Risperidone for attention‐deficit hyperactivity disorder in people with intellectual disabilities

Abstract

Background

Attention deficit hyperactivity disorder (ADHD) is increasingly recognised as occurring in people with intellectual disability (ID), although treatment of ADHD in this population has not ben tested widely. Risperidone has been used to treat ADHD in people with ID, although the evidence for its effectiveness is unclear.

Objectives

To examine the effectiveness of risperidone for the treatment of attention deficit hyperactivity disorder in people with intellectual disabilities.

Search methods

In February 2009, MEDLINE, PsycINFO, EMBASE, AMED, ISI Web of Science and WorldCat Dissertations were searched using an extensive list of synonyms for ADHD and ID. CENTRAL, CCDPLP, Current Controlled Trials meta‐register (mRCT), CenterWatch, NHS National Research Register, clinicaltrials.gov were searched, pharmaceutical companies and experts in the field were contacted. Reference lists of review articles were examined and citation searches were performed in ISI Web of Knowledge.

Selection criteria

All randomised controlled trials (RCTs), both published and unpublished, in any language, in which children or adults with ADHD and ID were treated with risperidone.

Data collection and analysis

Data collection and analyses were planned but not performed due to a lack of suitable studies.

Main results

Eleven studies were considered but none were suitable for inclusion.

Authors' conclusions

There is no evidence from RCTs that risperidone is effective for the treatment of ADHD in people with ID. Prescribing in this population can only be based on open‐label studies or extrapolation from research in people with autism and disruptive behaviour disorders; however these studies have not investigated people with ID separately so there are reservations regarding the applicability of these findings. Research into effectiveness and tolerability is urgently needed.

Plain language summary

Risperidone for ADHD in people with intellectual disabilities

Attention‐deficit hyperactivity disorder (ADHD) is more common in people with intellectual disability than in the general population.  As in the general population, ADHD adversely affects the ability to learn and is associated with behavioural disturbance, and therefore any intervention to reduce these symptoms is important.

Risperidone is a 'newer' atypical antipsychotic medication, prescribed to people with ID for many reasons, including disruptive behaviour, ADHD and psychosis. Most of the research into using risperidone for hyperactivity or disruptive behaviour has been performed in people with autism who do not have a clear diagnosis of ADHD. The aim of this review was to examine the effectiveness of risperidone in people (children and adults) with intellectual disability and ADHD.

No trials were found, and therefore there is no randomised controlled trial evidence to support or warn against the use of risperidone in this group of people.  It is important that this reseearch question is answered as many people with intellectual disability and ADHD are prescribed this medication. 

Background

Description of the condition

Attention deficit hyperactivity disorder (ADHD) is a developmental disorder usually diagnosed in childhood and characterised by symptoms of inattention, hyperactivity and impulsivity which are present in two or more settings and associated with significant functional impairment (APA 2000). It is one of the most common psychiatric disorders in childhood, with an estimated worldwide prevalence of 5.29% in children (Polanczyk 2007). Intellectual disability (ID) ‐ known as learning disability in the UK and referred to as mental retardation by the International Classification of Disease, 10th Edition (ICD‐10) and the Diagnostic and Statistical Manual, Revised 4th Edition (DSM‐IV‐TR) ‐ is defined as subaverage general intellectual functioning (IQ below 70) associated with significant impairment or deficits of adaptive functioning (APA 2000; WHO 1992). ID affects approximately 3% of the general population. Although symptoms of inattention, hyperactivity and impulsivity are frequently observed in children with ID, these have traditionally been considered by clinicians and researchers to be consistent with delayed developmental age. The current diagnostic criteria for ADHD emphasise that symptoms must be inappropriate for the developmental level, which may discourage making the diagnosis in the presence of ID. Nevertheless, there is increasing evidence to support the validity and clinical utility of making a diagnosis of ADHD in people with ID (Antshel 2006; Dekker 2003; Hastings 2005).

Estimates of prevalence of ADHD in populations with ID vary; one US study suggested that, at the very least, 15% of individuals with severe and profound levels of ID may meet diagnostic criteria for ADHD, even when mental age has been taken into account (Fox 1998). Rates of ADHD in children and adults with ID vary from 4‐ 42% depending on the severity of ID and the context in which each study was conducted. Estimates of prevalence are higher from studies which only measure target symptoms, such as hyperactivity, poor concentration and impulsivity (Dekker 2003; Fox 1998; Hardan 1997; Kadesjo 2001; Rojan 1993; Strømme 2000).

