Safety and acceptability of clozapine and risperidone in progressive multiple sclerosis: a phase 1, randomized, blinded, placebo-controlled trial

Abstract

Objective: Because clozapine and risperidone have been shown to reduce neuroinflammation in humans and mice, the 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, randomized, placebo-controlled trial with three parallel arms (n=12/arm). Participants with pMS were randomized to clozapine (100 to 150 mg/day), risperidone (2 to 3.5 mg/day), or placebo for six months. The primary outcome measures were safety (adverse events/serious adverse events) and acceptability (TSQM-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placebo (p=0.030 and 0.025, clozapine and risperidone, respectively) with all participants receiving clozapine being withdrawn during the titration period (mean dose=35±15 mg/day).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 adverse events than placebo (p=0.00001) but not serious adverse events. 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 pMS patients 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 MS-associated neuroinflammation, they highlight the need for further research to understand the pharmacodynamic profile and effect of clozapine and risperidone in pMS patients.

Modulation of monocyte responses by progressive multiple sclerosis therapy.

“…It therefore becomes important to clarify clozapine's effects on DR and cytokine expression. As we undertake a repurposing of clozapine in the MS setting based on its ability to modulated DR signalling, we support this approach with our work to date (La Flamme et al, 2020), and evidence in the literature suggesting the potential benefit of dopaminergic drugs for the treatment of MS (Marino and Cosentino, 2016).…”

“…The CRISP trial (CRISP; Clozapine and Risperidone for the Treatment of Progressive Multiple Sclerosis; ACTRN12616000178448) (La Flamme et al, 2020), was a blinded, randomized, placebo-controlled clinical trial conducted at Wellington Hospital (Wellington, NZ). The trial aimed to assess the safety and suitability of two atypical antipsychotics, clozapine and risperidone, as possible treatments for people with progressive MS.…”

“…The study comprised two cohorts: a progressive MS group (n = 9) and a healthy control group of age-and sex-matched individuals (n = 15). All MS participants were screened and enrolled as previously described (La Flamme et al, 2020;Luckey et al, 2015), and had either primary or secondary progressive disease with no significant confounding comorbidities and were not receiving any disease-modifying therapies.…”

“…Following on from the work in the animal model, our group conducted a small clinical trial to determine the safety of clozapine in patients with progressive MS (La Flamme et al, 2020). The trial outcome concluded that administering clozapine to MS participants based on guidelines for schizophrenia was not suitable for people with progressive MS. All participants were withdrawn from the trial.…”

“…PBMC were collected fresh and stored in liquid nitrogen until use (see Chapter 3). All MS participants were screened and enrolled as previously described (Luckey et al, 2015;La Flamme et al, 2020), and had either primary or secondary progressive disease with no significant confounding comorbidities and were not receiving any disease-modifying therapies. Subjects selected were from two clinical trial cohorts: the CRISP trial, which included healthy individuals and progressive MS (n = 9/group), and the MIS416 Phase 2b trial, which included only secondary progressive MS (n = 18 selected) (see 3.3.1, demographic data).…”