Restoring TADS: RIAT reanalysis of the Treatment for Adolescents with Depression Study.

BackgroundThe Treatment for Adolescents with Depression Study (TADS) continues to influence international clinical practice guidelines for adolescent depression.ObjectiveWe assessed TADS' effectiveness and harms through a Restoring Invisible and Abandoned Trials (RIAT)-led reanalysis.MethodsTADS was a phase-three multicentre, parallel four-arm randomised controlled superiority trial that randomised adolescents (n = 439) to fluoxetine alone (FLX), CBT alone (CBT), open-label fluoxetine plus CBT (COMB) or placebo pill alone (PBO) over 12 weeks. COMB and CBT groups were unblinded to their treatment allocation. Primary outcomes were the Children's Depression Rating Scale-Revised (CDRS-R) and Clinical Global Impression-Improvement scale (CGI-I).ResultsOur ITT reanalysis showed a significant decrease in CDRS-R at 12 weeks in COMB compared with PBO (-6.65; p < 0.001) and CBT (-7.63, p < 0.001), but not FLX (-4.07, p = 0.063). There was no difference between FLX, CBT and PBO. There was a higher proportion of CGI-I responders in COMB (73.72% [SE 4.43]) compared with all other arms: FLX (64.16% [SE 4.76]), CBT (51.06% [SE 5.29]) and PBO (38.76% [SE 4.87]; all p < 0.001); FLX had more responders than PBO (p = 0.004). 369 adverse events were reported for 171 participants, with 66% occurring in those taking fluoxetine. We found 32 serious adverse events (22 in those taking fluoxetine), which varied from original authors' reporting.ConclusionsOur reanalysis replicated the original investigators' reporting that COMB demonstrated the most robust outcomes and that FLX was not superior to PBO. In contrast to the original TADS Team's reporting, there was a higher level of harm uncovered in allocation groups taking fluoxetine, including 11 unreported suicide-related adverse events. Overall, the marked increase in harms among participants taking fluoxetine warrants further circumspection when prescribing it to adolescents.