University of Groningen
Off-label use of antipsychotic medication in people with intellectual disabilities
Ramerman, Lotte
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Changes in health-related quality
of life in people with intellectual
disabilities who discontinue
long-term used antipsychotic drugs for
challenging behaviours
Lotte Ramerman, MSc
Pieter J. Hoekstra, MD, PhD
Gerda de Kuijper, MD, PhD
Published in the Journal of Clinical Pharmacology (2019); 59(2), 280-287.
CHAPTER 5
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Off-label use of antipsychotic medication in people with intellectual disabilities Health-related quality of life and the discontinuation of antipsychotic drugs
Abstract
Health-related quality of life in people with intellectual disabilities can be affected by challenging behaviours and side-effects of antipsychotics. The aim of this study was to evaluate the effect of discontinuation antipsychotic drugs on health-related quality of life, including data from two discontinuation trials: an open-label trial of various antipsychotic drugs and a double-blind trial of risperidone. In both studies antipsychotics were discontinued in 14 weeks, with steps of 12.5% of the baseline dosage every two weeks. Health-related quality of life was measured at baseline and at 16 weeks and 40 weeks after baseline, by means of the RAND-36 (domains on physical well-being, role limitations caused by physical or emotional problems, vitality, pain, mental well-being, social functioning, general health and changes in health). Participants who had completely discontinued antipsychotics according to the scheduled discontinuation and were still free of use at 40 weeks were compared with those who had incompletely discontinued. Physical well-being showed an increase in the group that had achieved complete discontinuation. Social functioning showed a decrease in the group that incompletely discontinued, which recovered at up. Mental well-being decreased at 16 weeks, but recovered at follow-up, regardless of complete or incomplete discontinuation. To conclude, discontinuation of antipsychotics had a positive effect on physical well-being when complete discontinuation was possible. When complete discontinuation was not possible, there was a negative effect on health-related quality of life domains. However, none of the unfavourable effects were irreversible.
Introduction
Antipsychotic drugs are frequently prescribed in people with intellectual disabilities for the management of challenging behaviours (O’dwyer et al., 2017); the prevalence rate of antipsychotic drug use in the Netherlands is 29.6% (de Kuijper et al., 2010; de Kuijper & Hoekstra, 2017). Contrary to what antipsychotic drugs were developed for, i.e. the treatment of psychotic symptoms and schizophrenia, the drugs are more often prescribed outside of this licensed indication (off-label) in people with intellectual disabilities. Of the prescriptions in the Netherlands, 95% was off-label, mainly for challenging behaviours (de Kuijper & Hoekstra, 2017; Ramerman, de Kuijper, & Hoekstra, 2017). Despite conflicting evidence for their effectiveness in this indication, treatment is often long-term (Ahmed et al., 2000; de Kuijper, Evenhuis, Minderaa, & Hoekstra, 2014; Gagiano, Read, Thorpe, Eerdekens, & Van Hove, 2005; Tyrer et al., 2008; Zarcone et al., 2001). Moreover, there is a risk of side-effects of antipsychotic drugs, for example metabolic symptoms, neurological symptoms, and endocrine symptoms (Matson & Mahan, 2010), with 53% of those on long-term antipsychotics having one or more extrapyramidal symptoms, 46% overweight or obesity, and 64% clinically elevated prolactin levels in our previous study (de Kuijper et al., 2013).
Challenging behaviours and the side-effects of antipsychotic drug use can affect health-related quality of life (Allison, Mackell, & McDonnell, 2003; Faulkner, Cohn, Remington, & Irving, 2007; Koch et al., 2015; Ramerman, Hoekstra, & de Kuijper, 2018; Scheifes et al., 2016). Health-related quality of life describes the health status of a person comprehensively. Both physical and emotional well-being are considered, as well as the role limitations caused by physical or emotional problems (i.e., the ability to participate and perform normal daily tasks and activities), social functioning (the ability to participate in normal social activities), pain, and general health (Hays & Morales, 2001; Wilson & Cleary, 1995). We previously showed that parkinsonism and autonomic symptoms decreased the physical well-being component of quality of life and also that challenging behaviours, such as lethargy and irritability influenced quality of life negatively despite the use of antipsychotic drugs (Ramerman et al., 2018).
