CHILDREN’S TRIAL

A six-month open-label study of risperidone in improvement of disruptive behaviour and quality of life of children and adolescents with intellectual disability previously treated with psychological therapy

 

 

Stephen G Read MD, FRCPsych

 

Professor of Psychiatry,SchoolofHumanand Health Sciences,UniversityofHuddersfield,HaroldWilsonBuilding, Queensgate,Huddersfield,HD1 3DH,UK

 

 

Correspondence to:

 

Professor Stephen G Read

SchoolofHumanand Health Sciences

UniversityofHuddersfield

Room 208

HaroldWilsonBuilding

Queensgate

Huddersfield

HD1 3DH

UK

 

Tel:      +44 (0) 1484 343211

Fax:     +44 (0) 1484 472794

Email:  s.read@hud.ac.uk

 

 

Target journal: British Journal of Learning Disabilities

Running title: Risperidone in paediatric intellectual disability

Keywords: Intellectual disability, Disruptive Behaviour Disorders, Risperidone, Quality of Life, Children

 

Acknowledgements
The study was funded by Janssen-Cilag Ltd. The author would like to thank Dr Maurice Gleeson for his significant contribution to the preparation of the final manuscript.

Abstract

Background: Disruptive behaviours are often difficult to manage and have profound implications for health and quality of life (QoL).

Methods: Children with disruptive behaviour and mild, moderate or severe intellectual disability (n=19) who had previously been under the care of a clinical or educational psychologist, received oral risperidone (0.25–4mg/day) in a 6-month, open-label study.  The primary efficacy variable was the Aberrant Behaviour Checklist (ABC); secondary efficacy measures included ABC subscales, Hostility Checklist, and Clinical Global Impressions-Severity (CGI-S).  Carer-rated QoL was measured using the Child Health-Related QoL rating scale (CQOL).

Results: Patients demonstrated significant improvements from baseline to endpoint in total ABC score (‑43.8±25.7; p<0.001); all ABC subscale scores (Irritability, Lethargy, Stereotypy, Hyperactivity, Inappropriate Speech; p≤0.0335); Hostility Checklist total and subscale scores (Violence, Self-Injury; p<0.001); CGI-S (p<0.0001), and 3 of 4 CQOL domains (Function, Upset, Satisfaction; p≤0.0017).  The CQOL Global item did not reach statistical significance (p=0.557).  Risperidone was generally well tolerated.

Conclusion: This six-month study suggests that risperidone may be effective in the treatment of disruptive behaviours in children with intellectual disability.

 


Introduction

 

There is much evidence demonstrating that children with intellectual disability are more likely to engage in disruptive behaviours, including those more serious such as violence and self-harm, than children who are developing normally (Einfeld & Aman 1995; Chadwick et al. 2000). Reported prevalence of behavioural and psychiatric disorders in this population varies from 10% to 80% due to differences in definitions, disorders included, recognition and methodology (Aman et al. 2004). Indeed, the Disruptive Behaviour Disorders (DBD), such as conduct disorder, oppositional defiant disorder, and intermittent explosive disorder, are among the most common mental health problems seen in people with intellectual disability (American Psychiatric Association [DSM-IV-TR], 2000; Moss et al. 2000).

 

Additionally, the symptoms are more persistent in this population and often resistant to treatment (Simonoff et al. 2004). These behaviours are often difficult to manage and have profound implications for the individuals’ health and quality of life, increasing the risk of fewer academic and social opportunities and needing specialist care or institutionalisation (Felce et al. 1998; Symons et al. 1999; Felce & Emerson 2001).

 

Since impairments in adaptive functioning and behaviour, rather than below normal Intelligence Quotient (IQ), are usually the presenting symptoms, the principle focus of treatment is on behavioural disturbances. The management of DBDs usually involves behavioural therapy or psychotherapy, complemented by pharmacotherapy for symptom control (Deb & Unwin 2006; Royal College of Psychiatrists et al. 2007; Pappadopulos et al. 2003). Over the years, there has been a high rate of antipsychotic use for the treatment of behaviours, such as aggression, irritability and self-injury, in people with intellectual disability, especially in institutionalised populations (Singh et al. 1997). Atypical antipsychotics (e.g. risperidone and olanzapine) have been recommended for patients when DBDs remain uncontrolled with psychosocial interventions and primary psychiatric disease management (Reyes et al. 2006; Findling 2008). They are selected in preference to conventional antipsychotics for the treatment of children with intellectual disability as they potentially have fewer serious side effects, such as extrapyramidal symptoms (EPS) (Santosh & Baird 1999). This is particularly important for these individuals in whom side effects tend to be more frequent (Handen & Gilchrist 2006).

