or autistic spectrum disorder--a systematic review.

Research in Developmental Disabilities 35 (2014) 711–725

Contents lists available at ScienceDirect

Research in Developmental Disabilities

Review article

The effectiveness of aripiprazole in the management of problem behaviour in people with intellectual disabilities, developmental disabilities and/or autistic spectrum disorder – A systematic review Shoumitro Deb a, Baldeep K. Farmah b, Ebrahim Arshad c, Tanya Deb a, Meera Roy d,*, Gemma L. Unwin e a

Imperial College, London, UK School of Psychiatry, West Midlands Deanery, Birmingham, UK c University of Birmingham, UK d Birmingham Community Healthcare NHS Trust, UK e School of Psychology, University of Birmingham, UK b

A R T I C L E I N F O

A B S T R A C T

Article history: Received 23 October 2013 Accepted 10 December 2013 Available online 7 January 2014

The management of problem behaviours (PB) in individuals with intellectual disabilities (ID), developmental disabilities (DD) and/or autistic spectrum disorders (ASD) can be challenging. Antipsychotic medications are commonly prescribed where other strategies have failed. A systematic review (SR) was conducted to establish the research evidence for the efficacy of aripiprazole in the management of PB in adults and children with ID, DD and/or ASD. Although included studies supported the efficacy of aripiprazole for this indication, the overall quality of studies was poor. Of the 20 studies included in this systematic review there were only two randomised controlled trials (RCTs) on children with ASD and/or ID/DD, both of which were conducted by the pharmaceutical company that manufactures aripiprazole, and it is not clear whether a number of same participants were included in both RCTs. One of the RCTs was extended into an open label long term follow up, which showed that aripiprazole’s efficacy lasted over 52 weeks and the adverse effects were tolerable. Four studies were open label prospective studies, 11 were retrospective case reports which included four single case reports, and two were prospective case series. Most studies reported adverse effects from aripiprazole in the form of weight gain, increased appetite, sedation, tiredness, drooling and tremor. However, aripiprazole improved serum prolactin level in some participants and overall did not show any adverse effect on QTc interval. There is a need for more carefully designed RCTs into the use of aripiprazole in the management of PB in people with ID/DD and/or ASD, which should be carried out independent of pharmaceutical companies. ß 2013 Elsevier Ltd. All rights reserved.

Keywords: Aripiprazole Intellectual disabilities ASD Developmental disabilities Problem behaviour Self-injurious behaviour Aggression

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

* Corresponding author. Tel.: +44 1214658851. E-mail address: [email protected] (M. Roy). 0891-4222/$ – see front matter ß 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ridd.2013.12.004

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S. Deb et al. / Research in Developmental Disabilities 35 (2014) 711–725

2.1. 2.2.

3.

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Search strategy . . . . . . . . . . . . . . . . . . . . . . . . Criteria for selecting studies for this review . 2.2.1. Types of studies . . . . . . . . . . . . . . . . Types of participants . . . . . . . . . . . . 2.2.2. Sample size . . . . . . . . . . . . . . . . . . . 2.2.3. Types of interventions . . . . . . . . . . . 2.2.4. Types of outcome measures . . . . . . 2.2.5. Selection process . . . . . . . . . . . . . . . . . . . . . . 2.3. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Search strategy . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Included studies . . . . . . . . . . . . . . . . . . . . . . . 3.2. Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Adverse effects . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction Aripiprazole (Abilify1, Bristol Myers Squibb) is an atypical antipsychotic and a quinolinone derivative. It is a partial agonist at dopamine D2 and 5-HT1A receptors and is an antagonist at 5-HT2 receptors. It has been described as a dopamine system stabiliser as, in high levels of dopamine production, it will act as an antagonist and where dopamine activity is low, it will act as an agonist. This means that aripiprazole is able to modulate the degree of the blockade of these receptors. Aripiprazole also has strong affinity for D3 receptors, moderate affinity for D4, 5-HT2C, 5-HT7, alpha-1 adrenergic receptors, histamine H1 receptors and serotonin reuptake transporter, with no appreciable affinity at the cholinergic muscarinic receptor. Aripiprazole has selective effects on the mesolimbic and frontal dopaminergic pathways. Selectively reducing dopamine synthesis in the ventral tegmental area is a possible therapeutic mechanism for the long-term efficacy of aripiprazole in controlling schizophrenia symptoms with minimum extrapyramidal adverse effects (Han, Huang, & Deng, 2009). Aripiprazole is licensed for treatment of schizophrenia, treatment and prevention of recurrence of mania and control of agitation and disturbed behaviour in schizophrenia in the UK. Additionally in the USA, it has been licensed by the food and drug administration (FDA) in 2002 for the treatment of irritability associated with autistic spectrum disorder (ASD). Aripiprazole remains unlicensed in the UK at present for the treatment of symptoms associated with intellectual disabilities (ID), developmental disabilities (DD), ASD and pervasive developmental disorder (PDD) such as problem (challenging) behaviour (PB). Among psychotropic medications, atypical antipsychotics, particularly risperidone, are used most commonly to manage PB in people with ID, DD, ASD and PDD (see Deb, 2013 for a review). It has been reported that 20–45% of people with ID are on psychotropic medication and 14–30% are receiving medication to manage a PB such as aggression or self-injurious behaviour (SIB) in the absence of a diagnosed psychiatric disorder (Deb & Fraser, 1994). Almost two thirds of psychotropic medications prescribed to people with ID are antipsychotics (Deb, 2013). This paper systematically reviews the evidence for the effectiveness of aripiprazole in the management of PB in people with ID, DD, ASD and PDD. 2. Methods 2.1. Search strategy Electronic databases of journal articles, namely EMBASE, PsycINFO, MEDLINE and Cochrane were the primary focus of the search. In order to lessen bias due to language limitation all papers with an abstract in English were included even if the full text was in another language. Broad search terms were used to describe ID, DD and ASD along with PB combined with aripiprazole (Abilify, Aripiprex) (see Appendix A). The search terms were adopted from the systematic reviews carried out to develop a national and an international guide for the use of psychotropic medications for the management of PB in adults with ID (Deb, Sohanpal, Soni, Unwin, & Lenoˆtre, 2007; Deb et al., 2009; Unwin & Deb, 2010, 2011). A specialist librarian also advised on the search terms. 2.2. Criteria for selecting studies for this review A list of criteria was devised which the studies had to meet in order to merit inclusion. The criteria were adopted from similar systematic reviews on psychotropic medications that have been published recently by some of the co-authors of this paper (Deb et al., 2007; Unwin & Deb, 2011) (see Appendix A).