Discontinuation studies have shown that discontinuation of long-term used antipsychotics may improve behavioural functioning (Ahmed et al., 2000; de Kuijper et al., 2014; de Kuijper & Hoekstra, 2018). We previously showed that this is especially feasible in clients on lower doses of antipsychotics and with less severe challenging behaviour (de Kuijper & Hoekstra, 2018). As health-related quality of life is related to physical impairments as well as to maladaptive behaviour, it may be a useful outcome to use during the discontinuation of off-label prescribed antipsychotics (Ramerman et al., 2018). In the present study, we therefore investigated the effects
of discontinuation of long-term used antipsychotics for challenging behaviours on health-related quality of life. We made a comparison between participants who were and were not able to withdraw completely from antipsychotic medication. Furthermore, changes in health-related quality of life were analysed in relation to changes in physical symptoms associated with antipsychotic medication and in relation to changes in challenging behaviours.
Methods
Approval from the medical ethical committee of the University Medical Center Groningen was obtained for both studies (open-label: 2014/402; double-blind: 2015/171). Informed consent was provided by legal representatives or participants themselves when they were competent.
Study design and procedures
In this study data from two different discontinuation trials (de Kuijper & Hoekstra, 2018; Ramerman, de Kuijper, & Hoekstra, Submitted) were combined, an open-label discontinuation trial (registered in The Netherlands National Trial Register: NTR5519) and a double-blind placebo-controlled discontinuation trial (registered in The Netherlands National Trial Register (NTR5509)). For the current study all data at baseline, 16 weeks (two weeks after scheduled discontinuation), and 40 weeks (follow-up, i.e., 40 weeks after baseline) were used from the open-label trial and from the discontinuation group of the blind trial. The control group from the double-blind trial was excluded from the analysis.
In total, nine organizations (two mental health care organizations and seven service providers of intellectual disability care, including medical and psychological services) participated in the studies. Two of the seven service providers participated in both studies. These two organizations included their clients using risperidone into the double-blind study and the other antipsychotic drug users into the open-label study. In both studies, participants received a proposal for discontinuation from their physician.
Participants
Participants were eligible for both studies, when they had an intellectual disability (IQ<70; according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) or when mentioned in patient’s records), were six years of age or older, used antipsychotic drugs for at least one year, had not attempted discontinuation in the last six months and had no diagnosis of psychosis, schizophrenia or bipolar disorder according to DSM-IV. Due to practical reasons, participants from the double-blind trial were asked to taper their dosage to a maximum of 5 mg before the start of the trial, when needed. Participants were allowed to use other psychotropic drugs and could receive additional psychological or psychosocial interventions.
Intervention
In both trials discontinuation was scheduled as a 12.5% reduction every two weeks of the baseline antipsychotic drug dose. In the double-blind trial, participants were prescribed the fluid form of risperidone (1mg/ml) to enable stepwise, placebo-controlled discontinuation. Every participant received two bottles of medication. In the discontinuation group, the first bottle contained risperidone and the second bottle placebo. During the 14-week withdrawal phase, the amount taken from the first bottle lowered with 12.5%, while the amount taken from the placebo increased with 12.5% every two weeks.
In both trials, participants were allowed to stop the withdrawal of antipsychotic drugs at any time, to taper off more slowly, or restart antipsychotic drugs after complete discontinuation. The decision to stop the scheduled discontinuation or the restart of the antipsychotic drugs was the responsibility of the participant’s physician. Reasons to stop the scheduled discontinuation could be an increase in challenging behaviours, the emergence of psychotic symptoms, or withdrawal symptoms.
Outcomes
Outcomes were collected at baseline, 16 weeks (2 weeks after scheduled discontinuation) and 40 weeks (follow-up) for all participants. Data collection also continued for participants of the open-label study when the physician stopped further discontinuation or slowed down the tapering off and in the double-blind study when the physician stopped discontinuation and the participant was deblinded.