 

Risperidone has been relatively well studied for the management of DBDs in children, adolescents and adults with subaverage IQ (Ahmed et al. 2000; Aman et al. 2002; Buitelaar 2000; Croonenberghs et al. 2005; Findling et al. 1997; Findling et al. 2000; Findling et al. 2008; Gagiano et al. 2005; McDougle et al. 1997; Nicolson et al. 1998; Reyes et al 2006; Santosh & Baird 1999; Snyder et al. 2002; Turgay et al. 2002; Tyrer et al. 2008; Van Bellinghen & De Troch 2001). It has demonstrated benefits within the first few weeks of treatment initiation, maintained efficacy for up to one year, and been found to be well tolerated, typically with a side effect profile including weight gain and mild and transient somnolence. Not all studies have been positive however, and there is still much debate regarding the place of antipsychotic medication in the treatment of disruptive behaviours in people with intellectual disability (Tyrer et al. 2008; Ahmed et al. 2000).

 

There is increasing interest in improving the daily living conditions of people with intellectual disability (Symons et al. 1999). Outcome measures in studies of people with disruptive behaviours and intellectual disability should not be limited to the frequency, duration and intensity of the target behaviours but include outcomes associated with quality of life, such as overall functioning and relationships. However, the majority of studies to date have focused on symptom control.

 

A major reason for conducting quality of life studies in people who may have limitations on their capacity to consent, such as those with severe intellectual disability or children, is that they cannot express a preference as to whether they take a medication or not. Parents may feel that the treatment is warranted because they benefit from caring for a less aggressive individual. Quality of life studies determine that the individual also benefits from, for example, improvement in social life and school work. It is reasonable to assume that if quality of life is improved, the patient would likely consent to the intervention (had they the capacity to do so), thus further justifying the administration of the medication.

 

Recently, we reported a 12-week, non-comparative, open-label study evaluating the use of flexible-dose risperidone monotherapy to treat specifically violent and self-injurious behaviour in adults with moderate, severe or profound intellectual disability and DBDs (Read & Rendall, 2007).  The study examined the hypothesis that if patients’ disruptive behaviour is suppressed, communication skills are improved, enabling greater understanding and satisfaction of needs.  Additional to ameliorating symptoms of DBD, significant improvements in quality of life, specifically in endpoints evaluating homelife, activity and skills, were found using a modified version of the Composite Autonomic Symptom Scale after 12 weeks of risperidone therapy.

 

Improvements in quality of life associated with behavioural symptom control in the intellectually disabled population remains inadequately investigated. The present study specifically addresses quality of life of children with disruptive behaviours and intellectual disability receiving risperidone, in addition to monitoring safety and efficacy outcomes of this medication treating DBDs. Since DBDs often require treatment in the long-term, and improvements in quality of life may take longer to become evident than symptom control, participants were enrolled for six months.

 

Methods

 

Participant Selection

 

Children and adolescents aged 5 to 16 years who still reached the minimum threshold for disruptive behaviour (Hostility Checklist score of 8 or more) despite adequate intervention by a clinical or educational psychologist, were considered as potential candidates for this study. Subjects were required to have an Axis II diagnosis of mild, moderate or severe mental retardation, which represent IQ ranges of 55 to 75, 35 to 55, and ≥20 to 35, respectively, according to the Diagnostic and Statistical Manual of Mental Disorders – IV (IQ measured at screening using the Wechsler Intelligence Scale for Children (WISC, 1991) or Leiter International Performance Scale (Johnson, 1982).  Participants were otherwise healthy according to results of a prestudy physical examination, medical history and electrocardiogram, and had a responsible person to accompany them to clinical assessments. A negative pregnancy test at screening was required for females of childbearing potential.

 

Each participant must have had a psychological assessment and report, been in receipt of a statement of educational needs, and been attending a school (full or part-time) at study entry. They also must have been under the supervision of a clinical or educational psychologist for at least six months prior to study entry, and must have received psychological therapy (unless such therapy was not indicated, e.g. in subjects with an IQ of less than 50 or demonstrating very severe self-harming behaviour), Such therapy could include family therapy and/or behaviour therapy. Lastly, despite treatment, they still had a degree of hostility that was above the threshold value for inclusion in the study, namely a Hostility Checklist score of 8 or more.

 

Excluded were participants who were experiencing EPS not adequately controlled by medication, or a seizure disorder requiring frequent changes in medication, or a history of tardive dyskinesia, neuroleptic malignant syndrome, or known hypersensitivity to neuroleptics.  Use of concomitant antipsychotic drugs was not permitted. After entering the trial, all previous specific psychological interventions were withdrawn. Subjects continued to attend special school, and the Research Nurse would visit at home occasionally. Apart from this, there were no other specific psychological interventions.

