Jesner2007 (Risperidona)

Risperidone for autism spectrum disorder (Review)
Jesner OS, Aref-Adib M, Coren E
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2007, Issue 1
http://www.thecochranelibrary.com
Risperidone for autism spectrum disorder (Review)

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Analysis 1.1. Comparison 1 Clinical global impression (CGI) (RR), Outcome 1 Number of participants improved/very
much improved. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Analysis 2.1. Comparison 2 ABC (Aberrant Behavior Checklist), Outcome 1 Irritability. . . . . . . . . . . 23
Analysis 2.2. Comparison 2 ABC (Aberrant Behavior Checklist), Outcome 2 Social withdrawal / lethargy. . . . . 24
Analysis 2.3. Comparison 2 ABC (Aberrant Behavior Checklist), Outcome 3 Hyperactivity. . . . . . . . . . 25
Analysis 2.4. Comparison 2 ABC (Aberrant Behavior Checklist), Outcome 4 Stereotypy. . . . . . . . . . . 25
Analysis 2.5. Comparison 2 ABC (Aberrant Behavior Checklist), Outcome 5 Inappropriate speech. . . . . . . 26
Analysis 3.1. Comparison 3 Adverse events, Outcome 1 Weight gain. . . . . . . . . . . . . . . . . . 26
ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
Risperidone for autism spectrum disorder (Review) i

[Intervention Review]
Risperidone for autism spectrum disorder
Ora S Jesner1 , Mehrnoosh Aref-Adib1 , Esther Coren2

1 c/oChris Champion, ME, CDPLPG, School for Policy Studies, Bristol, UK. 2 Social Work, Community and Mental Health, Can-
terbury Christ Church University, Canterbury, UK
Contact address: Chris Champion, School for Policy Studies, University of Bristol, 8 Priory Road, Bristol, BS8 1TZ, UK.
[email protected].
Editorial group: Cochrane Developmental, Psychosocial and Learning Problems Group.

Publication status and date: Edited (no change to conclusions), published in Issue 1, 2010.
Review content assessed as up-to-date: 3 April 2006.
Citation: Jesner OS, Aref-Adib M, Coren E. Risperidone for autism spectrum disorder. Cochrane Database of Systematic Reviews 2007,
Issue 1. Art. No.: CD005040. DOI: 10.1002/14651858.CD005040.pub2.
ABSTRACT
Background
Autistic spectrum disorder encompasses a wide variety of behavioural and communicative problems. Both the core features and non-
core features of autism have been targeted in a variety of therapies. Atypical antipsychotic medications, including risperidone, have been
used for symptom and behaviour improvement and have shown beneficial outcomes, particularly in certain aspects of the disorder.
However, given the nature of the condition presenting in young patients, the risks of these potentially long term therapies must be
weighed against the benefits.
Objectives
To determine the efficacy and safety of risperidone for people with autism spectrum disorder.
Search methods
Electronic databases: CENTRAL (Cochrane Central Register of Controlled Trials) 2006 (Issue 3); MEDLINE (1966 to April 2006);
EMBASE (1980 to April 2006); PsycINFO (1887 to April 2006); CINAHL (1982 to April 2006); LILACS (1982 to April 2006 );
Clinicaltrials.gov (USA) (accessed April 2006); ZETOC (1993 to April 2006); National Research Register (NRR) (UK) 2006 (Issue 1)
were searched. In addition further data were retrieved through contact with pharmaceutical companies and authors of published trials.
Selection criteria
All randomised controlled trials of risperidone versus placebo for patients with a diagnosis of autism spectrum disorder. All trials had
to have at least one standardised outcome measure used for both intervention and control group.
Data collection and analysis
Data were independently evaluated and analysed by the reviewers. Data were evaluated at the end of each randomised controlled trial.
Unpublished data were also considered and analysed.
Main results
Only three randomised controlled trials were identified. Meta-analysis was possible for three outcomes. Some evidence of the benefits
of risperidone in irritability, repetition and social withdrawal were apparent. These must however be considered against the adverse
effects, the most prominent being weight gain.
Risperidone for autism spectrum disorder (Review) 1
Authors’ conclusions
Risperidone can be beneficial in some features of autism. However there are limited data available from studies with small sample sizes.
In addition, there lacks a single standardised outcome measure allowing adequate comparison of studies, and long-term followup is
also lacking. Further research is necessary to determine the efficacy pf risperidone in clinical practice.
PLAIN LANGUAGE SUMMARY
Risperidone for autism spectrum disorder
Risperidone is an antipsychotic medication that has been used for symptom relief and behavioural improvement in autism. This review
encompasses three randomised controlled trials and concludes that risperidone may be beneficial for various aspects of autism including
irritability, repetition and hyperactivity. However, all studies were relatively small and used different ways to assess effectiveness, making
comparisons difficult. In addition, side effects were identified, notably weight gain. Further studies are therefore necessary to determine
the long term benefits, if any, compared with the potential risks.
BACKGROUND cases having no identifiable underlying condition (Lissauer 2002).

