John S. March, MD, MPH
Coordinating Center Principal Investigator
Duke Clinical Research Institute
Funded by the National Institute of Mental Health, coordinated by the Duke Clinical Research Institute, and conducted in 13 academic and community centers in the United States, the Treatment for Adolescents with Depression Study (TADS) is a randomized controlled trial that evaluates the effectiveness of four treatments for adolescents with moderate to severe major depression. These are clinical management with fluoxetine, cognitive-behavioral psychotherapy (CBT), their combination (fluoxetine plus CBT), and clinical management with a sugar pill (placebo). Medications were administered double-blind; cognitive-behavior therapy and combined treatment were administered unblinded. Blinding for the primary outcomes was maintained by means of an Independent Evaluator. This summary statement addresses the Stage I (acute treatment) findings following 12 weeks of treatment.
The outcome of the study is unambiguous and the clinical implications are straightforward. TADS patients exhibit a major depression disorder, with the majority in the moderate to moderately severe range, are comorbid for other forms of mental illness about half the time, and include both boys and girls, younger and older teens, excellent minority representation, and wide variability in socioeconomic circumstances. Thus, the results are thought to apply to the full spectrum of clinically ill depressed teens seen in clinical practice. Rates of response defined as much or very much improved were: 71.0% for the combination of fluoxetine and CBT, 60.6% for fluoxetine alone, 43.2% for cognitive-behavioral psychotherapy alone, and 34.8% for placebo. Thus, the combination of fluoxetine and cognitive-behavioral psychotherapy appears to produce the greatest improvement in symptoms of major depression. Fluoxetine alone is effective, but not as effective as the combination of fluoxetine and CBT. Cognitive-behavioral psychotherapy alone is less effective than fluoxetine and not significantly more effective than placebo.
TADS treatments proved acceptable and well tolerated. Fluoxetine related adverse events were mostly mild, expected, resolved with dose adjustment, and occurred at rates consistent with previous fluoxetine studies. With respect to the risk for harm-related adverse events, we differentiate between suicidal ideation and harm-related behavior. Almost 30% of TADS participants had suicidal ideation at the start of the study; 2% had intense suicidal ideation. Suicidality decreases substantially over 12 weeks of treatment. Improvement in suicidal ideation is greatest for the combination of fluoxetine and CBT and least for fluoxetine alone. Importantly, fluoxetine does not appear to increase suicidal ideation. In contrast, harm-related behavioral events though uncommon were more common in patients receiving fluoxetine as follows: fluoxetine (11.9%), the combination of fluoxetine and CBT (8.4%), cognitive-behavioral psychotherapy (4.5%) and placebo (5.4%). Thus, consistent with its impact on suicidal ideation, cognitive-behavioral psychotherapy may protect against these events in patients taking fluoxetine. Only 1.6% of patients (7 or 439) patients made a suicide attempt; there were no completed suicides.
Taking both benefit and risk into account, the benefit to risk ratio is 17 to 1 for the combination of fluoxetine and cognitive-behavioral psychotherapy and 5 to 1 for fluoxetine alone. The more robust benefit to risk ratio for combination treatment stems from its greater impact on symptoms of MDD and on a reduction in harm-related adverse events relative to patients treated with fluoxetine alone.
At this juncture in the TADS, we make the following recommendations regarding the treatment of depressed adolescents to health care decision makers at all levels: First, given high prevalence, morbidity and mortality associated with major depression in teens, it is imperative that teens with major depression be identified and offered evidence-based treatments. Second, despite calls to restrict access to medications, medical management of major depression with fluoxetine, including careful monitoring for adverse events, should be made widely available, not discouraged. Third, given incremental improvement in outcome when cognitive-behavioral psychotherapy is combined with medication and, as if not more importantly, increased protection from suicidality, cognitive-behavioral psychotherapy also should be readily available as part of comprehensive treatment for depressed adolescents.