged after 12 weeks of treatment (end of stage 1).² The data on change in IE-rated or self-reported depressive symptoms and IE-rated improvement in depressive illness suggest that the best treatment results were seen with the COMB intervention (Table 2) [Table restricted. Please see print edition for content]. Results for COMB treatment were clearly superior to those for the CBT and placebo groups. Improvement in depressive symptoms and functional outcomes appeared to be better in patients who were treated with fluoxetine than in those who received CBT and placebo, but not as good as in patients who received COMB.

Overall response rates in the 4 groups after 12 weeks of treatment are presented in the Figure and suggest the superiority of the COMB intervention. Also of interest are the remission rates after 12 weeks of treatment. "Remission" was considered to reflect an excellent outcome in terms of decreased depressive symptoms compared with "response," which meant that the patient achieved at least a good response. As expected, remission rates at 12 weeks were lower than the response rates (COMB, 37%; fluoxetine, 23%; CBT, 16%; placebo, 17%) but were still significantly better with COMB treatment.⁹

In secondary analyses, COMB treatment not only improved depressive symptoms and depressive illness more than the other treatments, it also led to better change in functioning and quality of life.⁷

Safety outcomes suggested a somewhat different pattern in the primary analyses.² CBT was associated with very low rates of medically-related adverse events, psychiatric adverse events, or suicidality; the rates in this group were even lower than those in the placebo group. Whether this reflects actual protective effects against adverse events by CBT or methodological variance in assessing adverse events across conditions is not clear.