Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression: Treatment for Adolescents with Depression Study (TADS) randomized controlled trial

Abstract

Treatment for Adolescents With Depression Study (TADS) Team. JAMA 2004;292:807-20.Context Initial treatment of major depressive disorder in adolescents may include cognitive-behavioral therapy (CBT) or a selective serotonin reuptake inhibitor. However, little is known about their relative or combined effectiveness.Objective To evaluate the effectiveness of 4 treatments among adolescents with major depressive disorder.Design Randomized controlled trial.Setting The trial was conducted at 13 US academic and community clinics between spring 2000 and summer 2003.Participants Volunteer sample of 439 patients, ages 12 to 17 years, with a primary Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis of major depressive disorder.Interventions Twelve weeks of (1) fluoxetine alone (10 to 40 mg/d), (2) CBT alone, (3) CBT with fluoxetine (10 to 40 mg/d), or (4) placebo (equivalent to 10 to 40 mg/d). Placebo and fluoxetine alone were administered in a double-blinded fashion; CBT alone and CBT with fluoxetine were administered in unblinded fashion.Main outcome measures Children's Depression Rating Scale-Revised total score and, for responder analysis, a (dichotomized) Clinical Global Impressions improvement score.Results Compared with placebo, the combination of fluoxetine with CBT was statistically significant (P = .001) on the Children's Depression Rating Scale-Revised. Compared with fluoxetine alone (P = .02) and CBT alone (P = .01), treatment of fluoxetine with CBT was superior. Fluoxetine alone was a superior treatment to CBT alone (P = .01). Rates of response for fluoxetine with CBT were 71.0% (95% CI, 62% to 80%); fluoxetine alone, 60.6% (95% CI, 51% to 70%); CBT alone, 43.2% (95% CI, 34% to 52%); and placebo, 34.8% (95% CI, 26% to 44%). On the Clinical Global Impressions improvement responder analysis, the 2 fluoxetine-containing conditions were statistically superior to CBT and to placebo. Clinically significant suicidal thinking, which was present in 29% of the sample at baseline, improved significantly in all 4 treatment groups. Fluoxetine with CBT showed the greatest reduction (P = .02). Seven (1.6%) of 439 patients attempted suicide; there were no completed suicides.Conclusions The combination of fluoxetine with CBT offered the most favorable tradeoff between benefit and risk for adolescents with major depressive disorder.Comment Treatment of adolescents with major depression, and particularly the possibility of an increased risk of suicidal behavior associated with antidepressant drug treatment, have become issues of major controversy in recent months. Adolescent patients, their parents, and their physicians face heightened concerns in weighing the potential benefits and risks in making choices about treating major depression, a disorder marked by considerable suffering, functional impairment, and risk of death from suicide. This report of the 12-week primary results of the Treatment for Adolescents with Depression Study (TADS) provides important empiric data bearing on this clinical issue. This trial was the first to evaluate the efficacy in adolescents of combined treatment with a serotonin-selective antidepressant (fluoxetine) and CBT compared with fluoxetine alone, CBT alone, and placebo. Combined treatment was superior on most measures of response. Fluoxetine was administered in an unblinded fashion in the combined treatment group—a design limitation that might have advantaged the combined treatment group due to positive expectational effects. Suicidal thinking decreased with all 4 treatments, even placebo, reflecting the importance and clinical relevance of the careful monitoring and attention offered to all of the patients and parents in this multicenter, randomized, controlled trial. The results agree with previous trials in adult patients indicating that combined treatment with an evidence-based psychotherapy and antidepressant medication is optimal for most patients with major depression. Treatment for Adolescents With Depression Study (TADS) Team. JAMA 2004;292:807-20. Context Initial treatment of major depressive disorder in adolescents may include cognitive-behavioral therapy (CBT) or a selective serotonin reuptake inhibitor. However, little is known about their relative or combined effectiveness. Objective To evaluate the effectiveness of 4 treatments among adolescents with major depressive disorder. Design Randomized controlled trial. Setting The trial was conducted at 13 US academic and community clinics between spring 2000 and summer 2003. Participants Volunteer sample of 439 patients, ages 12 to 17 years, with a primary Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis of major depressive disorder. Interventions Twelve weeks of (1) fluoxetine alone (10 to 40 mg/d), (2) CBT alone, (3) CBT with fluoxetine (10 to 40 mg/d), or (4) placebo (equivalent to 10 to 40 mg/d). Placebo and fluoxetine alone were administered in a double-blinded fashion; CBT alone and CBT with fluoxetine were administered in unblinded fashion. Main outcome measures Children's Depression Rating Scale-Revised total score and, for responder analysis, a (dichotomized) Clinical Global Impressions improvement score. Results Compared with placebo, the combination of fluoxetine with CBT was statistically significant (P = .001) on the Children's Depression Rating Scale-Revised. Compared with fluoxetine alone (P = .02) and CBT alone (P = .01), treatment of fluoxetine with CBT was superior. Fluoxetine alone was a superior treatment to CBT alone (P = .01). Rates of response for fluoxetine with CBT were 71.0% (95% CI, 62% to 80%); fluoxetine alone, 60.6% (95% CI, 51% to 70%); CBT alone, 43.2% (95% CI, 34% to 52%); and placebo, 34.8% (95% CI, 26% to 44%). On the Clinical Global Impressions improvement responder analysis, the 2 fluoxetine-containing conditions were statistically superior to CBT and to placebo. Clinically significant suicidal thinking, which was present in 29% of the sample at baseline, improved significantly in all 4 treatment groups. Fluoxetine with CBT showed the greatest reduction (P = .02). Seven (1.6%) of 439 patients attempted suicide; there were no completed suicides. Conclusions The combination of fluoxetine with CBT offered the most favorable tradeoff between benefit and risk for adolescents with major depressive disorder. Comment Treatment of adolescents with major depression, and particularly the possibility of an increased risk of suicidal behavior associated with antidepressant drug treatment, have become issues of major controversy in recent months. Adolescent patients, their parents, and their physicians face heightened concerns in weighing the potential benefits and risks in making choices about treating major depression, a disorder marked by considerable suffering, functional impairment, and risk of death from suicide. This report of the 12-week primary results of the Treatment for Adolescents with Depression Study (TADS) provides important empiric data bearing on this clinical issue. This trial was the first to evaluate the efficacy in adolescents of combined treatment with a serotonin-selective antidepressant (fluoxetine) and CBT compared with fluoxetine alone, CBT alone, and placebo. Combined treatment was superior on most measures of response. Fluoxetine was administered in an unblinded fashion in the combined treatment group—a design limitation that might have advantaged the combined treatment group due to positive expectational effects. Suicidal thinking decreased with all 4 treatments, even placebo, reflecting the importance and clinical relevance of the careful monitoring and attention offered to all of the patients and parents in this multicenter, randomized, controlled trial. The results agree with previous trials in adult patients indicating that combined treatment with an evidence-based psychotherapy and antidepressant medication is optimal for most patients with major depression.