Problems usually present in early childhood and continue through-
out life. Autistic children have a triad of difficulties (social rela-
Description of the condition tionships, social language and communication skills) evident be-
fore the age of 3 years and about two-thirds have a general learning
disability (Lissauer 2002). Non-core features of the condition may
Autism spectrum disorder present with serious behavioural disturbances such as self-injuri-
ous behaviour, aggression and tantrums.
Described for the first time in 1943 by Leo Kanner infantile autism
was characterised by inability to relate to people, speech devel-
opment failure and abnormal responses to environmental objects
and events (Kanner 1943). Today autism is defined by three core Description of the intervention
features; abnormal interaction, communication impairment and
stereotyped behaviours with limited activities and interests.
There is no universal classification for autism spectrum disorder Management Options for Autism
(ASD) with diagnoses made using a number of instruments (eg, Despite the regular claims for curative interventions, there is no
ADOS (Lord 1989), ADI-R (Lord 1994) , DISCO (Wing 1999), specific treatment for autism and therapies target the symptoms
CARS (Schopler 1988), Developmental, Dimensional and Diag- of autism. Given the devastating nature of the condition, parents
nostic Interview (3di) (Skuse 2004)), or by using established di- are often keen to try any intervention available. The heterogeneity
agnostic criteria (ICD-10 (WHO 1993), DSM-IV (APA 1994)). of the symptoms means that therapies should be tailored to the
Conditions included in the autism spectrum are Childhood autism individual. The varying age at which ASD is diagnosed, and subse-
or autistic disorder, Pervasive Developmental Disorder - Not Oth- quent timing of delivery of intervention, are important. Early de-
erwise Specified (PDD-NOS), Asperger Syndrome and Atypical tection, and interventions (which may include education for par-
autism. In addition ICD-10 categories of other childhood dis- ents, behavioural therapy and /or pharmacological management)
orders of social functioning, specified (F94.8) and unspecified may all play a role in improving outcomes (Bryson 2003).
(F94.9), and other codes for behaviour and language disturbances Most behavioural treatment programs for children with autism
may also be relevant. include clear instructions to the child, prompting him or her to
The largest study to date reported a prevalence of 1.1 per 1000 perform specific behaviours, within a framework of gradually in-
children with full syndrome autism (Croen 2002). Autism is ap- creasing reinforcement as target tasks are made more complex.
proximately four times more common in boys (Fombonne 1999). Pharmacological interventions have been used as adjuncts to be-
The aetiology of autism is unknown, possibly genetic, with most havioural treatments in both children and adults, and may reduce
specific autistic symptoms and behaviours (such as self-injury or METHODS
aggression) which may interfere with the success of behavioural
treatments (Posey 2001). Pharmacological treatments available in-
clude antipsychotics, selective serotonin reuptake inhibitors, stim-
ulants, antihistamines and anxiolytics. Potential benefits include Criteria for considering studies for this review
improvements in sleep disturbance, mood disorder, concentration/
attention and self-harm or aggression (Gringas 2000).
Types of studies
Atypical Antipsychotics Randomised controlled trials with at least one standardised mea-
Antipsychotic drugs generally tranquillise without impairing con- sure (eg a behaviour checklist) used for the intervention and con-
sciousness and relieve psychotic symptoms (BNF 2003). Atypical trol group.
antipsychotics are termed ’atypical’ because of their tendency to
cause fewer unwanted motor side effects than the typical antipsy-
chotics. Examples of this class of drug include amisulpride, cloza- Types of participants
pine, olanzapine, quetiapine and risperidone. They are a main-
Participants of any age with a diagnosis of disorder on the autism
stay treatment for schizophrenia and other psychoses. They act by
spectrum using either a standardised diagnostic instrument or es-
blocking dopamine receptors (D2) in the brain, and may also af-
tablished diagnostic criteria..
fect cholinergic, alpha-adrenergic, histaminergic and serotonergic
receptors.
Types of interventions
Autism and risperidone
Risperidone, any dose and duration, by any means of delivery. The
Antipsychotic drugs are the most frequently prescribed psychoac- control group had to be a placebo.
tive agent used in autism (Campbell 1999). Typical antipsychotics,
specifically haloperidol, have been found to be useful in reducing
motor stereotypies, hyperactivity, temper tantrums and improving
Types of outcome measures
social relatedness (Anderson 1984). Extrapyramidal side effects
have limited the use of these drugs (Campbell 1997), resulting in 1. Core features of autism such as social interaction, communica-
the introduction of the atypical antipsychotics. tion and behavioural problems including stereotypy or obsessional
behaviour;
2. Non-core behaviours such as sleep disturbance, self-mutilation,
aggression, attention and concentration problems, and gastroin-
Why it is important to do this review testinal function
Risperidone has been the most widely used atypical antipsychotic 3. Global impression of health
in autism. In one open trial of risperidone in children with autism, 4. Adverse events
the authors concluded that risperidone may be effective for ame- 5. Quality of life for the individual or their carers
liorating dysfunctional behaviours in children with autistic spec- 6. Economic outcomes
trum (Findling 1997). Another study which looked at olanzapine Outcomes were divided into short-term (less than three months)
suggested that the drug improved language use and response after medium term (three-12 months) and long term (over one year).
eight and 12 weeks of treatment (Potenza 1999). Types of measures
Atypical antipsychotics can have quite different pharmacodynamic 1. Standardised diagnostic assessment instruments (eg Aberrant
properties and different adverse effects. This review set out to Behaviour Checklist (Aman 1986), Autism Behaviour Checklist
evaluate the efficacy and potential harms of risperidone in people (Krug 1980), Childhood Autism Rating Scale (Schopler 1988),
with autism spectrum disorder. Autism Diagnostic Interview-Revised (Lord 1994), Autism Diag-
nostic Observation Schedule (Lord 1989), Diagnostic Interview
for Social and Communication Disorders (Wing 1999))
2. Standardised communication assessments
3. Quality of life questionnaires
OBJECTIVES 4. Behaviour scales
To determine the efficacy and safety of risperidone in the treatment 5. Global Impression Rating Scales
of autism spectrum disorder. 6. Other Health Outcome Rating Scales

Search methods for identification of studies substance, mesh subject heading)
33. anti-psycho$.mp. (mp=title, original title, abstract, name of
Relevant trials were identified through searching the following
substance, mesh subject heading)
databases:
34. exp Antipsychotic Agents/
CENTRAL (Cochrane Central Register of Controlled Trials)
35. beclamide.mp. (mp=title, original title, abstract, name of sub-
2006 (Issue 3)
stance, mesh subject heading)
MEDLINE, accessed through OVID (1966 to April 2006)
36. benperidol.mp. (mp=title, original title, abstract, name of sub-
EMBASE, accessed through OVID (1980 to April 2006)
PsycINFO, accessed through Silverplatter (1887 to April 2006)
37. benzamide.mp. (mp=title, original title, abstract, name of sub-
CINAHL, accessed through OVID (1982 to April 2006)
LILACS (1982 to April 2006)
38. butyrophenone$.mp. (mp=title, original title, abstract, name
Clinicaltrials.gov (USA) (July 2005)
of substance, mesh subject heading)
ZETOC (1993 to April 2006)
39. chlorpromazine.mp. (mp=title, original title, abstract, name
National Research Register (NRR) (UK) 2006 (Issue 1)
ERIC, accessed through DataStar (1966 to April 2006)
40. clozapine.mp. (mp=title, original title, abstract, name of sub-
The search strategy was devised to capture trials both for this review
and for future reviews on other antipsychotics and ASD. Search
41. dibenzoxazepine$.mp. (mp=title, original title, abstract, name
terms for MEDLINE were as follows:
1. randomized controlled trial.pt.
42. diphenylbutylpiperidine.mp. (mp=title, original title, abstract,
2. controlled clinical trial.pt.
name of substance, mesh subject heading)
3. randomized controlled trials.sh.
43. dipiperone.mp. (mp=title, original title, abstract, name of sub-
4. random allocation.sh.
5. double blind method.sh.
44. dixyrazine.mp. (mp=title, original title, abstract, name of sub-
6. single-blind method.sh.
7. or/1-6
45. droperidol.mp. (mp=title, original title, abstract, name of sub-
8. (animal not human).sh.
9. 7 not 8
46. eltoprazine.mp. (mp=title, original title, abstract, name of sub-
10. clinical trial.pt.
11. exp clinical trials/
47. flupenthixol.mp. (mp=title, original title, abstract, name of
12. (clin$ adj25 trial$).ti,ab.
13. ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or
48. flupentixol.mp. (mp=title, original title, abstract, name of sub-
mask$)).ti,ab.
14. Placebos.sh.
49. fluphenazine.mp. (mp=title, original title, abstract, name of
15. placebo$.ti,ab.
16. random$.ti,ab.
50. haloperidol.mp. (mp=title, original title, abstract, name of sub-
17. research design.sh.
18. or/10-17
51. loxapine.mp. (mp=title, original title, abstract, name of sub-
19. 18 not 8
20. 19 not 9
52. methotrimeprazine.mp. (mp=title, original title, abstract,
21. comparative study.sh.
22. exp evaluation studies/
53. milenperone.mp. (mp=title, original title, abstract, name of
23. follow up studies.sh.
24. prospective studies.sh.
54. neuroleptic$.mp. (mp=title, original title, abstract, name of
25. (control$ or prospectiv$ or volunteer$).ti,ab.
26. or/21-25
55. olanzapine.mp. (mp=title, original title, abstract, name of sub-
27. 26 not 8
28. 27 not (9 or 20)
56. oxypertine.mp. (mp=title, original title, abstract, name of sub-
29. 9 or 20 or 28
30. (substituted adj benzamide$).mp. (mp=title, original title, ab-
57. penfluridol.mp. (mp=title, original title, abstract, name of sub-
stract, name of substance, mesh subject heading)
31. amisulpiride.mp. (mp=title, original title, abstract, name of
58. pericyazine.mp. (mp=title, original title, abstract, name of sub-
32. antipsycho$.mp. (mp=title, original title, abstract, name of

