Abstract：
BACKGROUND: Clozapine-induced inflammation, such as myocarditis and pneumonia, can occur during initial titration and can be fatal. Fever is often the first sign of severe inflammation, and early detection and prevention are essential. Few studies have investigated the effects of clozapine titration speed and concomitant medication use on the risk of clozapine-induced inflammation.
OBJECTIVE: We evaluated the risk factors for clozapine-associated fever, including titration speed, concomitant medication use, gender and obesity, and their impact on the risk of fever and the fever onset date.
METHODS: We conducted a case-control study. The medical records of 539 Japanese participants with treatment-resistant schizophrenia at 21 hospitals in Japan who received clozapine for the first time between 2010 and 2022 were retrospectively investigated. Of these, 512 individuals were included in the analysis. Individuals were divided into three groups according to the titration rate recommended by international guidelines for East Asians: the faster titration group, the slower titration group and the ultra-slower titration group. The use of concomitant medications (such as antipsychotics, mood stabilisers, hypnotics and anxiolytics) at clozapine initiation was comprehensively investigated. Logistic regression analysis was performed to identify the explanatory variables for the risk of a fever of 37.5°C or higher lasting at least 2 days.
RESULTS: Fever risk significantly increased with faster titration, male gender and concomitant use of valproic acid or quetiapine. No increased fever risk was detected with the use of other concomitant drugs, such as olanzapine, lithium or orexin receptor antagonists. Fever onset occurred significantly earlier with faster titration. Multivariate analysis identified obesity as being a factor that accelerated fever onset.
CONCLUSIONS: A faster titration speed and concomitant treatment with valproic acid and quetiapine at clozapine initiation increased the risk of clozapine-associated fever. Clinicians should titrate clozapine with caution and consider both the titration speed and concomitant medications.
OBJECTIVE: We evaluated the risk factors for clozapine-associated fever, including titration speed, concomitant medication use, gender and obesity, and their impact on the risk of fever and the fever onset date.
METHODS: We conducted a case-control study. The medical records of 539 Japanese participants with treatment-resistant schizophrenia at 21 hospitals in Japan who received clozapine for the first time between 2010 and 2022 were retrospectively investigated. Of these, 512 individuals were included in the analysis. Individuals were divided into three groups according to the titration rate recommended by international guidelines for East Asians: the faster titration group, the slower titration group and the ultra-slower titration group. The use of concomitant medications (such as antipsychotics, mood stabilisers, hypnotics and anxiolytics) at clozapine initiation was comprehensively investigated. Logistic regression analysis was performed to identify the explanatory variables for the risk of a fever of 37.5°C or higher lasting at least 2 days.
RESULTS: Fever risk significantly increased with faster titration, male gender and concomitant use of valproic acid or quetiapine. No increased fever risk was detected with the use of other concomitant drugs, such as olanzapine, lithium or orexin receptor antagonists. Fever onset occurred significantly earlier with faster titration. Multivariate analysis identified obesity as being a factor that accelerated fever onset.
CONCLUSIONS: A faster titration speed and concomitant treatment with valproic acid and quetiapine at clozapine initiation increased the risk of clozapine-associated fever. Clinicians should titrate clozapine with caution and consider both the titration speed and concomitant medications.
摘要：
背景：氯氮平诱导的炎症，比如心肌炎和肺炎,可能在初始滴定期间发生，并且可能是致命的。发烧通常是严重炎症的第一个征兆，及早发现和预防至关重要。很少有研究调查氯氮平滴定速度和伴随用药对氯氮平诱导的炎症风险的影响。
目的：我们评估了氯氮平相关性发热的危险因素，包括滴定速度，伴随用药,性别和肥胖，以及它们对发烧风险和发烧发病日期的影响。
方法：我们进行了病例对照研究。回顾性调查了2010年至2022年期间在日本21家医院首次接受氯氮平治疗的539名日本精神分裂症患者的医疗记录。其中,分析中包括512个人。根据东亚人国际指南推荐的滴定速度，将个人分为三组：滴定速度较快的组，较慢滴定组和超较慢滴定组。合并用药（如抗精神病药，情绪稳定剂,全面研究了氯氮平起始时的催眠药和抗焦虑药）。进行Logistic回归分析以确定持续至少2天的37.5°C或更高的发烧风险的解释变量。
结果：随着滴定速度的加快，发烧风险显着增加，男性和伴随使用丙戊酸或喹硫平。使用其他合并药物未发现发热风险增加，比如奥氮平,锂或食欲素受体拮抗剂。随着滴定速度更快，发烧发作明显更早。多变量分析确定肥胖是加速发烧发作的因素。
结论：较快的滴定速度以及氯氮平开始时使用丙戊酸和喹硫平的联合治疗会增加氯氮平相关发热的风险。临床医生应谨慎滴定氯氮平，并考虑滴定速度和合并用药。
目的：我们评估了氯氮平相关性发热的危险因素，包括滴定速度，伴随用药,性别和肥胖，以及它们对发烧风险和发烧发病日期的影响。
方法：我们进行了病例对照研究。回顾性调查了2010年至2022年期间在日本21家医院首次接受氯氮平治疗的539名日本精神分裂症患者的医疗记录。其中,分析中包括512个人。根据东亚人国际指南推荐的滴定速度，将个人分为三组：滴定速度较快的组，较慢滴定组和超较慢滴定组。合并用药（如抗精神病药，情绪稳定剂,全面研究了氯氮平起始时的催眠药和抗焦虑药）。进行Logistic回归分析以确定持续至少2天的37.5°C或更高的发烧风险的解释变量。
结果：随着滴定速度的加快，发烧风险显着增加，男性和伴随使用丙戊酸或喹硫平。使用其他合并药物未发现发热风险增加，比如奥氮平,锂或食欲素受体拮抗剂。随着滴定速度更快，发烧发作明显更早。多变量分析确定肥胖是加速发烧发作的因素。
结论：较快的滴定速度以及氯氮平开始时使用丙戊酸和喹硫平的联合治疗会增加氯氮平相关发热的风险。临床医生应谨慎滴定氯氮平，并考虑滴定速度和合并用药。
