Risperidone for autism spectrum disorder
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
The aim of this systematic review is to determine the efficacy and safety of risperidone in the treatment of autism spectrum disorder.
Background
Autism Spectrum Disorder
Described for the first time in 1943 by Leo Kanner infantile autism was characterised by inability to relate to people, speech development failure and abnormal responses to environmental objects and events [Kanner 1943]. Today autism is defined by three core features; abnormal interaction, communication impairment and stereotyped behaviours with limited activities and interests.
There is no universal classification for autism spectrum disorder with diagnoses made using either DSM‐IV [APA 1994] or ICD‐10 [WHO 1993]. Conditions included in the autism spectrum are Childhood autism or autistic disorder, Pervasive Developmental Disorder ‐ Not Otherwise Specified [PDD‐NOS], Asperger Syndrome and Atypical autism. In addition ICD‐10 categories of other childhood disorders of social functioning, specified [F94.8] and unspecified [F94.9], and other codes for behaviour and language disturbances may also be relevant.
The largest study to date reported a prevalence of 1.1 per 1000 children with full syndrome autism [Croen 2002]. Autism is approximately four times more common in boys [Fombonne 1999] and is more common in social classes I and II [Katona 2000]. The aetiology of autism is unknown, possibly genetic, with most cases having no identifiable underlying condition [Lissauer 2002].
Problems usually present in early childhood and continue throughout life. Autistic children have a triad of difficulties evident before the age of 3 years and about two‐thirds have a general learning disability [Lissauer 2002]. Non‐core features of the condition may present with serious behavioural disturbances such as self‐injurious behaviour, aggression and tantrums.
Management Options for Autism
Despite the regular claims for curative interventions, there is no specific treatment for autism. Given the devastating nature of the condition, parents are often keen to try any intervention available. The heterogeneity of the symptoms means that therapies should be tailored to the individual. Therapies tend to target the symptoms rather than the cause. The varying age of onset and timing of delivery of intervention are two important variables when considering outcomes of treatment. Early detection, intervention, education and pharmacological management all play a role [Bryson 2003].
To this date no drug has been found to cure autism. Pharmacological interventions have been used as adjuncts to behavioural treatments, and may reduce specific autistic symptoms and behaviours [Posey 2001]. The pharmacological treatments available include antipsychotics, selective serotonin reuptake inhibitors, stimulants, antihistamines and anxiolytics. Potential benefits include improvements in sleep disturbance, mood disorder, concentration/attention and self‐harm or aggression [Gringas 2000].
Atypical Antipsychotics
Antipsychotic drugs generally tranquilise without impairing consciousness and relieve psychotic symptoms [BNF 2003]. Atypical antipsychotics are termed 'atypical' antipsychotics because of their tendency to cause less unwanted motor side effects than the typical antipsychotics. Examples of this class of drug include amisulpride, clozapine, olanzapine, quetiapine and risperidone. They are a mainstay treatment for schizophrenia and other psychoses. They act by blocking dopamine receptors (D2) in the brain, and may also affect cholinergic, alpha‐adrenergic, histaminergic and serotonergic receptors.
Autism and Atypical Antipsychotics
Antipsychotic drugs are the most frequently prescribed psychoactive 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 social relatedness [Anderson 1984]. Extrapyramidal side effects have limited the use of these drugs [Campbell 1997], resulting in the introduction of the atypical antipsychotics. Risperidone has been the most widely used atypical antipsychotic in autism. In one open trial of risperidone in children with autism, the authors concluded that risperidone may be effective for ameliorating dysfunctional behaviors in children with autistim spectrum [Findling 1997]. Another study which looked at olanzapine suggested that the drug improved language use and response after eight and 12 weeks of treatment [Potenza 1999].
As atypical antipsychotics can have quite different pharmacodynamic properties and different adverse effects, we propose a series of linked reviews to examine their effects and safety. This review will set out to evaluate the efficacy and potential harms of risperidone in people with autism spectrum disorder.
Objectives
The aim of this systematic review is to determine the efficacy and safety of risperidone in the treatment of autism spectrum disorder.
Methods
Criteria for considering studies for this review
Types of studies
1.Trials included will be randomised controlled trials only.
2.Trials must include at least one standardised measure such as a behaviour checklist used for the intervention and control group.