Both ADHD and ID are independently associated with increased lifelong rates of psychiatric morbidity. For example, adults with ID have increased rates of affective disorder (Richards 2001), and adults with ADHD have increased rates of affective disorders, anxiety disorders and substance use disorders (Kessler 2006). The available data indicate that the co‐ocurrence of ID and ADHD increases the risk of other psychiatric morbidity, particularly behavioural disorders. When compared to peers with ADHD and normal intellectual ability, children with ADHD and ID have similar, if not heightened, risk for persistence of ADHD from childhood into adolescence, are more likely to have comorbid separation anxiety disorder and behavioural disturbance in adolescence, and have more restrictive educational placements (Aman 1993; Aman 2002; Lambert 1987). ADHD is associated with challenging behaviour in people with ID. A follow‐up study of 51 people with ADHD and moderate to borderline ID found that many continued to have behavioural problems and take prescribed medication at 1 to 5 years follow‐up (Handen 1997). Bullying and violent behaviour have been found to be associated with hyperactivity in adolescents with ID (Reiter 2007) and a study of medication for disruptive behaviour in children with ID reported high rates of co‐morbid ADHD (Aman 2002). Thus, treatment of ADHD may have a role in the management of challenging behaviour in this group. The comorbidities present in people with ID represent a further diagnostic challenge and may influence both the types of treatment offered and its efficacy.

Description of the intervention

Risperidone is a second generation antipsychotic drug which is a mixed serotonin (5HT2A) and dopamine (D2) receptor antagonist with higher affinity for 5HT2A than D2 receptors. It also has alpha‐1 and alpha‐2 adrenergic activity and is antihistaminergic (Janssen 1988; Leysen 1988).

How the intervention might work

Reduction in impulsivity and inattention may result from attenuation of dopamine activity in the attention and response inhibition circuits of the prefrontal cortex. Early studies of first generation antipsychotics reported reductions in hyperactivity and stereotyped behaviour (Grabowski 1973; Alexandris 1968), although this may be due to general behavioural suppression rather than specific effects (Baumeister 1993). Some antipsychotics (e.g. haloperidol) are licensed in the USA for the short‐term treatment of hyperactive children who show excessive motor activity with accompanying conduct disorders.

Why it is important to do this review

It is estimated that just under 1/3 of people with ID are prescribed antipsychotic medication, commonly for psychiatric disorder or target behaviours such as aggression and self‐injury (Valdovinos 2003), although a systematic review found little evidence to support their use in this context (Brylewski 2004). A prescribing survey in the USA reported far greater rates of antipsychotic prescribing compared to stimulants in children with intellectual and developmental disabilities (Lott 2004), and British learning disability psychiatrists report a tendency to prescribe antipsychotics rather than stimulants for ADHD in this group (Bramble 1999). Although risperidone has a lower incidence of extrapyramidal side effects than first generation antipsychotics, it may be more likely to cause metabolic side effects such as weight gain (Findling 2004; Reyes 2006; Snyder 2002) and there are reports of diabetes mellitus associated with its use (Koller 2004). Given these concerns, it is important to systematically examine the evidence for its effectiveness.

Objectives

To examine the effectiveness of risperidone for the treatment of attention deficit hyperactivity disorder in people with intellectual disabilities.

Methods

Criteria for considering studies for this review

Types of studies

All randomised controlled trials (RCTs) in which patients with a diagnosis of ID and ADHD are treated with risperidone were included. Trials using cluster randomisation or a cross‐over design were considered. Published or unpublished trials in any language were considered.

Types of participants

Male and female children, adolescents or adults with a diagnosis of ID and ADHD. The diagnosis of ID may be made on the basis of psychometric testing or clinical diagnosis. All categories of ID ‐ mild, moderate, severe and profound ‐ were considered. The diagnosis of ADHD must be made according to diagnostic criteria specified in ICD‐10 (WHO 1992), DSM‐III (APA 1987), DSM‐IV‐TR (APA 2000) or equivalent.

Studies in which participants have a comorbid diagnosis of Pervasive Developmental Disorder or Autism, or in which participants have diagnosed congenital syndromes were considered for inclusion. Studies were excluded if participants have uncontrolled epilepsy, comorbid psychotic illness or a history of head injury.

Types of interventions

Trials which investigate treatment with risperidone compared to medication placebo were included. Treatment may be delivered in any setting, such as home, hospital or residential care. Studies which also involve a psychosocial intervention, such as psycho‐education or behaviour therapy, were considered for inclusion, provided that any such intervention was identical between the active and placebo medication groups.

Types of outcome measures

A number of instruments have been developed to assess different dimensions of psychopathology in people with ID; however, many psychiatric scales which were not developed for use with people with ID appear in studies undertaken within this population. Where possible, we selected the former for analyses in this review and considered the appropriateness of outcome measures in the context of available research.