The primary outcome was health-related quality of life as assessed by the 36-item Research and Development survey (RAND-36). The RAND-36 is a health-related quality of life questionnaire, with domains on physical well-being, role limitations caused by physical or emotional problems, social role limitations, mental well-being, vitality, pain, general health and changes in health status. The domain of physical well-being includes items on physical activity (such as walking stairs or lifting). Furthermore, emotional/mental well-being includes items on happiness, anxiety and being down-hearted. Role limitations caused by physical or emotional problems includes items on how limitations in physical or emotional well-being impact daily activities, such as work or ambitions. The Social functioning domain assessed the impact of physical and mental well-being on social activities and participation, the Pain domain the amount of pain experienced and the level of influence pain had on normal daily functioning, the Vitality domain included assessed energy and tiredness, and the domains of general health and health changes assessed
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a current estimation of health status, the changes that had occurred recently, and expectations of future health.
All domains were scored on a scale of 0-100%, with 100% being the highest quality of life on that particular domain. The RAND-36 was completed by a proxy (direct support staff or parent/ caretaker) or by a proxy along with the participant by completing a hard copy questionnaire or by completing the questionnaire online.
Achievement of complete discontinuation was defined as being discontinued at 16 weeks (2 weeks after scheduled discontinuation) and remaining off antipsychotic drugs at follow-up (40 weeks after the start of discontinuation).
Secondary outcomes included challenging behaviours and physical side-effects that were associated with health-related quality of life domains, according to our previous study, i.e., symptoms of parkinsonism, autonomic symptoms, irritability, lethargy and stereotypy (Ramerman et al., 2018). Challenging behaviours were measured with the subscales irritability, lethargy, and stereotypy of the Aberrant Behavior Checklist (ABC). Parkinsonism was assessed with the Unified Parkinson’s Disease Rating Scale (UPDRS; items 20, 21, 22, 31); and autonomic symptoms with the Scale for Outcomes in Parkinson’s disease Autonomic symptoms (SCOPA-AUT).
Statistical analysis
Baseline differences regarding the participants’ characteristics age, sex, severity of intellectual disability, total antipsychotic drug dose converted into Defined Daily Dose (DDD), and use of other psychotropic drugs were analysed by Independent t-test for continuous variables and Chi-square test for categorical variables. Differences at baseline, at the time point of 16 weeks (2 weeks after the scheduled discontinuation, and at 40 weeks (follow-up), between the complete discontinuation group and the incomplete discontinuation group were assessed with a mixed model for repeated measures. The continuous domains of the RAND-36 were the dependent variables in the analysis, with group (complete or incomplete discontinuation)*time (baseline, 16 weeks and 40 weeks), group, and time as fixed effect. Analyses were done according to an intention-to-treat principle. An unstructured covariance matrix was used.
The domains of the RAND-36 with significant time*group, time or group effects were included in a mixed model for repeated measures analysis, with the irritability, lethargy, and stereotypy subscales of the ABC, and the total scores on the UPDRS and SCOPA-AUT as covariates (fixed effects). If these covariates had a univariate association with the domains of the RAND-36
(P<0.05), they were added as covariates in a multivariate model. Analyses were done according to an intention-to-treat principle. An unstructured covariance matrix was used. The significance threshold for all analyses was p< 0.05. All analyses were performed with the IBM Statistical Package for the Social Sciences, 23th edition.
Results
Table 1. presents the baseline characteristics of participants. In total 128 participants started discontinuation from antipsychotic drugs. A total of 42% achieved complete discontinuation at both 16 and 40 weeks. There were significant differences in sex and severity of intellectual disability between participants who achieved complete discontinuation at the time point of 16 weeks (2 weeks after scheduled discontinuation) and remained off-medication until 40 weeks, and those who had not.
