SPECIAL ARTICLE
Treatment for Adolescents With Depression Study (TADS): Rationale, Design, and Methods

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ABSTRACT

Objectives

A rapidly growing empirical literature on the treatment of major depressive disorder (MDD) in youth supports the efficacy of short‐term treatment with depression‐specific cognitive‐behavioral therapy or medication management with a selective serotonin reuptake inhibitor. These studies also identify a substantial probability of partial response and of relapse, which might be addressed by more intensive, longer‐term treatments.

Method

Funded by the National Institute of Mental Health, the Treatment for Adolescents With Depression Study (TADS) is a multicenter, randomized, masked effectiveness trial designed to evaluate the short‐term (12‐week) and long‐term (36‐week) effectiveness of four treatments for adolescents with MDD: fluoxetine, cognitive‐behavioral therapy, their combination, and, acutely, pill placebo. A volunteer sample of 432 subjects aged 12‐17 years (inclusive) with a primary DSM‐IV diagnosis of MDD who are broadly representative of patients seen in clinical practice will enter the study. The primary dependent measures rated blindly by an independent evaluator are the Children's Depression Rating Scale and, for responder analysis, a dichotomized Clinical Global Impressions‐Improvement score. Consistent with an intent‐to‐treat analysis, all patients, regardless of treatment status, return for all scheduled assessments.

Results

This report describes the design of the trial, the rationale for the design choices made, and the methods used to carry out the trial.

Conclusion

When completed, TADS will improve our understanding of how best to initiate treatment for adolescents with MDD. J. Am. Acad. Child Adolesc. Psychiatry, 2003, 42(5):531‐542.

Section snippets

RATIONALE

At the time TADS was initiated in 1998, existing empirical literature supported the short‐term efficacy for both psychosocial and pharmacological interventions for adolescents with MDD. Developments since that time have expanded and consolidated this literature, especially for medication management, without substantively altering the rationale for TADS.

Cognitive‐behavioral therapy (CBT) as a treatment for MDD in youth has obtained strong empirical support for close to two decades (Harrington et

SPECIFIC AIMS AND DESIGN

The specific research objectives were clearly spelled out by the National Institute of Mental Health (NIMH) in the RFP:

Using a sufficiently large sample of patients representative of those found in clinical practice, (a) What is the long‐term effectiveness of pharmacological treatment of adolescents with major depression? What is the impact of treatment on symptom reduction, disorder remission, and level of functioning in school, at home, or in the community, and on the use of auxiliary

PRIMARY OUTCOME MEASURES

Two well‐validated primary outcome measures—one scalar and one categorical—as rated by an independent evaluator were selected: (1) the Children's Depression Rating Scale‐Revised total score based on the synthesis of information collected from interviewing both the adolescent and the parent (Poznanski and Mokros, 1995); and (2) responder status (dichotomized at much improved or better) on the Clinical Global Impressions‐Improvement (CGI‐I) scale (Guy, 1976). Secondary outcome measures (as

SAMPLE SIZE AND POWER ESTIMATES

The primary endpoint used in the sample size estimate was treatment response rate at the end of stage I, which, based on convention and existing literature, was defined as a CGI‐I score of 1 or 2 (very much or much improved, respectively) assigned by the independent evaluator. Using a χ2 statistic, power estimates for detecting differences in treatment response in the four groups were then computed with the following assumptions: (1) Ha: P(FLX) = 0.60, P(CBT) = 0.60, P(COMB) = 0.80, and P(PBO)

SAMPLING FRAME AND SUBJECT RECRUITMENT

TADS will recruit a volunteer sample of 432 youth aged 12‐17 years (inclusive) with a primary DSM‐IV diagnosis of MDD. The most important inclusion and exclusion criteria are presented in TABLE 3, TABLE 4, respectively. Potential patients who refuse consent or fail eligibility requirements are offered clinically appropriate open treatment outside the study. Records are kept to allow comparison of those entering and not entering the study for purposes of assessing sample representativeness and

Overview

TADS treatments are designed according to “best practice” standards to allow ready dissemination (if warranted) into clinical practice at the conclusion of the trial. Using flexible dosing in the medication condition and a mix of required and modular session topics in CBT plus strategies for maintaining treatment gains, TADS treatments are carefully designed to maximize benefits and to minimize adverse events and patient noncompliance. Adjunctive Services and Attrition Prevention (ASAP)

PATIENT SAFETY AND ASAP

To ensure patient safety, evaluate the tolerability of treatment, and minimize the potential for cross‐site differences in protocol delivery, TADS provides integrated procedures for adverse event (AE) monitoring and ASAP, including manual‐based procedures for monitoring and responding to (1) worsening MDD, (2) adverse events, (3) concomitant medications, and (4) adjunctive services in response to, for example, emerging suicidality.

With respect to adverse event monitoring, TADS stays carefully

ASSESSMENTS

Following recommendations outlined by Burns and by Jensen and their colleagues (Burns, 1996; Jensen et al., 1996), the TADS assessment battery was crafted to provide information regarding the impact of treatment across multiple domains and informants.

As noted earlier, the two primary outcome measures targeting the symptoms of MDD as rated by an independent evaluator are (1) a clinical summary score on the Children's Depression Rating Scale‐Revised and (2) a dichotomized CGI‐I score. Secondary

QUALITY ASSURANCE

To ensure that all sites conduct the protocol in the same manner, quality assurance (QA) procedures covering administration of treatment and assessment protocols are critical to the success of a large, complex, multicenter trial such as TADS (Meinert, 1986). In particular, QA procedures are necessary to guarantee (1) consistent standardized administration of TADS treatments and (2) reliability of assessments defined as consistent standardized ascertainment of the study entry diagnosis and the

ORGANIZATION

TADS is funded by the NIMH as a contract to the Coordinating Center at Duke University Medical Center, with collaborating Program staff at the NIMH, statistical and other consultants, and collaborating scientists at 12 study centers. Under the direction of the Principal Investigator, John March, M.D., M.P.H., the Statistical Principal Investigator, Susan Silva, Ph.D., and the TADS Project Leader, Steven Petrycki, R.N., the Duke Clinical Research Institute provides overall leadership for the

STUDY TIMELINE

Year 1 (1999) was devoted to protocol development, recruiting and training sites, and piloting the CBT and medication protocol and assessment procedures in the above‐mentioned TADS feasibility study. It is expected that subject recruitment for the full trial will be completed in the spring of 2003 and all active treatment by the middle of year 6 of the award period. Stage IV follow‐up will be completed in the middle of year 7. Per the TADS Publication Guidelines, core paper(s) will be published

CONCLUSION

TADS stands at the confluence of current efforts to improve the treatment of adolescent depression and related outcomes. In a clinical context, TADS assessment and treatment protocols represent current “best practice” in the initial treatment of adolescents with MDD. Given links to related NIMH‐funded effectiveness studies, such as the Treatment of Resistant Depression in Adolescents (TORDIA) and the Treatment of Adolescent Suicide Attempters (TASA), TADS represents an important building block

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    Article Plus (online only) materials for this article appear on the Journal's Web site: www.jaacap.com.

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