Types of participants
Participants may be of any age. Due to the limitations of reaching agreement for diagnoses using currently available diagnostic tools, inclusion will be limited to individuals with a diagnosis of disorders on the autism spectrum. Diagnosis must have been made using a standardised diagnostic instrument (eg, ADOS [Lord 1989], ADI‐R [Lord 1994] , DISCO [Wing 1999], CARS [Schopler 1988], Developmental, Dimensional and Diagnostic Interview (3di) [Skuse et al 2004]), or by using established diagnostic criteria (ICD‐10 [WHO 1993], DSM‐IV [APA 1994]).
Types of interventions
Risperidone, any dose and duration. Any means of delivery. The control group must be a placebo group or a wait‐list control group.
Types of outcome measures
Types of outcomes:
1.Core features of autism such as social interaction, communication and behavioural problems including stereotypy or obsessional behaviour;
2.Non‐core behaviours such as sleep disturbance, self‐mutilation, aggression, attention and concentration problems, and gastrointestinal function
3.Global impression of health
4.Quality of life for the individual or their carers
5. Economic outcomes
Outcomes will be divided into short‐term (less than three months) medium term (three‐12 months) and long term (over one year).
Types of measures
1. Standardised diagnostic assessment instruments (eg Aberrant Behaviour Checklist [Aman 1986], Autism Behaviour Checklist [Krug 1980], Childhood Autism Rating Scale [Schopler 1988], Autism Diagnostic Interview‐Revised [Lord 1994], Autism Diagnostic Observation Schedule [Lord 1989], Diagnostic Interview for Social and Communication Disorders [Wing 1999])
2. Standardised communication assessments
3. Quality of life questionnaires
4. Behaviour scales
5. Global Impression Rating Scales
6. Other Health Outcome Rating Scales
Search methods for identification of studies
Relevant trials will be identified through searching the Cochrane Central Register of Controlled Trials (CENTRAL) and the following databases:
Biomedical Sciences Databases:
LILACS
MEDLINE
EMBASE
PsycINFO
CINAHL
Clinicaltrials.gov (USA)
ZETOC
National Research Register (NRR) (UK)
Social Sciences and general references databases:
ERIC
The search strategy has been devised to capture trials both for this review and for future reviews on other antipsychotics and ASD. Search terms for MEDLINE will be as follows:
1. randomized controlled trial.pt.
2. controlled clinical trial.pt.
3. randomized controlled trials.sh.
4. random allocation.sh.
5. double blind method.sh.
6. single‐blind method.sh.
7. or/1‐6
8. (animal not human).sh.
9. 7 not 8
10. clinical trial.pt.
11. exp clinical trials/
12. (clin$ adj25 trial$).ti,ab.
13. ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$)).ti,ab.
14. Placebos.sh.
15. placebo$.ti,ab.
16. random$.ti,ab.
17. research design.sh.
18. or/10‐17
19. 18 not 8
20. 19 not 9
21. comparative study.sh.
22. exp evaluation studies/
23. follow up studies.sh.
24. prospective studies.sh.
25. (control$ or prospectiv$ or volunteer$).ti,ab.
26. or/21‐25
27. 26 not 8
28. 27 not (9 or 20)
29. 9 or 20 or 28
30. (substituted adj benzamide$).mp. [mp=title, original title, abstract, name of substance, mesh subject heading]
31. amisulpiride.mp. [mp=title, original title, abstract, name of substance, mesh subject heading]
32. antipsycho$.mp. [mp=title, original title, abstract, name of substance, mesh subject heading]
33. anti‐psycho$.mp. [mp=title, original title, abstract, name of substance, mesh subject heading]
34. exp Antipsychotic Agents/
35. beclamide.mp. [mp=title, original title, abstract, name of substance, mesh subject heading]
36. benperidol.mp. [mp=title, original title, abstract, name of substance, mesh subject heading]
37. benzamide.mp. [mp=title, original title, abstract, name of substance, mesh subject heading]
38. butyrophenone$.mp. [mp=title, original title, abstract, name of substance, mesh subject heading]
39. chlorpromazine.mp. [mp=title, original title, abstract, name of substance, mesh subject heading]
40. clozapine.mp. [mp=title, original title, abstract, name of substance, mesh subject heading]
41. dibenzoxazepine$.mp. [mp=title, original title, abstract, name of substance, mesh subject heading]
42. diphenylbutylpiperidine.mp. [mp=title, original title, abstract, name of substance, mesh subject heading]
43. dipiperone.mp. [mp=title, original title, abstract, name of substance, mesh subject heading]
44. dixyrazine.mp. [mp=title, original title, abstract, name of substance, mesh subject heading]
45. droperidol.mp. [mp=title, original title, abstract, name of substance, mesh subject heading]
46. eltoprazine.mp. [mp=title, original title, abstract, name of substance, mesh subject heading]