Table 1. Baseline characteristics of participants Participant characteristics Complete
discontinuation at 16 and 40 weeks (n=54) Incomplete discontinuation at 16 and/or 40 weeks (n=74) Test value
Age in years (mean (SD a))b 47.6 (17.8) 47.7 (14.7) te=0.030 (p=0.976)
Sex (%) χ2f=9.37 (p=0.01)
Male 62.6 77
Female 37.4 23
Severity of Intellectual Disability (%) χ2=36.47 (p<0.001)
Mild 21.5 11.7
Moderate 31.1 14.5
Severe 37.1 54.5
Profound 10.4 19.3
DDDc (mean (SD)) 0.54 (0.48) 0.62 (0.45) t=1.686 (p=0.093)
Use of other psychotropic drugs (%) 32.4 43.9 χ2=5.96 (p=0.051)
Living situationd (%) χ2=3.513 (p=0.319)
Congregated centre 54.7 59.2 Community centre 26.4 21.0 Community living facility 13.2 7.9
Missing 5.7 11.8
Living situation. group size (%) χ2=5.325 (p=0.256)
1-4 persons 15.1 21.1
5-8 persons 45.3 43.4
9-12 persons 24.5 14.5
Independent 5.7 3.9
Missing 9.4 17.1
Type of antipsychotic drug (%)
Risperidone 30.2 18.4
Pipamperone 32.1 35.5
Table 1. Continued
Participant characteristics Complete discontinuation at 16 and 40 weeks (n=54) Incomplete discontinuation at 16 and/or 40 weeks (n=74) Test value Haloperidol 3.8 6.6 Periciazine 7.5 1.3 Aripiprazole 0 2.6 Clozapine 0 3.9 Quetiapine 1.9 1.3 Pimozide 7.5 3.9 Olanzapine 5.7 10.5 Levomepromazine 1.9 2.6 Zuclopenthixol 3.8 6.6 Missing 5.7 6.6 a SD= Standard Deviation
b Both adults and children were included. 7.5% was aged under 18 years.
c DDD= Defined Daily Dosage: Average maintenance dosage calculated by dividing the actual dosage by the
DDD defined by The World Health Organization.
d Congregated centres are large campus facilities, community centres are larger living facilities (>50 residents)
in the community; community living facilities are group homes in the community (<20 residents).
e t is the test value gained from the independent t-test, with p as the significance level. f χ2 is the test value gained from the Chi-square test, with p as the significance level.
Table 2 and Figure 1 show the scores on the domains of the RAND-36 at baseline, 16 weeks and 40 weeks. A significant time*group effect was found for physical well-being, indicating a steeper increase in well-being scores for the complete discontinuation group. Both social functioning and role limitations caused by physical problems had a significant time*group interaction, showing a deterioration at the time point of scheduled discontinuation, followed by an improvement at follow-up in the incomplete discontinuation group, while the complete discontinuation group remained stable. In addition, general health also had a significant time*group interaction, showing a steeper increase in the complete discontinuation group during discontinuation, that returned to the baseline value at 40 weeks.
Ta bl e 2 . C ha ng e i n h ea lth -r el at ed q ua lit y o f l ife d om ai ns in in di vid ual s wit h i nt el le ct ual d is ab ilit ie s wh o d is co nt in ue d l on g-te rm u se d a nt ip sy ch ot ic d ru gs fo r ch al le ng in g be ha vi ou r. Com pl et e di sc on ti nu at ion g rou p (m ea n ( CI 9 5% a)) In com pl et e di sc on ti nu at ion g rou p (m ea n ( CI 9 5%) ) Ba se line 16 w ee ks ( 2 w ee ks af te r sc he du le d di sc on ti nu at ion ) 40 w ee ks (f ol lo w -up ) Ba se line 16 w ee ks ( 2 w ee ks af te r sc he du le d di sc on ti nu at ion ) 4 0 w ee ks (f ol lo w -up ) F( p) b Ph ys ic al w ell -b ei ng 66 .4 (57 .9 -7 4. 