59. perphenazine.mp. (mp=title, original title, abstract, name of 87. aripiprazole.mp.
substance, mesh subject heading) 88. ziprasidone.mp.
60. phenothiazine$.mp. (mp=title, original title, abstract, name of 89. atypical antipsychotic$.mp.
substance, mesh subject heading) 90. 30 or 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38 or 39 or
61. pimozide.mp. (mp=title, original title, abstract, name of sub- 40 or 41 or 42 or 43 or 44 or 45 or 46 or 47 or 48 or 49 or 50 or
stance, mesh subject heading) 51 or 52 or 53 or 54 or 55 or 56 or 57 or 58 or 59 or 60 or 61 or
62. pipamperone.mp. (mp=title, original title, abstract, name of 62 or 63 or 64 or 65 or 66 or 67 or 68 or 69 or 70 or 71 or 72 or
substance, mesh subject heading) 73 or 74 or 75 or 76 or 86 or 87 or 88 or 89
63. pipothiazine.mp. (mp=title, original title, abstract, name of 91. 29 and 85 and 90
substance, mesh subject heading) Search terms were altered where necessary, to meet the require-
64. pipotiazine.mp. (mp=title, original title, abstract, name of sub- ments of individual databases. The optimally sensitive search strat-
stance, mesh subject heading) egy for randomised controlled trials, developed for the Cochrane
65. prochlorperazine.mp. (mp=title, original title, abstract, name Collaboration (Higgins 2005), was combined with medical sub-
of substance, mesh subject heading) ject headings and text words specific for antipsychotics and autism
66. promazine.mp. (mp=title, original title, abstract, name of sub- and pervasive development disorders. Search terms were mod-
stance, mesh subject heading) ified to meet the requirements of individual databases regard-
67. prothipendyl.mp. (mp=title, original title, abstract, name of ing differences in fields and syntax. The aim of the search strat-
substance, mesh subject heading) egy was for high precision and recall. There were no language
68. quetiapine.mp. (mp=title, original title, abstract, name of sub- restrictions. Authors of retrieved papers were contacted for on-
stance, mesh subject heading) going or unpublished work (Shea 2004b, Shea 2005, Scahill
69. risperidone.mp. (mp=title, original title, abstract, name of sub- 2005a, Scahill 2005b, Zarcone 2005), as were relevant pharma-
stance, mesh subject heading) ceutical companies (S-Synthelabo 2004, Novartis 2004, Eli Lilley
70. sertindole.mp. (mp=title, original title, abstract, name of sub- 2004, Astra Zeneca 2004, Orion Pharma 2004, Lundbreck 2004,
stance, mesh subject heading) Janssen-Cilag 2004). We searched data bases designed to identify
71. sulpiride.mp. (mp=title, original title, abstract, name of sub- grey literature and ongoing studies including ZETOC, Clinical-
stance, mesh subject heading) Trials.gov (USA) and the National Research Register (NRR UK).
72. thioridazine.mp. (mp=title, original title, abstract, name of
73. thioxanthene$.mp. (mp=title, original title, abstract, name of
Data collection and analysis
74. tranquil$.mp. (mp=title, original title, abstract, name of sub-
75. trifluoperazine.mp. (mp=title, original title, abstract, name of
76. zuclopenthixol.mp. (mp=title, original title, abstract, name of Selection of studies
substance, mesh subject heading) Titles and abstracts identified in the search were considered in-
77. autistic disorder.mp. or exp Autistic Disorder/ dependently by two authors (OJ, MA). Full text articles were re-
78. autis$.mp. (mp=title, original title, abstract, name of sub- trieved for all that appeared to meet the inclusion criteria. These
stance, mesh subject heading) were then independently assessed by the two authors (OJ, MA).
79. kanner$.mp. (mp=title, original title, abstract, name of sub- Disagreement was resolved by discussion with the third author
stance, mesh subject heading) (EC) and articles that did not fulfil inclusion criteria were ex-
80. (childhood adj3 schizophren$).mp. (mp=title, original title, cluded.
abstract, name of substance, mesh subject heading)
81. (speech adj3 disorder$).mp. (mp=title, original title, abstract,
82. (language adj3 delay$).mp. (mp=title, original title, abstract, Data extraction and management
Data were organised using Review Manager 4.2. Data extraction
83. pdd.mp. (mp=title, original title, abstract, name of substance,
forms were developed a priori and included information regarding
mesh subject heading)
methods, participant details, dose and frequency of administra-
84. exp Child Development Disorders, Pervasive/
tion, other concurrent interventions and/or health problems, and
85. 77 or 78 or 79 or 80 or 81 or 82 or 83 or 84
outcomes. Data were independently extracted by two reviewers
86. zotepine.mp.
(OJ,MA).

Assessment of risk of bias in included studies Assessment of reporting biases
A funnel plot was not considered relevant due to an insufficient
number of studies. Should more studies be identified at the next
Quality Assessment
update, we plan to reconsider issues around any relationship be-
Two independent reviewers (OJ, MA) evaluated included stud- tween effect size and study precision, as such a relationship could
ies for methodological quality and appropriateness. Two review- have been due to publication or related biases or due to system-
ers (OJ, MA) independently assigned each selected study to qual- atic differences between small and large studies. If a relationship is
ity categories described in the Cochrane Collaboration Reviewer’s identified in future, clinical diversity of the studies will be further
Handbook (Higgins 2005). The following relates to allocation examined as a possible explanation. (Egger 1997). Every attempt
concealment alone: has been made, and will in future be made, to obtain unpublished
(A) indicates adequate concealment of the allocation (for example, data.
by telephone randomisation, or use of consecutively numbered,
sealed, opaque envelopes);
(B) indicates uncertainty about whether the allocation was ade- Data synthesis
quately concealed (for example, where the method of concealment Meta-analyses were performed for three outcomes:
was not known); - Clinical Global Impression Scale (CGI) - where data were avail-
(C) indicates that the allocation was definitely not adequately con- able, represented as ’numbers of participants improved/ signifi-
cealed (for example, open random number lists or quasi-randomi- cantly improved’, in all three included studies (McDougle 1998,
sation such as alternate days, odd/even date of birth, or hospital RUPP 2002, Shea 2004);
number). - ’Aberrant Behavior Checklist’ (ABC) between the two trials
The reviewers (OJ, MA) also assessed the extent to which both which utilised the scale (RUPP 2002 and Shea 2004).
participants and outcome assessors were blind to the allocation - weight gain
status of participants. The blinding was recorded as ’met’, ’unmet’
or ’unclear’. The use of intention-to-treat was also documented
(see below). Subgroup analysis and investigation of heterogeneity
A sufficient number of studies was not retrieved and thus subgroup
analyses were not performed.
Measures of treatment effect
Sensitivity analysis
Binary data
Sensitivity analyses to assess the impact of study quality on results
Meta-analysis of binary data was conducted and results expressed
of meta-analysis were inappropriate, as insufficient data were iden-
as relative risk with a 95% confidence interval. A random effects
tified.
model was used.
Continuous data
Differences in means were calculated using a 95% confidence in- RESULTS
terval. A random effects model was used.
Dealing with missing data Description of studies

Loss to follow up and dropouts were assessed for each included See: Characteristics of included studies; Characteristics of excluded
study and reported in the review. In addition missing outcome studies.
data were noted.
Results of the search

Assessment of heterogeneity 580 citations were found using the search strategy used in June
Heterogeneity was assessed in the using the I2 measure (Higgins 2004, of which 24 qualified for further inspection. One investiga-
2002) and the Chi squared test of heterogeneity as well as visual tor responded to the authors’ request for unpublished trials with
inspection of the graph. Due to heterogeneity in the results, ran- information concerning further data (Zarcone 2005). One study
dom effects analysis was undertaken. Clinical heterogeneity was (RUPP 2002) produced two additional papers (McDougle 2005,
discussed in the text of the review. Arnold 2003). Searches were rerun in April 2006 at which time

180 citations were found of which 8 required further inspection. repetitive thoughts, whereas the last 5 items determine the severity
Of these seven were randomised controlled trials, of which three of repetitive behaviour.
were eligible for inclusion within the review.
Included studies 3. Ritvo-Freeman Real Life Rating Scale (Freeman 1986)

