Effects of Clozapine Add-On to Risperidone vs. Risperidone Monotherapy on Agitation in Paranoid Schizophrenia: A Quasi-experimental Pilot Study

Abstract

Background: Second-generation antipsychotics, including risperidone and clozapine, are widely used for paranoid schizophrenia. Clozapine is typically considered in treatment-resistant cases, but the evidence for add-on therapy in agitation symptoms remains limited. Objectives: This study aimed to compare the effects of risperidone monotherapy versus risperidone plus clozapine add-on therapy on agitation symptoms in patients with paranoid schizophrenia. Methods: A retrospective observational quasi-experimental study was conducted at a psychiatric unit in West Sumatra, Indonesia, from January to December 2023. A total of 47 inpatients diagnosed with paranoid schizophrenia were included: Thirty-eight received risperidone monotherapy and 9 received risperidone plus clozapine combination therapy. Agitation was assessed using the Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) in its validated Indonesian version. Sociodemographic characteristics and PANSS-EC score changes were analyzed using non-parametric tests. Results: Both treatment groups showed reductions in PANSS-EC scores. The risperidone monotherapy group showed a mean reduction of 4.26 ± 3.20 points, while the combination therapy group showed a slightly higher mean reduction, although the difference was not statistically significant. The mean length of hospitalization was 20.95 ± 6.18 days for the risperidone group and 20.00 ± 4.69 days for the combination group (P = 0.878). No significant associations were found between sociodemographic variables and agitation improvement. Conclusions: Clozapine add-on to risperidone showed a non-significant trend toward greater reduction in agitation symptoms compared to risperidone alone. However, the small and unequal sample sizes, lack of dosage and adherence data, and short follow-up limited the strength and generalizability of the findings. Future prospective studies with larger samples, standardized dosage reporting, and longer-term follow-up are needed.