 

Study Design

 

Participants referred to a children’s intellectual disability clinic were recruited to this prospective, non-randomised, open-label trial at a single centre in theUK.  This was a state-sponsored clinic, in an urban setting, specifically established to address disruptive behaviours. The clinic accepted referrals of children and adolescents whose behaviour represented a danger to themselves or others. Referrals were from a variety of sources, most commonly from paediatricians, community Intellectual Disability Teams, general practitioners, and child and adolescent psychiatrists.

 

Written informed consent was given by each participant’s next of kin or carer before inclusion.  The children were informed of the likely side effects of the medication, were asked to choose between tablet or liquid forms, and were asked to complete several consent forms. The study was carried out in accordance with the Declaration of Helsinki (Hong Kong1989) and its subsequent revisions, current International Conference on Harmonisation and Good Clinical Practice guidelines, and was approved by an Independent Ethics Committee.

 

Participants received risperidone either in oral tablet form (tablet 0.5 mg or 1 mg; orodispersible 1 mg or 2 mg) or as an oral suspension (1 mg/ml).   Participants began treatment at 0.25 mg/day or 0.5 mg/day based on the clinician’s judgement for the first two days; older participants with a larger body weight were permitted to use the starting dose of 1 mg/day. At the discretion of the clinician and depending on clinical response, the dose could be titrated to 0.5 mg/day or 1 mg/day on day 3 and, thereafter could be raised in increments of 0.25 mg/day to 1.0 mg/day at weekly intervals to a maximum of 4 mg/day. Treatment compliance was monitored by tablet count and liquid volume, and supplemented by the reports of parents or carers.

 

No antipsychotic treatments other than risperidone were allowed during the trial.  Anticholinergic medications were discontinued at trial entry and any sedative/hypnotic medication was kept to the minimum clinically required dose.  In cases of emergent EPS, the dose of risperidone was reduced, followed by the introduction of anticholinergic medication if considered necessary and after completion of the Extrapyramidal Symptom Rating Scale (Chouinard et al. 1980).  Doses of medications used to treat organic disorders were maintained constant. Participants were withdrawn from the study at the investigators discretion, if any serious adverse events occurred, or if consent by next of kin or carer was withdrawn.

 

Assessment Procedures

 

All assessments were scored by the investigator or research nurse in collaboration with the primary carer of each child. Baseline scores were assessed at screening over a one-week period up to Day 0, and safety and efficacy was assessed after 1, 2, 3 and 4 weeks and 2, 3, 4, 5 and 6 months (8, 12, 16, 20 and 24 weeks, respectively) of  treatment.

 

The primary efficacy variable was the change from baseline to final visit (Last Observation Carried Forward (LOCF)) for the total score of the Aberrant Behaviour Checklist (ABC), which was measured at all visits) (Aman et al. 1985).  This 58-item questionnaire, which assesses target behaviours, scores each item on a 4-point scale (0, behaviour not a problem to 3, behavioural problem is severe).  There are five subscales: irritability (15 items), lethargy and social withdrawal (16 items), stereotypic behaviour (7 items), hyperactivity (16 items) and inappropriate speech (4 items).

 

Secondary efficacy variables included changes from baseline to months 3 and 6 of the total ABC score, and the ABC subscales and the Hostility Checklist (measured at all visits; Read 1998). The Hostility Checklist comprises 24 items; 14 hostile behaviour, 10 self-injurious behaviours, all scored on a 3-point scale (absent, moderate, severe).  The change from baseline to the last recorded assessment in the overall level of clinical severity was also evaluated using the Clinical Global Impressions – Severity (CGI-S) scale (measured at all visits; 7-point scale ranging from absent to extreme severity; Guy 1976).

 

Quality of Life was measured at baseline and at months 3 and 6 using the Child Health-Related Quality of Life rating scale (CQOL) (Graham et al. 1997), which consists of 15 domains.  In each domain, the parent or carer of the child is asked to score the performance of the child with respect to the domain, how upset they are by the child’s level of performance and how satisfied they are by the child’s level of performance.  Each domain is scored with respect to function/performance, upset and satisfaction, and a final question (‘over the past month how do you think the quality of your child’s life has been?’) evaluates the global score (function/performance, satisfaction, and global score: 1=best possible, 7=worst possible; upset score: 1=worst possible, 7=best possible). The combined total score was not considered appropriate for this participant population; the individual domains were felt more accurately to reveal where any changes in quality of life reside.

