RationaleLong-acting injectable antipsychotic therapies may offer benefits over oral antipsychotics in patients with schizophrenia.ObjectiveThis study aimed to explore the safety, tolerability, and treatment response of paliperidone palmitate once-monthly in non-acute but symptomatic adult patients switched from previously unsuccessful monotherapy with frequently used oral atypical antipsychotics.MethodsThis was a post hoc analysis of a prospective, interventional, single-arm, international, multicenter, open-label, 6-month study.ResultsThe patients (N = 472) were switched to paliperidone palmitate once-monthly (PP1M) from daily oral treatment with either aripiprazole (n = 46), olanzapine (n = 87), paliperidone extended-release (n = 104), quetiapine (n = 44), or risperidone (n = 191). In all groups, mean Positive and Negative Syndrome Scale total (p < 0.0001) and Clinical Global Impression-Severity scores improved significantly (p = 0.0004 to p < 0.0001). An improvement of ≥50 % in the Positive and Negative Syndrome Scale total score was observed in 21.7 % (aripiprazole), 29.9 % (olanzapine), 29.8 % (paliperidone extended-release), 27.3 % (quetiapine), and 37.2 % (risperidone) of patients. The patients showed significant improvements in the Personal and Social Performance score (aripiprazole p = 0.0409, all others p ≤ 0.0015); Mini International Classification of Functionality, Disability and Health Rating for Activity and Participation Disorders in Psychological Illnesses total scores (all p < 0.01); and Treatment Satisfaction Questionnaire for Medication Global Satisfaction score (olanzapine and risperidone p < 0.0001, quetiapine p = 0.0465, paliperidone extended-release p = 0.0571, aripiprazole p = NS). Paliperidone palmitate once-monthly was well tolerated, presenting no new safety signals.ConclusionsThese data illustrate that stable, non-acute but symptomatic patients on oral antipsychotic monotherapy may show clinically meaningful improvement of symptoms, functioning, and treatment satisfaction after direct transition to PP1M. The findings are limited by the naturalistic study design; thus, further studies are required to confirm the current findings.Electronic supplementary materialThe online version of this article (doi:10.1007/s00213-016-4445-0) contains supplementary material, which is available to authorized users.