713

2.2.1. Types of studies All types of trials, including controlled trials to case series in which the effectiveness of aripiprazole was evaluated in the management of PB in people with ID, DD and/or ASD/PDD were included. Only those studies where data were presented on PB outcome pre- and post-intervention with aripiprazole were included in this review. 2.2.2. Types of participants Individuals of any age were included. Individuals were required to have either ID (IQ below 70 associated with impairment in adaptive behaviour/social function, or as defined by the authors), and/or DD, and/or ASD/PDD. Furthermore they exhibited PB as defined by the authors such as SIB, physical and verbal aggression towards others and property, and any other type of PB, which were the primary targets for intervention with aripiprazole. Papers including participants presenting with a comorbid psychiatric diagnosis, attention deficit hyperactivity disorder (ADHD), or personality disorder (PD) were included if the study intervention was primarily and specifically to treat a PB. Those described as having borderline intelligence were also considered. 2.2.3. Sample size There were no lower or upper limits to the sample size. 2.2.4. Types of interventions The intervention to be assessed was aripiprazole. 2.2.5. Types of outcome measures Any outcome related to the PB before and after the intervention was assessed using an objective assessment tool. If there was no objective result, the authors’ subjective opinion was used. Each database was searched up to and on the 4th October 2013, with no restriction on the date of publication. Once the search for each database was completed, all citations were combined and duplicates removed manually by going through each of the titles. 2.3. Selection process Initially 258 titles were examined against the inclusion/exclusion criteria of which 126 were found to be suitable. The abstracts for the selected titles were examined against the inclusion/exclusion criteria using a pre-piloted proforma which was developed using NICE guideline (www.nice.org.uk) by some of the co-authors in the context of developing a national and an international guide for the use of medication for the management of PB in adults with ID (Deb et al., 2009; Unwin & Deb, 2010), and unsuitable abstracts were then excluded. Twenty-nine full texts were acquired for further scrutiny. Several were obtained due to abstracts not providing enough information to reliably include or exclude the article. Access to the full texts allowed us to decide whether these papers were suitable and of the 29 full texts evaluated against the inclusion/exclusion criteria, 20 were accepted for data extraction. Two reviewers carried out this process independently (BF and EA), where there were disagreements or uncertainties; these were settled by discussion and consultation with a third reviewer (MR). The data from each of the studies that met the inclusion criteria were extracted on pre-piloted data extraction forms (Deb et al., 2007) and the quality of each study was concurrently assessed using a standardised quality appraisal tool, the quality index (Downs & Black, 1998). This tool was developed to create a checklist for the assessment of the methodological quality of both randomised and non-randomised studies of health care interventions. The checklist consists of 27 items divided under subheadings such as reporting (10), external validity (3), internal validity-bias (7), internal validity-confounding (6), and power (1). Most items could be scored as 1 or 0, the power item is scored between 0 and 5, and one other item is scored between 0 and 2. Therefore, the total score possible for this quality index is 32. A higher score indicated a more reliable study. The quality index has shown overall good psychometric properties such as internal consistency (0.89), test–retest (r 0.88) and inter-rater (r 0.75) reliability (Downs & Black, 1998). The results of this can be seen in Table 1. 3. Results 3.1. Search strategy Two hundred and fifty eight citations were identified (EMBASE: 131, PsycINFO: 76, MEDLINE: 51, Cochrane: 0) and by combination duplicates were removed leaving 198 unique citations (see Fig. 1). Twenty-nine full texts were acquired of which 20 were included in this systematic review. The reason for identifying a large number of irrelevant titles was to do with the broad search terms (see Appendix A) used in order to be over inclusive at the outset. The primary reason for exclusion of papers on full text was that the excluded studies reported primarily the adverse effects of aripiprazole as opposed to its effects on PB. 3.2. Included studies In total 20 studies were found from the searches that fulfilled the inclusion criteria for this systematic review. Of the 20 studies included in this systematic review, there were only two randomised controlled trials (RCTs) (Marcus et al., 2009;

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Table 1 Participant inclusion and exclusion criteria for the studies. Study

Participant inclusion criteria

Target behaviour

Quality index

Owen et al. (2009)

Age 6–17 years DSM-IV criteria for ASD and diagnosis confirmed by ADI-R CGI-S 4 and ABC irritability score of 18 at screening and baseline Exclusion: current diagnosis of bipolar disorder, psychosis, schizophrenia, major depression, Fragile X syndrome or diagnosis of another disorder on the ASD including PDDNOS, history of NMS, suicide risk, history of seizures, history of head injury/stroke, unstable medical condition, abnormal lab tests, allergy/hypersensitivity to aripiprazole

Disruptive behaviours and SIB

25

Marcus et al. (2009)

(Same criteria as Owen et al., 2009) Exclusion: (same criteria as Owen et al., 2009)


25

Marcus et al. (2011a)

Age 6–17 years, body weight 15 kg DSM-IV criteria for ASD and diagnosis confirmed by ADI-R CGI-S score of 4 and ABC irritability score of 18 at screening and baseline Exclusion: current diagnosis of bipolar disorder, psychosis, schizophrenia, major depression, Fragile X syndrome or diagnosis of another disorder on the autism spectrum disorder including PDD-NOS


20

Stigler et al. (2009)

Age 5–17 years DSM-IV criteria for Asperger’s disorder or PDD-NOS Mental age of at least 18 months determined by Wechsler Intelligence Scale for children (WISC) Free of psychotropic medication for at least 2 weeks (4 weeks for fluoxetine) CGI-S score of 4 and ABC irritability score of 18 Exclusion: DSM-IV diagnosis of another PDD, other primary psychiatric disorder, active seizure disorder, other significant medical conditions, positive urine pregnancy test or history of NMS


22

Erickson et al. (2011)

Age 5–35 years, body weight 15 kg Fragile X syndrome diagnosis confirmed by southern blot and PCR with 200 CGG repeat expansion in FMR1 gene Mental age of less than 18 months determined by Wechsler scale of intelligence Free of psychotropic medication for at least 2 weeks CGI-S score of 4 and ABC irritability score of 18 Exclusion: DSM-IV diagnosis of psychotic disorder, bipolar disorder, active seizure disorder, other significant medical conditions, positive urine pregnancy test or history of NMS


16

Masi et al. (2009)

Age 4.5–15 years DSM-IV criteria for ASD or PDD-NOS Childhood Autism Rating Scale (CARS) score of 30 Exclusion: co-morbid medical or neurological conditions


14

Fung et al. (2012)

Age 4–18 years ADI-R diagnosis of ASD

Sensory impairments Problem behaviours

8

Ishitobi et al. (2012)

Age 9–25 years DSM-IV criteria for PDD

Problem behaviours

Valicenti-McDermott and Demb (2006)

Age 5–19 years DSM-IV criteria for PDD


20

Basgul and Uneri (2011)

Children and adolescents

Maladaptive behaviours

7

Hellings et al. (2011)

Children and adolescents 8–18 years Developmental disabilities including autism assessed by US Board certified psychiatrists

Disruptive behaviours

13


Age 5–18 years DSM-IV for PDD

Maladaptive behaviours

12

Jordan et al. (2012)

Adults over age 18 years ADI-R and ADOS diagnosis of ASD supported by expert clinicians diagnosis

Behaviour disorder

6


715

Table 1 (Continued ) Study

Participant inclusion criteria

Target behaviour

Quality index


Age 4–11 years PDD method of diagnosis not defined

Irritability Hyperactivity Social withdrawal

6

Ku¨ltu¨r et al. (2009)

Age 10–16 years DSM-IV for PDD-NOS and ID confirmed by two independent psychiatrists

Problem behaviours

15

Huang et al. (2010)

Age 7–11 years ASD and PDD-NOS (unspecified diagnosis method)

Primarily ASD symptoms but also problem behaviours

11

Dratcu et al. (2007)

Age 41 years Asperger’s and schizophrenia defined by DSM-IV

Primarily ASD symptoms but also problem behaviours

13

Shashtri et al. (2006)

Adults over age 18 years ASD and ID (unspecified diagnosis method)

Problem behaviours

9

Staller (2003)

Age 34 years DSM-IV for Asperger’s and ID

Core symptoms of ASD but also irritability

8

Pardini et al. (2010)

Age 29 years ASD (diagnosed by experienced clinicians and validated scales)

Coprophagia

4

DSM-IV-TR, diagnostic and statistical manual of mental disorders, fourth edition, text revision; ASD, autistic spectrum disorder; ADI-R, autism diagnostic interview – revised; CGI-S, clinical global impressions – severity; ABC, aberrant behaviour checklist; PDD-NOS, pervasive developmental disorder – not otherwise specified; NMS, neuroleptic malignant syndrome; SIB, self-injurious behaviour; PCR, polymerase chain reaction; ID, intellectual disabilities; DD, developmental disabilities; ADOS, autism diagnostic observation schedule.

EM EMBASE

PsycINFO

MEDLINE

Cochrane Database

131 Citaons

76 Citaons

51 Citaons

0 Citaons

Citaons Combined and duplicates removed 198 Citaons

Excluded on Title

126 Citaons

Excluded on Abstract 29 Citaons

Excluded on Full Text 20 Citaons Fig. 1. Flow chart for paper selection.