9) 68 .8 (6 0. 3-77. 2) 72 .8 ( 64 .7 -8 0. 9) 74 .8 (67 .3 -8 2. 3) 76 .8 (6 9. 6-84 .1) 71 .5 (6 4.5 -7 8. 3) 3. 211 (p = 0. 04 4) So cia l f un cti on in g 73 .1 (6 6. 0-80 .3 ) 75 .6 (6 6. 8-84 .4) 76 .0 (6 8. 8-83 .2 ) 77 .7 (7 1. 3-84 .0 ) 61 .9 (5 4. 5-69 .3 ) 72 .1 (6 5. 8-78 .3 ) 4.1 94 (p = 0. 018 ) Ro le l im ita tio ns ca us ed b y p hy si ca l pr ob le m s 80 .9 (7 5. 0-86 .7 ) 82 .3 (7 4. 9-89 .6 ) 79 .3 (7 2. 20 -8 6. 5) 87. 0 ( 81 .9 -9 2. 2) 75. 6 ( 69 .5 -8 1. 8) 77 .2 (7 0. 9-83 .4 ) 3.7 43 (p = 0. 027 ) Ro le l im ita tio ns ca us ed b y e m ot io na l pr ob le m s 74 .3 (6 6.3 -8 2.3 ) 74. 1 ( 64. 0-84. 2) 73 .9 (6 5. 4-82 .4) 74 .0 (6 6. 8-81 .2 ) 58 .7 ( 50 .5 -6 6. 9) 64 .0 (5 6. 5-7 1. 4) 2. 58 0 (p = 0. 080 ) M en tal / E m ot io nal w el l-b ei ng 66 .8 (6 2.6 -7 1. 1) 61 .9 (5 5.9 -6 7.9 ) 64 .6 (5 9. 3-69. 9) 63 .5 (59 .8 -67 .2 ) 53 .1 (4 8.1 -5 8.1 ) 59 .1 (5 4. 5-63 .8 ) 1. 17 0 ( p= 0. 314 ) Vit al it y 59 .6 (5 4. 6-64. 5) 57 .8 (5 1. 8-63 .9 ) 59 .6 (5 4.6 -6 4.6 ) 57 .7 (5 3. 4-61 .9 ) 54 .3 (4 9. 3-59. 2) 55 .9 (51. 6-60 .3 ) 0. 15 2 (p = 0. 859 ) Pa in 81 .9 (7 7.1 -8 6. 8) 79 .3 (73 .0 -85 .6 ) 82 .4 (7 6. 5-88 .3 ) 88 .1 (8 3. 8-92 .3 ) 83 .4 (7 8. 2-88 .7 ) 84 .2 (7 9. 1-89 .2 ) 0. 51 0 (p = 0. 602 ) G en er al h ealt h 63. 3 ( 56 .8 -6 9. 8) 67 .3 ( 60 .9 -7 3.7 ) 61 .1 (5 4. 4-67. 8) 62 .8 (57 .2 -6 8. 4) 59 .4 (5 34. 0-64. 8) 61 .0 (5 5. 3-66 .8 ) 4. 37 1 (p = 0. 015 ) H ealt h c ha ng e 50 .9 (4 6. 1-55 .8 ) 53 .1 (46 .8 -5 9. 5) 50 .2 (4 3. 4-57. 0) 52 .9 (4 8. 5-57. 4) 47 .5 (4 2. 2-52. 8) 49 .3 (4 3. 5-55 .1 ) 1. 35 5 (p = 0. 26 2) CI 9 5% = c on fid en ce i nt er va l o f 9 5% . F i s t he t es t v al ue g ai ne d f ro m t he m ix ed m et ho ds a na ly sis , w ith p a s t he s ig ni fic an ce l ev el .
5
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Off-label use of antipsychotic medication in people with intellectual disabilities Health-related quality of life and the discontinuation of antipsychotic drugs
Figu re 1 . C ha ng e ov er t im e ( ba se lin e, 1 6 w ee ks a nd 4 0 w ee ks ) i n h ea lth -r el at ed q ua lit y o f l ife do m ai ns o f p eo pl e w ith i nt el le ct ua l d is ab ili tie s f or p ar tic ip an ts w ith com ple te a nd in com ple te d isc on tin ua tion o f lon g-te rm u se d a nt ip sy ch ot ic d rug s f or c ha lle ng in g b eh av io ur .
Figure 1 presents the overall development of the quality of life domains over time, for the complete and incomplete discontinuation group. The domain for emotional well-being had a significant time effect (F=9.516; p<0.001) and a significant group effect (F=4.749; p=0.031). Emotional well-being was lower at all time points for the incomplete discontinuation group. Furthermore, emotional well-being scores deteriorated in both groups at the time point of 16 weeks, followed by an improvement in both groups at 40 weeks.
Table 3. The association between the change in domains of the RAND-36a during discontinuation of
antipsychotic drugs with the change in severity of challenging behaviour symptoms and change severity of symptoms of side-effects.
