Figure 1. Model of the causal pathway between antidepressant medication use and viral suppression, with time-varying confounding by indication.

Depression severity confounds the observed relationship between antidepressant medication use and viral suppression, because patients with more severe depression are more likely to be prescribed antidepressant medication and are also more likely to have worsened virologic outcome. Over the course of longitudinal follow up, depression severity may be improved by past treatment with antidepressant medication. It is therefore part of the causal pathway of interest (leading from antidepressant medication treatment to improved virologic outcome). Conventional statistical adjustment, i.e., including depression severity as a time-dependent variable in a regression model, may bias the estimated treatment effect towards the null by conditioning on part of the effect of interest.