The adverse effects of long-term exposure to anticholinergics among people with intellectual disabilities: a scoping review

Background: Older adults with intellectual disability are exposed to a higher anticholinergic burden compared to general older adults. This is due to a higher rate of both mental and neurological disorders among people with intellectual disability. The use of medications with a high anticholinergic burden is associated with adverse effects including daytime dozing, constipation and higher dependence level in the Barthel index for measuring activities of daily living. This scoping review aims to map and examine the existing research on physical and cognitive adverse effects associated with the long-term impact of anticholinergics among people with intellectual disabilities. Methods: The search was conducted in: PubMed, Cochrane library, EMBASE, Medline, Science Direct, CINAHL Complete and PsycINFO. Preliminary studies, grey literature, and conference papers were searched in related electronic databases. The search terms included terms related to ‘anticholinergic’, ‘long-term exposure’, ‘intellectual disability’ and ‘adverse drug reaction’ with Boolean operator ‘and’. Studies with at least three months’ exposure to anticholinergics were included. The search was restricted to research papers on people with intellectual disability aged 40 or over and publication in the English language only. Initially, it was conducted in May and June 2021 and covered the publication period between 1970 and 2021. It was re-run in October 2021. Results: The conducted search provided 509 records of publications and grey literature. Duplicates were removed using EndNote 20 and resulted in 432 remaining records. Then, 426 further records were excluded because they were deemed irrelevant, or non-longitudinal studies or conducted on different populations. Only six full articles were retrieved to assess their eligibility and all were excluded due to different study populations. This resulted in no studies meeting the stated inclusion criteria. Conclusions: Further research is urgently required to examine the long-term adverse effects associated with higher anticholinergic scores among older people with intellectual disability.


SYSTEMATIC REVIEW
The adverse effects of long-term exposure to anticholinergics among people with intellectual disabilities: a scoping review Lamya Al Shuhaimi 1  Background: Older adults with intellectual disability are exposed to a higher anticholinergic burden compared to general older adults. This is due to a higher rate of both mental and neurological disorders among people with intellectual disability. The use of medications with a high anticholinergic burden is associated with adverse effects including daytime dozing, constipation and higher dependence level in the Barthel index for measuring activities of daily living. This scoping review aims to map and examine the existing research on physical and cognitive adverse effects associated with the long-term impact of anticholinergics among people with intellectual disabilities. Methods: The search was conducted in: PubMed, Cochrane library, EMBASE, Medline, Science Direct, CINAHL Complete and PsycINFO. Preliminary studies, grey literature, and conference papers were searched in related electronic databases. The search terms included terms related to 'anticholinergic', 'long-term exposure', 'intellectual disability' and 'adverse drug reaction' with Boolean operator 'and'. Studies with at least three months' exposure to anticholinergics were included. The search was restricted to research papers on people with intellectual disability aged 40 or over and publication in the English language only. Initially, it was conducted in May and June 2021 and covered the publication period between 1970 and 2021. It was re-run in October 2021. Results: The conducted search provided 509 records of publications and grey literature. Duplicates were removed using EndNote 20 and resulted in 432 remaining records. Then, 426 further records were excluded because they were deemed irrelevant, or non-longitudinal studies or conducted on different populations. Only six full articles were retrieved to assess their eligibility and all were excluded due to different study populations. This resulted in no studies meeting the stated inclusion criteria. Conclusions: Further research is urgently required to examine the long-term adverse effects associated with higher anticholinergic

Approval Status AWAITING PEER REVIEW
Any reports and responses or comments on the article can be found at the end of the article.

