Off-label use of antipsychotic medication in people with intellectual disabilities
Ramerman, Lotte
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Ramerman, L. (2019). Off-label use of antipsychotic medication in people with intellectual disabilities:
adherence to guidelines, long-term effectiveness, and effects on quality of life. Rijksuniversiteit Groningen.
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Is risperidone effective in
reducing challenging behaviours
in individuals with intellectual
disabilities after one year or
longer use? A placebo-controlled,
randomised, double-blind
discontinuation study
Lotte Ramerman, MSc,
Gerda de Kuijper, MD, PhD
Tom F.H. Scheers, MD
Marianne Vink, MD
Paul Vrijmoeth, MD,
Pieter J. Hoekstra, MD, PhD
Accepted in the Journal of Intellectual Disabilities Research 2019
CHAPTER 6
Abstract
BackgroundMany people with intellectual disabilities use risperidone long-term for the management of challenging behaviours, despite its limited proof of effectiveness and its clear association with adverse events. Therefore, this study aimed to investigate the effectiveness of ongoing treatment with risperidone in reducing challenging behaviours versus controlled discontinuation on behaviour and health parameters.
Method
This was a placebo-controlled, double-blind, randomised discontinuation trial of risperidone. In the discontinuation group, risperidone was gradually replaced by a placebo over 14 weeks, while the control group maintained their existing dosage. Eight weeks after discontinuation behaviour (as measured by the “Aberrant Behavior Checklist”) and health parameters (dyskinesia, akathisia, parkinsonism, weight, waist circumference, sedation and laboratory outcomes) were compared in both groups.
Results
A total of 25 participants were included in the trial, of which 11 were randomised into the discontinuation group and 14 were randomised into the continued treatment group. In the discontinuation group, 82% completely withdrew from risperidone. There was no significant change in irritability, compared to the continuation group, although there was a group*time effect on stereotypical behaviour in favour of the continuation group. Significant group*time effects were also found for weight, waist, BMI, prolactin levels and testosterone levels, with beneficial effects for the discontinuation group.
Conclusion
Discontinuation of long-term risperidone for reducing challenging behaviours is possible, without an increase in irritability. Discontinuation of risperidone may have beneficial effects on weight, waist circumference, prolactin levels and testosterone levels. The study suffered from difficulties in achieving the required sample size, which affected study power and generalizability.
Introduction
Risperidone is widely used in people with intellectual disabilities for the management of challenging behaviours, such as aggression, irritability, stereotypic behaviour, or hyperactivity (Poppes, Van der Putten, & Vlaskamp, 2010; Tyrer et al., 2008). Such use for challenging behaviour is almost always off-label; its on-label use for challenging behaviour according to the European Medicines Agency is limited to “the short-term symptomatic treatment (up to 6 weeks) of persistent aggression in conduct disorder in children from the age of 5 years and adolescents with sub-average intellectual functioning or mental retardation diagnosed according to DSM-IV criteria, in whom the severity of aggressive or other disruptive behaviours require pharmacologic treatment”. In practice, however, risperidone is very often used for periods longer than one year (94.3%), while treatment may go up to ten years and over (27%) (Ramerman, de Kuijper, & Hoekstra, 2017).
The effectiveness of risperidone for the short-term management (up to one year) of aggression and disruptive behaviour disorder is backed by several studies (Aman et al., 2002; Amore, Bertelli, Villani, Tamborini, & Rossi, 2011; Gagiano, Read, Thorpe, Eerdekens, & Van Hove, 2005; Reyes, Buitelaar, Toren, Augustyns, & Eerdekens, 2006; Zarcone et al., 2001), albeit one study did not confirm this (Tyrer et al., 2008). Risperidone is, however, heavily associated with adverse metabolic, hormonal and neurological effects (Croonenberghs et al., 2005; Findling et al., 2004). Components of the metabolic syndrome (i.e., too high Body Mass Index, and waist circumference, and disturbed plasma levels of glucose and lipids) are often present in people who use risperidone). Furthermore, risperidone users may also experience neurological side effects, such as extrapyramidal symptoms (dyskinesia, akathisia and parkinsonism), autonomic symptoms and sedation (de Kuijper et al., 2013; Matson & Mahan, 2010).
