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. 2024 Apr;58(4):355-364.
doi: 10.1177/00048674231218623. Epub 2023 Dec 21.

Treatment guesses in the Treatment for Adolescents with Depression Study: Accuracy, unblinding and influence on outcomes

Jon Jureidini  1 , Joanna Moncrieff  2 , Julie Klau  1 , Natalie Aboustate  1 , Melissa Raven  1
Affiliations

Treatment guesses in the Treatment for Adolescents with Depression Study: Accuracy, unblinding and influence on outcomes

Jon Jureidini et al. Aust N Z J Psychiatry. 2024 Apr.

Abstract

Objective: We evaluated the presence and impact of unblinding during the influential Treatment for Adolescents with Depression Study (ClinicalTrials.gov Identifier: NCT00006286).

Method: Our analysis was part of a Restoring Invisible and Abandoned Trials reanalysis. Treatment for Adolescents with Depression Study trialled fluoxetine, placebo, cognitive behaviour therapy or their combination, in treating adolescents with major depressive disorder. We analysed the accuracy of guesses of fluoxetine or placebo allocation, and their effects on change in Children's Depression Rating Scale-Revised at 12 weeks.

Results: Of 221 participants allocated to fluoxetine or placebo, 151 adolescents (68%) had their guess about pill-treatment-arm allocation recorded at week 6, and guesses were recorded for 154 independent evaluators, 159 parents and 164 pharmacotherapists. All of these groups guessed treatment allocation more accurately than would be expected by chance (60-66% accuracy; all p-values ⩽ 0.004). Guesses did not become more accurate between 6 and 12 weeks and were not predicted by adverse events, though event documentation was poor. Treatment guess had a substantial and statistically significant effect on outcome (Children's Depression Rating Scale-Revised change mean difference 9.12 [4.69; 13.55], β = 0.334, p < 0.001), but actual treatment arm did not (1.53 [-2.83; 5.89], β = 0.056, p = 0.489). Removing guess from the analysis increased the apparent effect of treatment arm, making it almost statistically significant at the conventional alpha-level of 0.05 (p = 0.06).

Conclusions: For Treatment for Adolescents with Depression Study, treatment guesses strongly predicted outcomes and may have led to the exaggeration of drug effectiveness in the absence of actual effects. The integrity of double-blinding in trials should be routinely assessed and reported.

Keywords: Randomised controlled trial blinding; adolescent depression; antidepressant; placebo; selective serotonin reuptake inhibitor.

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Conflict of interest statement

Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: J.J. affirms that the manuscript is an honest, accurate and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained. J.M. is involved in grant-funded research on methods to reduce antidepressants, receives royalties from books on psychiatric drugs and is co-chair person of the unfunded Critical Psychiatry Network.

Figures

Figure 1.
Figure 1.
Randomised treatment allocations in TADS showing adolescents for whom guesses were documented at week 6 and who had CDRS-R scores at week 12.
Figure 2.
Figure 2.
Change from baseline to week 12 in CDRS-R according to adolescents’ guesses about treatment allocation at week 6. $The upper line represents the mean change in CDRS-R for adolescents allocated to FLX and the lower line represents the change in CDRS-R for adolescents allocated to PBO.
Figure 3.
Figure 3.
Change from baseline to week 12 in CDRS-R, according to adolescents’ guesses and confidence of guesses about treatment allocation at week 6. $The upper line represents the mean change in CDRS-R for adolescents allocated to FLX, and the lower line represents the mean change for adolescents allocated to PBO.
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