Primary outcomes

The primary outcome was change in symptoms of inattention and hyperactivity as measured by a validated scale rated by parents, teachers, carers, assessors or clinicians e.g. Revised Conners Parent and Teacher Rating Scales (Goyette 1978) or Barkley Scale (Barkley 1990).

Secondary outcomes

We also planned to consider the following secondary outcomes, if available:

1. Response to treatment as a dichotomous outcome ‐ this may be defined by the study e.g. as a percentage reduction in symptom scale scores, or by a rating of improvement on a Clinical Global Impression (NIMH 1985) scale;

2. Cognitive ability ‐ as measured by standardised psychometric tests of IQ, attention and working memory;

3. General level of impairment ‐as measured by a scale such as a Karnofsky Scale (Karnofsky 1948), Global Assessment of Functioning (APA 2000), Children's Global Assessment Scale (Shaffer 1983) or Clinical Global Impression (NIMH 1985) scales;

4. General level of functioning ‐as measured by a standardised activities of daily living scale e.g. Barthel Index (Collin 1988; Mahoney 1965), Functional Status Questionnaire (Cleary 2000; Jette 1986);

5. Challenging behaviour ‐ as measured by a standardised scale such as the Aberrant Behaviour Checklist (Aman 1985) or the Challenging Behaviour Checklist (Harris 1990);

6. Substance abuse, as measured by estimates of frequency and amount of drug or alcohol use;

7. Psychiatric morbidity ‐ as measured by a validated rating scale, e.g. Beck Depression Inventory (Beck 1979), Montgomery‐Åsberg Depression Rating Scale (Montgomery 1979), Beck Anxiety Inventory (Beck 1988), Hamilton Depression Rating Scale (Hamilton 1960), Hamilton Anxiety Rating Scale (Hamilton 1959), Brief Psychiatric Rating Scale (Ventura 1993), SCL‐90 Symptom Checklist (Derogatis 1973). Where data are available, a scale which has been validated in a population with ID will be preferred;

8. Carer burden ‐ as measured by a validated scale e.g. Montgomery Borgotta Caregiver Burden Scale (Montgomery 1985);

9. Side effects ‐ either clinical outcomes such as weight gain, blood glucose and lipid levels, blood pressure abnormalities, prolactin increase ‐ or as measured using a side effect symptom checklist such as the Barkley Side Effect Scale (Barkley 2006) or the Fawcett side effect scale (Fawcett 1987);

10. Acceptability of the treatment ‐ as rated by patients, parents or carers;

11. Drop‐out rates ‐ classified by reasons for withdrawal.

Search methods for identification of studies

The search strategy aimed to identify all RCTs of medication for ADHD in people with ID, from which studies investigating risperidone were considered for this review. All searches were conducted in February 2009.

Electronic searches

1) MEDLINE, PsycINFO, EMBASE and AMED were searched using the Highly Sensitive Search Strategy described in the Cochrane Handbook for Systematic Reviews of Interventions Version 4.2.6 (Higgins 2006) plus additional terms for ADHD, ID and medication (Table 1)