RAND-36
domains Symptoms of side-effects and challenging behaviours Parameter estimate (Standard error) F(p) e Physical well-being Parkinsonism (UPDRSb) -2.77 (0.70) 15.594 (p<0.001) Autonomic symptoms (SCOPA-AUTc) -0.84 (0.18) 21.952 (p<0.001) Role limitations caused by physical problems Parkinsonism (UPDRS) -2.31 (0.75) 9.521 (p<0.001) Autonomic symptoms (SCOPA-AUT) -0.53 (0.15) 12.516 (p<0.001) Social functioning Irritability (ABCd) -0.95 (0.21) 19.859 (p<0.001)
Lethargy (ABC) -0.80 (0.26) 9.411 (p=0.003) Stereotypy (ABC) 0.32 (0.37) 0.744 (p=0.392) Mental/emotional well-being Irritability (ABC) -0.66 (0.13) 24.411 (p<0.001) Lethargy (ABC) -0.32 (0.14) 5.111 (p=0.028) Stereotypy (ABC) -0.05 (0.24) 0.038 (p=0.847) General Health Parkinsonism (UPDRS) -1.64 (0.61) 7.357 (p=0.011)
Autonomic symptoms (SCOPA-AUT)
-0.38 (0.12) 10.262 (p=0.002) Lethargy (ABC) -0.51 (0.14) 12.466 (p<0.001)
a RAND-36=36-item Research and Development survey.
b UPDRS= Unified Parkinson’s Disease Rating Scale.
c SCOPA-AUT= Scales for Outcomes in Parkinson’s disease- Autonomic symptoms.
d ABC= Aberrant Behavior Checklist.
e F is the test value gained from the mixed methods analysis, with p as the significance level.
Table 3. shows the association between the change that occurs in the domains of the RAND-36 during discontinuation with the change that occurred in severity of side-effects and with the change in severity of challenging behaviours. There was a negative main effect of the UPDRS and SCOPA-AUT scores on physical well-being. Moreover, changes in irritability and lethargy were negatively associated with changes in both mental well-being and social functioning.
Last, general health was negatively associated with scores on the UPDRS, SCOPA-AUT, and the lethargy subscale of the ABC.
Discussion
The aim of the study was to investigate the effects of discontinuation of long-term used antipsychotics prescribed for the management of challenging behaviours, on health-related quality of life. Physical well-being improved in participants who achieved complete discontinuation. This increase in physical well-being may be related to the attenuation of side-effects, e.g. of parkinsonism. This beneficial effect of discontinuation adds to the findings of previous studies that showed favourable effects of discontinuation on weight, body mass index, waist circumference, and prolactin and testosterone levels (de Kuijper, Mulder, Evenhuis, Visser, & Hoekstra, 2013; de Kuijper, Mulder, Evenhuis, Visser, & Hoekstra, 2014; Ramerman et al., Submitted).
Full or attempted discontinuation led to a decline in mental well-being which subsequently recovered. The initial worsening may be a direct consequence of withdrawing the therapeutic effect of the antipsychotic medication. It is reassuring and of clinical relevance that the worsening was only temporal, also when participants remained off-medication. Mental well-being was lower at all time points in the group of participants with incomplete discontinuation, compared to the participants with complete discontinuation. This probably indicates that those who were not able to discontinue their antipsychotics had more severe challenging behaviours, including irritability and lethargy.
The changes in mental well-being were negatively related to changes in symptoms of irritability and lethargy, indicating an increase in mental well-being when there is a decrease in challenging behaviours. The association of challenging behaviours, such as irritability and lethargy with mental well-being is in line with previous studies (Koch et al., 2015; Ramerman et al., 2018). In addition, during a previous discontinuation study, we found an increase in the severity of individually chosen target behaviours as measured with a Visual Analogue scale at the time point of scheduled discontinuation in those with incomplete discontinuation of the antipsychotic drugs and no change in those with complete discontinuation (de Kuijper et al., 2014). Furthermore, McNamara (2017) found an increase in aggression and irritability in those who discontinued risperidone (McNamara et al., 2017).