716


Owen et al., 2009) on children with ASD and/or ID/DD (see Table 1), both of which were conducted by the pharmaceutical company that manufactures aripiprazole, and it is not clear whether a number of same participants were included in both RCTs. Marcus and colleagues’ (2009) RCT was extended into an open label long term follow up (Marcus et al., 2011a), which showed that aripiprazole’s efficacy lasted over 52 weeks and the adverse effects were tolerable. Of the participants included in the extended study, 174 received aripiprazole treatment in the preceding RCT, 70 were in the placebo group, and another 86 were included de-novo. The participants took aripiprazole 2–15 mg/day. The eligibility criteria were the same as that of the RCT that preceded the extension study. Four studies were open label prospective studies (Erickson et al., 2011; Ku¨ltu¨r, Tiryaki, & Tasgin, 2009; Stigler et al., 2009, 2011), 11 were retrospective case reports (Basgul & Uneri, 2011; Fung, Chahal, Libove, Bivas, & Hardan, 2012; Hellings, Boehm, Yeh, Butler, & Schroeder, 2011; Huang, Tsai, & Yang, 2010; Ishitobi et al., 2012; Jordan, Robertson, Catani, Craig, & Murphy, 2012; Masi et al., 2009; Valicenti-McDermott & Demb, 2006), which included three single case reports (Pardini, Guida, & Gialloreti, 2010; Shashtri, Alla, & Sabaratnam, 2006; Staller, 2003), and one was a prospective case series (Stigler, Posey, & McDougle, 2004) and another one was possibly a prospective single case report (Dratcu, McKay, Singaravelu, & Krishnamurthy, 2007). Shashtri and colleagues’ (2006) study reported effect of aripiprazole on five adults with ID but of them four were treated for psychosis and only one was treated for PB. Therefore, data on one adult with PB were included in this systematic review. 3.3. Design Quality index scores of the studies ranged from 4 to 25 out of a possible maximum score of 32 (see Table 1). There were 843 participants of which 755 received aripiprazole treatment and 88 received placebo. Of the 755 participants who received aripiprazole treatment, 637 had a primary diagnosis of ASD/PDD, 68 DD, and further 50 ID (see Table 2). ASD and PDD diagnoses were used interchangeably and so were the diagnoses of DD and ID. There was also overlap between ASD/PDD and ID/DD diagnoses. The age of the participants in the studies ranged from 5 to 41 years, although most studies recruited children and adolescents, with the average daily dose of aripiprazole at study end point ranging from 3.2 mg to 30 mg. Only Jordan and colleague’s (2012) retrospective case series and Shashtri and colleagues’ (2006) retrospective single case report included adults exclusively. Settings varied from outpatient (Erickson et al., 2011; Marcus et al., 2009, 2011a; Owen et al., 2009; Valicenti-McDermott & Demb, 2006) to inpatient (Dratcu et al., 2007) and a combination of both (Hellings et al., 2011; Masi et al., 2009). In total there were 687 outpatients and 36 inpatients. The status of the rest of the participants was unknown. There was a single community based patient (Shashtri et al., 2006). One study included patients with Fragile X syndrome (Erickson et al., 2011). Fragile X syndrome was associated with either ASD or ID. Hellings and colleagues (2011) included 21 patients with ID and/or ASD of which 18 had a concomitant diagnosis of ADHD further to which five also had a diagnosis of bipolar disorder. Seventeen of the 20 studies reported diagnoses of ASD/PDD in some or all of the individuals studied. Furthermore four studies included overall 16 patients with Asperger’s syndrome among them (Dratcu et al., 2007; Jordan et al., 2012; Staller, 2003; Stigler et al., 2009). Most studies examined the effects of aripiprazole on aggressive behaviours and some also looked at self-injurious behaviour (SIB). Three studies looked at the effects of aripiprazole on social interaction (Dratcu et al., 2007; Huang et al., 2010; Ku¨ltu¨r et al., 2009). A single case report looked at the effects of aripiprazole on coprophagia in ASD (Pardini et al., 2010). One case series reported effects of aripiprazole on both sensory abnormalities and PB in participants with ASD (Fung et al., 2012). The vast majority of participants were described as having undergone trials with several psychotropic medications prior to starting aripiprazole and many displayed behaviours considered to be refractory to treatment. Two studies in fact switched patients from risperidone to aripiprazole (Ishitobi et al., 2012; Stigler et al., 2011). Of these two studies, Stigler and colleagues (2011) only switched those patients to aripiprazole who were considered non-responders to risperidone. Both studies compared adverse effect profiles between aripiprazole and risperidone. Additionally Stigler and colleagues’ (2011) study considered aripiprazole’s efficacy on those who did not respond to risperidone therapy. In Ishitobi and colleagues’ study (2012) a number of adverse effect produced by risperidone were shown to have improved with aripiprazole treatment. Interestingly Stigler and colleagues’ (2011) study also assessed comparative efficacy among six patients who were switched to aripiprazole treatment alone (ARI group) with another six patients who were switched over to aripiprazole treatment but additionally received behaviour therapy in the form of parental training (COMB group). Their finding is interesting in that they found a significant improvement at end point of trial in the COMB group but not in the ARI group according to most of the outcome measured used. Aripiprazole was commenced in 755 patients with a starting range of 1.25–10 mg per day with 77% being commenced at 2 mg. The maximum dose of aripiprazole varied from 5 mg (Ku¨ltu¨r et al., 2009) to 30 mg (Jordan et al., 2012; ValicentiMcDermott and Demb 2006) with 92% having an end dose of 15 mg. In fact in Jordan and colleagues’ study (2012) the one participant who received aripiprazole at 30 mg a day dose was the only non-responder among the group of five and the only one who developed adverse effect in the form of akathasia. Most studies did not clarify whether or not aripiprazole was used as an adjunct but six studies declared no concomitant psychotropic medication use. Four studies described the use of concurrent psychotropic medications in the participants studied. Six participants were prescribed stimulants, two were prescribed antidepressants and one was titrated down from risperidone over the initial six weeks of a fifty-two week study. Some were also prescribed antiepileptic medication in the form of either sodium valproate or carbamazepine.

Table 2 Characteristics of the included studies with outcome data. Dose of ARI at EP

Patient type

Number

Outcome

Result

Owen et al. (2009)

Double blind RCT Flexible dose

10 mg

ASD: 98

N: 75 ARI: 39 P: 36 FU: 8 wks

ABC-I CGI-I CGI-S CYBOCS

ABC-I showed significant improvement for ARI 12.9 (p < 0.001) group vs. P 5.0 CGI-I showed significant mean improvement of 2.2 (much improved) in ARI group compared with 3.6 for placebo (no change) CGI-S showed significant improvement of 1.2 from ‘‘markedly ill’’ to ‘‘moderately ill’’ for ARI and 0.8 for P


Double blind RCT Fixed dose

Placebo 5 mg 10 mg 15 mg

ASD: 218

N: 218 ARI: 166 P: 52 FU: 8 wks

ABC-I CGI-I CGI-S CYBOCS

ABC-I showed significant improvement for ARI group vs. P Mean ABC-I change from BL P 8.4, ARI 5 mg 12.4 (p < 0.32), ARI 10 mg 13.2 (p < 0.008), ARI 15 mg 14.4 (p < 0.001) CGI-I showed statistically significant greater improvement in ARI vs. P P 3.3, ARI 5 mg 2.6 (p < 0.003) ARI 10 mg 2.5 (p < 0.001) ARI 15 mg 2.5 (p < 0.001) CGI-S showed average mean change of 1.0 for ARI and 0.6 for P (not significant)


Open label flexible dose Continuation of Marcus et al.’s (2009) RCT

0 mg 2 mg 5 mg 10 mg 15 mg

ASD: 330

N: 330 ARI: 330 FU: 52 wks

ABC-I CGI-I CGI-S CYBOCS PedsQL CGSQ

ABC-I improved by 8.0 for de-novo participants, 6.1 for participants on placebo in the previous RCT and a decrease of 0.6 for those on aripiprazole in the previous RCT CGI-I showed significant improvement with 58% scoring either 1 (very much improved) or 2 (much improved) CGI-S showed improvement of 0.8 for de-novo participants and 0.4 for participants who were on placebo in the previous RCT, and no change for those who had been on aripiprazole in the previous RCT


Open label flexible dose

15 mg

DD: 21 ASD: 4

N: 25 ARI: 25 FU: 14 wks

ABC-I CGI-I VABS CYBOCS

ABC-I showed improvement from BL 29 7.3 to EP 8.1 7.5 (p < 0.001) CGI-I showed improvement from BL 4.0 0.0 to EP 1.6 0.9 (p < 0.0001)


Open label Flexible dose

9.8 mg

Fragile X with ASD: 12

N: 12 ARI: 12 FU: 12 wks

ABC-I CGI-S CYBOCS SRS

ABC-I showed significant improvement with average decrease of 18.2 points from BL 25.3 (p < 0.001) CGI-S showed improvement from 4.5 0.5 at BL to 3.5 0.5 at EP (p < 0.008) 87% showed improvement as per CGI-I score of 1 or 2

Masi et al. (2009)

Case series Retrospective

8.1 mg

DD: 24 ASD: 10

N: 34 ARI: 34 FU: 28 12 wks

CGI-I CGI-S C-GAS CARS

Mean CGI-I at EP was 3.1 1.0 with 32% scoring either 1 or 2 (very much improved to much improved), 35% scoring 3 (minimally improved), 21% scoring 4 (unchanged) and 9% scoring 5 (worsened) BL CGI-S was 5.7 0.8