47. flupenthixol.mp. [mp=title, original title, abstract, name of substance, mesh subject heading]
48. flupentixol.mp. [mp=title, original title, abstract, name of substance, mesh subject heading]
49. fluphenazine.mp. [mp=title, original title, abstract, name of substance, mesh subject heading]
50. haloperidol.mp. [mp=title, original title, abstract, name of substance, mesh subject heading]
51. loxapine.mp. [mp=title, original title, abstract, name of substance, mesh subject heading]
52. methotrimeprazine.mp. [mp=title, original title, abstract, name of substance, mesh subject heading]
53. milenperone.mp. [mp=title, original title, abstract, name of substance, mesh subject heading]
54. neuroleptic$.mp. [mp=title, original title, abstract, name of substance, mesh subject heading]
55. olanzapine.mp. [mp=title, original title, abstract, name of substance, mesh subject heading]
56. oxypertine.mp. [mp=title, original title, abstract, name of substance, mesh subject heading]
57. penfluridol.mp. [mp=title, original title, abstract, name of substance, mesh subject heading]
58. pericyazine.mp. [mp=title, original title, abstract, name of substance, mesh subject heading]
59. perphenazine.mp. [mp=title, original title, abstract, name of substance, mesh subject heading]
60. phenothiazine$.mp. [mp=title, original title, abstract, name of substance, mesh subject heading]
61. pimozide.mp. [mp=title, original title, abstract, name of substance, mesh subject heading]
62. pipamperone.mp. [mp=title, original title, abstract, name of substance, mesh subject heading]
63. pipothiazine.mp. [mp=title, original title, abstract, name of substance, mesh subject heading]
64. pipotiazine.mp. [mp=title, original title, abstract, name of substance, mesh subject heading]
65. prochlorperazine.mp. [mp=title, original title, abstract, name of substance, mesh subject heading]
66. promazine.mp. [mp=title, original title, abstract, name of substance, mesh subject heading]
67. prothipendyl.mp. [mp=title, original title, abstract, name of substance, mesh subject heading]
68. quetiapine.mp. [mp=title, original title, abstract, name of substance, mesh subject heading]
69. risperidone.mp. [mp=title, original title, abstract, name of substance, mesh subject heading]
70. sertindole.mp. [mp=title, original title, abstract, name of substance, mesh subject heading]
71. sulpiride.mp. [mp=title, original title, abstract, name of substance, mesh subject heading]
72. thioridazine.mp. [mp=title, original title, abstract, name of substance, mesh subject heading]
73. thioxanthene$.mp. [mp=title, original title, abstract, name of substance, mesh subject heading]
74. tranquil$.mp. [mp=title, original title, abstract, name of substance, mesh subject heading]
75. trifluoperazine.mp. [mp=title, original title, abstract, name of substance, mesh subject heading]
76. zuclopenthixol.mp. [mp=title, original title, abstract, name of substance, mesh subject heading]
77. autistic disorder.mp. or exp Autistic Disorder/
78. autis$.mp. [mp=title, original title, abstract, name of substance, mesh subject heading]
79. kanner$.mp. [mp=title, original title, abstract, name of substance, mesh subject heading]
80. (childhood adj3 schizophren$).mp. [mp=title, original title, abstract, name of substance, mesh subject heading]
81. (speech adj3 disorder$).mp. [mp=title, original title, abstract, name of substance, mesh subject heading]
82. (language adj3 delay$).mp. [mp=title, original title, abstract, name of substance, mesh subject heading]
83. pdd.mp. [mp=title, original title, abstract, name of substance, mesh subject heading]
84. exp Child Development Disorders, Pervasive/
85. 77 or 78 or 79 or 80 or 81 or 82 or 83 or 84
86. zotepine.mp.
87. aripiprazole.mp.
88. ziprasidone.mp.
89. atypical antipsychotic$.mp.
90. 30 or 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38 or 39 or 40 or 41 or 42 or 43 or 44 or 45 or 46 or 47 or 48 or 49 or 50 or 51 or 52 or 53 or 54 or 55 or 56 or 57 or 58 or 59 or 60 or 61 or 62 or 63 or 64 or 65 or 66 or 67 or 68 or 69 or 70 or 71 or 72 or 73 or 74 or 75 or 76 or 86 or 87 or 88 or 89
91. 29 and 85 and 90
Search terms will be altered where necessary, to meet the requirements of individual databases. The optimally sensitive search strategy for randomised controlled trials, developed for the Cochrane Collaboration [Alderson 2003] will be combined with medical subject headings and textwords specific for autism and pervasive development disorders, as developed by the Cochrane Developmental, Psychosocial and Learning Problems Group. Search terms will be modified to meet the requirements of individual databases regarding differences in fields and syntax.
