Koenig Michael, McCollum Betsy, Spivey Julie K, Coleman Jerry K, Shelton Charles, Cotes Robert O, Goldsmith David R, De Leon Jose
Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
Eastern State Hospital, Lexington, KY, USA.
Neuropsychopharmacol Hung. 2022 Mar 1;24(1):29-41.
Objectives: Clozapine-induced myocarditis may be a hypersensitivity reaction due to titration that was too rapid for a patient's clozapine metabolism. Obesity, infections, and inhibitors (e.g., valproate) may lead to clozapine poor metabolizer (PM) status. The hypothesis that 4 patients with clozapine-induced myocarditis from two United States hospitals were clozapine PMs was tested by studying their minimum therapeutic clozapine doses and titrations. Methods: Using methodology from a prior myocarditis case series of 9 Turkish patients, we studied: 1) the concentration-to-dose (C/D) ratio; 2) minimum therapeutic dose required to reach 350 ng/ml (a marker for PM status); and 3) titration speed. Results: All 4 patients were possible clozapine PMs (their respective minimum therapeutic doses were: 134, 84, 119 and 107 mg/day). The identified possible contributors to clozapine PM status were: 1) valproate in Cases 1, 2 and 4; 2) obesity and a urinary tract infection in Case 2; and 3) obesity and very rapid titration in Case 4. Case 3, who was given a normal US titration, appeared to be a genetic clozapine PM. He developed clozapineinduced drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome after rechallenge using 12.5 mg/day > 3 months later. The results were similar to 9 Turkish cases, all of which were PMs (6 on valproate, 4 with obesity, 1 with infection and 1 possibly genetic). Conclusions: Future studies using clozapine levels and considering the role of clozapine PM status should explore whether or not all cases of clozapine-induced myocarditis could be explained by lack of individualized titration. (Neuropsychopharmacol Hung 2022; 24(1): 29-41).
氯氮平所致心肌炎可能是一种超敏反应，原因是患者氯氮平代谢的滴定速度过快。肥胖、感染和抑制剂（如丙戊酸盐）可能导致氯氮平慢代谢者（PM）状态。通过研究来自美国两家医院的4例氯氮平所致心肌炎患者的最低治疗氯氮平剂量和滴定情况，对他们是氯氮平PM这一假设进行了检验。方法：采用先前9例土耳其心肌炎病例系列的方法，我们研究了：1）浓度与剂量（C/D）比；2）达到350 ng/ml（PM状态标志物）所需的最低治疗剂量；3）滴定速度。结果：所有4例患者均可能为氯氮平PM（他们各自的最低治疗剂量分别为：134、84、119和107 mg/天）。确定的可能导致氯氮平PM状态的因素有：1）病例1、2和4中的丙戊酸盐；2）病例2中的肥胖和尿路感染；3）病例4中的肥胖和滴定速度极快。病例3接受了美国常规滴定，似乎是遗传性氯氮平PM。3个月多后，他在再次使用12.5 mg/天进行激发试验后出现了氯氮平诱导的伴有嗜酸性粒细胞增多和全身症状的药物反应（DRESS）综合征。结果与9例土耳其病例相似，所有这些病例均为PM（6例使用丙戊酸盐，4例肥胖，1例感染，1例可能为遗传性）。结论：未来使用氯氮平水平并考虑氯氮平PM状态作用的研究应探讨是否所有氯氮平所致心肌炎病例都可以用缺乏个体化滴定来解释。（《匈牙利神经精神药理学》2022年；24(1): 29 - 41）
