SPECIAL SECTION: TREATMENT FOR ADOLESCENTS WITH DEPRESSION STUDY-TADS
Acute Time to Response in the Treatment for Adolescents With Depression Study (TADS)

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ABSTRACT

Objective

To examine the time to response for both pharmacotherapy and psychotherapy in the Treatment for Adolescents with Depression Study (TADS).

Method

Adolescents (N = 439, ages 12 to 17 years) with major depressive disorder were randomized to fluoxetine (FLX), cognitive-behavioral therapy (CBT), their combination (COMB), or pill placebo (PBO). Defining response as very much improved or much improved on the Clinical Global Impression-Improvement Scale (CGI-I), survival analyses using Cox proportional hazards models, and Kaplan-Meier curves were conducted to evaluate time to first response and time to stable response for subjects receiving pharmacotherapy (COMB, FLX, PBO) as well as for subjects receiving CBT (COMB, CBT). Direct comparisons between pharmacotherapy and CBT were not made because of differences in visit schedules.

Results

Based on pharmacotherapist CGI-I scores, COMB and FLX showed faster onset of benefit than PBO on time to response and time to stable response (p < .001), and COMB was faster than FLX on time to stable response (p = .034). The probability of sustained early response was approximately threefold greater for COMB than PBO, twofold greater for FLX than PBO, and 1.5-fold greater for COMB than FLX. On the psychotherapist CGI-I scores, both first response and stable response occurred faster in COMB than CBT (p < .001), with a probability of sustained early response approximately threefold greater for COMB than CBT.

Conclusions

In the acute treatment of depressed adolescents, FLX and COMB accelerate response relative to PBO, and COMB accelerates response relative to CBT alone. J. Am Acad. Child Adolesc. Psychiatry, 2006;45(12):XXX-XXX.

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The primary analyses of the Treatment for Adolescents With Depression Study (TADS) supported the short-term effectiveness of fluoxetine alone and fluoxetine in combination with cognitive-behavioral therapy (CBT), relative to CBT alone or to placebo, on response

METHOD

The rationale, design, and methods (TADS, 2003), sample characteristics (TADS, 2005), and 12-week acute treatment outcomes (TADS, 2004) for the intention-to-treat population have been presented previously and are discussed in the introduction to this special section by March et al. (2006).

RESULTS

The TADS treatments were generally acceptable, with 81.8% (359/439) of subjects remaining in their assigned treatment arm throughout the 12 weeks of acute treatment. There were no statistical differences between the four treatment arms with regard to percentage of subjects remaining in their assigned treatment arm for the duration of the acute trial: 86.0% in COMB, 83.5% in FLX, 78.4% in CBT, and 79.5% in PBO.

DISCUSSION

Few trials have reported time to response as an outcome variable, and yet this factor has significant clinical implications, both in knowing the likelihood of time to improvement and to reassure patients who have a slower response that they should continue to adhere to treatment. In the TADS, COMB and FLX had significantly faster time to response than PBO (as assessed by the pharmacotherapist), and COMB had significantly faster time to response than CBT (as assessed by the CBT clinician). In

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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. Kratochvil receives research support from Eli Lilly and Cephalon; is a consultant for Eli Lilly, Pfizer, Cephalon, AstraZeneca, Organon, and Shire; and is on the speakers' bureau of Eli Lilly. Dr. Emslie receives research support from Eli Lilly, Organon, and Forest Laboratories; is a consultant for Eli Lilly, GlaxoSmithKline, Forest Laboratories, Wyeth-Ayerst, and Pfizer; and is on the speakers' bureau of McNeil. Dr. Silva is a consultant to Pfizer. Elizabeth Weller is a consultant for and receives grants from Otsuka, Johnson & Johnson, AstraZeneca, Organon, Pharma, Shire, and GlaxoSmithKline. John Walkup receives grants/research support from Lilly, Pfizer, and Abbott; is a consultant for Lilly, Pfizer, Jazz, and Cephalon; and has received honoraria from Lilly and Pfizer. Dr. Pathak receives research support from Forest Laboratories. Dr. March receives research support from and consults to Eli Lilly, Pfizer, and Wyeth. Dr. Casat has research contracts with Eli Lilly, GlaxoSmithKline, Shire, Bristol-Myers Squibb, AstraZeneca, Sanofi Synthelabo, Pfizer, and McNeil; is on the advisory board and the speakers' bureau of Eli Lilly and GlaxoSmithKline. The other authors have no financial relationships to disclose.

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