Open-label discontinuation studies showed that approximately a third can withdraw from antipsychotic drugs after long-term use without deterioration of behaviour (Ahmed et al., 2000; de Kuijper, Evenhuis, Minderaa, & Hoekstra, 2014). Recently, Sheehan and Hassiotis (2016) provided an overview of the current literature on discontinuation of antipsychotic drugs, showing mixed results. At follow-up, between 4-74% could fully discontinue antipsychotic drugs, between 19-83% was maintained on a reduced dosage, and between 0-96% was unsuccessful in reducing antipsychotic drugs (Sheehan & Hassiotis, 2016). Furthermore, a recent pilot placebo-controlled discontinuation trial of off-label risperidone also found that discontinuation is mostly possible, but that the willingness to discontinue risperidone is often hampered by limited availability of alternative (behavioural) interventions to manage challenging behaviour (McNamara et al., 2017).
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In order to create more clarity on the long-term effectiveness of risperidone in reducing challenging behaviours in people with intellectual disabilities, we set up a study comparing ongoing treatment in comparison to controlled discontinuation to placebo. Our study hypothesis was that there would be no differences in behaviour, as measured by the irritability subscale of the Aberrant Behavior Checklist (ABC), between participants with ongoing risperidone use and participants who were tapered-off to placebo.
Methods
Study designThis was a randomised, double-blind, placebo-controlled, five centre discontinuation trial that compared the continued use of risperidone with gradual discontinuation to placebo over 24 weeks. If the clinical condition of a participant necessitated breaking the code, the blind could be broken and the participant stopped further participation in the study. This study has been approved by the Medical Ethical Committee of the University Medical Centre Groningen (METc 2015/171) and registered in The Netherlands National Trial Register (NTR5509).
Participants
Participants (n=25) had used risperidone for challenging behaviour for at least a year and received 24-hour care or supervision from either family or living facilities of intellectual disability care organizations, to enable monitoring of challenging behaviours, side-effects, and the administration of study medication. All had an intellectual disability (registered intelligence quotient <70 or mention of intellectual disability in the medical record) and were aged six years or older. Patients were excluded from the trial if they had a diagnosis of psychosis, schizophrenia or bipolar disorder, or had attempted discontinuation in the last year. Patients who used depot risperidone or risperidone combined with other antipsychotic drugs were also excluded. Participants were recruited for the study between January 4th 2016 and February 28th 2017, through their physicians of the medical services from five different care organizations. These physicians selected eligible participants and provided them and their legal representatives with information on the study, after which informed consent was obtained from the participant or their legal representative. At baseline, data were gathered from the medical records on the presence of mental health conditions (DSM-IV diagnosis), use of other psychotropic drugs and of anticonvulsants.
Intervention
Participants were randomly assigned in a 1:1 ratio to either continued active medication at the same maintenance dose for 24 weeks or to 2 weeks on active study medication followed by
gradual withdrawal to placebo over a 14-week period and 8 weeks of complete placebo. All participants were allowed to use any kind of co-medication or receive any kind of psychosocial interventions if already ongoing before the trial. The study medication was taken at the same time schedule as before the study. The study medication kits consisted of fluid risperidone (1mg/ ml) and placebo matched on colour, smell and taste. One participant, with a baseline dosage of 6 mg, was tapered-off to 5 mg in two steps of 0.5mg, two weeks in between, before starting the usage of the study medication.
Participants received their medication from two bottles: one containing risperidone (bottle A) and one containing either risperidone or placebo (bottle B). The first two weeks only bottle A was used. From week 3 through week 16 participants step-by-step (12.5% every two weeks) changed from bottle A to B. From week 16 to week 24 only bottle B was used, meaning that participants either used their original dosage or were using a placebo. To monitor the adherence to the study medication protocol, a medication diary was used, specifying for each day, per time point, the amount of medication that should be administered from bottle A and bottle B. Every intake had to be signed-off by the person administering the medication and checked and signed by another authorised person.
Outcome measures
At baseline and after 24 weeks (i.e., 8 weeks after complete discontinuation) collection of outcome measures took place. If a participant was de-blinded prematurely, a blinded assessment was collected just before breaking the blind. At 18 weeks after planned de-blinding, the renewed use of antipsychotic drugs was recorded. Additional data collection took place every four weeks during the first 16 weeks, to enable active monitoring of challenging behaviours and side-effects.