1. MEDLINE, PSYCinfo, EMBASE, AMED search strategy.

Search Terms

1. randomized controlled trial.pt. 2. controlled clinical trial.pt. 3. Randomized Controlled Trials/ 4. Random Allocation/ 5. Double‐Blind Method/ 6. Single‐Blind Method/ 7. or/1‐6 8. animal/ not human/ 9. 7 not 8 10. clinical trial.pt. 11. exp Clinical Trials/ 12. (clinic$ adj25 trial$).tw. 13. ((singl$ or double$ or trebl$ or tripl$) adj (mask$ or blind$)).tw. 14. Placebos/ 15. placebo$.tw. 16. random$.tw. 17. Research Design/ 18. or/10‐17 19. 18 not 8 20. 19 not 9 21. Comparative Study/ 22. exp Evaluation Studies/ 23. Follow‐Up Studies/ 24. Prospective Studies/ 25. (control$ or prospectiv$ or volunteer$).tw. 26. or/21‐25 27. 26 not 8 28. 27 not (9 or 20) 29. 9 or 20 or 28 30. exp Attention Deficit Disorder with Hyperactivity/ 31. (attention adj5 deficit).mp. [mp=title, original title, abstract, name of substance word, subject heading word] 32. (adhd or adhkd or addh or adhs).tw. 33. hyperactiv$.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 34. exp Child Behavior Disorders/ 35. exp hyperkinesis/ 36. hyperkine$.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 37. (minimal$ adj brain adj3 disorder$).tw. 38. (minimal$ adj brain adj3 dysfunction).tw. 39. (minimal$ adj brain adj3 damage$).tw. 40. or/30‐39 41. exp Learning Disorders/ 42. (education$ adj5 subnorm$).tw. 43. (intellect$ adj5 def$).tw. 44. (intellect$ adj5 disab$).tw. 45. (intellect$ adj5 disorder$).tw. 46. (intellect$ adj5 handicap$).tw. 47. (intellect$ adj5 impair$).tw. 48. (intellect$ adj5 subnorm$).tw. 49. (learn$ adj5 difficult$).tw. 50. (learn$ adj5 disab$).tw. 51. (learn$ adj5 disorder$).tw. 52. (mental$ adj5 def$).tw. 53. (mental$ adj5 disab$).tw. 54. (mental$ adj5 handicap$).tw. 55. (mental$ adj5 impair$).tw. 56. exp Mental Retardation/ 57. (mental$ adj5 retard$).tw. 58. (mental$ adj5 subnorm$).tw. 59. exp Child Development Disorders, Pervasive/ 60. autis$.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 61. asperger$.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 62. (pervasive adj25 development$ adj25 disorder$).mp. [mp=title, original title, abstract, name of substance word, subject heading word] 63. or/41‐62 64. 40 and 63 65. 29 and 64 66. exp Central Nervous System Stimulants/ 67. exp Phenylacetates/ 68. methylphenidate.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 69. exp Amphetamines/ 70. (dexamphetamine or dexamfetamine or dextroamphetamine or dextroamfetamine or amphetamine or amfetamine or dexedrine or benzedrine).mp. [mp=title, original title, abstract, name of substance word, subject heading word] 71. adderall.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 72. modafinil.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 73. caffeine.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 74. exp Imidazolines/ 75. clonidine.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 76. guanfacine.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 77. exp Guanidines/ 78. exp Oxazoles/ 79. pemoline.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 80. nicotine.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 81. exp Adrenergic Agents/ 82. atomoxetine.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 83. exp Antidepressive Agents/ 84. amitriptyline.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 85. amoxapine.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 86. clomipramine.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 87. Dosulepin.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 88. dothiepin.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 89. Doxepin.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 90. Imipramine.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 91. Lofepramine.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 92. Nortriptyline.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 93. Trimipramine.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 94. citalopram.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 95. escitalopram.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 96. fluoxetine.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 97. fluvoxamine.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 98. paroxetine.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 99. sertraline.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 100. venlafaxine.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 101. bupropion.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 102. exp Antipsychotic Agents/ 103. Benperidol.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 104. Chlorpromazine.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 105. Flupentixol.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 106. Flupenthixol.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 107. Fluphenazine.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 108. Haloperidol.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 109. Levomepromazine.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 110. Pericyazine.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 111. Periciazine.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 112. Perphenazine.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 113. Pimozide.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 114. Prochlorperazine.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 115. Promazine.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 116. Stelazine.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 117. Sulpiride.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 118. Thioridazine.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 119. Trifluoperazine.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 120. Zuclopenthixol.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 121. Amisulpiride.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 122. Aripiprazole.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 123. Clozapine.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 124. Olanzapine.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 125. Quetiapine.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 126. Risperidone.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 127. Sertindole.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 128. Ziprasidone.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 129. Zotepine.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 130. exp Carnitine/ 131. acetylcarnitine.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 132. exp Fatty Acids, Unsaturated/ 133. exp Amantadine/ 134. amantadine.mp. 135. exp Naloxone/ 136. exp Naltrexone/ 137. exp Buspirone/ 138. exp Benzodiazepines/ 139. diazepam.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 140. exp Anticonvulsants/ 141. lamotrigine.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 142. carbamazepine.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 143. or/66‐142 144. 65 and 143

2) ISI Web of Science and WorldCat Dissertations were searched using the search strategy described in Table 2 and Table 3