Fung et al. (2012)


10.8 mg

ASD: 13

N: 13 ARI: 13 FU: 24.4 wks

ABC SPQ

ABC: significant improvement in all subscales (p = 0.002) SPQ: significant improvement in some subscales: poor registration (p = 0.031); inattention/destructibility (p = 0.009)


Case series Retrospective Switch from risperidone to aripiprazole

2.8 1.3 mg

PDD: 23

N: 23 ARI: 23 FU: 14.9 8.4 wks

CGI-I CGI-S Score changes compared from the time of switch over from risperidone

Mean CGI-S score from pre-ARI 4.7 1.4 to post ARI 4.6 1.3 (non-significant) CGI-I: 4/23 (17.3%) ‘much improved’ (2), 6/23 (26.1%) ‘minimally improved’ (3), 12/23 (52.1%) ‘unchanged’ (4), 1/23 (4.3%) ‘worsened’ (5)



10.55 mg

DD: 18 ID: 14

N: 32 ARI: 32 FU: 26 12 wks

GCI

ARI was found to be effective in 18 children (56%). Predominant improvement in aggression in 15 of 28, and in hyperactivity in 10 of 21

717

Study type


Study

Study type

Dose of ARI at EP

Patient type

Number

Outcome

Result


Case series Possibly retrospective

NS

ID: 15 ASD: 13

N: 28 ARI: 28 FU: 8 wks

Subjective opinion CGI-I

Subjective opinion: all of the patients appear to benefit from aripiprazole



8.4 mg

ID: 21

N: 21 ARI: 21 FU: 61 wks

CGI-I

11 of 21 patients (52%) met CGI-I response criterion of CGI 2


Case series Prospective

12 mg

ASD: 2 NS: 3

N: 5 ARI: 5 FU: 12 wks

CGI-I

2 Cases showed CGI-I score of 1 (very much improved) and 3 cases of CGI-I score of 2 (much improved)



7.5–30 mg

ASD: 5

N: 5 FU: varied from weeks to months

CGI-I

4/5 (80%) patients were rated ‘much improved’ or ‘very much improved’ according to CGI-I


Open label Prospective

PDD: 12

N: 12 ARI: 6 ARI + behaviour therapy (COMB): 6 (all 12 are non-responders to risperidone therapy) FU: not reported

ABC subscales CGI-I

CGI-I: COMB: 2 0.6 (p = 0.001); ARI: 3 1.3 (not significant) ABC-I: COMB: 26.6 3.8 to 13.4 6.3 (p = 0.006); ARI: 31.2 5.2 to 23 9.8 (not significant) ABC-H: COMB: (p = 0.02); ARI: (not significant) ABC-SW: COMB: (p = 0.08); ARI: (not significant)


Open label Prospective

5–10 mg

DD: 3


ABC-I CGI-I CPRS

ABC-I showed slight improvement CGI-I showed 1 patient to have much improvement and 2 patients to have minimal improvement

Huang et al. (2010)

Case series Possibly retrospective

5 mg mg

DD: 2 ASD: 1


CBCL

Case 1 showed an improvement of 63% on the CBCL and case 2 showed an improvement of 38.8%. Case 3 was not scored on CBCL and a subjective opinion described improvements in his disruptive behaviours


Case Report Possibly prospective

15 mg

ASD: 1


Subjective opinion

Favourable change in the participant’s overall behaviour and psychological state


Case report Retrospective

15 mg

ID: 1


Subjective assessment

Incidents reduced from 16–20 per month to 1–2 per month

Staller (2003)


10 mg

ASD: 1


Subjective opinion

Patient became more calm, co-operative, patient and attentive



15 mg

ASD: 1


Subjective reporting

Coprophagia diminished within 8 weeks though marked reduction at 4 weeks

QI, quality index; RCT, randomised controlled trial; N, number; ARI, aripiprazole; P, placebo; FU, follow up; Wks, weeks; BL, baseline; EP, endpoint; CGI-I, clinical global impression – improvement; CYBOCS, Children’s Yale-Brown Obsessive Compulsive Scale; PedsQL, Paediatric Quality of Life Inventory; CGSQ, Caregiver Strain Questionnaire; VABS, Vineland Adaptive Behaviour Scale; SRS, Social Responsiveness Scale; C-GAS, Children’s Global Assessment Scale; CARS, Childhood Autism Rating Scale; GCI, Global Clinical Impression; CPRS, Comprehensive Psychopathological Rating Scale; CBCL, Child Behaviour Checklist; SPQ, Sensory Profile Questionnaire; ABC-I, Aberrant Behaviour Checklist-Irritability subscale; ABC-H, ABC-hyperactivity subscale; ABC-SW, ABC-social withdrawal subscale.


Study

718

Table 2 (Continued )


719

There was a large variety of studies included in this systematic review that used several different outcome measures. There was no standardisation between studies which made it difficult to directly compare the different studies and some of the outcome measures used contain a subjective component which can create bias. Similarly no meta-analysis of study data could be undertaken as there were only two RCTs published by the same group in the same year, which did not clarify the possible overlap of participants in these two studies. Therefore in this paper we summarised findings from all included studies in a descriptive manner in the text and in the tables. The most common outcome measure used in eight studies was clinical global impressions-improvement (CGI-I) (Guy, 1976a,b). Six studies also used Aberrant Behaviour ChecklistIrritability (ABC-I), and some studies also included other subscales of ABC (Aman, Burrow, & Wolford, 1995). A further five studies used Clinical Global Impressions-Severity (CGI-S) scale (Guy, 1976a,b). Five studies included Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS) (Scahill et al., 1997) and six studies reported outcome based only on a subjective opinion. 3.4. Outcome Outcome data from the included studies are summarised in Table 2. All the studies found an improvement with the use of aripiprazole for management of PB in people with ID, DD and/or ASD/PDD. The Clinical Global Impression-Improvement Scale (CGI-I) is a seven point scale that requires the clinician to assess how much the patient’s illness has improved or worsened relative to a baseline state at the beginning of the intervention and rated as: 1, very much improved; 2, much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; or 7, very much worse. Both RCTs found the outcome ‘much improved’ on the CGI-I scale for aripiprazole compared with placebo which was ‘minimally improved’. In Marcus and colleagues’ (2009) study the outcome among three different dosage of aripiprazole was not significant. Five further studies showed an improvement in CGI-I score in the participants who were treated with aripiprazole (Hellings et al., 2011; Jordan et al., 2012; Ku¨ltu¨r et al., 2009; Stigler et al., 2004, 2009). There were some reports of non-response to aripiprazole. For example, in Jordan and colleagues’ (2012) study one out of five participants did not respond. Masi and colleagues (2009) although showed mainly improvement, 30% showed no improvement or worsening. Ishitobi and colleagues’ (2012) study showed ‘much improved’ (score ‘20 ) only on 17% participants and the rest showed worse outcome. However, it is worth remembering that in this study most patients already showed improvement on risperidone leaving little scope for further improvement when switched over to aripiprazole from risperidone as the reason for the switch over was not lack of response but emergence of adverse effects from risperidone treatment. The Clinical Global Impression-Severity scale (CGI-S) is also a seven point scale that requires the clinician to rate the severity of the patient’s illness at the time of assessment, relative to the clinician’s past experience with patients who have the same diagnosis, with the same scoring method as CGI-I. General improvement was noted across four studies. Masi and colleagues (2009) measured CGI-S at baseline only. The Aberrant Behaviour Checklist, or ABC, seeks to quantify the analysis by evaluating the participants on the outward manifestation of PB. There are 58 listed symptoms on the ABC checklist ranging from crying to hitting or breaking things. The scores are categorised into five subscales, one of which is ‘Irritabiltiy, agitation and crying’ (ABC-I). Most studies showed significant improvement on ABC-I except Ku¨ltu¨r and colleagues’ (2009) study which only showed slight improvement. Marcus and colleagues’ (2011a) open label continuation study which followed their RCT (2009) showed an improvement on ABC-I score for de-novo participants (participants who had not been involved in the preceding RCT) and participants who received placebo in the preceding RCT. Participants who were in the aripiprazole treatment group in the preceding RCT maintained their improvement obtained in the RCT. Five studies gave a subjective opinion as an outcome measure which stated general improvement in participants’ symptoms (see Table 2). Shashtri and colleagues (2006) found that there was a reduction in incidents of PB from 12–16 per month to 1–2 per month. 3.5. Adverse effects Data related to adverse effects are summarised in Table 3. Eighteen of the 20 studies reported adverse effects except Basgul and Uneri (2011), and Marcus et al. (2011a). However, in a separate paper Marcus et al. (2011b) reported adverse effect profile on the participants studied in their open label extension study (2011a), which was not included in this systematic review as that paper does not contain any new aripiprazole effectiveness data. The two RCTs (Marcus et al., 2009; Owen et al., 2009) were the only studies that were able to compare adverse effects in the aripiprazole group with a placebo group. According to these two RCTs the rate of adverse effects in the aripiprazole group was significantly higher than the placebo group. Adverse effects were usually mild or moderate and treatment was only withdrawn on a minority of patients. However, both in Ishitobi and colleagues’ (2012) and Stigler and colleagues’ (2011) studies a comparison was made of adverse effects of risperidone vs. aripiprazole as in both studies participants were switched over from risperidone treatment to aripiprazole treatment. Ishitobi and colleagues (2012) in fact reported improvement in a number of adverse effects from risperidone when the participants were switched over to aripiprazole. Weight related changes were discussed in several studies either by direct reference to weight change or change in body mass index (BMI). Owen and colleagues (2009) recorded a mean weight gain of 2 kg in the aripiprazole group compared with 0.8 kg (p = 0.005) in the placebo group. There was one case of clinically significant weight gain of 7% increase from baseline in


