SPECIAL SECTION: TREATMENT FOR ADOLESCENTS WITH DEPRESSION STUDY-TADS
Treatment for Adolescents With Depression Study (TADS): Safety Results

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ABSTRACT

Objective

To compare the rates of physical, psychiatric, and suicide-related events in adolescents with MDD treated with fluoxetine alone (FLX), cognitive-behavioral therapy (CBT), combination treatment (COMB), or placebo (PBO).

Method

Safety assessments included adverse events (AEs) collected by spontaneous report, as well as systematic measures for specific physical and psychiatric symptoms. Suicidal ideation and suicidal behavior were systematically assessed by self- and clinician reports. Suicidal events were also reanalyzed by the Columbia Group and expert raters using the Columbia-Classification Algorithm for Suicidal Assessment used in the U.S. Food and Drug Administration reclassification effort.

Results

Depressed adolescents reported high rates of physical symptoms at baseline, which improved as depression improved. Sedation, insomnia, vomiting, and upper abdominal pain occurred in at least 2% of those treated with FLX and/or COMB and at twice the rate of placebo. The rate of psychiatric AEs was 11% in FLX, 5.6% in COMB, 4.5% in PBO, and 0.9% in CBT. Suicidal ideation improved overall, with greatest improvement in COMB. Twenty-four suicide-related events occurred during the 12-week period: 5 patients (4.7%) in COMB, 10 (9.2%) in FLX, 5 (4.5%) in CBT, and 3 (2.7%) in placebo. Statistically, only FLX had more suicide-related events than PBO (p =.0402, odds ratio (OR) = 3.7, 95% CI 1.00-63.7). Only five actual attempts occurred (2 COMB, 2 FLX, 1 CBT, 0 PBO). There were no suicide completions.

Conclusions

Different methods for eliciting AEs produce different results. In general, as depression improves, physical complaints and suicidal ideation decrease in proportion to treatment benefit. In this study, psychiatric AEs and suicide-related events are more common in FLX-treated patients. COMB treatment may offer a more favorable safety profile than medication alone in adolescent depression.

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Placebo-controlled, randomized clinical trials (RCTs) are the gold standard for evaluating efficacy and are also of critical importance in assessing safety and tolerability (March et al., 2004). Although they provide substantial information on the measurement of safety,

METHOD

The rationale, design, methods, and sample characteristics have been described in prior reports (TADS, 2003, TADS, 2005) and are included in the Special Section introduction by March et al. The patients were adolescents (N = 439), ages 12 to 17 years (mean ± SD, 14.6 ± 1.5 years), who were outpatients, with a primary DSM-IV diagnosis of MDD. The baseline mean Children's Depression Rating Scale-Revised (CDRS-R) total score was 60.1, and 86% of the sample were in their first episode of MDD.

Patient Disposition

TADS treatments proved acceptable and tolerable. Of the 439 randomized patients, 359 (81.8%) remained in their assigned treatment arm through 12 weeks of acute treatment, although eight of these missed the week 12 assessment visit. The proportion of patients who remained in the assigned treatment arm was greater with fluoxetine-treated patients. Specifically, 86.0% in COMB, 83.5% in FLX, 78.4% in CBT, and 79.5% in PBO were in their assigned treatment arm at the week 12 assessment point. There

DISCUSSION

The TADS was the first study to compare efficacy and safety of FLX, CBT, their combination, and placebo in the treatment of pediatric depression. The study is also among a relatively small number of trials that used systematic assessment of AEs, as well as the general inquiry used in most clinical trials. Over 80% of the adolescents completed 12 weeks of treatment in their assigned treatment arm, indicating the TADS treatments were generally acceptable and tolerable.

Depressed adolescents had

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    The Columbia Suicidality Classification Group is led by Kelly Posner, Ph.D., Maria Oquendo, M.D., Madelyn Gould, Ph.D., M.P.H., and Barbara Stanley, Ph.D.

    TADS is supported by contract N01 MH80008 from the National Institute of Mental Health to Duke University Medical Center (John S. March, Principal Investigator).

    The authors thank and acknowledge the independent expert raters from the Columbia Suicidality Classification Project: David Brent, M.D., Greg Brown, Ph.D., David Rudd, Ph.D., Cheryl King, Ph.D., Anthony Spirito, Ph.D., A.B.P.P., Peter Marzuk, M.D., Patrick O'Carroll, M.D., M.P.H., Annette Beautrais, Ph.D., Kees Van Heeringen, M.D., Ph.D., and Alec Miller, Psy.D.

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

    Disclosure: 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. Kratochvil is a consultant or scientific advisor to Eli Lilly, Shire, Cephalon, Organon, AstraZeneca, Boehringer-Ingelheim, Abbott and Pfizer; receives research support from Eli Lilly, McNeil, Cephalon, and Abbott; receives study drug for an NIMH-funded study from Lilly; and is on the Eli Lilly speakers' bureau. Dr. Silva is a consultant to Pfizer. Dr. Weller is a consultant to and receives grants from Otsuka, Johnson & Johnson, AstraZeneca, Organon, Pharma, Shire, and GlaxoSmithKline. Dr. Waslick receives research support from Eli Lilly. Dr. Casat receives research support from Eli Lilly, GlaxoSmithKline, Shire, Bristol-Myers Squibb, AstraZeneca, Sanofi-Synthelabo, Pfizer, and McNeil; is on the Advisory Board and the speakers' bureaus of Eli Lilly and GlaxoSmithKline. Dr. Walkup receives research support from Eli Lilly, Pfizer, and Abbott; is a consultant to Eli Lilly, Pfizer, Jazz, and Cephalon; and has received honoraria from Eli Lilly and Pfizer. Dr. Pathak receives research support from Forest. Dr. Posner has received research support from GlaxoSmithKline, Forest, Eisai, AstraZeneca, Johnson & Johnson, Abbott, Wyeth, Organon, Bristol-Myers Squibb, Sanofi-Aventis, Cephalon, Novartis, Shire, and UCB Pharma. Dr. March is on the speakers' bureaus of Pfizer and Eli Lilly and has received research support from Eli Lilly, Pfizer, and Wyeth. The other authors have no financial relationships to disclose.

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