2. ISI Web of Knowledge Search Strategy.

Search Terms

1. TS=((attention SAME deficit) OR hyperactiv* OR hyperkine* OR ADHD OR ADHS OR ADDH OR ADHKD OR (minimal* SAME brain SAME disorder*) OR (minimal* SAME brain SAME dysfunction) OR (minimal* SAME brain SAME damage*)) DocType=All document types; Language=All languages; Database=SCI‐EXPANDED; Timespan=1900‐2009 2. TS=((education* SAME subnormal) OR (intellect* SAME def*) OR (intellect* SAME dis*) OR (intellect* SAME handicap*) OR (intellect* SAME impair*) OR (intellect* SAME subnorm*) OR (learn* SAME difficult*) OR (learn* SAME dis*) OR (mental* SAME def*) OR (mental* SAME disab*) OR (mental* SAME handicap*) OR (mental* SAME impair*) OR (mental* SAME retard*)) DocType=All document types; Language=All languages; Database=SCI‐EXPANDED; Timespan=1900‐2009 3. TS=((pervasive SAME development* SAME dis*) OR autis* OR asperger*) DocType=All document types; Language=All languages; Database=SCI‐EXPANDED; Timespan=1900‐2009 4. #2 OR #3 5. #1 AND #4 6. TS=(stimulant* OR methylphenidate OR amphetamine OR amfetamine OR dextroamphetamine OR dextroamfetamine OR dexamphetamine OR dexamfetamine OR dexedrine OR benzedrine OR adderal OR modafinil OR caffeine OR clonidine OR guanfacine OR pemoline OR nicotine OR atomoxetine OR venlafaxine) DocType=All document types; Language=All languages; Database=SCI‐EXPANDED; Timespan=1900‐2009OR 7. TS=(tricyclic OR amitriptyline OR amoxapine OR clomipramine OR dosulepin OR dothiepin OR Doxepin OR Imipramine OR Lofepramine OR Nortriptyline OR Trimipramine OR "serotonin reuptake inhibitor*" OR SSRI* OR citalopram OR escitalopram OR fluoxetine OR fluvoxamine OR paroxetine OR sertraline OR bupropion) DocType=All document types; Language=All languages; Database=SCI‐EXPANDED; Timespan=1900‐2009 8. TS=(Antipsychotic* OR neuroleptic OR Benperidol OR Chlorpromazine OR Flupentixol OR Flupenthixol OR Fluphenazine OR Haloperidol OR Levomepromazine OR Pericyazine OR Periciazine OR Perphenazine OR Pimozide OR Prochlorperazine OR Promazine OR Stelazine OR Sulpiride OR Thioridazine OR Trifluoperazine OR Zuclopenthixol OR Amisulpiride OR Aripiprazole OR Clozapine OR Olanzapine OR Quetiapine OR Risperidone OR Sertindole OR Ziprasidone OR Zotepine) DocType=All document types; Language=All languages; Database=SCI‐EXPANDED; Timespan=1900‐2009 9. TS=(Carnitine OR acetylcarnitine OR "Fatty Acid*") DocType=All document types; Language=All languages; Database=SCI‐EXPANDED; Timespan=1900‐2009 10. TS=(Amantadine OR Naloxone OR naltrexone OR Buspirone) DocType=All document types; Language=All languages; Database=SCI‐EXPANDED; Timespan=1900‐2009 11. TS=(Benzodiazepine* OR diazepam OR Anticonvulsant* OR antiepileptic* OR lamotrigine OR carbamazepine) DocType=All document types; Language=All languages; Database=SCI‐EXPANDED; Timespan=1900‐2009 12. #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 13. #5 AND #12 14. TS=(random* OR control* OR trial OR placebo* OR prospective OR ((singl* OR doubl* OR trebl* OR tripl*) SAME (mask* OR blind*))) DocType=All document types; Language=All languages; Database=SCI‐EXPANDED; Timespan=1900‐2009 15. #13 AND #14

3. WorldCat Dissertations Search Strategy.

Search Terms

(kw: attention w deficit OR kw: hyperactiv* OR kw: hyperkine* OR kw: ADHD OR kw: ADHS OR kw: ADDH OR kw: ADHKD OR su= "attention‐deficit hyperactivity disorder" OR kw: minimal w brain w disorder OR kw: minimal w brain w dysfunction OR kw: minimal w brain w damage OR kw: MBD) and ((kw: education* w subnorm* OR kw: intellect* w def* OR kw: intellect* w disab* OR kw: intellect* w disorder* OR kw: intellect* w handicap* OR kw: intellect* w impair* OR kw: intellect* w subnormal* OR kw: learning w difficult* OR kw: learning w disab* OR kw: learning w disorder* OR kw: mental* w def* OR kw: mental* w disab*OR kw: mental* w handicap* OR kw: mental* w impair* OR kw: mental* w retard* OR su= "mental retardation" OR kw: mental* w subnormal) or (kw: pervasive n5 disorder OR kw: autism OR kw: autistic OR kw: asperger OR su= "autism"))

3) CENTRAL, Current Controlled Trials meta‐register (mRCT), CenterWatch, NHS National Research Register, clinicaltrials.gov were searched using the search strategies described in Table 4, Table 5 and Table 6. UKCRN Study Portfolio was searched using the topic 'attention deficit hyperactivity conduct disorder'.

4. CENTRAL Search Strategy.

Search Terms

#1 MeSH descriptor Attention Deficit and Disruptive Behavior Disorders explode all trees #2 MeSH descriptor Learning Disorders explode all trees #3 MeSH descriptor Mental Retardation explode all trees #4 MeSH descriptor Child Development Disorders, Pervasive explode all trees #5 (#2 OR #3 OR #4) #6 (#1 AND #5)

5. mRCT Search Strategy.

