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

Introduction

Clozapine and risperidone are atypical antipsychotic agents originally developed in 1959 and 1992, respectively, and are used to treat several neurological disorders, including schizophrenia.1 Both are potent antagonists of a wide range of neuroreceptors, including dopamine and serotonin receptors,1 2 and recent studies indicate that these agents have anti-inflammatory actions on microglia.3 4 Given the known role for neuroinflammation in schizophrenia,5–7 it is now believed that this class of agents may provide superior benefits during schizophrenia due to their immune-modulatory activity in the central nervous system (CNS).5 6 8–10

Previous work has shown that clozapine and risperidone reduce disease severity and improve disease resolution in mouse models of multiple sclerosis (MS) including experimental autoimmune encephalomyelitis, a model of immune-mediated demyelination that recapitulates aspects of relapsing-remitting MS, and cuprizone intoxication, a model of non-immune demyelination, which models aspects of progressive multiple sclerosis (pMS).11–13 Protection correlates with reduced CNS inflammation and enhanced functional recovery, and can be achieved at doses that do not promote weight gain, a dose-dependent side effect of both clozapine and risperidone.12 13 Together, this preclinical work suggests that clozapine and risperidone, which readily pass through an intact blood–brain barrier and reduce neuroinflammation in mice and humans,1 may be useful to treat the chronic neuroinflammation and demyelination associated with pMS in contrast to current disease-modifying treatments which target peripheral immune responses but not those restricted to the CNS compartment.14–16

To this end, the Clozapine and Risperidone in Progressive Multiple Sclerosis (CRISP) trial was designed to investigate the suitability of clozapine and risperidone treatment for people with pMS. Although there have been several case reports describing the successful use of risperidone or clozapine in patients with MS to treat psychosis,17 18 this was the first trial of clozapine or risperidone in humans to treat MS itself. The primary aim of this study was to determine if doses of 100–150 mg of clozapine and 2.0–3.5 mg of risperidone are safe and well tolerated in patients with pMS.

Methods

Results

Between 8 April 2016 and 8 September 2017, 55 people were identified through visits to the Neurology Clinics at Wellington Hospital, hospital databases, regional MS societies and volunteer recruitment adverts. Of these, 12 were screened at Wellington Hospital for eligibility, and 9 were enrolled into the CRISP trial and randomly allocated to a treatment arm (figure 1). There were no significant differences in the baseline clinical parameters between the treatment groups (table 1), although a significant elevation in WBC and neutrophils (clozapine, p<0.001) and WBC (risperidone, p<0.01) compared with placebo was found (online supplementary table S1).

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Three participants (33%) completed the trial as per protocol, while six participants (67%) were withdrawn from the trial; four of whom were withdrawn within the first 2 weeks. Due to the high number of participants withdrawn from the trial, after completion of enrolment of the first block of nine participants, recruitment was halted for an interim analysis to assess safety (number and rate of adverse event (AE)/serious adverse event (SAE)) and acceptability (Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9)). We used number of the days on trial to compare the total time in the study between each treatment and placebo. The participants who completed the trial (ie, not withdrawn) were entered as censored observations in the Kaplan-Meier analysis (figure 2A). We found a significant difference in the time on trial between the groups (p=0.03, P vs C; and p=0.025, P vs R) with a mean time of 8±1 days for participants receiving clozapine and 94±41 days for risperidone compared with 178±3 days for placebo (figure 2B). Because the doses of the study medications were titrated during the first 2 weeks when four participants were withdrawn, we compared the per cent of the final study medication dose (figure 2C), which indicated that participants in the clozapine group received 23%±10% of the final dose or 35±15 mg/day, while those in the risperidone group received 81%±33% or 2.8±1.2 mg/day. A comparison of selected baseline parameters between those withdrawn (n=6) and those who completed the trial (n=3) revealed a higher white blood cell (WBC) count in those withdrawn (p=0.048 by Wilcoxon test) but no other significant differences (online supplementary table S2).