The three studies included within this review were all described This is an observational measure of a variety of symptoms of autism
as both “randomised” and “double blind” (McDougle 1998, comprising of 5 subscales: (I) sensory motor behaviours (e.g. hand
RUPP 2002, Shea 2004b) . The participant groups were adults flapping, rocking), (II) social relationship to people (e.g. appropri-
(McDougle 1998), 5-17 year olds (RUPP 2002), 5-12 year olds ate responses to interaction attempts, initiating appropriate phys-
(Shea 2004b) with a diagnosis of autism spectrum disorder or ical interactions), (III) affectual reactions (e.g. abrupt changes in
other pervasive developmental disorders based on DSM IV crite- affect, crying, temper outbursts), (IV) sensory responses (e.g. agi-
ria (APA 1994). The numbers of participants in the studies were tated by noises, rubbing surfaces, sniffing self or objects) and (V)
small (ranging from 31 to 101) and included people of both sexes. language (e.g. communicative use of language, initiating appro-
priate verbal communication. Each is scored on a four point scale
with 0 indicating “never” and 3 “almost always”. A higher score
Interventions indicates greater severity of autistic symptoms.
The intervention was risperidone and permitted comparison
groups comprised placebo only. Risperidone can be found in the
British National Formulary 2005 and is a licensed indication for
4. Aberrant Behavior Checklist- ABC (Aman 1986)
acute and chronic psychoses and mania (BNF 2005).
Consists of 58 items subdivided amongst 5 scales: irritability,
lethargy and social withdrawal, stereotypic behaviour, hyperactiv-
Outcomes ity/non compliance, and inappropriate speech. A score for each
In the three included studies, the primary outcome was improve- item ranged from 0 indicating “no problem” to 3 indicating “se-
ment in common symptoms of autism spectrum disorder, as per vere problem”.
inclusion criteria for this review. A variety of validated and un-
validated rating scales were used, but each study included at least
one validated measure. Outcome measures used are summarised
5. Nisonger Child Behavior Rating form - N-CBRF (Tasse
below and are also listed in Table 1:
1996)
This consists of 60 items subdivided among 6 scales: conduct prob-
Validated scales lem, insecure/anxious, hyperactive, self injury/stereotypic, self iso-
lated/ritualistic, and overly sensitive. A score for each item ranged
from 0 indicating “no problem” to 3 indicating “severe problem”.
1. Clinical Global Impression Scale -CGI scale (Guy 1976)

This is used to assess both severity of illness and clinical improve-
6. Vineland Adaptive Behavior Scales (Sparrow 1984)
ment, by comparing the conditions of the person standardised
against other people with the same diagnosis. A seven point scoring The maladaptive behavior domain is divided into two subscales.
system is usually used with low scores showing decreased severity. Part I consists of 27 items, including mood and anxiety-related
Seven indicates ’very much worse’, four ’no change’ and one is symptoms along with hyperactivity, lying, cheating, bed-wetting
’very much improved.’ and others. Part II consists of nine items, with more severe symp-
toms such as psychosis, self-injury, and property destruction. Each
item is scored on a three point scale where 0 indicates “no, never”,
1 indicates “sometimes or partially” and 2 signifies “yes, usually”.
2. The Yale-Brown Obsessive Compulsive Scale - Y-BOCS Therefore the range of scores for part 1 is 0-54 and the range for
(Goodman 1989a, Goodman 1989b) part 2 is 0-18, and the range for the total score is 0-72.
The Y-BOCS (modified) is a measure of obsessions and compul-
sions. Each of the ten items is scored on a five point scale from
0 indicating “least symptomatic”’ to 4 indicating “most symp-
tomatic”, so that the total Y-BOCS score ranges from 0 to 40. The 7. Self Injurious Behaviour Questionnaire - SIB-Q (Gualtieri
first five items of the Y-BOCS are designed to assess the severity of 2002)

This is a 25-item clinician- rated instrument developed by C. Risk of bias in included studies
Thomas Gualtieri that assesses self injurious behaviour, physical
See also ’Table of Characteristics of Included Studies’.
aggression towards others, destruction to property and other mal-
adaptive behaviour. Patients can receive a score of 0 indicating
“not a problem” to 4, “severe problem” on each of the 25 items
Sequence generation
(range for total score 0 to 100).
Randomisation for the all three included studies was judged to be
adequate. Where there was any doubt the authors were contacted
(Shea 2005, Scahill 2005a) and were able to give more informa-
Unvalidated scales
tion. One study (RUPP 2002) produced a paper describing the
methodology in more detail (Scahill 2001).
1. Visual Analog Scale (VAS) (used to measure clinicians’ Blinding

ratings of participants’ behaviour)
In all three studies both the participants and those delivering the
A visual analog scale (VAS) was used in one included study ( drug were blinded. The outcome assessors were either the parents
McDougle 1998). It was designed to help clinicians assess different or the clinicians or both and were thus also blinded. Therefore, all
mood states on a VAS scored on 100mm line where 0 indicates trials were assessed as adequate for this criterion.
“not at all” and 100 indicates “most ever”. The ten items included
“anxious or nervous”, “calm”, “depressed”, “eye contact”, “happy”,
“irritable”, “restless”, “social interaction”, “talkative” and “tired”. Attrition/Intention-to-treat
This scale was not validated.
All studies gave details of attrition and all reported using statistical
methods to account for missing data.
For RUPP 2002, 21 of 101 children withdrew from the study
early. Three children in the risperidone group withdrew as they
2. Visual Analog Scale (VAS) (used to measure parent/carer’s
did not find the treatment effective; one in the placebo group had
ratings of severity of participants’ ’troublesome’ symptoms)
a seizure and the rest withdrew from lack of efficacy (twelve), with-
Shea 2004 used a visual analog scale for the parents. At the base- drawal of consent (one), nonadherence (one). Data were missing
line visit the parent reported which symptom was the most trou- for a further three at followup (three). In Shea 2005 (n = 79) seven
blesome. The severity of that symptom was recorded with a verti- children withdrew, two from the treatment group due to adverse
cal mark on a 100-mm line, with lower scores indicating a better effects and the other due to insufficient response, and five from
condition. the placebo group: one because of adverse effects, two from ’in-
sufficient response’ and two following the withdrawal of consent.
In McDougle 1998 (n= 31) seven did not complete the trial: one
was withdrawn for agitation in the treatment group and four for
3. Parent-derived target symptoms scale agitation in the placebo group. One patient in the treatment group
In RUPP 2002 parent defined symptoms eg tantrums, aggression developed abnormal gait after four weeks and another had lack of
and hyperactivity were rated by blinded clinical judges on a nine significant improvement in symptoms.
point scale. 1= normalised, 5=unchanged, 9=disastrous. The lower All studies reported using intention to treat analyses to adjust for
the score, the larger the improvement. withdrawal of participants: McDougle and colleagues by using the
method of ’last observation carried forward’ (McDougle 1998);
likewise Shea et al reported that : ’The primary population for
safety assessments was the intention-to-treat (ITT) population,
Excluded studies
defined as all randomised subjects who received at least one dose
34 studies were excluded, two of which were randomised (Hellings of study medication. The primary population for efficacy assess-
2001; Zarcone 2005) but did not use the appropriate diagnostic ments was the ITT-efficacy population, defined as all randomised
inclusion criteria for our study. Two studies were excluded be- subjects who received at least one dose of study medication and for
cause they were run as open-label studies which developed into whom there was at least 1 post-baseline efficacy assessment. The
randomised discontinuation studies Troost 2005, RUPP 2005. It primary efficacy parameter was the change in irritability from base-
was common for studies to be excluded because many were case line to study endpoint (e.g. the last observation...’) (Shea 2004).
studies and not randomised controlled studies (see Table of Ex- Authors of RUPP 2002 reported simply that ’Data were analyzed
cluded Studies for further information). according to the intent-to-treat principle’.

