Kikuchi Yuki, Kurosawa Masahiro, Sakata Mutsumi, Takahashi Yu, Yamamoto Kyohei, Tomita Hiroaki, Yoshio Takashi, Yasui-Furukori Norio
Department of Psychiatry, Graduate School of Medicine, Tohoku University, Sendai, Miyagi, Japan.
Department of Psychiatry, Kodama Hospital, Ishinomaki, Miyagi, Japan.
Br J Psychiatry. 2024 Nov;225(5):492-498. doi: 10.1192/bjp.2024.113.
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.
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.
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.
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.
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.
氯氮平诱发的炎症，如心肌炎和肺炎，可在初始滴定过程中发生，且可能致命。发热往往是严重炎症的首要迹象，早期检测和预防至关重要。很少有研究调查氯氮平滴定速度和联合用药对氯氮平诱发炎症风险的影响。
我们评估了氯氮平相关发热的危险因素，包括滴定速度、联合用药、性别和肥胖，以及它们对发热风险和发热起始日期的影响。
我们进行了一项病例对照研究。回顾性调查了日本21家医院中539例2010年至2022年间首次接受氯氮平治疗的难治性精神分裂症日本参与者的病历。其中，512人纳入分析。根据东亚国际指南推荐的滴定率，将个体分为三组：较快滴定组、较慢滴定组和极慢滴定组。全面调查了氯氮平起始时联合用药（如抗精神病药、心境稳定剂、催眠药和抗焦虑药）的使用情况。进行逻辑回归分析以确定体温37.5°C或更高且持续至少2天的发热风险的解释变量。
滴定速度加快、男性以及联合使用丙戊酸或喹硫平会使发热风险显著增加。使用其他联合药物，如奥氮平、锂盐或食欲素受体拮抗剂，未检测到发热风险增加。滴定速度加快会使发热起始明显提前。多变量分析确定肥胖是加速发热起始的一个因素。
氯氮平起始时滴定速度加快以及联合使用丙戊酸和喹硫平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，并考虑滴定速度和联合用药情况。