The effects of discontinuation on social functioning were similar to those on role limitations caused by physical or mental problems. Overall, the results indicate that participants with incomplete discontinuation initially showed worse functioning, at the time point of scheduled
discontinuation, which improved again at follow-up, after discontinuation had been suspended. The results indicate that an increase in irritability and lethargy during discontinuation will decrease social functioning. Furthermore, the results also indicate that when symptoms of parkinsonism or autonomic symptoms decrease during discontinuation, experienced role limitations will improve.
This study is the first to study the effects of discontinuation of antipsychotic drugs on health-related quality of life, in people with intellectual disability. However, there are also some limitations. First, we used the RAND-36 as a measure of health-related quality of life, a scale widely used and validated, but not for the use in people with intellectual disabilities or for completion by proxies. Validation of this scale for people with intellectual disabilities (and their proxies) may support future research on this subject. Second, we combined two studies with a different design. Although the schedule of discontinuation was the same, there might be a difference in results between blind discontinuation and open discontinuation. It can be expected that participants in the double-blind study are more inclined to continue with discontinuation, even when discontinuation becomes more difficult, by for example an increase in challenging behaviour. Moreover, there may be a difference in bias between the two trials on the completion of the RAND-36 and other scales, by the caregivers. In the open-trial, the caregivers were not blinded and all participants were discontinuing antipsychotic drugs. In contrast, in the double-blind trial, caregivers were double-blinded on the discontinuation of their client when completing the questionnaires at baseline and week 16. This may have affected the answers provided on the scales. Last, there was no control group to compare the normal fluctuation in health-related quality of life with.
Clinical implications
The results of this study have implications for clinical practice. There is evidence that successful complete discontinuation of antipsychotic drugs has beneficiary effects on physical well-being. Even if unsuccessful discontinuation may negatively affect the mental functioning of the client, this will only be temporary.
Conclusion
To conclude, health-related quality of life is both positively and negatively influenced by the discontinuation of antipsychotic drugs. The changes in domains of health-related quality of life are negatively associated with changes in challenging behaviours and symptoms of parkinsonism. Physical well-being improves when complete discontinuation is possible. Mental well-being can be expected to show a temporary decrease, independent of the achievement
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of complete discontinuation. Furthermore, in those with incomplete discontinuation social functioning is clearly affected however this is also temporarily. These results suggest that attempting discontinuation will not permanently affect the domains of health-related quality of life. Moreover, when complete discontinuation of antipsychotic drugs is possible, an increase in physical well-being may be expected.
References
Ahmed, Z., Fraser, W., Kerr, M. P., Kiernan, C., Emerson, E., Robertson, J., ... Thomas, J. (2000). Reducing antipsychotic medication in people with a learning disability. The British Journal of
Psychiatry: The Journal of Mental Science, 176,
42-46.
Allison, D. B., Mackell, J. A., & McDonnell, D. D. (2003). The impact of weight gain on quality of life among persons with schizophrenia. Psychiatric
Services, 54(4), 565-567.
de Kuijper, G., Evenhuis, H. M., Minderaa, R., & Hoekstra, P. J. (2014). Effects of controlled discontinuation of long‐term used antipsychotics for behavioural symptoms in individuals with intellectual disability. Journal
of Intellectual Disability Research, 58(1), 71-83.
de Kuijper, G., & Hoekstra, P. J. (2018). An open label discontinuation trial of long-term used off-label antipsychotic medication in people with intellectual disability; determinants of success and failure. The Journal of Clinical Pharmacology, Jun 19.
de Kuijper, G., Mulder, H., Evenhuis, H. M., Scholte, F., Visser, F., & Hoekstra, P. J. (2013). Determinants of physical health parameters in individuals with intellectual disability who use long-term antipsychotics. Research in Developmental
Disabilities, 34(9), 2799.
de Kuijper, G., Mulder, H., Evenhuis, H. M., Visser, F., & Hoekstra, P. (2013). Effects of controlled discontinuation of long-term used antipsychotics on weight and metabolic parameters in individuals with intellectual disability. Journal of Clinical Psychopharmacology,
33(4), 520.
de Kuijper, G., Hoekstra, P., Visser, F., Scholte, F., Penning, C., & Evenhuis, H. (2010). Use of antipsychotic drugs in individuals with intellectual disability (ID) in the Netherlands: Prevalence and reasons for prescription. Journal
of Intellectual Disability Research, 54(7), 659-667.
de Kuijper, G. M., Mulder, H., Evenhuis, H., Visser, F., & Hoekstra, P. J. (2014). Effects of discontinuation of long-term used antipsychotics on prolactin and bone turnover markers in patients with intellectual disability. Journal of Clinical
Psychopharmacology, 34(1), 157-159.
de Kuijper, G., & Hoekstra, P. (2017). Physicians’ reasons not to discontinue long‐term used off‐label antipsychotic drugs in people with intellectual disability. Journal of Intellectual
Disability Research, 61(10), 899-908.