Behavioural outcomes
The primary outcome measure of this study was the irritability subscale of the Aberrant Behavior Checklist (ABC), a reliable subscale previously used to measure the effects of antipsychotic drugs on challenging behaviour (Aman, 2012). Additional behavioural outcomes were the other subscales of the ABC, i.e., lethargy, stereotypy, hyperactivity and inadequate speech. The ABC was completed by the main caregiver (parent or direct care staff). In addition, the Clinical Global Impression Scale-Improvement (CGI-I) was completed by the coordinating clinician with regard to changes in challenging behaviour on a 7-point scale (1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, 7 = very much improved).
Health parameters
The main caregiver also completed the Epworth Sleepiness Scale, assessing sedation, a ten-question scale that was slightly adapted to apply to people with intellectual disabilities. Furthermore, a questionnaire was administered, by a trained research assistant on autonomic symptoms: Scale for Outcomes in Parkinson’s disease for Autonomic Symptoms (SCOPA-AUT; autonomic symptoms), that has also been used in our previous antipsychotic drugs discontinuation studies to evaluate these symptoms in people with intellectual disabilities (de Kuijper & Hoekstra, 2018).
Other physical outcomes that were assessed by a trained research assistant, included weight, Body Mass Index (BMI), waist circumference, blood pressure and pulse (measured by an electronic blood pressure device). In addition, laboratory testing was done, including fasting -glucose, -triglycerides, -total cholesterol, -low-density lipoprotein cholesterol and -high-density lipoprotein cholesterol. Endocrine parameters were assessed for prolactin and testosterone (only in boys and men).
Extrapyramidal symptoms were assessed with help of the Abnormal Involuntary Movement Scale (AIMS; dyskinesia), Barnes Akathisia Rating Scale (BARS; akathisia) and the items 20, 21, 22 and 31 of the Unified Parkinson’s Disease Rating Scale (UPDRS; parkinsonism).
Randomisation and blinding
Participants were randomised by blocks of six into the control arm (no discontinuation) or the placebo arm (discontinuation), through a computer-generated randomisation list. Medication kits were linked to randomisation numbers during manufacturing. Every six randomisation numbers, three kits included placebo and three kits only had risperidone. Complete blocks of six were allocated to each of the five organizations. Randomisation was prior to baseline. Randomisation numbers were assigned by the local research physician. The study was blind, so participants, investigators and physicians did not know to which condition the participant was assigned. After 24-weeks all participants were de-blinded, while premature de-blinding was allowed at any time, when necessary.
Sample size calculation
The calculation of the planned sample size was done based on the results of an open-label discontinuation study of antipsychotic drugs by De Kuijper et al. (2014a). Based on the mean change on the irritability subscale (6.5), the standard deviation (8.5), a probability level of 0.05 and a statistical power level of 0.90, a sample size of 86 was required (43 per arm). When an attrition rate of 15% was assumed, a total sample size of 100 participants was necessary (50 per arm).
Statistical analysis
The differences at baseline and week-24 between the discontinuation group and the continuation group were assessed with a mixed model for repeated measures. The continuous outcome measures were used as a dependent variable, with group (discontinuation or continuation)*time point (baseline and 24 weeks) as a fixed-effect. An unstructured covariance matrix was used. Analyses were done following the intention-to-treat principle. That is, data from participants who decided to prematurely stop the discontinuation trial were still included in the analysis using the outcome measures obtained at the time the participant stopped with the trial.
The CGI-I was dichotomised into worsened (very much and much worse) and not worsened (all else). As a sensitivity analysis, the CGI-I was also dichotomised into worsened (very much, much and minimally worse) and not worsened (all else). The dichotomised CGI-I results were analysed between groups (discontinuation and continuation) with a Chi-square test. Differences in baseline characteristics of age, sex, severity of intellectual disability and dosage were analysed by an Independent t-test or a Chi-square test. The significance threshold for all analyses was
p<0.05.
Results
The CONSORT diagram (Figure 1) shows the flow of participants. Of the 238 eligible patients, 25 were included in the study. Reasons for not participating were exclusion by physician, fear of returning challenging behaviours and the possibility of being in the control condition. Eleven participants were allocated to the discontinuation group and fourteen were allocated to the control group. Three participants in the control group (21%) were de-blinded prematurely, due to an increase in challenging behaviours, compared to two in the discontinuation group (18%). All 25 participants were included in the analysis, with the last measurement carried forward for the participants who were de-blinded prematurely.
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Figure 1. Flow chart of participants.
Table 1. presents the baseline characteristics of the discontinuation group and the continuation group. Both groups did not differ significantly on age, sex, severity of intellectual disability and dosage. However, three participants in the discontinuation group had a diagnosis of a mood disorder versus none in the continuation group (χ2= 4.339; p=0.037).
