Background

Clozapine is uniquely effective in treatment-resistant psychosis. In the UK, patients must discontinue clozapine indefinitely if they are placed on the Central Non-Rechallenge Database (CNRD) after their haematological parameters fall below particular thresholds. Under exceptional circumstances, patients can be rechallenged on clozapine under an off-licence agreement. In the USA in 2015, restrictive practice was discontinued to allow greater flexibility for clozapine maintenance. The absolute neutrophil count leading to treatment interruption was lowered from less than 1·5 × 10⁹/L to less than 1·0 × 10⁹/L and platelet and white cell count monitoring were ceased. We aimed to investigate the implications of a similar policy change on clozapine use in the UK.

Methods

This was a modelling study of all patients registered on the UK CNRD. First, we determined the proportion of patients placed on the database in the UK who would have had to discontinue clozapine treatment under the US Food and Drug Administration (FDA) criteria. Second, we compared the haematological characteristics of patients who did or did not meet FDA criteria for discontinuing clozapine, including the time to registration from clozapine initiation and the proportion of cases of severe neutropenia at registration. Third, we investigated the success rates of clozapine re-challenge for patients that had been placed on the CNRD. Successful rechallenge was defined as no recurrence of CNRD registration.

Findings

Between May 2, 2002 and March 1, 2021, 3731 patients were placed on the CNRD, with a mean age of 47 years (SD 15), including 1420 (38%) women and 2311 (62%) men, of whom 3089 (83%) were White, 360 (10%) were Black, 190 (5%) were Asian, and 92 (2%) were classified as other. 566 (15%) of 3731 patients met the equivalent criteria for clozapine discontinuation under the FDA guidelines. The median time to CNRD registration from clozapine initiation was 1·6 years (IQR 0·2–4·9). Data for 519 rechallenged patients were examined; 419 (81%) were successful. Clozapine rechallenge success rates were broadly similar between individuals who did not meet the US CNRD registration criteria (36 [78%] of 46) and those who did meet the criteria (383 [81%] of 473).

Interpretation

Implementing the revised FDA monitoring criteria in the UK would substantially reduce clozapine discontinuation for haematological reasons, which would greatly improve the mental health outcomes of these patients without having a major effect on their physical health.

Funding

None.

中文翻译：

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放宽进入 UK Clozapine Central Non-Rechallenge Database 的标准：一项建模研究

背景

氯氮平对难治性精神病具有独特的疗效。在英国，如果患者在血液学参数低于特定阈值后被列入中央非再挑战数据库 (CNRD)，则必须无限期停用氯氮平。在特殊情况下，患者可以根据非许可协议重新接受氯氮平治疗。2015 年，美国停止了限制性做法，以提高氯氮平维持的灵活性。导致治疗中断的中性粒细胞绝对计数从小于1·5 × 10 ⁹ /L 降至小于1·0 × 10 ⁹ /L，停止血小板和白细胞计数监测。我们旨在调查类似政策变化对英国氯氮平使用的影响。

方法

这是对在英国 CNRD 注册的所有患者的建模研究。首先，我们确定了英国数据库中根据美国食品和药物管理局 (FDA) 标准必须停止氯氮平治疗的患者比例。其次，我们比较了符合或不符合 FDA 停用氯氮平标准的患者的血液学特征，包括从开始使用氯氮平到注册的时间以及注册时严重中性粒细胞减少症病例的比例。第三，我们调查了接受 CNRD 的患者再次使用氯氮平的成功率。成功的再挑战被定义为 CNRD 注册没有复发。

发现

在 2002 年 5 月 2 日至 2021 年 3 月 1 日期间，3731 名患者被纳入 CNRD，平均年龄为 47 岁（SD 15），其中包括 1420 名（38%）女性和 2311 名（62%）男性，其中 3089 名（ 83%) 是白人，360 (10%) 是黑人，190 (5%) 是亚洲人，92 (2%) 被归类为其他。根据 FDA 指南，3731 名患者中有 566 名（15%）符合停用氯氮平的同等标准。从开始使用氯氮平到注册 CNRD 的中位时间为 1·6 年（IQR 0·2-4·9）。检查了 519 名再次受到挑战的患者的数据；419 (81%) 人成功。不符合美国 CNRD 注册标准的人（46 人中的 36 人 [78%]）和符合标准的人（473 人中的 383 人 [81%]）之间的氯氮平再激发成功率大致相似。

解释

在英国实施修订后的 FDA 监测标准将大大减少因血液学原因而停用氯氮平的情况，这将大大改善这些患者的心理健康结果，而不会对他们的身体健康产生重大影响。

资金

没有任何。