Sample size/ power calculation the items. Just as in the McDougle 1998 study, there were im-
Sample sizes varied but were small. The smallest sample size was provements in the subscales of subscale I and III, and also subscale
31 (McDougle 1998), and the largest study contained 101 partic- IV. A meta-analysis was not performed as the two studies used
ipants (RUPP 2002). different observers to measure change in the patients’ scores (clin-
icians vs. parents). In the McDougle 2005 re-analysis, further re-
sults were reported for outcomes not discussed in previous papers.
In subscale I of the Ritvo-Freeman RLRS, the risperidone group
Effects of interventions changed from 1.0 (SD 0.52) to 0.59 (SD 0.42), compared with
Due to the small number of studies meeting the inclusion criteria placebo which changed from 0.93 (SD 0.58) to 0.91 (SD 0.6)
for this review, the heterogeneity in populations (adults and chil- (p = 0.002). In subscale II risperidone showed an improvement
dren), the wide range of instruments used to measure outcomes, from 0.6 (SD 0.43) to 0.15 (SD 0.42) compared with 0.72 (SD
and the variety in presentation of results, meta-analysis was pos- 0.43) to 0.46 (SD 0.52) in the placebo group (n.s). In subscale
sible within the current version of this review for three outcomes III the baseline for the risperidone group was 1.68 (0.64) chang-
only (the ABC, the CGI, and weight gain). Most findings are ing to 0.88 (SD 0.56) compared with placebo 1.84 (SD 0.64) to
therefore presented narratively, in the order of outcomes outlined 1.6(0.71) (p < 0.001). In subscale IV risperidone improved sen-
in the protocol. sory responses from 1.13 (SD 0.53) to 0.60 (SD 0.38) compared
to placebo 1.21(SD 0.53) to 1.07 (SD 0.54) (p = 0.004). In sub-
scale V the change was smaller, from 0.28 (SD 0.38) to 0.03(SD
1. Core features of autism (social interaction and 0.29) compared with the placebo 0.46 (SD 0.42) to 0.34 (SD
behavioural problems and stereotypy or obsessional 0.41) (non-significant).
behaviour)
The Yale-Brown Obsessive Compulsive Scale - Y-BOCS (
Aberrant Behavior Checklist- ABC (Aman 1986)
Goodman 1989a, Goodman 1989b)
In McDougle 1998 the authors reported that repetitive behavior For this outcome, meta-analysis was possible as both Shea 2004
reduced with the use of risperidone. This effect began at week 4 and RUPP 2002 used this measure throughout five subscales, albeit
and after 12 weeks the Y-BOCS score for the risperidone group had in different forms: Shea 2005 reporting changes scores and RUPP
reduced from 16.15 (SD 3.58) to 12.77 (SD 3.63) (p< 0.01). In 2002, end point data. These were combined in a meta-analysis
the placebo group the change was minimal, with a mild worsening using a random effects model and had the following results:
of symptoms - 14.29 (SD 3.50) to 14.35 (SD 3.02) (p< 0.01). In
McDougle 2005 (which reported further results from RUPP 2002)
ABC Subscale 01: Irritability
only the compulsion subscale was used. The mean score changed
from 15.51 (SD 2.73) to 11.65 (SD 4.02) in the risperidone group Results for the ABC subscale concerning irritability yielded a mean
compared to 15.18 (SD 3.88) to 14.21 (SD 4.81) in the placebo score on treatment of 8.09 lower than on control (95% CI = -
group. No significance values were reported. 12.99, -3.19). The I2 for this outcome is = 77.7% (Analysis 2.1).
Ritvo-Freeman Real Life Rating Scale (Freeman 1986) ABC Subscale 02: Social withdrawal/ Lethargy
On the five aspects of this scale used in the McDougle study ( Results for the ABC subscale concerning social withdrawal/
McDougle 1998) there was statistically significant improvement lethargy yielded a mean score on treatment of 3.00 lower than on
in sensory motor behaviors (subscale I) and affectual reactions control (95% CI = -5.03, -0.97). The I2 = 0% (Analysis 2.2).
(subscale III). In subscale I the risperidone group reduced in score
from 0.79 (SD 0.65) to 0.38 (SD 0.38) versus the placebo group
ABC: Subscale 03: Hyperactivity
which changed from 0.71 (SD 0.58) to 0.64 (SD 0.49) (p< 0.004).
In subscale III affectual reaction symptoms were reduced from 1.02 Results for the ABC subscale concerning hyperactivity yielded a
(SD 0.39) to 0.35 (SD 0.37) in the risperidone group, whereas the mean score on treatment of 8.98 lower than on control (95% CI
placebo group changed from 0.78 (SD 0.49) to 0.82 (SD 0.57) = -12.01, -5.94). The I2 = 19.80% (Analysis 2.3).
(p < 0.001).
Other symptoms such as social relationship to people, sensory
responses and language did not show significant improvement and ABC: Subscale 04: Stereotypy
the results for these were not published. Results for the ABC subscale concerning stereotypy yielded a mean
In the second analysis of the RUPP study (RUPP 2002; McDougle score on treatment of 1.71 lower than on control (95% CI = -
2005) the investigators modified the scale to allow parents to rate 2.97, -0.45). The I2 = 0% (Analysis 2.4).

ABC: Subscale 05: Inappropriate speech much improved.’ This showed an improvement in the CGI with
Results for the ABC subscale concerning inappropriate speech a relative risk of improvement of 4.83 (95% CI = 2.21, 10.59).
yielded a mean score on treatment of 1.93 lower than on control These results indicate a significant difference between groups, but
(95% CI = -3.79, -0.07). The I2 = 75.5% (Analysis 2.5). heterogeneity appears substantial (I2 = 43%) (Analysis 1.1).
All results of the ABC outcome appear significantly to favour the
intervention group, with the exception of inappropriate speech.
4. Adverse events
Nisonger Child Behavior Rating form - N-CBRF (Tasse 1996)

Shea 2004 reported benefit in the parent version of the Nisonger
scale. The trial showed mean decreases of the study end-point of General
10.4 in the risperidone group versus 6.6 in the placebo (p <0.01).
All three studies reported extractable adverse event data. In Shea
There were decreases in all the subscales secure/anxious, hyper-
2004 100 per cent of participants in the risperidone group and
active, overly sensitive (statistically significant), self-injury/stereo-
79.5 per cent of participants in the placebo group reported adverse
typic and self-isolated/ritualistic (not statistically significant) sub-
events. The most frequent adverse events reported in the risperi-
scales.
done group were somnolence, upper respiratory tract infections,
rhinitis and increased appetite. The most common events in the
Vineland Adaptive Behavior Scales (VABS) (Sparrow 1984) placebo group were aggressive reaction, fever, upper respiratory
tract infection, insomnia, vomiting, diarrhoea and emotional la-
In McDougle 2005 (which reported further results from RUPP
bility. In the RUPP 2002 study 60 adverse events were recorded,
2002) the total maladaptive behavior domain (part I and part II)
29 of which occurred in 5 percent or more of the children. The
was calculated . The results were 33.26 (SD 8.38) at baseline, to
most common ones included increased appetite, nasal congestion,
20.34 (SD 7.93) at week 8 for risperidone, compared with 33.51
fatigue, enuresis and drowsiness. All of these adverse effects were
(SD 8.29) to 30.27(SD 8.87) in the placebo group (p < 0.001).
present in both groups. In McDougle 1998, 87 per cent of risperi-
done treated patients had at least one adverse effect including seda-
2. Non-core behaviours such as sleep disturbance, tion, dry mouth, agitation, weight gain, enuresis, dyspepsia, diar-
self-mutilation, aggression, attention and rhoea, constipation, abnormal gait and sialorrhea. In the placebo
concentration problems, and gastrointestinal function group the only reported adverse event was agitation.
SIB-Q Vital signs

