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Review
. 2023 Jun 1;6(6):CD013851.
doi: 10.1002/14651858.CD013851.pub2.

Acetylcholinesterase inhibitors for autistic spectrum disorders

Alexandra Ure  1   2   3 , Georgina R Cox  1   4 , Richard Haslam  5   6 , Katrina Williams  1   2   3   6
Affiliations
Review

Acetylcholinesterase inhibitors for autistic spectrum disorders

Alexandra Ure et al. Cochrane Database Syst Rev. .

Abstract

Background: Autism spectrum disorder (autism) is a neurodevelopmental condition characterised by impairments in social communication and interaction, plus restricted, repetitive patterns of behaviour and interests. Whilst some people embrace autism as part of their identity, others struggle with their difficulties, and some seek treatment. There are no current interventions that result in complete reduction of autism features. Acetylcholine is a neurotransmitter for the cholinergic system and has a role in attention, novelty seeking, and memory. Low levels of acetylcholine have been investigated as a potential contributor to autism symptomatology. Donepezil, galantamine, and rivastigmine (commonly referred to as acetylcholinesterase inhibitors) all inhibit acetylcholinesterase, and have slightly different modes of action and biological availability, so their effectiveness and side-effect profiles may vary. The effect of various acetylcholinesterase inhibitor on core autism features across the lifespan, and possible adverse effects, have not been thoroughly investigated.

Objectives: To evaluate the efficacy and harms of acetylcholinesterase inhibitors for people with the core features (social interaction, communication, and restrictive and repetitive behaviours) of autism. To assess the effects of acetylcholinesterase inhibitors on non-core features of autism.

Search methods: In November 2022, we searched CENTRAL, MEDLINE, Embase, eight other databases, and two trials registers. We also searched the reference lists of included studies and relevant reviews, and contacted authors of relevant studies.

Selection criteria: Randomised controlled trials (RCTs), comparing acetylcholinesterase inhibitors (e.g. galantamine, donepezil, or rivastigmine) of varying doses, delivered orally or via transdermal patch, either as monotherapy or adjunct therapy, with placebo. People of any age, with a clinical diagnosis of autism were eligible for inclusion.

Data collection and analysis: We used standard methodological procedures expected by Cochrane. Our primary outcomes were core features of autism and adverse effects. Secondary outcomes were language, irritability, hyperactivity, and general health and function. We used GRADE to assess certainty of evidence.

Main results: We included two RCTs (74 participants). One study was conducted in Iran, the second in the USA, although exact location in the USA is unclear. Galantamine plus risperidone versus placebo plus risperidone One study compared the effects of galantamine plus risperidone to placebo plus risperidone (40 participants, aged 4 years to 12 years). Primary and secondary outcomes of interest were measured postintervention, using subscales of the Aberrant Behavior Checklist (score 0 to 3; higher scores = greater impairment). Very low-certainty evidence showed there was little to no difference between the two groups postintervention for social communication (mean difference (MD) -2.75, 95% confidence interval (CI) -5.88 to 0.38), and restricted and repetitive behaviour (MD -0.55, 95% CI -3.47 to 2.37). Overall autism features were not assessed. Adverse events may be higher in the galantamine plus risperidone group (75%) compared with the placebo plus risperidone group (35%): odds ratio 5.57, 95% CI 1.42 to 21.86, low-certainty evidence. No serious adverse events were reported. Low-certainty evidence showed a small difference in irritability (MD -3.50, 95% CI -6.39 to -0.61), with the galantamine plus risperidone group showing a greater decline on the irritability subscale than the placebo group postintervention. There was no evidence of a difference between the groups in hyperactivity postintervention (MD -5.20, 95% CI -10.51 to 0.11). General health and function were not assessed. Donepezil versus placebo One study compared donepezil to placebo (34 participants aged 8 years to 17 years). Primary outcomes of interest were measured postintervention, using subscales of the Modified Version of The Real Life Rating Scale (scored 0 to 3; higher scores = greater impairment). Very low-certainty evidence showed no evidence of group differences immediately postintervention in overall autism features (MD 0.07, 95% CI -0.19 to 0.33), or in the autism symptom domains of social communication (MD -0.02, 95% CI -0.34 to 0.30), and restricted and repetitive behaviours (MD 0.04, 95% CI -0.27 to 0.35). Significant adverse events leading to study withdrawal in at least one participant was implied in the data analysis section, but not explicitly reported. The evidence is very uncertain about the effect of donepezil, compared to placebo, on the secondary outcomes of interest, including irritability (MD 1.08, 95% CI -0.41 to 2.57), hyperactivity (MD 2.60, 95% CI 0.50 to 4.70), and general health and function (MD 0.03, 95% CI -0.48 to 0.54) postintervention. Across all analyses within this comparison, we judged the evidence to be very low-certainty due to high risk of bias, and very serious imprecision (results based on one small study with wide confidence intervals). The study narratively reported adverse events for the study as a whole, rather than by treatment group.

Authors' conclusions: Evidence about the effectiveness of acetylcholinesterase inhibitors as a medication to improve outcomes for autistic adults is lacking, and for autistic children is very uncertain. There is a need for more evidence of improvement in outcomes of relevance to clinical care, autistic people, and their families. There are a number of ongoing studies involving acetylcholinesterase inhibitors, and future updates of this review may add to the current evidence.