720 Table 3 Adverse effects described in the studies. Study

Adverse effects

Owen et al. (2009)

Increased appetite: ARI: 15%; P: 10% Fatigue: ARI: 21%; P: 4% Somnolence: ARI: 17%; P: 4% Sedation: ARI: 11%; P: 2% Vomiting: ARI: 15%; P: 4% Headache: ARI: 6%; P: 16% (Differences between treatment and placebo were not statistically significant)


Tremor: ARI: 10%; P 0% Sedation: ARI: 23%; P: 6% Fatigue: ARI: 14%; P: 0% Drooling: ARI: 9%; P: 0% Vomiting: ARI: 13%; P: 8% Somnolence: ARI: 8%; P: 4% Increased Appetite: ARI: 12%; P: 4% Headache: ARI: 7%; P: 4% (Differences between treatment and placebo were not statistically significant)


Refers to adverse effects in Marcus et al. (2009)


Tiredness: 60% Cough: 48% Increased Appetite: 44%

Nausea/vomiting: 40% Rhinitis: 40% Diarrhoea: 36%


Tiredness: 44% Nausea/vomiting: 25%

Drooling: 25% Insomnia: 19%

Masi et al. (2009)

Agitation: 26% Sleep disorders: 15%

Tremors: 3% Weight gain: 3%


Drowsiness: 19% Weight gain: 12%

Abdominal pain: 6% Aggression: 6%


No details of adverse effects


4 Individuals (19%) experienced significant increases in appetite and weight


Case 1: moderate daytime sedation for first 14 days Case 3: mild dizziness


Salivation Constipation

Decreased sleep Weight gain


BMI change: 17 2.1 to 20.3 2.6 (p = 0.0001) 10/12 Mild drooling 1/12 Mild muscle twitching 1/12 Mild tremor

Fatigue Mild headache Increased appetite Cough Mild vomiting

Fung et al. (2012)

11/13 Increased appetite 6/13 Sedation/tiredness 2/13 Drooling 1/13 Skin rash

1/13 Lower extremity tremor 1/13 Slurred speech 1/13 Olfactory abnormality Weight gain (0.9–12 kg) (5.2 3.9 kg)


One developed insomnia 2/2 Daytime sleepiness improved 7/11 Obesity improved 3/3 Hyperprolactinaemia improved 1/1 Amenorrhoea improved

Improvements were recorded after switching to aripiprazole in a number of adverse effects that appeared in a number of patients after treatment with risperidone


One patient developed akathasia who received 30 mg aripiprazole a day

This patient’s ASD symptoms also got worse with aripiprazole treatment

Huang et al. (2010)

Case 1, 2 and 3: no adverse effects


No adverse effects


Tremors in upper limbs after 4 months of treatment at 15 mg dosage

Staller (2003)

Minor fatigue


No adverse effects

the aripiprazole group. Owen and colleagues (2009) reported an average increase in BMI of 1.4 kg/m2 in the aripiprazole group compared with 0.3 kg/m2 for the placebo group. Marcus and colleagues (2009) reported an average weight gain at end point for the aripiprazole group was 1.5 kg compared with 0.3 kg for the placebo group. Marcus and colleagues (2009) recorded a small mean increase in BMI of 0.7 kg/m2 in the aripiprazole group compared with a mean increase of 0.3 kg/m2 in the placebo group. On the other hand, Erickson et al. (2011), and Masi and colleagues (2009) reported overall no significant changes in weight from baseline to end point. However, Masi and colleagues (2009) discussed one adolescent participant who experienced a weight gain of 9 kg.


721

Valicenti-McDermott and Demb (2006) measured BMI changes in 23 of the 32 participants enrolled in their study and reported a significant BMI increase from mean baseline measure of 23.3 7.2 kg/m2 to an end point measure of 24.1 7 kg/m2 (p = 0.003). It was suggested that a greater BMI change was found in children younger than 12 years. Hellings and colleagues (2011) reported a change from a mean baseline measure of BMI of 23.8 5.9 kg/m2 to an end point measure of 24.2 5.2 kg/m2. It was also discussed that changes in BMI were not significantly different between aripiprazole responders and non-responders. Two patients also showed marked weight increase of 7.8 kg over study period. Stigler and colleagues (2004) showed two subjects lost weight, two subjects had no change and one subject gained weight of 3.7 kg. Ku¨ltu¨r and colleagues (2009) reported a patient with weight increase of 2 kg per month for the whole duration of study. The overall findings of the studies included in this systematic review suggest that aripiprazole treatment is associated with an increase in body weight. Tremor was another commonly reported adverse effect. The two RCTs (Marcus et al., 2009; Owen et al., 2009) did not report any significant difference in adverse effects between the aripiprazole treatment group and the placebo group according to the score obtained by the Sympson Angus Extrapyramidal Scale (Simpson & Angus, 1970), Abnormal Involuntary Movement Scale (AIMS) (Guy, 1976a,b) and Barnes Akathasia Rating scale (BAS) (Barnes, 1989). However, Marcus and colleagues (2009) showed that there was a statistically significant improvement in AIMS score in aripiprazole group compared with the placebo group. Most studies did not measure prolactin level. Two RCTs (Owen et al., 2009; Marcus et al., 2009) found that either aripiprazole was effective in decreasing serum prolactin level when compared with the placebo or there was no significant change in serum prolactin level when compared with the placebo. In Marcus and colleagues’ (2009) study one participant showed elevated serum prolactin levels which was clinically relevant. In Ishitobi and colleagues’ (2012) study all three participants who developed hyperprolactinaemia from risperidone treatment improved significantly when switched over to aripiprazole. In Owen and colleagues’ RCT (2009) mean serum prolactin levels at baseline were 6.8 ng/ml for the placebo group and 9.8 ng/ml for the aripiprazole group respectively. At end point aripiprazole was associated with a significant decrease to 3.5 ng/ml compared with the placebo 8.4 ng/ml (p = 0.001). Three participants in the placebo group and one participant in the aripiprazole group experienced potentially clinically relevant prolactin elevation. In Marcus and colleagues’ RCT (2009) study serum prolactin levels were similar among aripiprazole treatment groups and placebo at baseline (placebo, 6.9 ng/ml; aripiprazole 5 mg/day, 7.2 ng/ml; aripiprazole 10 mg/day, 6.5 ng/ml; and aripiprazole 15 mg/day, 6.7 ng/ml). All aripiprazole doses were associated with significant decreases in serum prolactin levels at end point (aripiprazole 5 mg/day, 5.4 ng/ml; aripiprazole 10 mg/day, 5.2 ng/ml; and aripiprazole 15 mg/day, 5.8 ng/ml) compared with the placebo (+0.9 ng/ml) (all p = 0.001). No participants treated with aripiprazole had potentially clinically relevant elevated serum prolactin levels (greater than the upper limit of normal range) at end point as opposed to two participants (4.4%) in the placebo group. Stigler and colleagues (2009) showed prolactin levels decreased significantly over the 14 weeks from baseline mean measure of 9.3 5.2 ng/ml to end point measure of 2.9 3.4 ng/ml (p = 0.0001). Erickson and colleagues (2011) showed a decrease in serum prolactin from baseline measure of 9.1 6.3 ng/ml to end point measure of 4 5.3 ng/ml (p = 0.06). These findings suggest that treatment with aripiprazole is associated with a decrease in serum prolactin level. Some of the included studies investigated changes in QT interval (QTc). There was no clinically significant change between aripiprazole and placebo in the two RCTs. Owen and colleagues (2009) found that the mean change in QTc from baseline to end point was similar between the aripiprazole (baseline: 377.6 ms; end point: 378.2 ms) and the placebo (baseline: 376.3 ms; endpoint: 380.8 ms) groups. Marcus and colleagues (2009) showed a decrease in QTc interval from baseline to end point observed in the aripiprazole group (aripiprazole 5 mg at baseline: 373.5 ms and at end point: 372.7 ms; aripiprazole 10 mg at baseline: 380.2 ms and at end point: 375.7 ms; aripiprazole 15 mg at baseline: 378.2 ms and at end point: 373.8 ms) which were not significantly different to changes seen in the placebo group (baseline: 382.6 ms and end point: 382.6 ms). Stigler and colleagues (2009) found no significant changes in heart rate or blood pressure in addition to no significant changes between baseline and end point on ECG measures including QTc interval. Erickson and colleagues (2011) also found no clinically significant changes in pulse or blood pressure and ECG including QTc interval. Findings from the included studies suggest that aripiprazole treatment is not associated with an increase in QTc interval. 4. Discussion The scores according to the Quality Index used in this systematic review show that most studies included in this review are of poor quality except the two RCTs and one extension study from one of the RCTs. Our systematic review shows that there are currently only two RCTs demonstrating aripiprazole’s efficacy in improving PB among a cohort of children with ASD (Marcus et al., 2009; Owen et al., 2009) but no RCT on adults have been reported. However, both of these studies were carried out by Bristol-Myers Squibb, manufacturer of aripiprazole. It is also not clear whether or not there is overlap among the participants recruited in these two studies as they were published in the same year (2009) by almost the same group of authors using almost the same methodology and assessment tools. The only obvious difference is that Marcus and colleagues (2009) reported effects of three fixed doses of aripiprazole whereas Owen and colleagues (2009) reported effect of variable dose of aripiprazole. In these studies, it was not discussed how randomisation took place for each arm of the RCTs and also there were no power calculations to indicate strength of these studies. An extension open label study by the same authors as of one of the RCTs was also conducted by Bristol-Myers Squibb. All of these papers showed a general improvement with aripiprazole supported by their primary and secondary outcomes. It should be recognised that the studies by Bristol-Myers Squib contained 74% of all participants comprised in this systematic review (623 of total 843).

