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Combination Therapy Can Effectively Treat Depressed Adolescents
Twelve-week results from the Treatment for Adolescents with Depression Study (TADS) show the combination of fluoxetine and cognitive behavioral therapy effectively treats adolescents with depression, according to preliminary reports published in the December 2006 Journal of the American Academy of Child and Adolescent Psychiatry. In this study, 439 adolescents ages 12 to 17 with major depressive disorder were randomized at several study sites to receive one of four treatments: fluoxetine, cognitive behavioral therapy, a combination of fluoxetine and cognitive behavioral therapy, or pill placebo.
The researchers studied time-to-treatment response, patient remission and residual symptoms, patient functioning and quality of life, predictors of outcome, and treatment safety during the first 12 weeks of treatment.
Researchers used the Clinical Global Impression–Improvement Scale (CGI-I), Kaplan-Meier curves, and survival analyses using Cox proportional hazards models to evaluate time to first response and time to stable response for adolescents receiving pharmacotherapy (combination treatment, fluoxetine treatment, and pill placebo) and for adolescents receiving cognitive behavioral therapy (either combination treatment or cognitive behavioral therapy alone).
Based on pharmacotherapist CGI-I scores, combination therapy and fluoxetine had a faster onset of benefit than placebo in terms of both time to first response and time to stable response. Combination therapy was faster than fluoxetine on time to stable response. Additionally, combination therapy was three times more likely than placebo to sustain early response, while fluoxetine was twice as likely as placebo to sustain early response. Combination therapy was also one-and-a-half times more likely than fluoxetine to sustain early response.
According to psychotherapist CGI-I scores, both first response and stable response occurred faster in patients who received combination therapy than in patients who received cognitive behavioral therapy alone, and the probability of sustained early response was approximately three times higher in patients receiving combination therapy than in patients receiving cognitive behavioral therapy alone.
Remission and Residual Symptoms
The researchers also examined rates of remission using an end-of-treatment Children’s Depression Rating Scale–Revised (CDRS-R) total score of 28 or below as the criterion for remission with logistic regression, controlling for site. Additionally, loss of major depressive disorder diagnosis and residual symptoms in responders were examined across treatment groups. This was defined as a CGI-I score of 1 (very much improved) or 2 (much improved).
After 12 weeks of treatment, 102 (23%) of the 439 adolescents were in remission. The remission rate in the combination group (37%) was significantly higher than in the fluoxetine group (23%), the cognitive behavioral therapy group (16%), or the placebo group (17%). Additionally, 71% of adolescents participating in the study no longer met criteria for major depressive disorder at the end of 12 weeks. However, according to CGI-I criteria, 50% of the adolescents still suffered from residual symptoms, such as sleep or mood disturbances, fatigue, and poor concentration.
Functioning and Quality of Life
Functioning was measured with the Children’s Global Assessment Scale, while global health was measured with the Health of the Nation Outcome Scales for Children and Adolescents, and quality of life was measured with the Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire.
According to these measurements, combination treatment was effective in improving functioning, global health, and quality of life, while fluoxetine monotherapy effectively improved functioning.
Predictors of Outcome
To identify predictors and moderators of response to these acute treatments, potential baseline predictors and moderators were identified through a literature review. Then, a predicted score was derived from the CDRS-R during week 12. The researchers found that adolescents with the following attributes were more likely to benefit from acute treatment:
• Younger age
• Less chronicity of depression
• Higher level of functioning
• Less hopelessness with less suicidal ideation
• Fewer melancholic features or comorbid diagnoses
• Greater expectations for improvement.
Combined treatment was as effective as monotherapy in all instances. However, combined treatment was more effective than fluoxetine for mild to moderate depression and for depression with high levels of cognitive distortion, but not for severe depression or for depression with low levels of cognitive distortion. Interestingly, adolescents from high-income families were as likely to benefit from cognitive behavioral therapy alone as they were from combined therapy.
Adverse events were determined by spontaneous report and by systematic measures for specific physical and psychiatric symptoms. Adolescent and clinician reports were used to assess suicidal ideation and suicidal behavior.
Depressed adolescents reported high rates of physical symptoms at baseline, which improved as depression improved. Conditions such as sedation, insomnia, vomiting, and upper abdominal pain occurred in approximately 2% of adolescents treated with fluoxetine, either alone or in combination with cognitive behavioral therapy. This was double the rate seen in adolescents who received placebo. The rate of psychiatric adverse events was 11% in adolescents taking fluoxetine, 5.6% in adolescents receiving combination therapy, 4.5% in patients taking placebo, and 0.9% in patients receiving cognitive behavioral therapy. Suicidal ideation improved overall, with the greatest improvement observed in those receiving combination therapy. During the 12 weeks of the study, 24 suicide-related events occurred: 10 in the fluoxetine group, five in the combination group, five in the CBT group, and three in the placebo group. Only five actual suicide attempts occurred, and there were no completions.
—Michelle Stephenson
Suggested Reading
Curry J, Rohde P, Simons A, et al. Predictors and moderators of acute outcome in the Treatment for Adolescents with Depression Study (TADS). J Am Acad Child Adolesc Psychiatry. 2006;45:1427-1439.
Emslie G, Kratochvil C, Vitiello B, et al. Treatment for Adolescents with Depression Study (TADS): safety results. J Am Acad Child Adolesc Psychiatry. 2006;45:1440-1455.
Kennard B, Silva S, Vitiello B, et al. Remission and residual symptoms after short-term treatment in the Treatment of Adolescents with Depression Study (TADS). J Am Acad Child Adolesc Psychiatry. 2006;45:1404-1411.
Kratochvil C, Emslie G, Silva S, et al. Acute time to response in the Treatment for Adolescents with Depression Study (TADS). J Am Acad Child Adolesc Psychiatry. 2006;45:1412-1418.
March J, Silva S, Vitiello B; TADS team. The Treatment for Adolescents with Depression Study (TADS): methods and message at 12 weeks. J Am Acad Child Adolesc Psychiatr. 2006;45:1393-1403.
Vitiello B, Rohde P, Silva S, et al. Functioning and quality of life in the Treatment for Adolescents with Depression Study (TADS). J Am Acad Child Adolesc Psychiatry. 2006;45:1419-1426.
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