The Treatment for Adolescents With Depression Study (TADS): Methods and Message at 12 Weeks

doi:10.1097/01.chi.0000237709.35637.c0

Journal of the American Academy of Child & Adolescent Psychiatry

Volume 45, Issue 12, December 2006, Pages 1393-1403

https://doi.org/10.1097/01.chi.0000237709.35637.c0 Get rights and content

ABSTRACT

Funded by the National Institute of Mental Health, the Treatment for Adolescents With Depression Study (TADS) is intended to evaluate the short-term (12 weeks) and longer-term (36 weeks) effectiveness of four treatments for adolescents with DSM-IV major depressive disorder: clinical management with fluoxetine (FLX), cognitive-behavioral therapy (CBT), FLX and CBT combined (COMB), and clinical management with placebo (PBO). We previously reported that COMB and FLX were more effective in reducing depression than CBT or PBO after 12 weeks of acute treatment. In this special section of the Journal, separate articles extend these findings to the impact of TADS treatments on remission, speed of response, function and quality of life, predictors of outcome, and safety during the first 12 weeks of treatment. To set the stage for the special section, we briefly review the rationale, design, and methods of the TADS; describe the TADS sample to which the TADS findings generalize; using all of the currently available data, summarize the intent-to-treat outcomes across multiple endpoints at 12 weeks; and consider the public health value of the TADS findings in the context of design decisions and methodological limitations of the TADS, including some that may have advantaged the combined treatment condition. Reflecting the ordering of effect sizes at week 12-COMB (0.98) > FLX (0.68) > CBT (−0.03)-combined treatment proved superior to PBO on 15 of 16 endpoints, to CBT on 14 of 16 endpoints, and to FLX on 8 of 16 endpoints, whereas FLX was superior to CBT on 8 of 14 and to PBO on 7 of 16 measures. CBT did not differ from PBO on any measure. Despite the fact that suicidality improved markedly across all of the treatment conditions, suicidal events were twice as common in patients treated with FLX alone than with COMB or CBT alone, perhaps indicating that CBT protects against suicidal events. Thus, combined treatment appears to accelerate recovery relative to CBT and, for some outcomes, FLX alone, while minimizing the risk of suicidality relative to FLX alone. Taking benefit and risk into account, we conclude that the combination of FLX and CBT appears superior to either monotherapy as a treatment for moderate to severe major depressive disorder in adolescents.

Section snippets

METHOD

Methods used in the TADS have been extensively documented in previous publications (Curry and Wells, 2005, Ginsburg et al., 2005, Kennard et al., 2005, Kratochvil et al., 2005, Rogers et al., 2005, Rohde et al., 2005, Simons et al., 2005, Sweeney et al., 2005, TADS, 2003, TADS, 2004, TADS, 2005) and are only briefly summarized here. Methodologies specific to the articles in this special section are detailed in the respective articles.

Patients were enrolled in the TADS between the spring of 2000

PATIENT CHARACTERISTICS AND GENERALIZABILITY

The TADS sample is representative of depressed adolescents seen in clinical practice (TADS, 2005). The mean (SD) age was 14.6 (1.5) years; 45.6% of the sample were male; 73.8% were white, 12.5% African American, and 8.9% Hispanic. Although the TADS sample spans the range from mild to severe depression, most patients (96%) fell in the moderate to severe range of illness. The mean (SD) CDRS-R raw score at entry was 60 (10.4), which translates to a normed T score (standardized to a mean of 50 and

ACUTE TREATMENT BENEFITS

Acute treatment (12 weeks) outcomes revealed that combination of FLX and CBT produced the greatest improvement in symptoms of MDD as indexed on the CDRS-R (TADS, 2004). FLX alone proved effective, but not as effective as the combination of FLX and CBT. CBT alone was less effective than FLX and not significantly more effective than PBO. Compared to PBO, random regression analyses on the slope term indicated a statistically significant advantage for the COMB treatment (p =.001), which was not

ACUTE TREATMENT HARMS

Eighty-six percent of subjects completed treatment in their assigned arms, indicating that TADS treatments were both acceptable and tolerable. FLX-related adverse events occurred at rates that are consistent with previous FLX studies and were mostly mild, expected, and resolved with dose adjustment. Of note, patients assigned to COMB had a significantly lower overall adverse event burden than did patients treated with FLX (Emslie et al., 2006, TADS, 2004).

Almost 30% of TADS participants had

DESIGN DECISIONS, OUTCOMES, AND LIMITATIONS OF THE TADS

Although TADS is generally considered the most sophisticated clinical trial ever conducted in youth with internalizing disorders (Apter et al., 2005, Carroll, 2005, Glass, 2004, Jensen, 2005), TADS has not avoided critical commentary. In light of the primary outcomes and findings of this special section, we take this opportunity to address the most prominent of these concerns: (1) the lack of a CBT + PBO group, (2) the inability to fully mask the two CBT-containing conditions, (3) construction

CONCLUSION

TADS was designed to answer clinically important questions concerning the short- and longer-term benefit(s) of clinical care with CBT, FLX, and their combination. Along with the intention-to-treat outcomes, the articles in this special section demonstrate that combined treatment accelerates recovery relative to CBT and, for some outcomes, FLX alone, while minimizing the risk of suicidality relative to FLX alone. Taking benefit and risk into account, we conclude that the combination of FLX and