Search Terms

("attention deficit" OR hyperactiv% OR hyperkine% ADHD OR ADHS OR ADDH OR ADHKD OR "minimal brain dysfunction" OR "minimal brain disorder" OR "minimal brain damage" OR MBD) AND ("education% subnormal" OR "intellectual% def%" OR "intellectual% dis%" OR "intellectual% impair%" OR "intellect% subnorm%" OR "learning difficult%" OR "learning dis%" OR "mental% def%" OR "mental% disab%" OR "mental% handicap%" OR "mental% impair%" OR "mental% retard%" OR "mental% subnormal")

6. National Research Register Search Strategy.

Search Terms

#1. ATTENTION DEFICIT AND DISRUPTIVE BEHAVIOR DISORDERS explode tree 1 (MeSH) #2. LEARNING DISORDERS explode all trees (MeSH) #3. CHILD DEVELOPMENT DISORDERS PERVASIVE explode all trees (MeSH) #4. MENTAL RETARDATION explode all trees (MeSH) #5. (#2 or #3 or #4) #6. (#1 and #5)

Searching other resources

Pharmaceutical Databases

Pharmaceutical companies were contacted and asked to give details of published and unpublished trials.

Personal Contact

Experts in the field were contacted and asked to identify other published and unpublished trials.

Citations

a) The reference lists of retrieved studies and relevant review articles were inspected to identify any further studies

b) For each included study, a citation search was performed in ISI Web of Knowledge to identify any later studies that may have cited it.

Data collection and analysis

Timeline

This is the first published version of this review. The search will be repeated within three years of publication and the review updated accordingly.

Selection of studies

Abstracts of potentially relevant studies were inspected by at least two of the reviewers and full articles requested if they appeared to be relevant. Had unpublished trials been identified, the investigators would have been contacted to request data (rewrite). Full papers were then inspected by at least two reviewers using a standardised assessment sheet to assess whether studies fulfil criteria for inclusion. Any disagreements were resolved by discussion among all the authors.

Data extraction and management

No studies were considered suitable for inclusion. The methods as described in the protocol are given in Table 7 and may be used in future updated versions of this review.

