Risk of Long-Term Clozapine Medication over Decades for Cardiac Adverse Events Including Heart Failure and Its Pathophysiology: A Japan and China Retrospective Cohort Analysis.

Background/Objectives: Clozapine is the sole antipsychotic approved for treatment-resistant schizophrenia, but it is a double-edged therapeutic option due to various lethal adverse reactions. This study aimed to assess the risk of long-term clozapine medication-induced cardiotoxicity, which has not yet been fully elucidated. Methods: This study is a multicenter retrospective cohort study of patients with schizophrenia in Japan and China who received clozapine monotherapy. Cases for which serum NT-proBNP concentration and LVEF derived from echocardiography were available in 2025 were included. In addition, blood examinations, including those administered by the Japanese Clozaril Patient Monitoring Service, were statistically analyzed as independent variables. Results: Among a total of 315 cases, including 99 Japanese (clozapine exposure duration: 57.5 ± 4.0 months) and 216 Chinese (208.1 ± 11.0 months) cases, were enrolled. In both Japan and China, age-standardized prevalence of heart failure among patients with prescribed clozapine were higher compared to general population, with odds ratios of 3.2 (95%CI: 1.4-6.4) and 6.9 (95%CI: 3.6-12.0), respectively. The risk factors for stage-B heart failure associated with clozapine were prolonged exposure duration, higher plasma levels of clozapine, and increasing monocytes. Unexpectedly, over 70% of cases with stage-B heart failure associated with clozapine identified in this study did not have metabolic complications. Other than those with cardiomyopathy, myocardial infarction, ileus, or chronic renal failure, no cases with ejection fraction < 50% were observed, suggesting that stage-B heart failure associated with clozapine is speculated to be likely suggestive of HFpEF. Conclusions: Traditionally, psychiatry has focused on myocarditis and cardiomyopathy developing several weeks and months after initiation of clozapine medication; however, this study revealed asymptomatic heart failure as a third cardiac adverse reaction of clozapine that develops years later. Therefore, regular monitoring of NT-proBNP contributes to improving long-term prognosis of treatment-resistant schizophrenia with prescribed clozapine.