The aim of the search strategy will be for high precision and recall. There will be no language restrictions. Authors of retrieved papers will be contacted for ongoing or unpublished work, as will relevant pharmaceutical companies. We will search data bases designed to identifty grey literature and ongoing studes including ZETOC, ClinicalTrials.gov (USA) and the National Research Register (NRR UK).
Data collection and analysis
Selection of Trials
Titles and abstracts identified in the search will be considered independently by two authors (OJ, MA). Full text articles will be retrieved for all that appear to meet the inclusion criteria. These will then be independently assessed by the two authors (OJ, MA). Disagreement will be resolved by discussion with the third author (EC) and articles that do not fulfil inclusion criteria will be excluded.
Quality Assessment
Two independent reviewers will evaluate studies under consideration for methodological quality and appropriateness. Disagreements will be negotiated with a third reviewer. Two reviewers will independently assign each selected study to quality categories described in the Cochrane Collaboration Reviewer's Handbook [Alderson 2003] These are as follows:
(A) indicates adequate concealment of the allocation (for example, by telephone randomisation, or use of consecutively numbered, sealed, opaque envelopes);
(B)indicates uncertainty about whether the allocation was adequately concealed (for example, where the method of concealment is not known);
(C)indicates that the allocation was definitely not adequately concealed (for example, open random number lists or quasi‐randomisation such as alternate days, odd/even date of birth, or hospital number).
The reviewers will also assess the extent to which both participants and outcome assessors are blind to the allocation status of participants. The blinding will be recorded as 'met', 'unmet' or 'unclear' criteria as described in the Cochrane Handbook [Alderson 2003].
Study quality will be further assessed based on intention‐to‐treat analysis and percentage loss to follow‐up. No quality scoring system will be used. Impact of study quality will be determined by sensitivity analysis, if sufficient studies are retrieved to make this meaningful. Where study quality aspects are unclear, authors will be contacted for clarification.
Data Management
Data will be organised using Review Manager. Data extraction forms will be developed a priori and will include information regarding methods, participant details, dose and frequency of administration, other concurrent interventions and/or health problems, and outcome. Data will be extracted by two independent reviewers and disagreements will be resolved by negotiation with a third reviewer.
Data synthesis and measures of treatment effect
A meta‐analysis will be performed if two or more homogenous studies, that are suitable for inclusion, are found.
Binary data
If outcomes from either standardised instruments or diagnostic evaluations are expressed as proportions, results will be expressed as relative risk and risk difference, with 95% confidence intervals.
Continuous data
Where standardised assessment tools generate a score as the outcome measure comparisons will be made between the means of these scores. For measures on the same scales meta‐analysis will be performed using a 'weighted' mean difference, and where measures are on different scales, a standardized mean difference will be utilized.
Missing data
Missing data and dropouts will be assessed for each included study and reported in the review. Reasons for missing data will be discussed and the extent to which the results of the review could be altered by these data will be assessed.
Where insufficient data are reported, trial authors will be contacted. If no reply is forthcoming or full data are not made available, data will be included in meta‐analysis where possible, and if this is not possible, a narrative summary of the results will be presented.
Assessment of heterogeneity
Heterogeneity will be assessed using the I2 squared test (Higgins 2002), and the Chi‐squared test of heterogeneity as well as visual inspection of the graph. Clinical heterogeneity will be discussed in the text of the review.
Data synthesis
If studies are homogenous, a fixed effect model will be used in meta‐analysis. In the event of heterogeneity, a random effects meta‐analysis will be undertaken. Where there is clinical heterogeneity, the statistical synthesis of results will use a random effects model.
Subgroup analysis
If a sufficient number of studies are retrieved, subgroup analysis will be undertaken either if clinically different interventions are identified (dose, duration, delivery) or there are clinically relevant differences between subject groups (age of participants, diagnostic classification).
Assessing Bias
If sufficient studies are found, funnel plots will be drawn to investigate any relationship between effect size and study precision (closely related to sample size). Such a relationship could be due to publication or related biases or due to systematic differences between small and large studies. If a relationship is identified, clinical diversity of the studies will be further examined as a possible explanation. [ Egger 1997]. Every attempt will be made to obtain unpublished data and data from conference proceedings.
Sensitivity Analysis
If sufficient studies are retrieved, sensitivity analyses will be conducted to assess the impact of study quality on the results of meta‐analyses.