Table 1. Participant characteristics at baseline and during the trial
Characteristics Discontinuation
(n=11) Continued use of risperidone (n=14) t/Pearson χ 2 (p)
Baseline
Age (mean±SD) 33±20.16 (range:
12-67) 28±16.10 (range: 10-68) t=-0.906 (p=0.37) ≤18 years of age (n(%)) 5 (45%) 6 (43%) >18 years of age (n(%)) 6 (55%) 8 (57%)
Sex (n(%)) Male/Female 9 (82%)/2 (18%) 10 (71%)/4 (29%) Pearson χ2=0.37
(p=0.55) Intellectual disability (n(%)) Mild 6 (55%) 7 (50%) Pearson χ2=3.10 (p=0.21) Moderate 1 (9%) 5 (36%) Severe 4 (36%) 2 (14%) profound 0 (0%) 0 (0%) Dosage of risperidone (mean±SD) 1.82mg±1.28 1.97mg±1.14 t=-0.30 (p=0.77) Use of other psychotropic drugs (n(%)) 6 (55%) 6 (43%) Pearson χ2=0.34 (p=0.56) Use of anticonvulsants (n(%)) 0 (0%) 1 (7%) Pearson χ2=0.82 (p=0.37) Presence of mental conditions (n(%)) Autism spectrum disorder 7 (64%) 7 (50%) Pearson χ2=0.47 (p=0.50) Attention-deficit/ hyperactivity disorder 0 (0%) 4 (29%) Pearson χ2=3.74 (p=0.053)
Mood disorder 3 (27%) 0 (0%) Pearson χ2=4.34
(p=0.037)
Anxiety disorder 2 (18%) 0 (0%) Pearson χ2=2.77
(p=0.096) Obsessive-compulsive disorder 1 (9%) 1 (7%) Pearson χ2=0.032 (p=0.86) Attachment disorder 1 (9%) 0 (0%) Pearson χ2=1.33 (p=0.25) During the trial
Visits to physicians (mean±SD) General practitioner 1.00±1.41 1.00±1.11 Pearson χ2=2.00 (p=0.74) Intellectual disability physician 1.10±0.88 0.5±0.85 Pearson χ2=7.69 (p=0.053) Specialist physician other 0.27±0.47 0.36±0.50 Pearson χ2=0.20 (p=0.65)
6
Table 1. Continued
Characteristics Discontinuation
(n=11) Continued use of risperidone (n=14) t/Pearson χ 2 (p) Additional other psychotropic drugs (n(%)) Sertraline 0 (0%) 1 (7%) Oxazepam 2 (18%) 2 (14%) Lorazepam 2 (18%)a 1 (7%) Ritalin 1 (9%) Additional non-pharmacological interventions (n(%)) Restrictive measures 0 (0%) 1 (7%) Structuring daily schedule 1 (9%) 2 (14%) Additional daytime activities 1 (9%) 0 (0%) Different approach to challenging behaviours by support staff 0 (0%) 1 (7%) Orthopaedic shoes 1 (9%) 0 (0%) Dietician 0 (0%) 1 (7%) Speech therapist 0 (0%) 1 (7%)
a In the discontinuation group lorazepam was prescribed for withdrawal dyskinesia.
There was no significant difference between the discontinuation group (82%) and the continuation group (79%) in the number of participants that needed premature de-blinding (Pearson χ2=0.041 (p=0.84)). In the discontinuation group, one participant restarted risperidone
(2 x 0.5mg, 50% of the baseline dosage) after a serious increase in challenging behaviours. The second participant briefly used aripiprazole after an out-of-home placement, but discontinued again before 24 weeks. Three months after de-blinding, 82% of the discontinuation group was still discontinued from risperidone.
The primary outcome, the irritability subscale of the ABC, did not change significantly over time in both groups, nor did most of the other ABC subscales (Table 2). However, we found a significant group*time interaction with regard to the ABC-Stereotypy subscale, indicating a more favourable course for the group on the continued use of risperidone. The CGI-I did show a higher percentage of participants that worsened at 24 weeks in the discontinuation group, but this difference was not significant, neither when defined worsening as very much to much (Pearson
χ2= 2.76 (p=0.097)), nor when defined as very much to minimally (Pearson χ2= 1.55 (p=0.213)).