7. Protocol for meta‐analysis.

Assessment of risk of bias Methodological quality will be assessed independently by two review authors according to the Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.0 (Higgins 2008). Review authors will independently assess the risk of bias within each included study based on the following five domains with ratings of 'Yes' (low risk of bias); 'No' (high risk of bias) and 'Unclear' (uncertain risk of bias): Sequence generation Description: the method used to generate the allocation sequence will be examined so as to assess whether it should have produced comparable groups; review authors' judgment: was the randomisation sequence adequately generated? Allocation concealment Description: the method used to conceal allocation sequence will be examined to assess whether intervention schedules could have been foreseen in advance of, or during, recruitment; review authors' judgment: was allocation adequately concealed? Blinding Description: any measures taken to blind participants, personnel and outcome assessors to knowledge of which intervention a given participant might have received; review authors' judgment: was knowledge of the allocated intervention adequately prevented during the study? Incomplete outcome data Description: data on attrition and exclusions was extracted, including the numbers involved (compared with total randomized), reasons for attrition/exclusion, and any re‐inclusions in analyses performed by review authors; review authors' judgment: were incomplete outcome data adequately addressed? Selective outcome reporting Description: attempts will be made to assess the possibility of selective outcome reporting by investigators. This included comparing published results to outcomes detailed in the study protocol or published methods, considering whether primary outcomes were stated a priori, and considering whether or not commonly used outcomes reported in similar studies were reported; review authors' judgment: are reports of the study free of suggestion of selective outcome reporting? Other sources of bias Description: other potential sources of bias will be considered. These include source of funding, competing interests, adequacy of washout period in cross‐over studies, and validity/reliability of outcome measures. Review authors' judgement: was the study free of other sources of bias? For the purposes of sensitivity analysis, studies will be described as being overall low, moderate or high risk of bias. Disagreements between authors will be resolved by discussion or the use of a third party opinion. Since standardised rating scales for the assessment of methodological quality may be more sensitive to the quality of reporting than validity of study design (Higgins 2008) such scales will not be used. If published articles do not contain sufficient detail to permit full assessment, the authors will be contacted and asked to clarify the methods used. Data Extraction A standardised extraction sheet will be designed to extract data from included trials independently by two authors. The study authors will be contacted to request missing data or clarifications where necessary. Measures of Treatment Effect If participants, interventions and outcome measures are sufficiently similar, meta‐analyses will be carried out. Data from the extraction sheets will be entered into an Excel spreadsheet and copied into Review Manager version 5.0 (RevMan). Data entry will be checked by entering the same data from a different author's extraction sheets into RevMan using the double data entry facility. Dichotomous data will be pooled using odds ratios. Ordinal data from rating scales will be treated as continuous data. Where the same rating scale has been used for all studies, data will be pooled using weighted mean differences; where different rating scales have been used to measure the same outcome, standardised mean differences will be used. Dichotomous Outcomes Response to medication (secondary outcome) will be defined as a 25% reduction in scores on a validated ADHD rating scale. Reported response rates will be pooled where they are sufficiently similar, however if this information is not reported, the raw data will be requested from study authors and response rates calculated. Cross‐over Trials Data from cross‐over trials will be pooled according to the methods described in the Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.0 (Higgins 2008a) and by Elbourne et al. (Elbourne 2002). Mean within‐participants difference and standard error of the mean difference will be entered into RevMan using the generic inverse outcome type. Where the standard error of the mean difference is not reported, the original data will be requested from study authors or the value will be imputed. Correlation coefficients will be calculated from studies where sufficient data is available and if these values are consistent they will be used to calculate the missing standard errors for other studies. Dealing with Missing Data If studies do not report intention‐to‐treat analyses, attempts will be made to obtain missing data by contacting the study authors. If dichotomous outcome data are not available, values will be imputed by assuming that all participants for whom data is missing did not experience a favourable outcome. If missing continuous data is not forthcoming, an available case analysis will be performed. Where studies do not report response rates, values will be imputed using the method described by Furukawa et al. (Furukawa 2005). Outcome data will be assumed to be normally distributed. Number of responders (n) will be calculated using the formula in Figure 1, where N is the number of participants at endpoint, x is 75% of the baseline mean score, mu is the endpoint mean score, sigma is the standard devation of the endpoint mean and phi is the cumulative distribution function. The validity of this method will be checked by applying it to studies which do report response rates and then calculating the correlation coefficient between reported and imputed response rates. Assessment of Heterogeneity The chi2 and I2 statistics will be used to assess heterogeneity between studies. Graphical representations will also be inspected. Where significant heterogeneity is suspected (p > 0.1, I‐squared > 50% or on visual inspection), a random‐effects meta‐analysis will be used. Fixed‐effect meta‐analyses will be used where significant heterogeneity is not suspected. Subgroup Analysis and Investigation of Heterogeneity Where heterogeneity is identified, it will be investigated by performing the following subgroup analyses: 1) Subgroups by severity of ID (mild, moderate, severe or profound); 2) Subgroups by different doses of drug (fixed doses rather than mg/kg as this reflects clinical practice) 3) Subgroups by whether participants have comorbid pervasive developmental disorder or not; 4) Subgroups by age ‐ whether participants are adults (18 years or over) or children (under 18 years old); 5) Subgroups by whether treatment is with dexamfetamine or mixed amfetamine salts, and with sustained release or immediate release preparations. Sensitivity Analysis A sensitivity analysis will be performed as follows to explore whether the results of the review are robust. 1) Studies will be grouped qualitatively into low, moderate or high quality and meta‐analyses performed by group. 2) Comparisons will be made between studies which use a cross‐over design and those with a separate control arm. 3) If missing data have been imputed for intention‐to‐treat analysis with dichotomous outcomes, a "best case/worst case" analysis will be performed. All participants for whom data is missing will be assumed to have had a favourable outcome (response to medication) and the results compared to the original, more conservative, analysis. These analyses will be compared with the original meta‐analysis and any effect on the results noted. Assessment of Reporting Bias 1) Publication bias will be assessed by constructing funnel plots. 2) If unpublished data is included in the review, a subgroup analysis will be performed to compare published and unpublished data.

1.

Results

Description of studies

Results of the search

The initial search identified over 2000 references. Fifteen references were considered possibly relevant and the full articles retrieved for consideration. None of the studies met inclusion criteria.

Excluded studies

The 15 papers considered reported on a total of 11 studies. Participants in four studies did not have ADHD (Gagiano 2005; Günther 2006; van Bellinghen 2001; Vanden Borre 1993), and in one study did not have ID (Armenteros 2007). Three studies had no placebo control group (Arman 2003; Correia Filho 2005; Croonenberghs 2005) and one study was a series of case reports (Dartnall 1999). Two studies were potentially of interest (Aman 2002; Snyder 2002): these were randomised controlled trials of risperidone for the treatment of challenging behaviour in children with borderline to moderate ID. A subgroup of 100 participants across both trials were reported as having both ADHD and ID ‐ this would potentially allow inferences to be made about the effect of risperidone in this group. However, as data were not reported separately for this group or available from the authors, these studies were excluded (Binder 2008).