 

Medical history, physical examination, vital signs, body weight and electrocardiogram (ECG) were assessed at screening (baseline).  Additionally, vital signs were assessed at all visits, body weight at months 3 and 6, and electrocardiogram at month 6.  Adverse events were recorded at each visit and concomitant medications, continued at the start of the trial or started during the trial, were also recorded.

 

Statistical Analysis

 

The sample size, to give 80% power (5% significance level, 2-sided test) to detect a reduction of 15 ± 20 points on the total ABC, was 15 participants (Gagiano et al. 2005). While the target sample size was 20 participants to allow for study dropouts, 19 participants were finally enrolled into the study. Three main analysis populations were defined.  The total population (all participants recruited, n=19) was used for baseline summaries; the intent-to-treat population (ITT, all participants who had at least one post-baseline efficacy assessment, n=18) was used for all participants’ details and efficacy; and the safety population (all participants who took at least one dose of study medication, n=19) was used for all summaries of safety.  Summary statistics were calculated using SAS software (SAS Institute Inc.,Cary,NC,USA).

 

Negative scores represent a positive response to treatment.  For total and subscale scores, when at least half of the items (questions) had been completed by the participant then the score was calculated as:

Score = Sum of the completed items x number of items in the score

Number of completed items

If fewer than half of the items had been completed, then a missing value was assigned to the score.  Where an item had subcategories, the item score was the average of the non-missing scores of the subcategories.

 

Statistical tests were interpreted at a 5% significance level (two tailed). Comparisons were made from baseline to a fixed time point and to the final visit (last observation carried forward (LOCF)) using the paired t-test (or the Wilcoxon matched pairs signed-rank test if the conditions for the t-test were not met). An additional PP analysis of the total ABC was carried out (as detailed above) to confirm the ITT analysis of the primary efficacy variable. Changes from baseline to LOCF are tabulated. Using the safety population, Kaplan-Meier estimates of the proportion of subjects who do not experience low blood pressure were determined.

 

Results

 

Participant Characteristics

 

At baseline, the 18 participants in the ITT population were all outpatients with a mean (± standard deviation) age of 11.5 ± 3.1 years and IQ of 55.9 ± 12.3.  The majority were male (16, 88.9%) and 15 (83.3%) were Caucasian (Table 1). Three (16.7%) participants had not received previous psychological treatment as it was considered inappropriate. None of the participants were in residential care; all were living at home with their families (either two-parent or single-parent families, there being a high proportion of marriage breakdown, and a lot of unsupported mothers).

 

In addition to intellectual disability (11, 3 and 4 participants with mild, moderate and severe mental retardation, respectively), four (22.2%) participants had epilepsy and four (22.2%) had insomnia.  Concurrent psychiatric conditions were present in five (27.8%) participants and one (5.6%) other participant had been diagnosed with autism at the age of 3.5 years.

Table 1 here

 

Before the start of the study, 4 (22.2%) participants were taking antiepileptics and 2 (11.1%) were taking psychoanaleptics.  Fifteen (83.3%) participants began concomitant medication during the study; the most common medication was an analgesic (11, 61.1% participants), three (16.7%) began treatment with psychoanaleptics (methylphenidate), one (5.6%) with antiepileptics (patient had taken an antiepileptic pre-study) and one (5.6%) participant began treatment with an antiparkinson drug (orphenadrine).

 

Discontinuations

 

Three of the 19 subjects discontinued the study: one subject was considered to be ineligible to continue in the trial and was withdrawn after screening, one was discontinued after week 1 following an adverse event (epilepsy, new case) and one was considered to have insufficient response to treatment and was discontinued after month 5.

 

Study Medication

 

Risperidone was initiated at 0.25 mg/day by one (5.3%) participant, at 0.5 mg/day by 14 (73.7%) participants and at 1 mg/day by four (21.1%) participants. The maximum permissible dose (4 mg/day) was taken by seven (36.8%) participants during the study. The final dose ranged from 0.5 mg/day to 4 mg/day. For most participants, the final dose was 1 mg/day (4, 21.1% participants) or 2 mg/day (3, 15.8% participants) or 4 mg/day (6, 31.6% participants).  Overall, treatment compliance (as assessed by tablet count, liquid volume, and parent/carer report) was judged to be good.

 

The mean duration of treatment was 155.7 ± 53.7 days (range 6-189 days), with 13 (68.4%) participants taking risperidone between 113 and 182 days and 4 (21.1%) participants taking risperidone for more than 182 days.

