TADS study raises concerns

EDITOR—We have additional concerns to those raised by Lenzer about the adolescents with depression study (TADS).1 2

TADS consists of two separate randomised studies: a double blind comparison of fluoxetine (109 subjects) with placebo (112), and an unblinded comparison between cognitive behaviour therapy alone (111) and fluoxetine plus cognitive behaviour therapy (107). The lack of patient blinding and placebo control in the latter group is likely to exaggerate the benefit seen in the fluoxetine plus cognitive behaviour therapy group, who receive more face to face contact and know (as do their doctors) that they are not receiving placebo.

Comparing results across all four groups is therefore misleading. The authors' claim that a cognitive behaviour therapy plus placebo arm would have been both too expensive and too artificial to have clinical relevance is unconvincing.

TADS found no statistical advantage of fluoxetine over placebo on the primary end point, the children's depression rating scale (CDRS-R; P = 0.10), but this was not mentioned in the abstract. This and the small or absent advantages of fluoxetine on other end points (table) and in other studies,3 shows that fluoxetine, like all other antidepressants, is of doubtful clinical importance for children.

Adverse events and suicidal behaviour may be greater than the TADS paper says. Despite small numbers, more subjects leaving the study than reporting adverse effects, and the splitting of adverse events into multiple groups, significantly more psychiatric adverse events occurred in the fluoxetine group than the placebo group (χ² test (1 df), P = 0.047). Despite small numbers and the exclusion of known suicidal behaviour, TADS found a trend to more suicidal behaviour (six attempts in the fluoxetine groups and one attempt in the non-fluoxetine groups), consistent with other trials of selective serotonin reuptake inhibitors (SSRIs). We are less reassured than the authors by the fact that no attempt was fatal. Suicide is a rare event so that a study the size of TADS should be expected to miss a significantly increased risk.

The data do not support the TADS authors' optimistic conclusions. The balance between benefit and harm of SSRI treatment for depression in childhood and adolescence has yet to be shown to be favourable.