SLOWER CLOZAPINE TITRATION THAN THE OFFICIAL JAPANESE PROTOCOL LED TO FEWER INFLAMMATORY ADVERSE EFFECTS

Abstract Background Higher frequencies of inflammatory adverse effects of clozapine have been reported in Japan (Kishi et al., 2013; Tsukahara et al., 2021). Tsukahara et al. reported 38 % (57/152) clozapine- induced fever, 5 % (7/152) myocarditis, 13 % (20/152) pleuritis, and 1 % interstitial nephritis (2/152) in 152 patients first introduced to clozapine. The international titration protocol for Asians has set slower dose titration than the Japanese package insert to prevent clozapine-induced inflammatory adverse effects (de Leon et al., 2022). Aims & Objectives We hypothesized that a dose titration speed slower than the recommendation of the guideline would be associated with fewer inflammatory-related adverse events. We aimed to investigate the relationship between the rate of clozapine dose titration and inflammatory adverse events in Japanese individuals. Method The medical records of all 272 patients who were first started on clozapine at seven hospitals between 2009 and 2023 were studied retrospectively. Of those, 241 were included in the analysis. The patients were divided into two groups regarding whether the titration speed was faster or slower than the guideline for Asians. The incidence of inflammatory adverse events with clozapine was compared between the groups. Results The frequency of inflammatory adverse events was 34 % (37/110) in the faster titration group and 13 % (17/131) in the slower titration group, and a significant difference was observed by Fisher exact test (odds ratio 3.38; 95 % confidence interval 1.71–6.91; p <0.001). Serious adverse effects, fever for more than five days, and clozapine discontinuation were significantly more frequent in the faster titration group. Logistic regression analysis indicated significantly more inflammatory adverse events in the faster titration group (adjusted odds ratio 4.01; 95 % confidence interval 2.02–7.87; p < 0.001) considering age, sex, body mass index, concomitant valproic acid, and smoking as confounding factors. Discussion & Conclusion Clozapine-induced inflammatory adverse events were less frequent in Japanese individuals when a titration rate was more gradual than the protocol recommended in the Japanese package insert. References 1. Kishi, T. et al. (2013) Efficacy and tolerability of clozapine in Japanese patients with treatment- resistant schizophrenia: results from a 12-week, flexible dose study using raters masked to antipsychotic choice. Asian J. Psychiatr. 6 (3), 200–207. 2. Tsukahara, M. et al. (2021) Clinical utility and safety of slower-than-recommended titration of clozapine for treatment-resistant schizophrenia: a retrospective cohort study. Psychiatr. Q. 92 (2), 703–713. 3. de Leon, J. et al. (2022) An international adult guideline for making clozapine titration safer by using six ancestry-based personalized dosing titrations, CRP, and clozapine levels. Pharmacopsychiatry 55 (2), 73–86.