Hiltgen S, Mantelet S, Pinabel F, Enjaume F
Hôpital Maison-Blanche-Avron, 27e secteur, Service du Dr Monduit de Caussade, 129, rue d'Avron, 75020 Paris.
Encephale. 2006 Oct;32(5 Pt 1):688-96. doi: 10.1016/s0013-7006(06)76220-0.
Clozapine, synthesized in the sixties, is an atypical antipsychotic drug whose history has been marked by its haematological toxicity. The purpose of this study was, ten years after it had been replaced at French psychiatrists' disposal, to gather data on the prescription modalities of clozapine, assess whether some factors could affect its efficacy, and describe the population of schizophrenic patients concerned.
Psychiatrists in the Paris region were asked to answer a questionnaire about their patients treated with clozapine. The information collected was about socio-demographic data, history of psychiatric disorder and the way clozapine was used. It was a retrospective study concerning 98 patients.
Subjects were 57 men and 41 women, with a mean age of 38 years. The majority of patients came from metropolitan France. Patients suffered from various clinical subtypes of schizophrenia, as assessed according to DSM IV criteria. Predominant symptomatology during lifetime was most often auditory hallucinations (41%). Mean duration of lifetime neuroleptic treatment was 10.3 years and breaks in follow-up were rare. Mean number of hospitalisations was 6.9 and a little less than half of the patients had been committed involuntarily. Lastly, 38% of patients had attempted suicide at least once and 35% had expressed hetero-agressive behavior. Main indication of clozapine was resistant schizophrenia (88.5% of patients) and mean duration of treatment was 2 years and 4 months. Treatment efficacy was assessed as good or medium in 77.9% of patients, at mean doses (322 mg per day) in keeping with data from the literature. Tolerance was considered on the whole as satisfactory by half of the clinicians. Among the 98 patients of the study, 21.6% had stopped taking clozapine. The reasons for withdrawal were: inefficacy (6.2%), granulopenia (5.2%), epilepsy (1%) and 8.2% for various reasons (half of these cases being non-compliance with treatment). The study of the 5 cases of granulopenia showed that 3 patients had another associated psychotropic medication: 1 patient received only clozapine as monotherapy, 1 data was missing. Two thirds of all patients were receiving another psychotropic drug in association with clozapine, mainly benzodiazepines (18.4%), antidepressants (15.3%) or mood stabilizers (7.1%). The "therapeutic efficacy" variable was compared with some variables in order to isolate factors possibly associated with a better efficacy of clozapine or, on the contrary, with a population of patients poorly responding to treatment. However, no statistically significant difference appeared according to the variables studied, such as gender or lifetime duration of neuroleptic treatment. Moreover, there was no statistically significant difference in efficacy according to schizophrenia subtype, main symptomatology during the course of illness or substance abuse. We studied whether any factor could affect the occurrence of granulopenia. No statistically significant difference was found. The mean age of patients having stopped the treatment because of granulopenia was higher than in the group with other reasons for interruption, but did not reach statistical significance. A trend also appeared towards female predominance (60% of women in the granulopenia group) and 3/4 of patients who had stopped their treatment because of agranulocytosis received another psychotropic drug in association with clozapine.
As expected, the main indication for prescribing clozapine was resistant schizophrenia, but contrary to data from the international literature, the efficacy profile was the same whatever the clinical subtype of schizophrenia. The tolerance to clozapine was considered on the whole as satisfactory, but the high proportion of granulopenias leading to treatment withdrawal (5.2% of patients) confirms the need to remain cautious and stresses the importance of regular haematological monitoring. Furthermore, the study of the prescription modalities of clozapine shows that contrary to the guidelines, clozapine is often associated with other psychotropic drugs. In this study, it is striking to note that 75% of granulopenias occurred in a coprescription situation.
氯氮平于20世纪60年代合成，是一种非典型抗精神病药物，其历史一直伴随着血液学毒性。本研究的目的是，在法国精神科医生可使用氯氮平十年后，收集有关氯氮平处方方式的数据，评估某些因素是否会影响其疗效，并描述相关精神分裂症患者群体。
要求巴黎地区的精神科医生回答一份关于其使用氯氮平治疗患者的问卷。收集的信息包括社会人口统计学数据、精神疾病史以及氯氮平的使用方式。这是一项针对98名患者的回顾性研究。
受试者中男性57名，女性41名，平均年龄38岁。大多数患者来自法国本土。根据《精神疾病诊断与统计手册》第四版标准评估，患者患有精神分裂症的各种临床亚型。一生中最常见的主要症状是幻听（41%）。一生中抗精神病药物治疗的平均时长为10.3年，随访中断情况罕见。平均住院次数为6.9次，略少于一半的患者曾被非自愿收治。最后，38%的患者至少尝试过一次自杀，35%的患者表现出过攻击他人的行为。氯氮平的主要适应证是难治性精神分裂症（88.5%的患者），平均治疗时长为2年4个月。77.9%的患者治疗效果评估为良好或中等，平均剂量（每日322毫克）与文献数据相符。一半的临床医生总体认为耐受性令人满意。在该研究的98名患者中，21.6%的患者停止服用氯氮平。停药原因包括：无效（6.2%）、粒细胞缺乏症（5.2%）、癫痫（1%）以及因各种原因停药（其中一半病例为治疗依从性差）（8.2%）。对5例粒细胞缺乏症病例的研究表明，3例患者同时使用了另一种精神药物：1例患者仅接受氯氮平单一疗法，1例数据缺失。所有患者中有三分之二在服用氯氮平的同时还使用了另一种精神药物，主要是苯二氮䓬类药物（18.4%）、抗抑郁药（15.3%）或心境稳定剂（7.1%）。将“治疗效果”变量与一些变量进行比较，以找出可能与氯氮平更好疗效相关的因素，或者相反，与对治疗反应不佳的患者群体相关的因素。然而，根据所研究的变量，如性别或一生中抗精神病药物治疗时长，未出现统计学上的显著差异。此外，根据精神分裂症亚型、病程中的主要症状或药物滥用情况，疗效也没有统计学上的显著差异。我们研究了是否有任何因素会影响粒细胞缺乏症的发生。未发现统计学上的显著差异。因粒细胞缺乏症而停药的患者平均年龄高于因其他原因中断治疗的组，但未达到统计学显著性。还出现了女性占优势的趋势（粒细胞缺乏症组中60%为女性），并且因粒细胞缺乏症而停药的患者中有四分之三在服用氯氮平的同时还使用了另一种精神药物。
正如预期的那样，氯氮平处方的主要适应证是难治性精神分裂症，但与国际文献数据相反，无论精神分裂症的临床亚型如何，疗效情况相同。总体认为氯氮平的耐受性令人满意，但导致停药的粒细胞缺乏症比例较高（5.2%的患者）证实仍需谨慎，并强调定期进行血液学监测的重要性。此外，氯氮平处方方式的研究表明，与指南相反，氯氮平经常与其他精神药物联合使用。在本研究中，值得注意的是，75%的粒细胞缺乏症发生在联合用药的情况下。