Table 2. Change in aberrant behaviour ratings in a placebo-controlled discontinuation trial of long-term used risperidone for challenging behaviour in individuals with intellectual disability
Baseline (mean (Cl 95%)) Follow-up (24 weeks) (mean (Cl
95%)) F(p)b Discontinuation (n=11) Continued use of risperidone (n=14) Discontinuation (n=11) Continued use of risperidone (n=14) ABC-Irritabilitya 15.36 (9.68-21.04) 13.57 (8.54-18.61) 14.18 (8.23-20.13) 10.36 (5.08-15.63) 0.759 (p=0.392) ABC-Lethargy 11.73 (5.02-18.44) 11.07 (5.12-17.02) 10.91 (4.44-17.38) 6.86 (1.12-12.60) 0.925 (p=0.345) ABC-Hyperactivity 17.27 (10.44-24.10) 19.14 (13.09-25.20) 15.27 (8.87-21.68) 12.86 (7.18-18.53) 2.100 (p=0.160) ABC-Stereotypy 4.82 (1.32-8.32) 5.29 (2.18-8.39) 8.91 (5.44-12.38) 2.57 (-0.50-5.65) 10.492 (p=0.003) ABC-Inadequate speech 3.64 (1.62-5.65) 4.57 (2.78-6.36) 3.18 (1.11-5.26) 2.43 (0.59-4.27) 3.527 (p=0.072)
a ABC: Aberrant Behavior Checklist
b F(p) for the Group*time effects by mixed-methods repeated-measures.
None of the extrapyramidal symptoms and SCOPA-AUT ratings had a significant group*time interaction (Table 3). However, in the discontinuation group, there were two participants with severe dyskinesia during the withdrawal of risperidone, versus none in those on continued use of risperidone. These two participants had a score of 8 and 12 at baseline and the scores increased up to 22 and 25 points out of 36-point maximum on the AIMS when they were at their worst. There was a significant time*group interaction for weight, waist circumference and BMI, indicating a more favourable course of these parameters in the discontinuation group (Table 3).
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Table 3. Change in health parameters in a placebo-controlled discontinuation trial of long-term used risperidone for challenging behaviour in individuals with intellectual disability
Baseline (mean (Cl 95%)) Follow-up (24 weeks) (mean (Cl
95%)) F(p)e Discontinuation (n=11) Continued use of risperidone (n=14) Discontinuation (n=11) Continued use of risperidone (n=14) EPS-dyskinesiaa 3.18 (1.09-5.27) 0.93 (-0.96-2.78) 4.46 (1.25-7.66) 1.71 (-1.13-4.55) 0.21 (p=0.650) EPS-akathisia 1.36 (0.41-2.32) 0.79 (-0.06-1.63) 1.73 (0.43-3.03) 0.93 (-0.22-2.08) 0.12 (p=0.73) EPS-parkinsonism 1.55 (0.41-2.68) 1.64 (0.63-2.65) 1.27 (0.24-2.31) 1.57 (0.65-2.49) 0.11 (p=0.75) SCOPA-AUT- totalb 28.6 (24.6-32.7) 29.7 (25.7-33.7) 32.7 (28.1-37.3) 33.0 (28.5-37.5) 0.77 (p=0.52) Waist circumference 87.7 (76.2-99.2) 83.3 (73.0-93.6) 82.26 (71.24-93.29) 82.4 (72.7-92.2) 7.48 (p=0.012) Weight 67.6 (54.2-81.0) 69.9 (58.0-81.7) 61.70 (48.95-74.45) 69.1 (57.8-81.7) 4.39 (p=0.046) BMIc 22.3 (18.5-26.2) 23.1 (19.7-26.5) 20.11 (16.61-23.61) 22.8 (19.7-25.9) 5.27 (p=0.030) Systolic blood pressure 117 (108-126) 115 (107-124) 102.36 (93.27-111.45) 114 (106-122) 9.50 (p=0.005) Diastolic blood pressure 68.1 (61.6-74.5) 70.5 (65.0-76.0) 64.55 (58.31-70.78) 70.2 (64.7-75.7) 0.51 (p=0.48) Sleepinessd 4.09 (1.65-6.53) 3.43 (1.27-5.59) 5.36 (1.69-9.04) 4.07 (0.81-7.33) 0.081 (p=0.79) a EPS= Extrapyramidal symptoms.
b SCOPA-AUT= Scale for Outcomes in Parkinson’s disease for Autonomic Symptoms; Results on the SCOPA-AUT
for each bodily area are added in supplement S1.
c BMI= Body Mass Index
d Sleepiness is measured by the ESS (Epworth Sleepiness Scale) e F(p) for the Group*time effects by mixed-methods repeated-measures.