Evaluation of Efficacy

 

Primary efficacy variable: Aberrant Behaviour Checklist

Considerable improvements were seen in total ABC scores by week 3 and steadily continued throughout the study (Table 2, Figure 1). The mean (± standard deviation) decrease in ABC total score from baseline to final visit (LOCF) was ‑43.8 ± 25.7 (p<0.0001) (PP population: n=12; -42.5 ± 29.6; p=0.0004). A positive response was seen in all treated patients, with the exception of one whose ABC total score increased from 119 at baseline to 142 at week 1 when he discontinued the study because of an adverse event (epilepsy; final dose 1 mg/day).

Table 2, Figure 1 here

 

Secondary efficacy variables

 

The mean (± standard deviation) decrease in ABC total scores from baseline to month 3 (-43.4 ± 20.9, p<0.0001) and to month 6 (-47.5 ± 20.9; p<0.0001) were highly significant.  Participants showed significant improvements from baseline to final visit in all ABC subscale scores (Irritability, Lethargy, Stereotypy, Hyperactivity and Inappropriate Speech; p≤0.0335; Table 2). Improvements mostly occurred during the first three weeks of treatment and were overall more gradual thereafter.

 

Significant improvements from baseline to final visit were also found for the total score of the Hostility Checklist (p<0.0001), and for both its Violence and Self-Injury subscale scores (p<0.0001; Table 3). Participants showed most improvement in the first two weeks and little sign of self injurious behaviour by month 4.

Table 3, Figure 2 here

 

Additionally, CGI-S was significantly better as measured from baseline at final visit (p<0.0001; Table 3).

 

Significant improvements were seen in the quality of life of participants, as measured by the Function, Upset and Satisfaction subscales of the CQOL rating scale (Table 3).  Improvement was noted on the Global item (i.e. a single question) but this did not reach statistical significance (p=0.557).

 

Evaluation of Tolerability

 

Adverse events

Thirteen (68.4%) participants reported 38 adverse events considered by the investigator to be possibly, probably or very likely drug-related.  Two events (suspected overdose of medication and grand mal convulsion) were serious and led to a temporary stop in trial medication; both participants made a full recovery. One event (epilepsy) led to withdrawal from the study and another (breast hypertrophy) reported at the final visit (thus not reported as a study discontinuation) led to a permanent stop in trial medication.  The most commonly affected body system was the nervous system (9 participants, 47.4%); drug-related events occurring in more than one (5.3%) participant are shown in Table 4.  Two of the aforementioned participants had three severe adverse events: one boy had breast hypertrophy (reported at final visit; final dose, 4 mg/day) and excess salivation; another boy with severe mental retardation and concomitant epilepsy had a grand mal convulsion after 21 weeks treatment (final dose 1.8 mg/day.  There were no reports of EPS or tardive dyskinesia.

Table 4 here

 

Other safety measurements

There were no changes of clinical significance seen in vital signs and physical findings, and all ECGs were considered within the normal range at the end of the study.  At the end of the study (month 6), changes (mean±SD) in body weight were 6.1±4.3 kg, pulse were 3.7±13.4 beats/min, respiration rate were 0.0±2.3 breaths/min and temperature were -0.22±0.72 oC.

 

Decreases in systolic (mean±SD; Month 6: -1.7±17.4 mmHg; p=0.7052; final visit LOCF: -0.8±17.2 mmHg) and diastolic (mean±SD; Month 6: -1.2±12.2 mmHg; p=0.7172; final visit LOCF: -1.6±11.7 mmHg) blood pressure were not statistically significant.  Two participants taking risperidone 1 mg/day were reported to have treatment-related hypotension, which was mild in severity. Kaplan-Meier estimates of the proportion of subjects who do not experience low blood pressure showed that the median time to first occurrence of either systolic or diastolic blood pressure decreasing >10 mmHg from baseline was week 4.

 

Discussion
The decision to prescribe powerful antipsychotic drugs to children and adolescents is not a decision that should be taken lightly. These drugs can have significant side effects and there may be longer term sequelae in this population that remain undefined due to a lack of clinical experience.  Some of the side effects of antipsychotics can be disabling in their own right. Weight gain can be a serious problem, from the point of view of the child’s physical health but also in terms of impairing mobility, which in turn may place an increased burden on the parents. Weight should be regularly monitored in the clinic and appropriate advice given regarding diet and exercise. In our clinic, we routinely monitor weight, vital signs, and electrocardiograms. We also obtain consent forms from parents for the off-label use of antipsychotics. The use of antipsychotics is not regarded in a trivial fashion.