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The rate of all AEs was significantly higher (p=0.00001 by Fisher’s exact test) in both clozapine and risperidone groups (37.5 and 11.0/100 person-days, respectively) compared with placebo (2.43/100 person-days, table 2). The most common AEs (≥3 occurrences) assigned a possible, probable or likely treatment association were drowsiness, dry mouth, dry eyes, muscle weakness, falls and increased prolactin (online supplementary table S3). Only three SAEs occurred over the whole course of the trial, and no significant differences were found in the rate between treatment groups. One participant receiving risperidone was hospitalised due to rapidly progressing MS. The other two SAEs resulted from a participant in the placebo group who broke her right wrist and left clavicle in a motor vehicle accident (table 2).

For those participants who completed at least 3 months of treatment (n=3, placebo, and n=2, risperidone), no difference in treatment acceptability was found in any of the three domains (efficacy, convenience and global satisfaction) assessed by the TSQM-9 (table 3). Additionally, after 3 months of treatment, there were no significant changes from baseline parameters, including bodyweight, body mass index, Expanded Disability Status Scale (EDSS), Functional System Score (FSS), Multiple Sclerosis Functional Composite (MSFC), WBC, neutrophils, TropT, and CRP except for an elevation in serum prolactin in the risperidone group as expected (table 4; online supplementary figure S1).24

Discussion

This study is the first report of the use of clozapine and risperidone to treat pMS and revealed an unexpected sensitivity in this population to clozapine and, to a lesser extent, risperidone. Specifically, all participants receiving active treatment were withdrawn from the study with the clozapine-treated group averaging only 8 days while the risperidone-treated participants remained in the trial for an average of ninety-four days. In comparison, all participants in the placebo group completed the trial as per protocol. The decreased time in trial was associated with an increased rate of AE but not SAE with the key AE being dry mouth, drowsiness, dry eyes, muscle weakness, and falls. This increased sensitivity to clozapine as well as risperidone in people with pMS is particularly unexpected given that the doses administered were exceptionally low for clozapine (35 mg/day at study termination) and moderate to low for risperidone (2.8 mg/day).21 25–27

When initiating atypical anti-psychotic treatment, a slow titration is recommended over a 2 week period until the therapeutic dose is reached.19 28 For schizophrenia, this dose is 350–400 mg/day for clozapine and 2–6 mg/day for risperidone.25 26 The titration allows a slow tolerisation to the drug and reduces side effects.1 For clozapine, a dose of 12.5 mg/day is recommended for the first dose when used for schizophrenia or Parkinson’s disease.19 In contrast, the starting clozapine dose in the CRISP trial was 5 mg/day allowing a very slow and conservative titration up to the target dose (100 mg/day) for the first 3 months. Despite the low dose, AEs occurred by day 3, equating to 15 mg/day, and participants were withdrawn at a mean dose of 35 mg/day. While 7.1% to 15.6% of patients may be withdrawn from clozapine due to AEs,21 this is the first report of a categorical sensitivity to clozapine at extremely low doses by a cohort of individuals.

During clozapine titration, a common AE is orthostatic hypotension, and this hypotension occurs even at a dose of 12.5 mg/day.29 Although we did not test specifically for orthostatic hypotension due to the progressive MS disability, no effect on blood pressure was detected at any time during the 4 hour monitoring period post-doses one and two of clozapine (online supplementary figure S2). In addition to the initial orthostatic hypotension, the most common AE occurring in more than one in ten patients administered clozapine are weight gain, drowsiness, sedation, dizziness, tachycardia, constipation, and hypersalivation.25 29 For the CRISP participants, all three patients allocated to clozapine developed a similar syndrome with lower limb weakness alone in one, lower limb weakness and poor balance in the second, and drowsiness followed by poor balance in the third. In the first two, it began at day five (35 mg) and worsened over 4 days (35–50 mg) until they could no longer walk. The third noted drowsiness after the third dose (15 mg) and unsteadiness the following day after 20 mg. Medication was stopped. She was worse the following day with a fizzy feeling in her fingers, an exacerbation of a pre-existing symptom, but recovered a day later. Rechallenge with a lower dose produced identical symptoms. In all three cases, the symptoms wore off within 48 hours and resembled an intoxication. Their EDSS scores at study entry were 6.5, 6.5, and 5.5, respectively. These observations suggest that patients with advanced MS with cerebellar and pyramidal tract dysfunction may be unusually susceptible to intoxication by clozapine.

