Northwell Health, New Hyde Park, NY, USA; Department of Psychiatry, Zucker Hillside Hospital, Glen Oaks, NY, USA; Institute of Behavioral Science, Feinstein Institutes of Medical Research, Manhasset, NY, USA.
Northwell Health, New Hyde Park, NY, USA; Department of Psychiatry, Zucker Hillside Hospital, Glen Oaks, NY, USA; Institute of Behavioral Science, Feinstein Institutes of Medical Research, Manhasset, NY, USA.
Lancet Psychiatry. 2024 Jun;11(6):443-450. doi: 10.1016/S2215-0366(24)00097-X. Epub 2024 Apr 30.
Agranulocytosis is a life-threatening side-effect of clozapine, the only approved drug for treatment-resistant schizophrenia. The long-term profile of this complication has not yet been well established. Here we aim to describe the risk of clozapine-induced agranulocytosis over the long term.
We used the entire population of Finland to identify people diagnosed with schizophrenia or schizoaffective disorder between 1972 and 2014 and developed a Kaplan-Meier model of time to diagnosis of agranulocytosis during clozapine versus non-clozapine treatment over a 22-year observation period (1996 to 2017). Next, we developed a nested case-control model for agranulocytosis matching by sex, age, time since diagnosis, and being in the incident cohort on a 1 to 5 ratio. Various durations of use for clozapine and non-clozapine antipsychotic treatment were compared to the modal antipsychotic use duration, deriving adjusted odds ratios (aORs) in a multivariable regression model. Recurrence and lethality rates for clozapine-induced agranulocytosis were described. These data reflect on all individuals with lived experience of schizophrenia in Finland during the study time, although individuals with lived experience were not included in the design of the study.
We identified 61 769 people with schizophrenia or schizoaffective disorder (14 037 individuals treated with clozapine and 47 732 individuals treated with non-clozapine antipsychotics), with a mean age of 46·67 years (IQR 34·44-57·61), of whom 30 721 (49·7%) were female and 31 048 (50·3%) were male (data on ethnicity not available). Among those, 398 individuals were diagnosed with agranulocytosis (231 individuals treated with clozapine and 167 individuals treated with non-clozapine antipsychotics), representing a cumulative incidence of agranulocytosis for 1·37% (95% CI 0·58-3·16) on clozapine and 0·13% (0·04-0·23) on non-clozapine antipsychotics. In the case (n=398) versus control (n=1987) model, the risk of clozapine-induced agranulocytosis decreased steeply over time from an aOR of 36·01 (95% CI 16·79-77·22) for less than 6 months on clozapine to 4·38 (1·86-10·34) for clozapine use of 54 months or more. Only one of 3559 individuals starting clozapine died because of clozapine-induced agranulocytosis.
The risk of clozapine-induced agranulocytosis decreases steeply over time but might be persistently greater than that of non-clozapine antipsychotics. This long-term risk excess seems small in absolute terms compared with the known magnitude of the advantages of clozapine in relevant outcomes, including life expectancy. Given the widespread underuse of clozapine, relaxing the long-term neutrophil monitoring could favour the advantages of long-term clozapine use, including greater life expectancy, without incurring the intolerable risk of clozapine-induced agranulocytosis.
Northwell Health and Sigrid Jusèlius Foundation.
氯氮平是治疗耐药性精神分裂症的唯一批准药物，其会导致粒细胞缺乏症，这是一种危及生命的副作用。这种并发症的长期情况尚未得到充分确立。在此，我们旨在描述氯氮平诱导的粒细胞缺乏症在长期治疗中的风险。
我们利用芬兰的全部人口数据，确定了 1972 年至 2014 年间被诊断为精神分裂症或分裂情感障碍的患者，并在 22 年的观察期（1996 年至 2017 年）内建立了氯氮平与非氯氮平抗精神病药物治疗期间粒细胞缺乏症的诊断时间的 Kaplan-Meier 模型。接下来，我们根据性别、年龄、诊断后时间和在发病队列中的比例为 1:5，建立了一个嵌套病例对照模型，用于匹配粒细胞缺乏症。比较了氯氮平和非氯氮平抗精神病药物治疗的各种持续时间与模式抗精神病药物治疗的持续时间，在多变量回归模型中得出调整后的优势比（aOR）。描述了氯氮平诱导的粒细胞缺乏症的复发率和死亡率。这些数据反映了在研究期间芬兰所有经历过精神分裂症的个体，但这些个体并未被纳入研究设计。
我们确定了 61769 名患有精神分裂症或分裂情感障碍的患者（14037 名接受氯氮平治疗的患者和 47732 名接受非氯氮平抗精神病药物治疗的患者），平均年龄为 46.67 岁（IQR 34.44-57.61），其中 30721 名（49.7%）为女性，31048 名（50.3%）为男性（种族数据不可用）。在这些患者中，有 398 名被诊断为粒细胞缺乏症（231 名接受氯氮平治疗，167 名接受非氯氮平抗精神病药物治疗），其累积发病率为 1.37%（95%CI 0.58-3.16）接受氯氮平治疗和 0.13%（0.04-0.23）接受非氯氮平抗精神病药物治疗。在病例（n=398）与对照（n=1987）模型中，氯氮平诱导的粒细胞缺乏症的风险随着时间的推移迅速下降，从氯氮平使用不足 6 个月的 aOR 36.01（95%CI 16.79-77.22）下降到氯氮平使用 54 个月或更长时间的 aOR 4.38（1.86-10.34）。在开始接受氯氮平治疗的 3559 名患者中，仅有 1 名因氯氮平诱导的粒细胞缺乏症而死亡。
氯氮平诱导的粒细胞缺乏症的风险随着时间的推移而急剧下降，但可能仍然大于非氯氮平抗精神病药物的风险。与氯氮平在相关结局（包括预期寿命）方面已知的优势相比，这种长期风险增加的幅度相对较小。鉴于氯氮平的广泛应用不足，放宽长期中性粒细胞监测可能有利于氯氮平的长期使用优势，包括延长预期寿命，而不会带来氯氮平诱导的粒细胞缺乏症无法承受的风险。
Northwell Health 和 Sigrid Jusèlius 基金会。
