Ethnicity-Based Personalized Clozapine Titration Strategies for Prevention of Clozapine-Induced Inflammation: Recommendations Based on Evidence from the Japanese Population.

Abstract

In Japan, the use of clozapine is strictly regulated compared with other countries. Only Novartis Pharma completely controls marketing and package inserts, with no generic drugs available. Countless requirements should be met, including that clozapine can only be prescribed by hospitals and psychiatrists registered with the Clozaril Patient Monitoring Service, hospitalization is mandatory when starting clozapine treatment, patients cannot be discharged or stay overnight outside the hospital for 3 weeks, and hospitalization for 18 weeks is recommended in principle. Blood monitoring standards are also strict. Under these circumstances, the Japanese clozapine package insert describes a titration protocol to 200 mg/day in 3 weeks, and our study has reported a high frequency of inflammatory adverse events in patients who followed this protocol. This narrative review summarizes the evidence regarding the relationship between clozapine titration speeds and inflammatory adverse events in Japanese individuals. Although several guidelines for preventing clozapine-induced inflammation are available, few studies have investigated whether the recommended titration protocols reduce the risk of inflammatory adverse events. In Japanese patients, clinicians encounter the challenge of identifying clozapine-poor metabolizers in advance, making it difficult to determine which patients would benefit from a slower titration protocol. In this article, we provided specific titration strategies to reduce inflammatory adverse events on the basis of evidence from studies in Japanese people. First, we provide an overview of the characteristics of clozapine-induced inflammation, particularly focusing on its properties as a continuum. We also propose a hypothesis regarding the immunological mechanisms by which clozapine causes inflammation on the basis of observed phenomena. Next, we summarize the risk factors for clozapine-induced inflammation. We then summarize the evidence of clozapine-induced inflammation in Japanese individuals and emphasize the importance of slower titration in this population to prevent inflammatory adverse effects. In the latter part, we propose a methodology for personalized titration in Japanese people, which involves measuring clozapine blood levels on day 8 to estimate individual clozapine metabolism capacity and adjusting the titration speed accordingly. Finally, we discuss how slower titration helps determine the minimum therapeutic dose while monitoring patients for side effects of clozapine. We hope that they may guide psychiatrists and pharmacists on clozapine titration speed and adjustment methodology, promoting the broader use of clozapine with fewer adverse events.