Risk of bias in included studies

Not applicable (no studies were identified which met inclusion criteria).

Effects of interventions

Not applicable (no studies were identified which met inclusion criteria).

Discussion

Summary of main results

We performed a systematic review to examine the effectiveness of risperidone for the treatment of attention deficit hyperactivity disorder in people with intellectual disability, based on evidence from randomised controlled trials. We identified and considered 15 published papers for inclusion. Although we identified two RCTs of risperidone in which a subgroup of participants had ADHD and ID, we were unable to extract data regarding these subgroups.

Overall completeness and applicability of evidence

The search we undertook was comprehensive and likely to identify any relevant research. Thus, there is currently no RCT evidence that risperidone is effective for the treatment of ADHD in people with ID.

Risperidone is one of the most widely prescribed psychotropic medications for people with ID (Lott 2004). The use of antipsychotic medication as a treatment for ADHD is increasing; a recent USA‐based survey in the general population found a 2.5‐fold increase in initiation of antipsychotic medication for ADHD or conduct disorder between 1996 and 2001, accounting for 43.1% of new prescriptions for in 2001 (Cooper 2004). However, this present review has not found sufficient evidence to support the use of risperidone as first‐line medication for ADHD in people with ID. Prescribing risperidone in this group can be based only on uncontrolled studies or on extrapolation from research in people without a diagnosis of ID.

As with any prescribing in this population it must be borne in mind that a significant proportion of people with ID may lack capacity to give informed consent (Arscott 1999; Wong 2000); in such cases the involvement of family members and carers may be necessary to fully consider the individual’s best interests. Although emphasis is increasingly given to the inclusion of people with ID in mainstream services where appropriate (Fyson 2003), the lack of research evidence and difficulty of prescribing decisions supports the maintenance of specialist psychiatric services for this group. Good quality, independent research is required to determine the efficacy and safety of risperidone for the treatment of ADHD in people with ID.

Authors' conclusions

Implications for practice.

1. For patients and their families 
 Prescribing of risperidone for ADHD in people with ID is based only on studies without placebo comparison groups or studies performed in people without ID.

2. For clinicians 
 ADHD symptoms are not only more common in people with ID compared to the population without ID, but they also tend to be more severe and have greater stability over time (Hastings 2005). Furthermore, there is concern that such have been reports of such symptoms may bebeing less responsive to medical treatment and people with ID may be being more susceptible to side effects (Aman 1996) . Without randomised controlled studies in this population, risperidone cannot be recommended as a first‐line medication; prescribing decisions can only be based on clinical judgement and studies in people without ID. For the reasons outlined above problems inherent in extrapolating from research in other patient groups are apparent.

3. For managers 
 Although service planning should aim to include people with ID in mainstream services where appropriate, managers should consider the need for access to professionals with relevant specialist prescribing experience.

Implications for research.

1.This review has highlighted the absence of randomised controlled trials investigating the efficacy of risperidone for the treatment of ADHD in people with ID. 
 2.In order to ensure validity of future trials, they should use outcome measures which have been specifically validated in people with ID and clearly measure and report adverse effects.

What's new

Date	Event	Description
14 April 2010	Amended	Contact details updated.

History

Protocol first published: Issue 1, 2008
 Review first published: Issue 2, 2009

Date	Event	Description
19 November 2008	Amended	Converted to new review format.
13 November 2008	New citation required and conclusions have changed	Substantive amendment

Characteristics of studies

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Aman 2002	RCT of risperidone for challenging behaviour in children with borderline to moderate intellectual impairment (IQ between 36 and 84); although a subgroup has ADHD and ID, data were not reported for this subgroup alone.
Arman 2003	No placebo control group
Armenteros 2007	Participants do not have ID
Correia Filho 2005	No placebo control group
Croonenberghs 2005	Open label study; not randomised or controlled; not all participants have ADHD and ID
Dartnall 1999	Case reports
Gagiano 2005	Participants do not have ADHD
Günther 2006	Participants do not have ADHD
Snyder 2002	RCT of risperidone for challenging behaviour in children with borderline to moderate intellectual impairment (IQ between 36 and 84); although a subgroup has ADHD and ID, data were not reported for this subgroup alone.
van Bellinghen 2001	Participants do not have ADHD
Vanden Borre 1993	Participants do not have ADHD

Contributions of authors

SM and EP wrote the "Background" section and were involved in searching, inclusion assessment and writing up.

AT wrote the protocol, developed the search strategies, and was involved in searching, inclusion assessment writing up.

KX reviewed the protocol, oversaw any disagreements regarding study inclusion or quality assessment, and was involved in writing up.

Declarations of interest

None known.

Edited (no change to conclusions)