Trial registration: ClinicalTrials.gov NCT01098383 NCT01887132 NCT00252603.

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Conflict of interest statement

Alexandra Ure (AU) is a Senior Psychologist with Monash Children's Hospital, where she is involved in child developmental assessments and the supervision of staff and students. She is also a Senior Research Fellow with Monash University, with an interest in complex neurodevelopmental disorders, including autism spectrum disorder. AU declares a Clinical Sciences Fellowship from Monash University for her work to embed research into new clinical service, involving assessments of children presenting with neurodevelopmental concerns and their families; paid to Monash University.

Georgina Cox (GC) is an Editor with Cochrane Developmental, Psychosocial and Learning Problems (DPLP) and Cochrane Common Mental Disorders. GC was not involved in the editorial process for this review.

Richard Haslam is the Director of Mental Health at the Royal Children's Hospital, Melbourne (salaried position). He has declared that he has no conflicts of interest.

Katrina Williams (KW) reports a grant from the National Health and Medical Research Council (NHMRC) for a phase III trial of cannabidiol for severe behaviour disorders in children with an intellectual disability, with or without autism, on which she is Chief Investigator (1 January 2020 to 31 May 2023); paid to institution, but KW benefited from this payment, or had access to the funds. KW also reports contracts with Epsilon Healthcare (formerly THC Global Group Ltd; ongoing since 1 January 2020), to develop an interventional product and placebo for children, which is being provided by the Victorian Government for a Medical Research Future Fund funded phase III multisite trial; and with Tilray (from 28 November 2018 to 27 November 2019) for the investigation drug and placebo for a pilot trial of cannabidiol for severe behaviour problems in children with intellectual disability, with or without autism; both paid to the institution. KW reports a grant from the NHMRC for an ongoing prognosis study about predictors of autism outcome, which will also publish diagnostic stability outcomes, and which could be included in an update of this systematic review; paid to the institution. Lastly, KW reports that she is an Editor with DPLP; however, she was not involved in the editorial process for this review.

Figures

1
1
PRISMA flow chart for study selection
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all studies
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study
1.1
1.1. Analysis
Comparison 1: Galantamine plus risperidone versus placebo plus risperidone, Outcome 1: Social interaction impairment postintervention
1.2
1.2. Analysis
Comparison 1: Galantamine plus risperidone versus placebo plus risperidone, Outcome 2: Repetitive and restricted behaviour postintervention
1.3
1.3. Analysis
Comparison 1: Galantamine plus risperidone versus placebo plus risperidone, Outcome 3: Adverse events
1.4
1.4. Analysis
Comparison 1: Galantamine plus risperidone versus placebo plus risperidone, Outcome 4: Adverse events; weight gain
1.5
1.5. Analysis
Comparison 1: Galantamine plus risperidone versus placebo plus risperidone, Outcome 5: Irritability postintervention
1.6
1.6. Analysis
Comparison 1: Galantamine plus risperidone versus placebo plus risperidone, Outcome 6: Hyperactivity postintervention
2.1
2.1. Analysis
Comparison 2: Donepezil versus placebo, Outcome 1: Real‐life Rating Scale (RLRS) total score postintervention
2.2
2.2. Analysis
Comparison 2: Donepezil versus placebo, Outcome 2: Social communication impairment postintervention
2.3
2.3. Analysis
Comparison 2: Donepezil versus placebo, Outcome 3: Restricted and repetitive behaviours postintervention
2.4
2.4. Analysis
Comparison 2: Donepezil versus placebo, Outcome 4: Behavioural difficulties postintervention
2.5
2.5. Analysis
Comparison 2: Donepezil versus placebo, Outcome 5: Attention and hyperactivity difficulties postintervention
2.6
2.6. Analysis
Comparison 2: Donepezil versus placebo, Outcome 6: General health and function postintervention
See this image and copyright information in PMC

Update of

  • doi: 10.1002/14651858.CD013851

References

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Arnold 2012 {published data only}
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NCT01887132 {published data only}
    1. NCT01887132. A trial of the drug donepezil for sleep enhancement and behavioral change in children with autism [A randomized controlled trial of donepezil for REM enhancement and behavioral change in autism]. clinicaltrials.gov/ct2/show/NCT01887132 (first received 22 June 2013).
Sahu 2013 {published data only}
    1. Sahu JK, Gulati S, Sapra S, Arya R, Chauhan S, Chowdhury MR, et al. Effectiveness and safety of donepezil in boys with fragile x syndrome: a double-blind, randomized, controlled pilot study. Journal of Child Neurology 2013;28(5):570‐5. [DOI: 10.1177/0883073812449381] [PMID: ] - DOI - PubMed

References to studies awaiting assessment

Niederhofer 2002 {published data only}
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References to ongoing studies

IRCT2017041333406N1 {published data only}IRCT2017041333406N1
    1. IRCT2017041333406N1. The efficacy of augmentation donepezil to risperidon in treatment of autism spectrum disorders [Assessment the efficacy of augmentation donepezil to risperidon in treatment of autism spectrum disorders]. en.irct.ir/trial/25769 (first received 20 September 2017).
NCT00252603 {published data only}
    1. NCT00252603. Galantamine versus placebo in childhood autism. clinicaltrials.gov/ct2/show/NCT00252603 (first received 9 November 2005).
Rahman 2018 {published data only}
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