When Pharmacology Meets Psychopathology: Switching, Tolerability, and the Real-World Use of Risperidone ISM

Nonadherence to antipsychotic treatment is not merely a behavioural or logistical problem: it is closely intertwined with core psychopathological dimensions of schizophrenia and schizoaffective disorder, including impaired insight, residual positive symptoms, negative and disorganised symptomatology, and the quality of the therapeutic alliance. Long-acting injectable (LAI) antipsychotics reduce relapse and hospitalisation, yet their psychopathological benefit has historically been limited by initiation regimens that are themselves clinically cumbersome, requiring loading doses, weeks of oral overlap, or mandatory post-injection observation. Risperidone ISM, a once-monthly intramuscular formulation based on an in situ forming polymeric matrix, was designed to close this gap by achieving therapeutic dopamine D2 receptor occupancy within hours of the first injection, without a loading dose or oral supplementation in patients with established risperidone tolerability. This article reviews the pharmacokinetic and pharmacodynamic rationale of risperidone ISM, the pivotal PRISMA trial programme and recent real-world cohorts, and translates this evidence into clinically usable guidance on initiation timing, switching from other LAIs (including paliperidone) and from oral antipsychotics (with particular attention to olanzapine and the risk of histaminergic and cholinergic rebound), and the management of adverse events, notably hyperprolactinaemia, with explicit reference to their psychopathological correlates: mood, apathy, self-image, and the extent to which extrapyramidal phenomena can be mistaken for, or coexist with, primary psychomotor and affective psychopathology. Three illustrative clinical vignettes are presented to ground these principles in practice.