Understanding how and under what circumstances a highly effective psychological intervention, improved symptoms of depression is important to maximise its clinical effectiveness.

To address this complexity, we estimate the indirect effects of potentially important mediators to improve symptoms of depression (measured with the Patient Health Questionnaire (PHQ-9)) in the Healthy Activity Program trial.

Interventional in(direct) effects were used to decompose the total effect of the intervention on PHQ-9 scores into the direct and indirect effects. The following indirect effects were considered: characteristics of sessions, represented by the number of sessions and homework completed; behavioural activation, according to an adapted version of the Behavioural Activation for Depression Scale – Short Form; and extra sessions offered to participants who did not respond to the intervention.

Of the total effect of the intervention measured through the difference in PHQ-9 scores between treatment arms (mean difference: −2.1, bias-corrected 95% CI −3.2 to −1.5), 34% was mediated through improved levels of behavioural activation (mean difference: −0.7, bias-corrected 95% CI −1.2 to −0.4). There was no evidence to support the mediating role of characteristics of the sessions nor the extra sessions offered to participants who did not respond to the treatment.

Findings from our robust mediation analyses confirmed the importance of targeting behavioural activation. Contrary to published literature, our findings suggest that neither the number of sessions nor proportion of homework completed improved outcomes. Moreover, in this context, alternative treatments other than extra sessions should be considered for patients who do not respond to the intervention.