A significant time*group interaction was found for prolactin and testosterone (Table 4). The discontinuation group had a significantly lowered level of prolactin, while the levels of prolactin remained unchanged in the continuation group.
Table 4. Change in laboratory parameters in a placebo-controlled discontinuation trial of long-term used risperidone for challenging behaviour in individuals with intellectual disability
Baseline (mean (Cl 95%)) Follow-up (24 weeks) (mean (Cl
95%)) Discontinuation (n=8) Continued use of risperidone (n=11) Discontinuation (n=8) Continued use of risperidone (n=11) F(p)c Glucose (mmol/l) 6.16 (5.65-6.68) 5.38 (4.81-5.95) 5.67 (5.13-6.22) 5.35 (4.72-5.98) 1.10 (p=0.31) Total cholesterol (mmol/l) 4.30 (3.79-4.81) 3.96 (3.39-4.52) 3.86 (3.39-4.32) 3.93 (3.41-4.45) 2.76 (p=0.11) LDL cholesterol (mmol/l)a 2.56 (2.11-3.00) 2.39 (1.90-2.88) 2.18 (1.79-2.57) 2.22 (1.78-2.66) 0.829 (p=0.38) HDL cholesterol (mmol/l)b 1.40 (1.21-1.59) 1.27 (1.06-1.48) 1.28 (1.08-1.48) 1.20 (0.98-1.43) 0.273 (p=0.61) Triglycerides (mmol/l) 1.05 (0.82-1.29) 0.96 (0.70-1.22) 1.05 (0.80-1.30) 1.01 (0.73-1.29) 0.202 (p=0.66) Prolactin (mU/l) 738 (532-944) 629 (390-867) 327 (144-509) 626 (417-835) 9.57 (p=0.007) Testosterone (nmol/l) 7.45 (4.77-11.8) 9.65 (4.76-14.5) 10.6 (4.77-16.43) 9.48 (2.92-16.0) 4.57 (p=0.048)
a LDL= low-density lipoprotein cholesterol b HDL= high-density lipoprotein cholesterol
c F(p) for the Group*time effects by mixed-methods repeated-measures.
Discussion
By means of a placebo-controlled, double-blind, randomised discontinuation trial, we aimed to study the influence of risperidone on reducing challenging behaviours in people with intellectual disabilities after at least one year of treatment. Without an increase in the primary outcome, irritable behaviours, 82% of the discontinuation group successfully withdrew from risperidone. However, stereotypical behaviours followed a more favourable course in the continuation group. Furthermore, the results of this study showed clear health benefits of discontinuing risperidone. The clinically important results that we found, should be considered in light of the main limitations of this study: the small sample size and the heterogeneity of the sample. The small sample size and heterogeneity of the sample resulted in limited power and generalizability. The complexity of the design and a fear for the reoccurrence of challenging behaviours made the recruitment difficult and warranted a pragmatic approach, resulting in a heterogeneous sample, including a wide age range and wide range in severity of intellectual disabilities. Furthermore,
there was a pre-selection by physicians that may have resulted in a selection bias. Last, the study reports on data shortly after discontinuation (8 weeks) and three months after de-blinding. We, therefore, cannot draw generalizable conclusions on remaining off-medication for a longer period of time.
McNamara et al. (2017) also experienced difficulties in achieving the required sample size in a similar study, finding that a lack of guidelines on discontinuing antipsychotic drugs may create reservations among physicians to attempt withdrawal (McNamara et al., 2017). Even though there are several initiatives in the Netherlands and abroad to decrease the inappropriate use of psychotropic drugs, reservations against withdrawal persist (de Kuijper & Hoekstra, 2017). To provide an evidence-base for the appropriate use of risperidone, studies like the present are necessary. In future studies, we would consider approaching a larger (international) population, setting a longer recruitment period to improve the recruitment of such a trial.