Faulkner, G., Cohn, T., Remington, G., & Irving, H. (2007). Body mass index, waist circumference and quality of life in individuals with schizophrenia. Schizophrenia Research, 90(1), 174-178.
Gagiano, C., Read, S., Thorpe, L., Eerdekens, M., & Van Hove, I. (2005). Short- and long-term efficacy and safety of risperidone in adults with disruptive behavior disorders. Psychopharmacology, 179, 629.
Hays, R. D., & Morales, L. S. (2001). The RAND-36 measure of health-related quality of life. Annuals
of Medicine, 33(5), 350-357.
Koch, A. D., Vogel, A., Becker, T., Salize, H., Voss, E., Werner, A., . . . Schützwohl, M. (2015). Proxy and self-reported quality of life in adults with intellectual disabilities: Impact of psychiatric symptoms, problem behaviour, psychotropic medication and unmet needs. Research in
Developmental Disabilities, 45, 136-146.
Matson, J. L., & Mahan, S. (2010). Antipsychotic drug side effects for persons with intellectual disability. Research in Developmental Disabilities,
31(6), 1570-1576.
McNamara, R., Randell, E., Gillespie, D., Wood, F., Felce, D., Romeo, R., . . . Davies, A. (2017). A pilot randomised controlled trial of community-led antipsychotic drug reduction for adults with learning disabilities. Health Technology
Assessment, 21(47), 1-92.
O’dwyer, M., Peklar, J., Mulryan, N., McCallion, P., McCarron, M., & Henman, M. (2017). Prevalence, patterns and factors associated with psychotropic use in older adults with intellectual disabilities in Ireland. Journal of Intellectual
Disability Research, 61(10), 969-983.
Ramerman, L., de Kuijper, G., & Hoekstra, P. J. (Submitted). Is risperidone effective in reducing challenging behaviours in individuals with intellectual disabilities after one year or longer use? A placebo-controlled, randomized, double-blind discontinuation study. Journal of
Intellectual Disability Research.
Ramerman, L., de Kuijper, G., & Hoekstra, P. J. (2017). Adherence of clinicians to guidelines for the prescription of antipsychotic drugs to people with intellectual disabilities. Advances in Mental
Health and Intellectual Disabilities, 11(3).
Ramerman, L., Hoekstra, P. J., & de Kuijper, G. (2018). Health-related quality of life in people with intellectual disability who use long-term antipsychotic drugs for challenging behaviour.
Research in Developmental Disabilities, 75, 49-58.
Scheifes, A., Walraven, S., Stolker, J. J., Nijman, H. L., Egberts, T. C., & Heerdink, E. R. (2016). Adverse events and the relation with quality of life in adults with intellectual disability and challenging behaviour using psychotropic drugs. Research in Developmental Disabilities,
49, 13-21.
Tyrer, P., Oliver-Africano, P. C., Ahmed, Z., Bouras, N., Cooray, S., Deb, S., . . . Crawford, M. (2008). Risperidone, haloperidol, and placebo in the treatment of aggressive challenging behaviour in patients with intellectual disability: A randomised controlled trial. Lancet, 371(9606), 57-63.
Wilson, I. B., & Cleary, P. D. (1995). Linking clinical variables with health-related quality of life: A conceptual model of patient outcomes. Journal
of the American Medical Association, 273(1), 59-65.
Zarcone, J. R., Hellings, J. A., Crandall, K., Reese, R. M., Marquis, J., Fleming, K., . . . Schroeder, S. R. (2001). Effects of risperidone on aberrant behavior of persons with developmental disabilities: I. A double-blind crossover study using multiple measures. American Journal of
Mental Retardation, 106(6).