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Participant-level data were abstracted from three NIH-sponsored trials of pharmacotherapy (Treatment of SSRI-Resistant Depression in Adolescents (TORDIA) Study, Treatment of Adolescent Depression Study (TADS), and the Combining Medications to Enhance Depression Outcomes Study (COMED)) in patients with MDD. Bayesian Hierarchical Models (BHMs) of individual treatment trajectories were developed using Hamiltonian Monte Carlo No U-Turn Sampling. The individual trajectory of improvement in depressive symptoms (Clinical Global Impression-Severity [CGI-S] and CGI-S equivalent from COMED) was modeled across studies and across individuals with logarithmic trend “random effects” coefficients BHMs. Age and sex (and their interaction) were examined categorically across patients.
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Mindfulness-based approaches show promise to improve emotional health in youth and may help treat and prevent adolescent depression and anxiety. However, there is a fundamental gap in understanding the neural reorganization that takes place as a result of such interventions. The Training for Awareness, Resilience, and Action (TARA) program, initially developed for depressed adolescents, uses a framework drawn from neuroscience, mindfulness, yoga, and modern psychotherapeutic techniques to promote emotional health. The goal of this study was to assess the effects of the TARA training on emotional health and structural white matter brain networks in healthy youth. We analyzed data from 23 adolescents who underwent the 12-week TARA training in a controlled within-subject study design and whose brain networks were assessed using diffusion MRI connectomics. Compared to the control time period, adolescents showed a significant decrease in anxiety symptoms with TARA (Cohen’s d = -0.961, p = 0.006); moreover, the node strength of the Right Amygdala decreased significantly after TARA (Cohen’s d = -1.026, p = 0.004). Post-hoc analyses indicated that anxiety at baseline before TARA was positively correlated with Right Amygdala node strength (r = 0.672, p = 0.001). While change in Right Amygdala node strength with TARA was not correlated with change in anxiety (r = 0.146, p = 0.51), it was associated with change in depression subscale of Anhedonia / Negative Affect (r = 0.575, p = 0.004, exploratory analysis), possibly due to overlapping constructs captured in our anxiety and depression scales. Our results suggest that increased structural connectivity of Right Amygdala may underlie increased anxiety in adolescents and be lowered through anxiety-reducing training such as TARA. The results of this study contribute to our understanding of the neural mechanisms of TARA and may facilitate neuroscience-based prevention and treatment of adolescent anxiety and depression.
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National Institute of Mental Health (NIMH) Program Staff participated in the design and implementation of the TADS, analysis of the data, and in authoring this article. Lilly, Inc. provided fluoxetine and matching placebo under an independent educational grant to Duke University but otherwise had no role in the design or implementation of the study, data analysis, or in authoring this manuscript. The authors are indebted to the TADS scientific advisors (Susan Essock, Ph.D., Mount Sinai School of Medicine; Barbara Geller, M.D., Washington University in St. Louis; Joel Greenhouse, Ph.D., Carnegie Mellon University; Robert Johnson, M.D., New Jersey Medical School; James Leckman, M.D., Yale University; Lydia Lewis, Depression and Bipolar Support Alliance; Sue Marcus, Ph.D., Mount Sinai School of Medicine; Kevin Stark, Ph.D., University of Texas at Austin) for their contributions to the design and methods of the study; to our cognitive-behavioral therapy consultants, David Brent, M.D., and Greg Clarke, Ph.D.; to the Columbia Suicidality Classification Group led by Kelly Posner, Ph.D., including Maria Oquendo, M.D., Madelyn Gould, Ph.D., M.P.H., and Barbara Stanley, Ph.D.; and to the members of the NIMH Data and Safety Monitoring Board for monitoring the progress of the study. The protocol and manuals used in this study can be found on the web at https://trialweb.dcri.duke.edu/tads/manuals.html. The opinions and assertions contained in this report are the private views of the authors and are not to be construed as official or as reflecting the views of the NIMH, the National Institutes of Health, or the Department of Health and Human Services.

TADS is supported by contract RFP-NIH-NIMH 98-DS-0008 from NIMH to Duke University Medical Center (John March, principal investigator).

Disclosure: Dr. March is a consultant or scientific advisor to Pfizer, Eli Lilly, Wyeth, GlaxoSmithKline, Jazz, and MedAvante; he is a stockholder in MedAvante; he is on the speakers' bureaus of Pfizer and Eli Lilly; and he receives research support from Eli Lilly, Pfizer, and Wyeth. Dr. Silva is a consultant for Pfizer. Dr. Vitiello has no financial relationships to disclose.

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SPECIAL SECTION: TREATMENT FOR ADOLESCENTS WITH DEPRESSION STUDY-TADSThe Treatment for Adolescents With Depression Study (TADS): Methods and Message at 12 Weeks

ABSTRACT

Section snippets

METHOD

PATIENT CHARACTERISTICS AND GENERALIZABILITY

ACUTE TREATMENT BENEFITS

ACUTE TREATMENT HARMS

DESIGN DECISIONS, OUTCOMES, AND LIMITATIONS OF THE TADS

CONCLUSION

Cogn Behav Pract

J Am Acad Child Adolesc Psychiatry

J Am Acad Child Adolesc Psychiatry

Cogn Behav Pract

J Am Acad Child Adolesc Psychiatry

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JAMA

Epidemiology of depressive disorders

SPECIAL SECTION: TREATMENT FOR ADOLESCENTS WITH DEPRESSION STUDY-TADS
The Treatment for Adolescents With Depression Study (TADS): Methods and Message at 12 Weeks