Introduction
Medicines with anticholinergic (AC) activity are widely used among older adults due to their potential clinical benefits in managing a wide range of medical conditions 1 . These medicines are usually used for peptic ulcer disorders, irritable bowel syndrome, urinary disorders, Parkinson's disease, neurological diseases, psychiatric conditions and as anaesthetic agents.
There are well-recognized adverse effects associated with the use of AC which include: dry, pale and cool skin, dry mouth with difficulty beginning to speak, urinary diseases, blurred vision, unsteady movement and falls, anxiety, tachycardia, cardiac arrhythmias, etc 2 . In addition, there are several central anticholinergic adverse effects associated with anticholinergic drugs that can cross the blood brain barrier such as memory impairment, agitation, hallucination, delirium, confusion and disorientation.
In certain medical conditions that are usually associated with aging, the benefits of AC use are greater than their risks; therefore, it is inevitable and appropriate that they be used 1 . These conditions include: psychiatric disorders (such as bipolar disorder, obsessive-compulsive disorders, severe insomnia, severe anxiety diseases, drug-induced acute dystonia, secondary Parkinsonism) and non-psychiatric conditions (such as gastroesophageal reflux disease, irritable bowel syndrome, urinary incontinence, neuropathic pain, cardiovascular disorders, muscle spasms and low back pain).
People with intellectual disabilities experience a higher incidence of morbidities, by 2.5 times, compared to the general population 3 . They have a higher incidence of some diseases such as dementia, dental disorders, psychiatric diseases, osteoporosis and epilepsy. Furthermore, prevalence of polypharmacy is higher in people with an intellectual disability, and they are described as one of the most medicated groups of the population. A study conducted in Ireland has identified that older adults with intellectual disability are exposed to excessive polypharmacy (10 medications or more) at rates 10 times higher than the general population 3 . Moreover, they are exposed to a high anticholinergic burden 4,5 due to the high prevalence of mental disorders and neurological disorders 6,7 . Furthermore, a Scottish cohort study reported that anticholinergic burden was relatively high among all age groups of people with intellectual disability including adults and older adults (17-94 years old) 5 . Notably, the greatest anticholinergic burden was observed in people aged ≥ 55 years and in females.
High anticholinergic burden was associated with a higher likelihood of reporting constipation, daytime dozing and use of multiple laxatives in the elderly with intellectual disabilities 4 . Another study reported that a higher Drug Burden Index (DBI) was associated with higher dependence scores in the Barthel index for measuring activities of daily living in older adults with intellectual disabilities 8 .
The long-term impact of anticholinergics has been examined by some studies among the general geriatric population. These studies have reported an association between long-term cumulative high anticholinergic burden and poorer physical function 9-11 , cognitive impairment 9-13 , and a higher incident of dementia 14 . Another study found that high anticholinergic burden can predict mortality among elderly patients discharged from hospital with a high Geriatric Depression Scale (GDS) score 15 .
According to our preliminary research, there has been no or limited research exploring the long-term impact of anticholinergics among older adults with an intellectual disability. Therefore, this scoping review aims to map and examine the existing research literature on physical and cognitive adverse effects associated with the long-term impact of anticholinergics among people with intellectual disabilities.

Methods
This scoping review followed the framework proposed by Arksey and O'Malley 16 and its developed version by Levac 17 . Moreover, the Joanna Briggs Institute reviewer's manual 18 and the Preferred Reporting Items for Systematic reviews and Meta-Analysis extension for Scoping Reviews (PRISMA-ScR) 19 were also followed. Accordingly, there were six stages in conducting the review: 1 Stage 1: Identification of the research question As per our best knowledge, there was no research exploring the adverse effects associated with the long-term exposure to anticholinergics among older adults with intellectual disabilities. This scoping review was therefore conducted to answer the following question: What are the adverse effects on cognitive and physical outcomes of long-term exposure to medications with anticholinergic activity among older adults with intellectual disabilities?
As a long-term goal, this review aimed to produce findings likely to enhance prescribing patterns among this vulnerable group of people.

Inclusion criteria
Study design All designs and types of study were included.

Study population
Only studies on people with intellectual disability were included. Intellectual disability usually occurs prior to age 18 and it is defined as "a disability characterized by significant limitations in both intellectual functioning and adaptive behaviour, which covers many everyday social and practical skills." [https://www.aaidd.org/]. Various types and stages of intellectual disability are included in this scoping review.
Furthermore, the review only included studies on older adults aged 40 or more with intellectual disability. Children and adults with intellectual disability who were aged less than 40 years were excluded from the review.
Intervention 'Long-term use' or 'Chronic use' of medicines has been defined as being on a medicine for at least three months or longer [https://www.medicinenet.com/]. Therefore, the review included all studies that examined the adverse outcomes associated with the use of anticholinergics for a period of three months or longer. There was no restriction on tools used to identify anticholinergic burden.

Context
The review included research papers in all different care settings where people with intellectual disability can live, including institutions, nursing homes, community group homes, with families or independently.