722


Not all participants in the reported case series showed improvement in target PB. Particularly interesting finding was presented by Stigler and colleagues (2011) in which six non-responders to risperidone when switched over to aripiprazole treatment alone did not show any improvement but in another group of six risperidone non-responders there was significant improvement with treatment with aripiprazole when combined with a behaviour management programme, particularly geared to training parents on behaviour management. It is, therefore, difficult to say whether it is the behaviour management or the aripiprazole that brought about the improvement in these participants. It is difficult to comment definitively at this stage whether or not there is any dose related effect of aripiprazole because of results available from a small number of participants. However, Owen and colleagues’ study point towards a possible better effect of aripiprazole 15 mg per day dose than 10 mg per day and subsequently may be a slightly better result from 10 mg a day dose compared with 5 mg per day. However, a small retrospective study (Jordan et al., 2012) showed that of the five participants included, one who received aripiprazole 30 mg per day also was the only non-responder who also developed adverse effect in the form of akathasia. Most studies reported adverse effects from aripiprazole in the form of weight gain, increased appetite, sedation, tiredness, drooling and tremor. Although adverse effects were noted, all the papers agreed that there were fewer adverse effects with aripiprazole compared with other psychotropic medications used prior to aripiprazole. In fact some studies showed improvement on a number of adverse effect produced by risperidone on a number of participants when switched to aripiprazole (Ishitobi et al., 2012). Nevertheless, a significant proportion of those who were treated with aripiprazole showed adverse effects and in fact the RCTs have reported that a significantly higher proportion of participant in the aripiprazole group showed adverse effects compared with the placebo group (the only studies providing evidence based on direct comparison with the placebo). However, the only long term study available (Marcus et al., 2011a) showed that overall aripiprazole was reasonably tolerated over a 52 week period with a minimum number of drop outs. On the positive side, aripiprazole improved serum prolactin level in some participants and overall did not show any adverse effect on QTc interval. There was a large variety of papers included in this systematic review that used several different outcome measures. There was no standardisation between papers which made it difficult to directly compare the different studies and the outcome measures used contain a subjective component which can create bias. The most commonly used primary outcome measure was ABC-I. Most studies on risperidone trials for people with ASD and/or ID used ABC-I score as the primary outcome measure rather than that the total ABC score which is not valid (Deb, 2013). However, ABC-I contains contradictory items such as aggression, agitation but also crying and depression. ABC-I was used in seven studies which showed a generalised improvement with the use of aripiprazole. Secondary measures included CGI-I and CGI-S. These secondary outcomes were used in nine of the studies and showed a generalised improvement on scores based on these scales. However, although very widely used in studies, CGI is a subjective measure and can cause major bias particularly in retrospective case reports, which have been the case in most studies included in this systematic review. Retrospective case notes based case reports also bring other associated bias and flaws with them. During the systematic review a number of papers which discussed the use of aripiprazole augmentation with other antipsychotics were removed. These studies were on people with ID, DD and ASD, however, the sole efficacy of aripiprazole could not be assessed and thus removed. However, aripiprazole augmentation may be a treatment modality that this difficult to treat group may benefit from but without further good quality research it is premature to comment on its prospect. Properly designed RCTs are required to compare aripiprazole’s efficacy against other psychotropic medications particularly other antipsychotics and mood stabilisers. There is limited evidence to support aripiprazole’s efficacy over risperidone (Ishitobi et al., 2012; Stigler et al., 2011) and comparable studies need to be completed to assess the long term efficacy. Similarly aripiprazole’s efficacy needs to be established against non-medication based management of PB (see Ishitobi et al., 2012 although number of participants included in this study is rather small). Behaviour may have improved in several participants due to the sedative effect of aripiprazole making the subjects drowsy and thus improving their behaviour outcome score. Overall, it is suggested that aripiprazole has some efficacy in the management of PB in people with ID, DD and ASD. In order to counteract the effect of sedation or other adverse effects on PB, ideally studies should have used a quality of life measure to assess the effect of aripiprazole on the participants’ quality of life (Hemmings, Deb, Chaplin, Hardy, & Mukherjee, 2013), which was not used in any of the included studies. The present study sought to present a comprehensive review of current literature on the effectiveness of aripiprazole in the management of PB in ID, DD and/or ASD, PDD. However, it is acknowledged that the search strategy may have missed some pertinent articles. The search terms used were broad and extensive (see Appendix A). However, as many different terms may be used for PB, the search may have failed to identify papers which investigated those which used different terms. Furthermore, whilst the search was inclusive to address studies with at least an abstract in English, it may be that some relevant studies were overlooked which did not have an abstract in English but overall we believe that this systematic review has managed to capture most if not all the relevant literature. The evidence presented in this paper on the effectiveness of aripiprazole has to be interpreted with caution. Most studies are case reports on a small number of participants. Also majority of the studies included in this systematic review are retrospective case notes based case reports. It is known that studies with positive findings are more likely to be published than studies with negative findings. This is likely to create a reporting bias for the published case reports. Some of the studies have used subjective opinion to assess outcome than a validated standardised measure, which creates problem with interpretation of findings. In most studies co-morbidities such as ADHD and other psychiatric disorders have not been taken into account. Similarly none of the case reports explain the effect of non-medication based interventions that may have been used simultaneously with aripiprazole. Most studies do not distinguish symptoms of psychiatric illness from those of PB,


