ObjectiveTo compare the risk of discontinuation of ambulatory antipsychotic treatment in persons treated with antipsychotic long-acting injections (LAIs) or by oral antipsychotics (OAPs). MethodsThe study was performed in a representative sample of persons newly treated with OAPs (n = 6904) affiliated to the French Insurance Healthcare system. The risk of all-cause discontinuation was compared in patients prescribed OAPs (n = 246) vs. matched patients prescribed LAIs (n = 246) using multivariate survival analyses. Confounding by indication was minimized by matching on type of antipsychotic drug and by the high-dimensional propensity score method. ResultsDiscontinuation was more frequent with OAPs (69%) compared to LAIs (57%) [adjusted relative risk (aRR) = 1.6, 95% CI 1.23-2.07]. Risk of discontinuation was higher for first-generation (FGA) OAPs vs. FGA LAIs (aRR = 1.94, 95% CI 1.22-3.08) as well as for second-generation (SGA) OAPs vs. SGA LAIs (aRR = 1.58, 95% CI 1.15-2.17). Over the 6-month period after discontinuation of LAIs, a new antipsychotic drug was dispensed in 58% of patients, the most frequent pattern being dispensing of the same LAI as that prescribed before discontinuation. ConclusionsAlthough less frequent than with OAPs, the rate of ambulatory treatment discontinuation was high with LAIs. Prescription of LAIs should be associated with intervention strategies aimed at promoting medication adherence.