Objective Because clozapine and risperidone have been shown to reduce neuroinflammation in humans and mice, the Clozapine and Risperidone in Progressive Multiple Sclerosis (CRISP) trial was conducted to determine whether clozapine and risperidone are suitable for progressive multiple sclerosis (pMS). Methods The CRISP trial (ACTRN12616000178448) was a blinded, randomised, placebo-controlled trial with three parallel arms (n=12/arm). Participants with pMS were randomised to clozapine (100–150 mg/day), risperidone (2.0–3.5 mg/day) or placebo for 6 months. The primary outcome measures were safety (adverse events (AEs)/serious adverse events (SAE)) and acceptability (Treatment Satisfaction Questionnaire for Medication-9). Results An interim analysis (n=9) revealed significant differences in the time-on-trial between treatment groups and placebo (p=0.030 and 0.025, clozapine and risperidone, respectively) with all participants receiving clozapine being withdrawn during the titration period (mean dose=35±15 mg/day). Participants receiving clozapine or risperidone reported a significantly higher rate of AEs than placebo (p=0.00001) but not SAEs. Specifically, low doses of clozapine appeared to cause an acute and dose-related intoxicant effect in patients with pMS who had fairly severe chronic spastic ataxic gait and worsening over all mobility, which resolved on drug cessation. Interpretation The CRISP trial results suggest that patients with pMS may experience increased sensitivity to clozapine and risperidone and indicate that the dose and/or titration schedule developed for schizophrenia may not be suitable for pMS. While these findings do not negate the potential of these drugs to reduce multiple sclerosis-associated neuroinflammation, they highlight the need for further research to understand the pharmacodynamic profile and effect of clozapine and risperidone in patients with pMS. Trial registration number ACTRN12616000178448.

中文翻译：

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氯氮平和利培酮在进行性多发性硬化症中的安全性和可接受性：I 期、随机、盲法、安慰剂对照试验

目的 因为氯氮平和利培酮已被证明可以减少人和小鼠的神经炎症，所以进行了氯氮平和利培酮在进行性多发性硬化症（CRISP）中的试验，以确定氯氮平和利培酮是否适用于进行性多发性硬化症（pMS）。方法 CRISP 试验 (ACTRN12616000178448) 是一项盲法、随机、安慰剂对照试验，具有三个平行组 (n=12/组)。患有 pMS 的参与者被随机分配到氯氮平（100-150 毫克/天）、利培酮（2.0-3.5 毫克/天）或安慰剂组，为期 6 个月。主要结局指标是安全性（不良事件 (AE)/严重不良事件 (SAE)）和可接受性（药物治疗满意度问卷 9）。结果 中期分析 (n=9) 显示治疗组和安慰剂之间的试验时间存在显着差异 (p=0. 030 和 0.025，分别为氯氮平和利培酮），所有接受氯氮平的参与者在滴定期间都被停用（平均剂量 = 35±15 毫克/天）。接受氯氮平或利培酮的参与者报告的 AE 发生率显着高于安慰剂（p = 0.00001），但没有 SAE。具体来说，低剂量的氯氮平似乎会在患有相当严重的慢性痉挛性共济失调步态和所有活动能力恶化的 pMS 患者中引起急性和剂量相关的中毒作用，这种情况在停药后得到解决。解释 CRISP 试验结果表明 pMS 患者可能对氯氮平和利培酮的敏感性增加，并表明为精神分裂症制定的剂量和/或滴定方案可能不适用于 pMS。虽然这些发现并没有否定这些药物减少多发性硬化症相关神经炎症的潜力，但它们强调需要进一步研究以了解氯氮平和利培酮对 pMS 患者的药效学特征和作用。试用注册号 ACTRN12616000178448。