Outcomes
This scoping review examined both cognitive and physical outcomes associated with the long-term exposure to anticholinergics in older adults with intellectual disability. The physical and cognitive outcomes include all of the reported and measured central and peripheral adverse effects associated the long-term use of these medications. There are no restrictions of tools used to report or measure the adverse outcomes. Figure 1 illustrates the process of study selection according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR).
information from each included article such as title, aim, population, results, conclusion and implications. However, none of the studies fitted the stated inclusion criteria. Therefore, there was no data to be charted, collated, summarized and reported.

Description of studies
The initial search conducted in May and June 2021 was re-run on 2021-10-05 and 2021-10-08 and provided 509 records of both publications and grey literature. Duplicates were removed by using EndNote 20 (RRID:SCR_014001) and resulted in 432 remaining records. Then, the records were screened for relevance based on the titles and abstracts by two members of the search team. After that, 426 further records were excluded because they were deemed irrelevant, or non-longitudinal studies or conducted on different populations. Only six full articles were retrieved to assess their eligibility to be included in the stated inclusion criteria. Two members (MO'D, LAA) of the research team assessed the remaining six records for their relevance and all were excluded due to different studied populations. This resulted in no studies meeting the stated inclusion criteria.

Consultation findings
Representative members from The Royal College of Psychiatrists of Ireland (Intellectual disability subgroup), Down Syndrome Ireland and the International Association for the Scientific Study of Intellectual and Developmental Disabilities (IAS-SIDD) replied to our consultation request. The representatives highlighted the reasons such prescribing occurs, the particular risk for persons with Down syndrome, the important role played by the longitudinal study findings and the acceptance that research in this area must become a scientific priority. No concerns were noted about the review findings.

Discussion
As far as we are aware, this is the first scoping review to examine the adverse effects of long-term exposure to anticholinergics among older adults with intellectual disability. This scoping review aimed to map and examine the available research. However, no studies were identified that met the inclusion criteria of the review and an empty review (a review with no studies eligible for inclusion based on the inclusion criteria 22 .) has been reported. This fits a pattern of 15 empty reviews out of 81 reported systematic reviews conducted on people with developmental, psychosocial and learning problems 23 .
Empty reviews help to identify important gaps in knowledge and to stimulate researchers towards topic areas that need to be studied 24 . According to studies that were screened in this scoping review, there is some limited identification of the prevalence of anticholinergic burden and the associated shortterm adverse effects among people with intellectual disability. In addition, the long-term adverse impact of anticholinergics has been examined among the general population 9-15 , patients with cognitive impairments, dementia and Alzheimer's disease [25][26][27][28][29] . That there are few or no studies conducted among people with intellectual disability in an area where there are published studies for the general population suggests people with intellectual disabilities still remain mostly excluded from participating in clinical research 6 . It is of further concern that there is therefore a restricted evidence base for safe use of these medicines among this vulnerable group of the population.

Conclusions
In conclusion, further research is urgently required to examine the long-term adverse effects associated with higher anticholinergic scores among older people with intellectual disability. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

David Harley
UQ Centre for Clinical Research, The University of Queensland, Herston, Qld, Australia This is a well written review dealing with an important issue in developmental disability medicine. As the authors point out, while it is an empty review this, again, highlights the importance of research on prescribing, particularly polypharmacy and drugs with significant adverse effects, to people with intellectual and developmental disability.
I have no substantive criticisms of the review. Below I note some minor areas for improvement of the manuscript.
In the introduction, change "Parkinson's disease, neurological diseases" to "neurological diseases including Parkinson's".

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In the sentence stating that people with intellectual disability experience "a higher incidence of morbidities, by 2.5 times, compared to the general population", I suspect "incidence" should be "prevalence". Please check and correct if appropriate.

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In the sentence "Another study found that high anticholinergic burden can predict mortality among elderly patients discharged from hospital with a high Geriatric Depression Scale (GDS) score "predict" should be replaced with a word or phrase implying association rather than causation.
○ I don't think team member initials need to be in inverted commas (only occurs once for member LAA).
○ Are the rationale for, and objectives of, the Systematic Review clearly stated? Yes

Are sufficient details of the methods and analysis provided to allow replication by others? Yes
Is the statistical analysis and its interpretation appropriate? I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.