Only one separate symptom-specific measure was used to mea- The Shea 2004 study reported changes from baseline in vital signs.
sure self-injury, the SIB-Q (Gualtieri 2002) in McDougle 1998. There was an increase in pulse and diastolic blood pressure in the
In this, risperidone was reported to be superior to placebo in re- risperidone group, which was not found in the placebo group.
ducing self-injurious behaviour, physical aggression to others and McDougle 1998 reported no clinically significant changes in blood
property destruction from the fourth week of administration and pressure, pulse, respiratory rate and temperature but did not pro-
this benefit continued through week 8 end of treatment (24.2 to vide the data. The RUPP 2002 study also did not provide data but
9.5 in the treated group versus 32.8 to 15 in the control group (p found no difference between the groups in blood pressure, pulse
< .001)). and routine laboratory tests but did not state whether any change
occurred within the groups.
3. Global impression of health
Weight gain
Clinical Global Impression Scale -CGI scale (Guy 1976) A meta-analysis was possible for data from two trials involving
As all three studies used this scale we were able to combine the similar age groups (RUPP 2002, Shea 2004) Risperidone subjects
results and perform meta-analysis. The seven point scale was con- increased in weight by a mean of 2.7kg (95% CI = 1.15, 2.41)
verted into binary data by all triallists using the scale (McDougle (Analysis 3.1) compared to 1.0 kg in the placebo (Shea 2004).
1998; RUPP 2002; Shea 2004) in an identical way, comparing ’no In McDougle 1998 (a trial on adults) the authors reported that
improvement’ to ’much improved/very much improved’. Seven the weight gain observed was not to the same degree as previous
indicates ’very much worse’, four ’no change’ and one is ’very studies on children, however no data were made available.

Extra-pyramidal effects (EP) These results must be considered alongside the limitations of the
These were experienced in 27.5 per cent of the risperidone group studies. The included RCTs were few and small, the largest con-
compared to 12.8 per cent of the placebo group in one trial (Shea sisting of 101 participants, and ages of participants varied. A con-
2004). The RUPP 2002 used the Abnormal Involuntary Move- siderable proportion of participants left two of the studies (20% to
ment Scale (Guy 1976) and the Simpson Angus scale (Simpson 25% in McDougle 1998 and RUPP 2002) and long- term efficacy
1970) and these showed no EPs in either group, however the par- data were lacking. In addition, the drug dosage regimens were not
ents did report extra-pyramidal side effects of which tremor was consistent in the three included RCTs.
most common. In the McDougle study there were no extra-pyra- As well as these limitations, there was evidence of a variety of
midal symptoms other than the development of abnormal gait in adverse effects, the most common and significant of which was
one patient. weight gain. This was marked in children aged 5 to 17 (weight
gain for adults was not reported).
5. Quality of life for the individual or their carers

Investigators in the Shea 2004 study asked parents or carers to AUTHORS’ CONCLUSIONS
rate severity of participants’ ’troublesome’ behaviour; however, an
unvalidated VAS was used. Implications for practice
The data from the RUPP 2002 study were used to measure changes Although this review reports encouraging improvement in some
in the symptoms of most concern to the parents or care giver. behavioural aspects of autism spectrum disorder, carers and clin-
Risperidone was superior to placebo in reducing symptoms of most icians should be aware of the paucity of evidence in administer-
concern to parents and carers of autistic children with irritable ing this drug in such a vulnerable group of people. This patient
behaviour. The most common symptoms identified by parents group will inevitably continue to present challenging behaviours
were tantrums, aggression and hyperactivity. Mean ratings at end over many years; therefore, it is vital to consider issues surrounding
point were 2.8 (SD 1.2) on risperidone compared with 4.5 (SD long-term use. As the RCTs are of short duration it is impossible
1.3) on placebo. to evaluate the long term side effects and efficacy of risperidone,
and this is particularly important .
6. Economic outcomes Implications for research

No data on costs were reported within any of the studies included There were a wide number of different rating instruments used
within this review. amongst the studies in this review. There is thus a need for a uni-
fied, reliable and valid rating scale to measure the different aspects
of autism spectrum disorders. In trials considered within this re-
view, even those which employed the same scales often modified
them, making meta-analysis difficult. This is a common prob-
DISCUSSION lem in systematic reviews of ASD. Further, improvements in one
Our review suggests that risperidone may be of some benefit for or more multi-symptom scales may not correlate with those that
behavioural problems in ASD, although findings must be inter- cause most concern to either patient or caregiver. This problem
preted with caution. was addressed in one paper (Arnold 2003), using the same par-
ticipants of the RUPP 2002 study, where the authors focused on
Meta-analysis suggests significant improvements in some core as- the problems of greatest concern to the parents. This important
pects of ASD, namely irritability, social withdrawal, hyperactivity aspect of the treatment of autism and its outcomes should be con-
and stereotypical behaviours as well as in more global, ’non-core sidered in further studies. Given that ASD is often diagnosed in
symptom’ assessment of severity . In results from a single study on early childhood and optimum duration for treatment is not estab-
adults with ASD, repetitive behaviour, sensory motor behaviours, lished, long term followup is essential for patients, caregivers and
affectual relations and self-injurious behaviour also appeared to clinicians.
improve (McDougle 1998). Improvements were noted in the par-
ent rated scales as well as the quality of life for carers in two studies
involving children with ASD (RUPP 2002; Shea 2004). However,
heterogeneity in outcomes and outcome measures within the in-
ACKNOWLEDGEMENTS
cluded studies precluded more in the way of meta-analysis, a prob-
lem which has been commented upon in other Cochrane work on Jo Abbott, Jane Dennis, Julian Higgins, Geraldine Macdonald,
autism (Sinha 2004; Williams 2005). Steve Milan, Julie Millener and Georgia Salanti of the Cochrane

Developmental, Psychosocial and Learning Problems Group.
Thanks also to Mark Fenton and Dr Christian Gold for helpful
comments.
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Tasse MJ, Aman MG, Hammer D, Rojahn J. The Nissonger unable to obtain) 2005 (13th May).
Behavior Rating Form: age and gender effect and norms. ∗
Indicates the major publication for the study

CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
McDougle 1998
Methods Allocation: randomised, computer generated. No further details.

Blindness: double-blind, identical appearing capsules.
Duration: 12 weeks (preceeded by 4 week absence of psychotropic drugs).
12 week open-label extension of risperidone given to placebo group
Participants Diagnosis: adults with autism or pervasive developmental disorder not otherwise specified (DSM IV).
History: at least “moderate severity” on Clinical Global Impression.
Y-BOCS (compulsion scale >10), SIB-Q >24 or a Ritvo-Freeman Real-Life Rating Scale overall score >0.
20.
Excluded if met DSMIV criteria for schizophrenia or had psychotic symptoms or if significant acute
medical condition was identified.
N=31
Age: 18-43, mean 28.1
Sex: 9 women, 22 men.
7 participants were not mentally retarded.
Location: 24 outpatient, 7 inpatients.
Interventions 1. Risperidone: commenced on 1mg/day increased up to 10mg/day. N= 15.

2. Placebo: 1mg/day increased to maximum of 10mg/day. N=16.
Identical capsules given at night.
Outcomes 1. Leaving the study early.

2. Clinical Global Impression.
3. Ritvo-Freeman Real-life Rating Scale.
4. Visual Analog Scale
5. SIB-Q
6. Physiological measures (sitting and standing blood pressure, pulse rate and weight).
7. Examination of extra pyramidal and other adverse effects.
Unable to use Y-BOCS (no data reported).
Notes
Risk of bias
Item Authors’ judgement Description
Allocation concealment? Unclear B - Unclear

RUPP 2002
Methods Allocation: randomisation conducted by National Institute of Mental Health.

Randomisation was blocked on anticonvulsant status and pubertal status within site.
Blindness: double-blind, multisite.
Duration: 8 week (preceded by a drug free period for 7-28 days). 4 month open-label extension in those
with positive response, followed by 2 month placebo-controlled discontinuation phase
Participants Diagnosis: 5-17 year olds meeting criteria for autistic disorder DSM-IV. Weight of at least 15 kg, mental
age of at least 18 months, free of serious medical disorders and other psychiatric disorders requiring
medication.
History: at least “moderate severity” on Clinical Global Impression - Severity (CGI-S)scale. Score at least
18 on Irritability subscale of Aberrant Behavior Checklist.
N=101
Age: 5-17, mean 8.8.
Sex: 82 boys, 19 girls.
Interventions 1. Risperidone: commenced on 0.5mg/day OD, increased to BD and by 0.5mg increments depending
on weight of the child. Up to a maximum 2.5mg/day (20-45 kg), 3.5mg/day (>45kg). N=49
2. Placebo. N=52.
Outcomes 1. Aberrant Behavior Checklist- Irritability subscale.

