Caregivers are regularly faced with decisions between competing treatments. Large observational health care databases provide a golden opportunity for research on heterogeneity in patient response to guide caregiver decisions, due to their sample size, diverse populations, and real-world setting. Local control is a promising tool for using observational data to detect patient subgroups with differential response on one treatment relative to another. While standard data mining approaches find subgroups with optimal responses for a particular population, detecting subgroups that reveal treatment differences while also adjusting for confounding in observational data is challenging. Local control utilizes unsupervised clustering to form non-parametric patient-level counterfactual treatment differences and displays them as an observed distribution of effect-size estimates. Classification and regression trees (CART) then find the factors that drive the greatest outcome differentiation between treatments. In this manuscript, we demonstrate the use of this two-step strategy using local control plus CART to identify depression patients most (least) likely to benefit from treatment with duloxetine relative to extended-release venlafaxine. Prior medication costs and age were found to be factors most associated with differential outcome, with prior medication costs remaining as an important factor after sensitivity analyses using a second dataset. Copyright © 2013 John Wiley & Sons, Ltd.