Our results are partly in line with a recent study that also found that discontinuation of risperidone was often possible, but that a slight increase in challenging behaviours may occur (McNamara et al., 2017). In contrast, a previous open-label study found that the participants, who successfully discontinued, improved on their challenging behaviours (de Kuijper et al., 2014; de Kuijper & Hoekstra, 2018). Furthermore, the results after long-term use seem to differ from the effects of discontinuation of risperidone after short-term use, where a higher reoccurrence of symptoms of challenging behaviours was found in the group that discontinued, compared to the maintenance group (Reyes et al., 2006; Troost et al., 2005). Clinicians observed a worsening in challenging behaviours in 40% of the discontinuation group, as scored on the CGI-I. Although this did not differ significantly from the control group, it does suggest that discontinuation of risperidone results in some increase in challenging behaviours.
Eight weeks after full discontinuation, favourable results were found for the discontinuation group on average weight, BMI and waist circumference. The weight loss of almost 6 kg corresponds with the average weight gain found after starting treatment with risperidone (Hellings, Zarcone, Crandall, Wallace, & Schroeder, 2001) and is in line with the effects of open-label discontinuation of antipsychotics that we previously found (de Kuijper, Mulder, Evenhuis, Visser, & Hoekstra, 2013). These results indicate clear health benefits associated with discontinuing risperidone.
The effects of discontinuation on prolactin and testosterone levels were also clearly apparent. After discontinuation, mean prolactin levels declined to close to the normal range again (<300 mmol/l). Discontinuation of risperidone also had a favourable effect on testosterone levels in males. The effects of discontinuation on prolactin levels and the concurrent effects on
testosterone levels were also found in a previous study (de Kuijper, Mulder, Evenhuis, Visser, & Hoekstra, 2014). The effect of discontinuation on decreasing prolactin levels were in line with the magnitude of increases in prolactin levels after starting risperidone (Hellings et al., 2005). Two of the 11 participants showed clear withdrawal-related dyskinesia. Previous trials of risperidone in children and adolescents showed comparable numbers of withdrawal dyskinesia of two out of thirteen (Malone, Maislin, Choudhury, Gifford, & Delaney, 2002; Nagaraj, Singhi, & Malhi, 2006). Thus, dyskinesia is relatively frequently seen when discontinuing risperidone but is most often a temporary phenomenon.
In conclusion, this study adds to the knowledge indicating that discontinuation of risperidone is possible after long-term use; although continued use of risperidone produced more favourable results with regard to the course of stereotypical behaviours, shortly after discontinuation. The health benefits of discontinuing risperidone were clear in this study: favourable outcomes were found for weight, waist circumference and BMI in the discontinuation group, compared to the continuation group Furthermore, there were beneficial effects on prolactin and testosterone levels. The difficulties in recruitment that we encountered in this study also provide important suggestions for the implementation of future randomised controlled trials in the care for people with intellectual disabilities, such as recruitment strategies. Although this study had some limitations, it does add to the literature that suggests that discontinuation of risperidone should be considered by clinicians, especially in light of the health benefits and the limited effects of discontinuation on challenging behaviours.
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Supplement S1. Change in SCOPA-AUTa parameters in a placebo-controlled discontinuation trial of
long-term used risperidone for challenging behaviour in individuals with intellectual disability
Baseline (mean (Cl 95%)) Follow-up (24 weeks) (mean (Cl 95%))
Discontinuation
(n=11) Continued use of risperidone (n=14)
Discontinuation
(n=11) Continued use of risperidone (n=14) SCOPA-AUT- Dysphagia 5.64 (4.40-6.88) 5.57 (4.47-6.67) 6.73 (5.39-8.06) 5.36 (4.18-6.54) SCOPA-AUT-gastrointestinal problems 4.55 (3.37-5.72) 3.93 (2.89-4.97) 4.55 (3.48-5.61) 4.21 (3.27-5.16) SCOPA-AUT- urinary problems 11.6 (9.33-14.0) 9.86 (7.82-11.90) 10.8 (8.02-13.6) 9.50 (7.02-12.0) SCOPA-AUT- dizziness 3.73 (3.27-4.18) 3.36 (2.95-3.76) 3.64 (3.08-4.19) 3.43 (2.94-3.92) SCOPA-AUT-temperature dysregulation 5.91 (4.49-7.33) 5.43 (4.17-6.69) 5.64 (4.63-6.65) 4.50 (3.61-5.40) SCOPA-AUT- pupillary adaptive functioning 1.55 (0.935-2.16) 1.57 (1.03-2.11) 1.36 (0.76-1.97) 1.64 (1.11-2.18)
a SCOPA-AUT= Scale for Outcomes in Parkinson’s disease for Autonomic Symptoms
