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Randomized Controlled Trial
. 2009 Mar;166(3):337-44.
doi: 10.1176/appi.ajp.2008.08040487. Epub 2009 Jan 15.

Assessment of safety and long-term outcomes of initial treatment with placebo in TADS

Betsy D Kennard  1 , Susan G Silva, Taryn L Mayes, Paul Rohde, Jennifer L Hughes, Benedetto Vitiello, Christopher J Kratochvil, John F Curry, Graham J Emslie, Mark A Reinecke, John S March; TADS
Collaborators, Affiliations
Randomized Controlled Trial

Assessment of safety and long-term outcomes of initial treatment with placebo in TADS

Betsy D Kennard et al. Am J Psychiatry. 2009 Mar.

Abstract

Objective: The authors examined whether initial assignment to receive placebo for 12 weeks followed by open active treatment as clinically indicated was associated with different levels of benefit and risk of harm across 36 weeks as compared with initial assignment to receive active treatments.

Method: Adolescents with major depressive disorder (N=439) were randomly assigned to receive an initial 12 weeks of treatment with fluoxetine, cognitive-behavioral therapy (CBT), combination treatment with fluoxetine and CBT, or clinical management with placebo; those assigned to placebo received open active treatment as clinically indicated after 12 weeks of placebo. Assessments were conducted every 6 weeks for 36 weeks. The primary outcome measures were response and remission based on scores on the Children's Depression Rating Scale-Revised and the Clinical Global Impression improvement subscale.

Results: At week 36, the response rate was 82% in the placebo/open group and 83% in the active treatment groups. The remission rate was 48% in the placebo/open group and 59% in the active treatment groups, a difference that approached statistical significance. Patients who responded to placebo generally retained their response. Those who did not respond to placebo subsequently responded to active treatment at the same rate as those initially assigned to active treatments. There were no differences between groups in rates of suicidal events, study retention, or symptom worsening.

Conclusions: Remission rates at 9 months were lower in patients treated initially with placebo, but 3 months of placebo treatment was not associated with any harm or diminished response to subsequent treatment.

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Figures

FIGURE 1
FIGURE 1. CONSORT Diagram for Participants Receiving Active Treatment or Placebo During Acute Treatment, Followed by Open Active Treatmenta
a Reasons for discontinuation prior to randomization have been previously reported (7, p. 811).
FIGURE 2
FIGURE 2. Flow Diagram for Participants Receiving Placebo During Acute Treatment, Followed by Open Active Treatmenta
a Response to treatment was defined as a score of 1 or 2 on the CGI improvement item at the last assessment completed in each stage; a score of 3 was interpreted as a partial response, and a score above 3 indicated no response. For participants who exited the study, the CGI improvement score from the last available assessment was used to determine response. “Premature termination” in stage 1 refers to participants for whom placebo was discontinued before the end of 12 weeks because of clinical crisis but who continued to participate in the assessment component of the study (and thus did not exit the study during stage 1). At the week 36 evaluation, 83 of the 112 participants in the placebo group were still active in the study, but only 75 completed the assessment.
FIGURE 3
FIGURE 3
CGI Improvement Item Response (Score of 1 or 2) Rates for the Active Treatment Group During Stage 1 and the Placebo/Open Group Nonresponders During the 12 Weeks Following Stage 1
FIGURE 4
FIGURE 4
Remission (Children’s Depression Rating Scale–Revised Score ≤28) Rates for the Placebo/Open and Active Treatment Groups Across Weeks 12–36
See this image and copyright information in PMC

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