723

therefore, making it difficult to establish whether aripiprazole has treated the PB per se or an underlying psychiatric disorder such as psychosis. It is important, however, to recognise the difficulty in carrying out RCTs involving people with ID (OliverAfricano et al., 2010), particularly because of securing consent from adults who lack capacity. Subsequently these people are deprived of the opportunity to have treatments that are based on strong evidence. PBs are usually long standing, therefore, short follow-up periods used in most studies, apart from Marcus and collegaues’ (2011a) open label extension study, meant that it is not possible to know whether patients would derive any benefit from aripiprazole in the long term. Only long term follow-up will determine the effect of many confounding factors such as environmental changes, etc. that are concomitant with the use of psychotropic medications. Most studies do not take into account the confounding effect of concomitant non-medication based management of behaviour, which may have a profound effect on the behaviour. Similarly in most studies aripiprazole was used as add-on therapy (two RCTs are the exception), which made it difficult to tease apart the confounding effect of the other medications that have been used simultaneously. For example, the use of anti-epileptic medications is common among adults with ID (Deb, 2007; Berney & Deb, 2012) and these medications may have an effect on the behaviour. However, a good quality RCT design with sufficient number of participants properly randomised should take care of some of these confounding effects. Another problem of interpreting the case report based data is that many patients who showed improvement on aripiprazole have had an unsuccessful trial of other medications that have been shown to be effective in other case studies. Therefore, the individualised response to specific medication is always going to be difficult to determine. There may be many causes for PB among people with ID and many factors including medical, psychological and social may influence behaviour. It is, therefore, imperative to carry out a detailed assessment of the causes and consequences of PB before an intervention is implemented (Deb et al., 2009). However, none of the studies included in this systematic review provide any detail of behaviour analysis. Future studies of aripiprazole should also assess its effect on family carer givers’ burden and cost effectiveness. In the absence of good quality evidence for the effectiveness of aripiprazole in particular but psychotropic medications in general, guidelines have been published in order to provide advice to clinicians when using psychotropic medications for the management of PB in people with ID with or without ASD (Banks et al., 2007; Deb et al., 2006, 2009; Einfeld, 2004; Reiss & Aman, 1998; Unwin & Deb, 2010). These guides advise clinicians that a thorough assessment of the causes and effects of the PB including organic, psychiatric, psychological and social factors should be carried out before a medication is prescribed. Before initiating medication, a formulation should be documented including the assessment and a rationale for the use of medication. Non-medication based management of PB should always be considered and be used either instead of or along with the medication when necessary. As much as possible, people with ID and their carer givers as well as the multidisciplinary team should be fully involved in the decision making process from the outset (Hall & Deb, 2008). There are accessible versions of information leaflets (with audio versions) on psychotropic medications (Unwin & Deb, 2007) including aripiprazole freely available for downloading from the web (www.ld-medication.bham.ac.uk). These should be handed over to patients and their carer givers where appropriate. The time, methods and personnel to conduct the follow-up assessment should be recorded at the outset. Both the impact of the intervention on the behaviour as well as the adverse effects should be assessed as objectively as possible, if necessary using validated instruments. At each follow-up, the original formulation should be reassessed, non-medication based interventions should be considered along with the possibility of withdrawing medication. The psychotropic medication, if needed, should be used with as small a dose as possible for as short a period of time as necessary. If medication is withdrawn, a relapse plan should be in place and the possibility of withdrawal symptoms in the form of PB should be considered before taking a decision to reinstate any psychotropic medication. The ultimate aim of the management should be symptom reduction as well as to improve the quality of life of the individual with ID. Appendix A. Search terms Terms for intellectual disability learning disab*

(truncated to include disabled, disability, disabilities)

intellectual* disab*

(truncated to include intellectual, intellectually, disabled, disability, disabilities)

intellectual* impair*

(truncated to include intellectual, intellectually, impairment, impaired)

development* disab*

(truncated to include development, developmental, developmentally, disabled, disability, disabilities)

development* impair*

(truncated to include development, developmental, developmentally, impair, impairment, impaired)

mental* retard*

(truncated to include mental, mentally, retardation, retarded)

mental* challenged

(truncated to include mental, mentally)

mental* handicap*

(truncated to include mental, mentally, handicap, handicapped)

mental* impair*

(truncated to include mental, mentally, impairment, impaired)

mental* deficien*

(truncated to include mental, mentally, deficient, deficiency)

724


subaverage intelligence Autistic Spectrum Disorder Autis*

(truncated to include autism, autistic)

Autis* spectrum disorder*

(truncated to include autistic, autism, disorder, disorders, disordered)

Autis* spectrum condition*

(truncated to include autistic, autism, condition, conditions)

Asperger*

(truncated to include Asperger, Aspergers, Asperger’s, Aspergoid, Aspergers syndrome)

Infant* Autis*

(truncated to include infant, infantile, autism, autistic)

Child* Autis*

(truncated to include children, childhood, autistic, autism)

Pervasive* development* disorder*

(truncate to include pervasive, pervasively, development, developmental, developmentally, disorder, disorders, disordered)

Autis* Psychopath*

(truncated to include autistic, autism, psychopath, psycopathy, psychopathies)

AS*

(truncated to include AS, ASD, ASC)

PDD Kanner* Syndrome

(truncated to include Kanner, Kanners, Kanner’s)

Atypical* Autis*

(truncated to include atypical, atypically, autism, autistic)

Aripiprazole Abilify Limits Limit to humans Limit to all age groups Exclude people with dementia Medical Subject Headings (MeSH) MeSH check words Target population: Adults or children With ID (IQ below 70 or author defined) or ASD/developmental disabilities Target Intervention: Aripiprazole Target Symptom: Any type of problem behaviour/maladaptive behaviour/challenging behaviour/disturbed behaviour/disruptive behaviour/ aggression/self-injurious behaviour Study Design: No restrictions on the study design – RCTs, controlled trials, open-label trials, prospective, retrospective, case series, single case report, etc. will be included. However, the study must be a primary research and there must be data relating to change in response to exposure to the target intervention – this could be within or between groups. Reviews will be excluded. Publication Criteria: No restrictions on type or year of publication (includes book chapters, conference proceedings, etc.) and language published in, so long as there is at least an abstract in English. References Aman, M. G., Burrow, W. H., & Wolford, P. L. (1995). The aberrant behavior checklist-community: Factor validity and effect of subject variables for adults in group homes. American Journal of Mental Retardation, 100(3), 283–292. Banks, R., Bush, A., Baker, P., Bradshaw, J., Carpenter, P., & Deb, S. (Eds.). (2007). Challenging behaviour: A unified approach (Clinical and service guidelines for supporting people with learning disabilities who are at risk of receiving abusive or restrictive practices). London, UK: The Royal College of Psychiatrists, The British Psychological Society and The Royal College of Speech and Language Therapists.. (College Report CR 144, June, 2007). Barnes, T. R. (1989). A rating scale for drug-induced akathisia. British Journal of Psychiatry, 154, 672–676. Basgul, S. S., & Uneri, O. (2011). Use of aripiprazole in children and adolescents: Case reports. Child and Adolescent Psychiatry, 20(S1), S7–S223,. P21-01.