2. Clinical Global Impression Scale.
3. Medication dose.
4. Adverse events including extra pyramidal symptoms.
5. Withdrawal from study.
2005 study:
6. Ritvo-Freeman Real life rating scale
7. Childrens Yale-Brown Obsessive Compulsive scale
8. The maladaptive behavior domain of the VIneland Adaptive Behavior Scales.
9. Parent-defined target symptoms rating scale.
Notes
Risk of bias
Shea 2004
Methods Allocation: randomised, randomisation codes kept under lock and key in pharmacy.
Blindness: double-blind.
Duration: 8 week multicenter study.
Participants Diagnosis: 5-12 year olds with DSM-IV for PDD.

History: At least 30 on Childhood Autism Rating Scale (CARS).
Excluded if diagnosed with schizophrenia or other psychotic disorders, clinically relevant nonneurologic
disease, clinically significant laboratory abnormalities, or a seizure disorder for which receiving anticonvul-
sants, or seizure in the last 3 months. Also excluded if hypersensitivity to neuroleptics, tardive dyskinesia,

Shea 2004 (Continued)
neuroleptic malignant syndrome, drug or alcohol abuse or human immunodeficiency virus infection.
N= 79.
Age: 5-12 years, mean 7.6.
Sex: 61 male, 18 female.
Location: outpatients.
Interventions 1. Risperidone (oral solution) 0.01mg/kg/day, maximum 0.06 mg/kg/day.

2. Placebo (oral solution) 0.01mg/kg/day.
Outcomes 1. Aberrant Behavior Checklist.

2. Clinical Global Impression change.
3. Nisonger Child Behavior Rating form (N-CBRF).
4. Visual Analog Scale (VAS).
5. Adverse events.
Notes
Risk of bias
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Alexander 2004 Open label, 3 patients
Aman 2005 Examined side effects, not efficacy
Anonymous 2002 Discussion of RUPP trial, not a randomised controlled trial.
Anonymous 2003 Discussion of RUPP trial, not a randomised controlled trial.
Bober 2005 Case study
Broadstock 2003 Review of literature, not a randomised controlled trial.
Caicedo 2002 Discussion or RUPP study, not randomised controlled trial.
Canitano 2006 Open label
Cohen 1998 Not a randomised controlled trial
Dartnall 1999 Not a randomised controlled trial

(Continued)
Di Martino 2001 Not a randomised controlled trial.
Dinca 2005 Systematic review
Findling 2004 Not a randomised controlled trial
Gagliano 2004 No control group
Gallucci 2006 Combination of two drugs
Gilman 1995 Review of literature, not randomised controlled trial.
Hellings 2001 Allocation: randomised, double-blind crossover study.

Participants: 20 individuals with mental retardation, age 6-65.
Intervention: risperidone versus placebo, 22 week trial.
Study did not used standardised diagnostic inclusion criteria and only looking at weight gain as the outcome
Hellings 2005 No behavioural outcomes, only prolactin levels
Horrigan 1997 Not a randomised controlled trial
King 2003 Observational study, not randomised controlled trial.
McAdam 2002 Allocation: randomised, double-blind crossover study.

Study did not used standardised diagnostic inclusion criteria and only looking at consumer satisfaction and
social validity as outcome measures
McCartney 1999 Case reports, not randomised controlled trial.
McCracken 2003 Discussion of RUPP trial, not randomised controlled trial.
McDougle 1995 Case report on 3 adults, not randomised controlled trial.
McDougle 2000 Background rationale for RUPP trial, not a randomised controlled trial
McDougle 2002 Unable to obtain poster.
McDougle 2003 Review of literature, not randomised controlled trial.
Mukaddes 2004 Pilot study, no control group
Natsukari 2004 Open label
RUPP 2000 Research on assessment of autistic disorder symptoms. Not testing drug with outcome measure

(Continued)
RUPP 2005 Discontinuation trial
Troost 2005 Discontinuation trial
Williams 2006 No control group
Zarcone 2001 Allocation: randomised.

Study did not used standardised diagnostic inclusion criteria

DATA AND ANALYSES
Comparison 1. Clinical global impression (CGI) (RR)
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 Number of participants 3 208 Risk Ratio (M-H, Random, 95% CI) 4.83 [2.21, 10.59]
improved/very much improved
Comparison 2. ABC (Aberrant Behavior Checklist)
No. of No. of
1 Irritability 2 178 Mean Difference (IV, Random, 95% CI) -8.09 [-12.99, -3.19]
2 Social withdrawal / lethargy 2 178 Mean Difference (IV, Random, 95% CI) -1.00 [-5.03, -0.97]
3 Hyperactivity 2 178 Mean Difference (IV, Random, 95% CI) -8.98 [-12.01, -5.94]
4 Stereotypy 2 178 Mean Difference (IV, Random, 95% CI) -1.71 [-2.97, -0.45]
5 Inappropriate speech 2 178 Mean Difference (IV, Random, 95% CI) -1.93 [-3.79, -0.07]
Comparison 3. Adverse events
No. of No. of
1 Weight gain 2 179 Mean Difference (IV, Random, 95% CI) 1.78 [1.15, 2.41]

Analysis 1.1. Comparison 1 Clinical global impression (CGI) (RR), Outcome 1 Number of participants
improved/very much improved.
Review: Risperidone for autism spectrum disorder
Comparison: 1 Clinical global impression (CGI) (RR)
Outcome: 1 Number of participants improved/very much improved
Study or subgroup Risperidone Placebo Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI
McDougle 1998 8/14 0/16 7.3 % 19.27 [ 1.21, 306.35 ]
RUPP 2002 37/49 6/52 45.3 % 6.54 [ 3.03, 14.12 ]
Shea 2004 21/39 7/38 47.4 % 2.92 [ 1.41, 6.06 ]
Total (95% CI) 102 106 100.0 % 4.83 [ 2.21, 10.59 ]

Total events: 66 (Risperidone), 13 (Placebo)
Heterogeneity: Tau2 = 0.20; Chi2 = 3.51, df = 2 (P = 0.17); I2 =43%
Test for overall effect: Z = 3.94 (P = 0.000082)
0.001 0.01 0.1 1 10 100 1000

Favours control Favours treatment
Analysis 2.1. Comparison 2 ABC (Aberrant Behavior Checklist), Outcome 1 Irritability.
Comparison: 2 ABC (Aberrant Behavior Checklist)
Outcome: 1 Irritability
Mean Mean
Study or subgroup Treatment Control Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI
RUPP 2002 49 11.3 (7.4) 52 21.9 (9.5) 49.7 % -10.60 [ -13.91, -7.29 ]
Shea 2004 39 -12.1 (5.8) 38 -6.5 (8.4) 50.3 % -5.60 [ -8.83, -2.37 ]
Total (95% CI) 88 90 100.0 % -8.09 [ -12.99, -3.19 ]

-10 -5 0 5 10
Favours treatment Favours control

Analysis 2.2. Comparison 2 ABC (Aberrant Behavior Checklist), Outcome 2 Social withdrawal / lethargy.
Outcome: 2 Social withdrawal / lethargy
Mean Mean
RUPP 2002 49 8.9 (6.4) 52 12 (8.3) 49.8 % -3.10 [ -5.98, -0.22 ]
Shea 2004 39 -8.6 (5.9) 38 -5.7 (6.9) 50.2 % -2.90 [ -5.77, -0.03 ]
Total (95% CI) 88 90 100.0 % -3.00 [ -5.03, -0.97 ]