 

The decision to treat must be justifiable. Antipsychotic treatment should not be regarded as the panacea for every child with a bad temper. The potential risks and benefits of treatment should be weighed against the potential risks and benefits of not treating, or of using some other intervention. One of the key criteria in this decision-making process is the risk to self and/or others. Many of these young people use weapons, set fires, attack their parents or siblings, and thus represent a considerable risk. It is incumbent upon mental healthcare professionals to tackle these problems and manage this risk.

 

There is a perception in some quarters that doctors are quite happy to dole out these drugs “like sweets”, but it is the experience of this author that clinicians working with young people with disruptive and challenging behaviours are very judicious in their use of these powerful drugs, which remain a second-line treatment to educational and psychological interventions.

 

DBDs are usually chronic conditions that require long-term management and, for children with intellectual disability who are particularly at risk of difficulties as adults, pharmacotherapy can play an important role in the management plan. Improvements in efficacy outcomes of disruptive behaviours, including violent and self-injurious behaviours, were seen in patients with mild, moderate or severe intellectual disabilities (who have previously undergone psychological therapy) treated with risperidone. The benefits seen with risperidone treatment were maintained for at least six months. No participants required hospitalisation and 14 (78%) participants continued risperidone treatment after study termination.

 

These findings are consistent with those of a previous four-week double-blind/48-week open-label study where risperidone monotherapy was successfully used to treat adults with mild and moderate intellectual disability and aggressive behaviours (Gagiano et al. 2005) and a three month open-label study of risperidone used to improve violent and self-injurious behaviours and quality of life of adults with moderate, severe or profound intellectual disability (Read & Rendell, 2007). They also support the findings of a 10-week, randomised, double-blind, placebo-controlled study that risperidone may have efficacy in the treatment of youths with conduct disorder (Findling et al. 2000), and of a six-week, multicentre, double-blind, placebo-controlled study in which risperidone was used in the treatment of severely disruptive behaviours in children with subaverage IQ (Aman et al. 2002).

 

Participants in the present study had disruptive and self injurious behaviour; where trialed, they were considered to have failed to respond to psychological therapy, and were typical of patients prescribed atypical antipsychotics. The majority of the study population was male, which is typical of the DBDs, as is the presence of comorbidities. The prevalence of epilepsy in people with an intellectual disability, for example, is reported to be higher than in the general population (McGrother et al. 2006).

 

The observed primary outcome of change from baseline to endpoint in the ABC total score is consistent with efficacy of oral risperidone in the treatment of disruptive behaviour in children and adolescents with intellectual disability within the first week of treatment and mostly within the first three weeks, and potential efficacy maintenance thereafter. After six-months treatment with risperidone, improvement for the group was over 50% from baseline. Participants had significantly less severe and overall fewer symptoms of irritability, hyperactivity, and inappropriate, violent and self injurious behaviours. Additionally, stereotypy, lethargy and inappropriate speech significantly improved. The results support previous findings that indicate individuals with more severe intellectual disability show a greater response to treatment than those with more mild deficiencies (Gagiano et al. 2005; Read & Rendell, in press).

Our findings with risperidone are also considered favourable with respect to a similar small study in adolescents with subaverage intelligence and DBDs treated with olanzapine in which improvements in lethargy, stereotypy, and inappropriate speech ABC subscales failed to reach statistical significance (Handen & Hardan 2006).

 

Interestingly, the faster rate of improvement seen in the Hostility Checklist total score compared with the ABC total score suggests that the behaviours measured on the ABC (irritability, lethargy, stereotypy, hyperactivity, and inappropriate speech) improve secondary to aggression (violent and self injurious behaviours). This supports previous findings that also suggest reduction in hostility to be the primary mode of action of risperidone, followed by other unwanted behaviours; in turn, improvement in autistic behaviour and depression are then seen (Read & Rendell, 2007).

 

Amelioration of symptoms and negative behaviours were reflected in an improvement in patients’ quality of life, with over a 20% improvement in all CQOL subscales measured.  Findings were significant regarding the subjects’ degree of functioning/performance, upset and satisfaction as evaluated on 15 domains. The CQOL global subscale is not a sum of all CQOL subscores but the response to a single question at the end of the CQOL questionnaire.  This overall improvement in quality of life did not reach statistical significance because the sample size was too small to detect a difference.  Other CQOL subscales had the composite score of 15 questions added together providing an additive effect. Regardless, the improvement in this subscale was the greatest at 26.5% from baseline and represents a clinically meaningful improvement in overall quality of life for youths with intellectual disability and DBDs.

