Emulated target trials allow assessment of the effect of a treatment on a clinical outcome outside of the existing license, using observational data.13 Using this approach, we assessed whether exposure to the 5-HT4R agonist prucalopride (an anti-constipation agent acting on 5-HT4R in the gut, but also with good brain penetration14) is associated with a lower risk of depression within 1 year since first prescription, compared with two alternative anti-constipation agents that have no known effect on 5-HT4Rs or the central nervous system. The gene discussed is HTR4; the disease is major depressive disorder.