Aripiprazole Long Acting and Clozapine: Between Efficacy and Tolerability

Background: Patients affected by schizophrenia often experience a poor quality of life. Antipsychotics currently used reduce treatment compliance because of their side effects and their high non-responder rate. Antipsychotic polytherapy, also with Long-acting injectables (LAI) formulation, may increase the efficacy in refractory and non-compliant patients. This systematic review examines the coadministration of clozapine and aripiprazole LAI, studying its efficacy, tolerability and side-effects. Methods: The research was conducted on 6 August 2025, using PubMed, Scopus and Web of Science. The query search tool used was “aripiprazole AND clozapine AND (Long acting OR injectable OR LAI OR combination)”. Only original papers written in English were considered; animal research, in vitro experiments, also studies not specifying the formulation of aripiprazole were excluded. Results: Our research produced 1637 records. Removing repeated, not written in English and off topic articles, six papers were selected for qualitative synthesis. Conclusions: Available evidence on the combined use of clozapine and long-acting injectable aripiprazole is limited and largely derived from small observational studies. The reviewed reports describe recurring clinical observations suggesting that this strategy may be applicable in selected patients with treatment-resistant schizophrenia, particularly in the presence of poor adherence or clozapine-related tolerability concerns. Reported outcomes include symptom stabilization, improved adherence, and possible benefits on residual symptoms and clozapine-related adverse effects. Nonetheless, the low certainty of the evidence prevents firm conclusions regarding efficacy and safety, highlighting the need for further prospective controlled studies.