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Berney, T., & Deb, S. (2012). Epilepsy in learning disability. In S. Shorvon, R. Guerrini, M. Cook, & S. Lahtoo (Eds.), Oxford textbook of epilepsy and epileptic seizures: Oxford textbooks in clinical neurology (pp. 195–199). Oxford, UK: Oxford University Press. Deb, S. (2007). Epilepsy in people with mental retardation. In J. W. Jacobson & J. A. Mulick (Eds.), Handbook of mental retardation and developmental disabilities (pp. 81–96). New York, USA: Kluwer Academic Publishers. Deb, S. (2013). Psychopharmacology. In E. Tsakanikos & J. McCarthy (Eds.), Handbook of psychopathology in intellectual disability: Research, practice, and policy, autism and child psychopathology series (pp. 307–324). New York, USA: Springer Science + Business Media.. (Series Editor: Johnny L. Matson; book chapter 19). Deb, S., Clarke, D., & Unwin, G. (2006). Using medication to manage behaviour problems among adults with a learning disability: Quick reference guide (QRG). London, UK: University of Birmingham, MENCAP, The Royal College of Psychiatrists.0855370947www.ld-medication.bham.ac.uk. Deb, S., & Fraser, W. I. (1994). The use of psychotropic medication in people with learning disability: Towards rational prescribing. Human Psychopharmacology, 9, 259–272. Deb, S., Kwok, H., Bertelli, M., Salvador-Carulla, L., Bradley, E., Torr, J., et al. (2009). International guide to prescribing psychotropic medication for the management of problem behaviours in adults with intellectual disabilities. World Psychiatry, 8(3), 181–186. Deb, S., Sohanpal, S. K., Soni, R., Unwin, G., & Lenoˆtre, L. (2007). The effectiveness of antipsychotic medication in the management of behaviour problems in adults with intellectual disabilities. Journal of Intellectual Disability Research, 51(10), 766–777. Downs, S. H., & Black, N. (1998). The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. Journal of Epidemiology and Community Health, 52(6), 377–438. Dratcu, L., McKay, G., Singaravelu, V., & Krishnamurthy, V. (2007). Aripiprazole treatment of Asperger’s syndrome in the acute psychiatric setting: Case report. Neuropsychiatric Disease and Treatment, 3(1), 173–176. Einfeld, S. L. (2004). Systematic management approach to pharmacotherapy for people with learning disabilities. Advances in Psychiatric Treatment, 7, 43–49. Erickson, C. A., Stigler, K. A., Wink, L. K., Mullett, J. E., Kohn, A., Posey, D. J., et al. (2011). A prospective open-label study of aripiprazole in fragile X syndrome. Journal of Psychopharmacology, 216(1), 85–90. Fung, L. K., Chahal, L., Libove, R. A., Bivas, R., & Hardan, A. Y. (2012). A retrospective review of the effectiveness of aripiprazole in the treatment of sensory abnormalities in autism. Journal of Child and Adolescent Psychopharmacology, 22(3), 245–248. Guy, W. (1976a). ECDEU assessment manual for psychopharmacology. Rockville, MD: CDHEW; No: 76-338, US Department of Health, Education and Welfare. Guy, W. (1976b). Abnormal involuntary movement scale (AIMS). ECDEU assessment manual for psychopharmacology. Rockville, MD: US Department of Health, Education and Welfare publication (ADM) 76-338, National Institute of Mental Health. Hall, S., & Deb, S. (2008). A qualitative study on the knowledge and views that people with learning disabilities and their carers have of psychotropic medication prescribed for behaviour problems. Advances in Mental Health and Learning Disabilities, 2(1), 29–37. Han, M., Huang, X-F., & Deng, C. (2009). Aripiprazole differentially affects mesolimbic and nigrostriatal dopaminergic transmission: Implications for long-term drug efficacy and low extrapyramidal side-effects. International Journal of Neuropsychopharmacology, 12(7), 941–952. Hellings, J. A., Boehm, D., Yeh, H. W., Butler, M. G., & Schroeder, S. R. (2011). Long-term aripiprazole in youth with developmental disabilities including autism. Journal of Mental Health Research in Intellectual Disabilities, 4(1), 40–52. Hemmings, C., Deb, S., Chaplin, E., Hardy, S., & Mukherjee, R. (2013). Research for people with intellectual disabilities and mental health problems: A view from the UK. Journal of Mental Health Research in Intellectual Disability, 6(2), 127–158. Huang, S. C., Tsai, S. J., & Yang, H. J. (2010). Aripiprazole improves social interaction in Taiwanese children with pervasive developmental disorder. Chang Gung Medical Journal, 33(2), 211–215. Ishitobi, M., Hiratani, M., Kosaka, H., Takahashi, T., Mizuno, T., Asano, M., et al. (2012). Switching to aripiprazole in subjects with pervasive developmental disorders showing tolerability issues with risperidone. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 37(1), 128–131. Jordan, I., Robertson, D., Catani, M., Craig, M., & Murphy, D. (2012). Aripiprazole in the treatment of challenging behaviour in adults with autism spectrum disorder. Psychopharmacology, 223(3), 357–360. Ku¨ltu¨r, S. E. C., Tiryaki, A., & Tasgin, E. (2009). Aripiprazole for maladaptive behavior in mental retardation: Case reports. Bulletin in Clinical Psychopharmacology, 19(3), 294–297. Marcus, R. N., Owen, R., Kamen, L., Manos, G., McQuade, R. D., Carson, W. H., et al. (2009). A placebo-controlled, fixed-dose study of aripiprazole in children and adolescents with irritability associated with autistic disorder. Journal of American Academy of Child and Adolescent Psychiatry, 48(11), 1110–1119. Marcus, R. N., Owen, R., Manos, G., Mankoski, R., Kamen, L., McQuade, R. D., et al. (2011a). Aripiprazole in the treatment of irritability in pediatric patients (aged 6– 17 years) with autistic disorder: Results from a 52-week, open-label study. Journal of Child and Adolescent Psychopharmacology, 21(3), 229–236. Marcus, R. N., Owen, R., Manos, G., Mankoski, R., Kamen, L., McQuade, R. D., et al. (2011b). Safety and tolerability of aripiprazole for irritability in pediatric patients with autistic disorder: A 52-week, open-label, multicenter study. Journal of Clinical Psychiatry, 72(9), 1270–1276. Masi, G., Cosenza, A., Millepiedi, S., Muratori, F., Pari, C., & Salvadori, F. (2009). Aripiprazole monotherapy in children and young adolescents with pervasive developmental disorders: A retrospective study. CNS Drugs, 23(6), 511–521. Oliver-Africano, P. C., Dickens, S., Ahmed, Z., Bouras, N., Cooray, S., Deb, S., et al. (2010). Overcoming the barriers experienced in conducting a medication trial in adults with aggressive challenging behaviour and intellectual disabilities. Journal of Intellectual Disability Research, 54(1), 17–25. Owen, R., Sikich, L., Marcus, R. N., Corey-Lisle, P., Manos, G., McQuade, R. D., et al. (2009). Aripiprazole in the treatment of irritability in children and adolescents with autistic disorder. Journal of American Academy of Child and Adolescent Psychiatry, 124(6), 1533–1540. Pardini, M., Guida, S., & Gialloreti, L. E. (2010). Aripiprazole treatment for coprophagia in autistic disorder. Journal of Neuropsychiatry, 22(4), 451-s.e33. Reiss, S., & Aman, M. G. (1998). Psychotropic medication and development disabilities: The international consensus handbook. Columbus, OH: Ohio State University. Scahill, L., Riddle, M. A., McSwiggin-Hardin, M., Ort, S. I., King, R. A., Goodman, W. K., et al. (1997). Children’s yale-brown obsessive compulsive scale: Reliability and validity. Journal of American Academy of Child and Adolescent Psychiatry, 36(6), 844–852. Shashtri, M., Alla, L., & Sabaratnam, M. (2006). Aripiprazole use in individuals with intellectual disability and psychotic or behavioural disorders: A case series. Journal of Psychopharmacology, 20(6), 863–867. Simpson, G. M., & Angus, J. W. (1970). A rating scale for extrapyramidal side effects. Acta Psychiatrica Scandinavica Supplement, 212, 11–19. Staller, J. A. (2003). Aripiprazole in an adult with Asperger disorder. Annals of Pharmacotherapy, 37(11), 1628–1631. Stigler, K. A., Diener, J. T., Kohn, A. E., Li, L., Ericson, C. A., Posey, D. J., et al. (2009). Aripiprazole in pervasive developmental disorder not otherwise specified and Asperger’s disorder: A 14-week, prospective, open-label study. Journal of Child and Adolescent Psychopharmacology, 19(3), 265–274. Stigler, K. A., Mcdougle, C. J., Scahill, L., Aman, M. G., Eugene, A. L., Johnson, C., et al. (2011). Medication and parent training in children with pervasive developmental disorders and serious behavior problems: Effectiveness and tolerability of aripiprazole in risperidone nonresponders. Neuropsychopharmacology, 36, S228. Stigler, K. A., Posey, D. J., & McDougle, C. J. (2004). Aripiprazole for maladaptive behavior in pervasive developmental disorders. Journal of Child and Adolescent Psychopharmacology, 14(3), 455–463. Unwin, G., & Deb, S. (2007). Psychotropic medication easy read information leaflets. UK: University of Birmingham.www.ld-medication.bham.ac.uk. Unwin, G. L., & Deb, S. (2010). The use of medication to manage problem behaviours in adults with a learning disability: A national guideline. Advances in Mental Health in Intellectual Disabilities, 4(3), 4–11. Unwin, G. L., & Deb, S. (2011). Efficacy of atypical antipsychotic medication in the management of behaviour problems in children with intellectual disabilities and borderline intelligence: A systematic review. Research in Developmental Disabilities, 32, 2121–2133. Valicenti-McDermott, M. R., & Demb, H. (2006). Clinical effects and adverse reactions of off-label use of aripiprazole in children and adolescents with developmental disabilities. Journal of Child and Adolescent Psychopharmacology, 16(5), 549–560.

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