 

The present study indicated that risperidone is well tolerated in this group of participants.  This is particularly important as risperidone has been shown to prevent relapse of DBD symptoms in children (Reyes et al. 2006b). The most common adverse events were headache, fatigue, somnolence and weight gain, which in the opinion of the investigator were of mild or moderate severity. No participants experienced extrapyramidal symptoms or tardive dyskinesia during the study. Fatigue and somnolence were not considered to be significant problem as the ABC lethargy subscale decreased. Some degree of somnolence or sedation may be considered a desired effect in treating symptoms of disruptive behaviour providing it does not impart a negative effect on cognitive function. Importantly, cognitive testing has demonstrated small improvements in performance tasks and verbal tests of children with DBDs and subaverage intelligence treated with risperidone (Reyes et al. 2006). Furthermore, a 48-week open-label study indicated that risperidone is effective in treating the symptoms of DBDs in children with subaverage IQ independent of the side effect of sedation (Turgay et al. 2002).

 

Weight gain was reported as an adverse event in three participants and increased for the group during the six month study. While possible weight changes may occur in participants taking risperidone, not all the weight gain should be attributed to risperidone.  Some of the weight gain should be attributed to the normal growth and development of these children and adolescents (Hamill et al. 1979). Weight gain (mean 6.1±4.3 kg) was comparable to that reported for subjects taking olanzapine in a recent small open-label trial in adolescents with subaverage intelligence and DBDs (Handen & Hardan 2006). However, a meta-analysis showed that risperidone was at the lower end of the scale of antipsychotics for inducing weight gain (Allison et al. 1999) and a systematic review of the atypical antipsychotics found risperidone to be associated with less weight gain than clozapine, olanzapine or quetiapine (Taylor & McAskill 2000). Weight gain associated with the use of atypical antipsychotics can be minimised in the developmentally disabled with psychiatric/behavioural syndromes by monitoring, diet and activity (McKee et al. 2005). Clinicians considering risperidone to treat symptoms of disruptive behaviour in subjects with intellectual disability should therefore counsel them and their caregivers in the management of this problem.  They are also recommended to monitor blood pressure, which may be reduced in some patients.

 

In this study, one 11-year-old boy was reported to have breast hypertrophy after six months treatment. Hyperprolactinaemia is a known adverse effect of antipsychotic medication, which can result in gynaecomastia (Haddad & Wieck 2004). Prolactin levels were not measured in this study, as it was expected that any initial increase would decline after the first few months of therapy (Findling et al. 2003).  However, clinicians should routinely screen young patients’ treated chronically with any of the antipsychotics for hyperprolactinemia and monitor for known sequelae.

 

One 15 year old boy (IQ 44) was withdrawn from the study following an adverse event indicating epilepsy. This adolescent was later diagnosed with a neurodegenerative disorder, which was likely to have been present at the time of the study, if not before. Examination of the efficacy results identified this patient to respond overall poorly to treatment, thus lowering the mean scores. This case highlights the difficulties in conducting trials in the intellectually disabled.

 

Limitations

Limitations of this study may extend to the general design and methods of all open-label studies, in that the unblinded design permits both investigator and patient bias. However, the open design is simpler to execute logistically and closer to the “real world” situation. The lack of a control group is a limitation, but there are no pharmacological treatments licensed in this indication to compare to, and it is unlikely that ethical approval would have been granted for the use of placebo beyond 4 to 6 weeks duration.

 

It is recognised that the participant numbers were relatively small. Also, although comedications were used by the study population, and may have influenced the findings, the situation does approximate the usual clinical situation.

 

Atypical antipsychotics have been associated with metabolic abnormalities (Haupt 2006), such as raised glucose and lipid levels, and these were not measured in this study. Neither were more formal methods of addressing weight gain in susceptible patients pursued above simple counselling regarding diet and exercise.

 

Furthermore, while providing treatment in the longer term, a further limitation is that, in the context of a child with disruptive behaviour, six months is still a short period of time, and it is possible that maximum improvements in quality of life may take longer. This may be particularly relevant where there is suggestion of continued improvement. It is therefore suggested that future research assesses even longer term quality of life.

 

Conclusions

Antipsychotic pharmacotherapy should be reserved for the treatment of those children who are causing havoc to themselves and other people and who have failed to respond adequately to primary intervention with educational or psychological treatments.

 

Results of this six-month study support the current literature that suggest that risperidone, along with antipsychotic drugs in general, may be effective in the treatment of disruptive behaviours in children with intellectual disability.  For the child with intellectual disability, disruptive behaviour may interfere with learning the skills necessary to become independent from the family, and compromise their inclusion in school and other activities. Moreover, a child with disruptive behaviours can be a major source of stress for the parents and other family members. The lack of control of disruptive, violent and self injurious behaviours may limit the potential for these youngsters to develop. Moreover, it may enable them to better function at home, at school and in the community compared to institutionalisation that may further compromise their social adjustment and quality of life.