Heterogeneity: Tau2 = 0.0; Chi2 = 0.01, df = 1 (P = 0.92); I2 =0.0%
-10 -5 0 5 10

Analysis 2.3. Comparison 2 ABC (Aberrant Behavior Checklist), Outcome 3 Hyperactivity.
Outcome: 3 Hyperactivity
Mean Mean
RUPP 2002 49 17 (9.7) 52 27.6 (10.6) 47.6 % -10.60 [ -14.56, -6.64 ]
Shea 2004 39 -14.9 (6.7) 38 -7.4 (9.7) 52.4 % -7.50 [ -11.23, -3.77 ]
Total (95% CI) 88 90 100.0 % -8.98 [ -12.01, -5.94 ]

Test for overall effect: Z = 5.80 (P < 0.00001)
-10 -5 0 5 10
Analysis 2.4. Comparison 2 ABC (Aberrant Behavior Checklist), Outcome 4 Stereotypy.
Outcome: 4 Stereotypy
Mean Mean
RUPP 2002 49 5.8 (4.6) 52 7.3 (4.8) 47.5 % -1.50 [ -3.33, 0.33 ]
Shea 2004 39 -4.3 (3.8) 38 -2.4 (4) 52.5 % -1.90 [ -3.64, -0.16 ]
Total (95% CI) 88 90 100.0 % -1.71 [ -2.97, -0.45 ]

-10 -5 0 5 10

Analysis 2.5. Comparison 2 ABC (Aberrant Behavior Checklist), Outcome 5 Inappropriate speech.
Outcome: 5 Inappropriate speech
Mean Mean
RUPP 2002 49 3 (3.1) 52 5.9 (3.8) 49.1 % -2.90 [ -4.25, -1.55 ]
Shea 2004 39 -2.6 (2.6) 38 -1.6 (3) 50.9 % -1.00 [ -2.26, 0.26 ]
Total (95% CI) 88 90 100.0 % -1.93 [ -3.79, -0.07 ]

-10 -5 0 5 10
Analysis 3.1. Comparison 3 Adverse events, Outcome 1 Weight gain.
Comparison: 3 Adverse events
Outcome: 1 Weight gain
Mean Mean
RUPP 2002 49 2.7 (2.9) 52 0.8 (2.2) 38.7 % 1.90 [ 0.89, 2.91 ]
Shea 2004 40 2.7 (2) 38 1 (1.6) 61.3 % 1.70 [ 0.90, 2.50 ]
Total (95% CI) 89 90 100.0 % 1.78 [ 1.15, 2.41 ]

Test for overall effect: Z = 5.55 (P < 0.00001)
-10 -5 0 5 10

ADDITIONAL TABLES
Table 1. Scales used in the review
Scale / measure McDougle 1998e RUPP 2002 Shea 2004
Clinical Global Impression Yes Yes Yes

Scale (CGI)
Yale Brown Obsessive Compul- Yes Yes- RUPP 2005

sive Scale (Y-BOCS)
Ritvo-Freeman Real Life Rating Yes Yes- RUPP 2005

Scale
Aberrant Behavior Checklist Yes Yes

(ABC)
Nisonger Child Behavior Rat- Yes

ing Form (N-CBRF)
Vineland Adaptive Behavior Yes- RUPP 2005

Scale
Self-injurious Behavior Ques- Yes

tionnaire (SIB-Q)
Visual Analog Scale- Clinician Yes

Rated (mood scale)
Visual Analog Scale- Yes

Parent rated (most troublesome
symptom)
WHAT’S NEW
Last assessed as up-to-date: 3 April 2006.
Date Event Description
22 October 2009 Amended Typographical errors corrected and a sentence rephrased in adverse effects section of results to clarify
presentation of analysis 3.1

HISTORY
Protocol first published: Issue 4, 2004
Review first published: Issue 1, 2007
Date Event Description
8 November 2008 Amended Converted to new review format.
18 October 2006 New citation required and conclusions have changed Substantive amendment
CONTRIBUTIONS OF AUTHORS
Ora Jesner and Mehrnoosh Aref-Adib wrote the protocol and planned the review with supervision and training from Esther Coren.
The search strategy was developed by the reviewers in concert with CDPLPG trial search coordinators Eileen Brunt and Jo Abbott.
The review was written by Ora Jesner and Mehrnoosh Aref-Adib.
DECLARATIONS OF INTEREST
None known.
INDEX TERMS
Medical Subject Headings (MeSH)
Antipsychotic Agents [adverse effects; ∗ therapeutic use]; Autistic Disorder [∗ drug therapy]; Randomized Controlled Trials as Topic;
Risperidone [adverse effects; ∗ therapeutic use]
MeSH check words

Humans


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Risperidone for autism spectrum disorder (Review)

Jesner OS, Aref-Adib M, Coren E

Risperidone for autism spectrum disorder (Review)

Risperidone for autism spectrum disorder (Review) i

Risperidone for autism spectrum disorder

Ora S Jesner1 , Mehrnoosh Aref-Adib1 , Esther Coren2

Editorial group: Cochrane Developmental, Psychosocial and Learning Problems Group.

PLAIN LANGUAGE SUMMARY

Risperidone for autism spectrum disorder

BACKGROUND cases having no identifiable underlying condition (Lissauer 2002).

Risperidone for autism spectrum disorder (Review) 3

Risperidone for autism spectrum disorder (Review) 4

Risperidone for autism spectrum disorder (Review) 5

Dealing with missing data Description of studies

Results of the search

Risperidone for autism spectrum disorder (Review) 6

Included studies 3. Ritvo-Freeman Real Life Rating Scale (Freeman 1986)

1. Clinical Global Impression Scale -CGI scale (Guy 1976)

Risperidone for autism spectrum disorder (Review) 7

1. Visual Analog Scale (VAS) (used to measure clinicians’ Blinding

Risperidone for autism spectrum disorder (Review) 8

Risperidone for autism spectrum disorder (Review) 9

Nisonger Child Behavior Rating form - N-CBRF (Tasse 1996)

SIB-Q Vital signs

3. Global impression of health

Risperidone for autism spectrum disorder (Review) 10

5. Quality of life for the individual or their carers

6. Economic outcomes Implications for research

Risperidone for autism spectrum disorder (Review) 11

Additional references Eli Lilley 2004

Risperidone for autism spectrum disorder (Review) 16

Characteristics of included studies [ordered by study ID]

Methods Allocation: randomised, computer generated. No further details.

Interventions 1. Risperidone: commenced on 1mg/day increased up to 10mg/day. N= 15.

Outcomes 1. Leaving the study early.

Item Authors’ judgement Description

Allocation concealment? Unclear B - Unclear

Risperidone for autism spectrum disorder (Review) 17

Methods Allocation: randomisation conducted by National Institute of Mental Health.

Outcomes 1. Aberrant Behavior Checklist- Irritability subscale.

Item Authors’ judgement Description

Allocation concealment? Unclear B - Unclear

Participants Diagnosis: 5-12 year olds with DSM-IV for PDD.

Risperidone for autism spectrum disorder (Review) 18

Interventions 1. Risperidone (oral solution) 0.01mg/kg/day, maximum 0.06 mg/kg/day.

Outcomes 1. Aberrant Behavior Checklist.

Item Authors’ judgement Description

Allocation concealment? Unclear B - Unclear

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Alexander 2004 Open label, 3 patients

Aman 2005 Examined side effects, not efficacy

Anonymous 2002 Discussion of RUPP trial, not a randomised controlled trial.

Anonymous 2003 Discussion of RUPP trial, not a randomised controlled trial.

Bober 2005 Case study

Broadstock 2003 Review of literature, not a randomised controlled trial.

Caicedo 2002 Discussion or RUPP study, not randomised controlled trial.

Canitano 2006 Open label

Cohen 1998 Not a randomised controlled trial