Galletly reported five patients with schizophrenia, one of whom also had muscular dystrophy, who reported an unpleasant sensation of weakness and reduced muscle tone during treatment with doses of clozapine between 100 and 500 mg/day.30 The patients complained of a feeling of weakness, difficulty walking and one also of imbalance more severe at night. There was no objective weakness or gait disturbance. Objective sedation and subjective asthenia, a sense of fatigue, are reported in about 30% of patients treated with clozapine.31 Galletly commented on the difficulty distinguishing the effects of these entities.30 Clozapine is a dibenzodiazepine reported to have muscle relaxant properties in animal studies.32 Galletly proposed that the patient experiences resulted from muscle relaxation and hypotonia, rather than from sedation.30 Our patients all had high EDSS, and quite a severe degree of spasticity and lower limb ataxia. They developed intolerable symptoms of weakness, and varying degrees of imbalance, and sedation similar to those reported by Galletly, although at a much lower dose. We suggest that the most likely cause of our patients’ adverse reactions were because they were much more susceptible to the central effects of clozapine, likely including those on muscle tone.

Although two participants experienced few AEs during the risperidone titration period, one participant experienced rashes after the first dose, treatment was halted, and then rechallenged 1 week later. However, the participant was unable to tolerate risperidone and was withdrawn. Adverse cutaneous reactions occur in 2%–5% of individuals treated with psychiatric medications including atypical antipsychotics and predominantly occur within the first 2 weeks.33 34 Exanthematous rashes have been associated with risperidone and resolve after discontinuing treatment.35

Other AE experienced by the risperidone-treated group included dry mouth, dry eyes, muscle weakness, falls and increased prolactin. Whereas dry eyes and dry mouth are common (1%–10%) AEs, muscle weakness is far less common (0.1%–1%). Risperidone is associated with elevated serum prolactin and by 3 months, the risperidone group had elevated levels of prolactin as expected.24 While there were a high number of falls in the risperidone-treated group, most (12 of the 13) occurred in one participant, whose MS was deteriorating relatively rapidly over months and who was barely able to walk at the time of recruitment. These falls were not initially classified as having a possible association with risperidone treatment. Interestingly, one side effect that was not observed in the risperidone group was weight gain, which has been reported in one study to occur in 58.4% of patients after 3 months (>7% gain).26 36

In conclusion, we report an increased sensitivity to clozapine and risperidone in a pMS cohort. Furthermore, the sensitivity is striking in that (1) it occurred at very low doses for clozapine and (2) the adverse reaction pattern was different from expected with no occurrence of hypotension or weight gain and increased reports of muscle weakness and falls. However, despite having statistically significant findings, this study has limitations that need to be considered, the most important of which is the very low number of participants in each treatment group. Although possible that our findings are within the expected AE pattern, the categorical early withdrawal of all participants from the active arms provides strength to our conclusions.21 An additional limitation is that with the unexpected withdrawal of 44% of the participants within the first 2 weeks, no samples were collected to confirm the serum levels of the study medication in these subjects. Finally, because this study was not powered to assess efficacy, the potential of these two atypical antipsychotics to treat the neuroinflammation associated with pMS, was not evaluated. However, current studies are underway to assess the safety and tolerability of quetiapine (300 mg daily), a clozapine analogue, as a remyelinating therapy in MS.37 38 Given the results of our trial using low doses of clozapine, our findings suggest that it may not be appropriate to administer either clozapine or risperidone in the same manner during pMS as during schizophrenia or the other neurological disorders for which they are indicated.