 

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 Table 1. Baseline characteristics and diagnoses for the intent-to-treat population (n=18)

Demographic  
Gender, n (%)MaleFemale 16 (88.9)2 (11.1)
Age, years mean±SD, (range) 11.5±3.1 (6-16)
Race, n (%)CaucasianAsian

Mixed race

15 (83.3)2 (11.1)

1 (5.6)

Intelligence Quotient mean±SD, (range)1 55.9±12.3 (26-73)
Weight, kg mean±SD, (range) 40.5±17.6 (20.5-98.7)
Height, cm mean±SD, (range) 141.0±16.4 (115.0-172.7)
Blood pressure, mmHg mean±SD, (range)SystolicDiastolic 115.0±11.2 (83-130)71.8±11.4 (38-88)
Pulse, bpm mean±SD, (range) 80.2±11.5 (57-111)
Respiratory rate, breaths/min, mean±SD, (range) 17.1±1.9 (14-21)
Temperature, oC, mean±SD, (range) 36.3±0.55 (35.0-37.2)
Diagnosis, n (%)  
Axis I
            Autism   1 (5.6)
            Attention-Deficit Hyperactivity Disorder   2 (11.1)
            Attention-Deficit Hyperactivity Disorder, Dyspraxia   1 (5.6)
            Conduct Disorder   1 (5.6)
            Intermittent Explosive Disorder   1 (5.6)
            Disruptive Behaviour Disorder – NOS   8 (44.3)
            Organic Behaviour Disorder   4 (22.2)
Axis II
            Mild mental retardation (IQ 55-75) 11 (61.1)
            Moderate mental retardation (IQ 35-55)   3 (16.7)
            Severe mental retardation (IQ 20-34)   4 (22.2)
Axis III  
            Epilepsy   4 (22.2)
            Insomnia   4 (22.2)
            Myopia/wears glasses   3 (16.7)
            Angelman syndrome   1 (5.6)
            Migranous headaches   1 (5.6)

1, n=16

 

 

 

 

 

 

 

 

 

 


Table 2. Change from baseline to final visit in ABC total and subscale scores in intent-to-treat population (n=18)

 

ABC subscale  

Baseline

(mean±SD)

Change to final visit LOCF

(mean±SD)

p value

Total

85.3 ± 24.8

‑43.8 ± 25.7

<0.00011

            – Irritability

27.7±8.7

-14.1±9.0

<0.00011

            – Lethargy

12.7±9.7

-7.8±8.7

0.00151

            – Stereotypy

5.9±5.0

-2.7±5.0

0.03351

            – Hyperactivity

33.8±8.2

-17.3±12.5

<0.00011

            – Inappropriate speech

5.3±3.5

-2.0±2.3

0.00201

1Paired t-test; a negative change indicates improvement.

 

 

 

 


Table 3. Change from baseline to final visit for secondary efficacy variables in intent-to-treat population (n=18)

 

Assessment 

Baseline

(mean±SD)

Change to final visit LOCF

(mean±SD)

p value

Hostility Checklist total

34.3±21.9

-25.8±15.9

<0.00011

            – Violence

22.7±14.9

-15.9±9.5

<0.00011

            – Self-Injury

11.6±9.6

-9.9±9.1

<0.00012

Clinical Global Impression – Severity

4.7±0.8

-2.9±1.1

<0.00012

Child Health-Related Quality of Life3

-

-

-

            – Function/performance

62.0±11.5

-12.7±14.3

0.00151

            – Upset

63.5±11.6

13.7±13.2

0.00041

            – Satisfaction

58.4±11.3

-13.6±15.5

0.00171

            – Global

4.9±1.9

-1.3±2.3

0.05572

1Paired t-test; 2Wilcoxon matched pairs signed-rank test; a negative change indicates improvement, except for the Child Health-Related Quality of Life Upset total score where a positive change indicates improvement; 3Each subscale is scored on 15 domains: getting about and using hands, doing thing for his/her self, soiling or wetting, school, out of school activities, friends, family relationships, discomfort due to bodily symptoms, worries, depression, seeing, communication, eating, sleeping, and appearance.


Table 4.  Adverse events considered possibly, probably or very likely related to treatment occurring in more than one (5.3%) patient (n=19)

 

Adverse event

n (%)

No. of  patients with adverse event

13 (68.4)

Headache

5 (26.3)

Fatigue

3 (15.8)

Somnolence

3 (15.8)

Weight increased

3 (15.8)

Dizziness

2 (10.5)

Hypotension

2 (10.5)

Urinary incontinence

2 (10.5)

 

 

 

 

 


 

 

 

 

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