Principal findings

As the first study in a representative population of older adults with intellectual disabilities, our findings reveal high levels of cumulative anticholinergic exposure, with 30% exposed to an ACB score of 5+. Multivariable regression analysis showed that those over 65 years and those with mental health conditions were much more likely to have high anticholinergic exposure. Antipsychotics, N04A anticholinergics, anti-epileptics and antidepressants were the most frequent classes contributing to the ACB. Antipsychotics accounted for over one-third of the cumulative burden, with a notably high prevalence of typical antipsychotics and with one in four of these individuals taking two or more antipsychotics. Our findings revealed that higher anticholinergic burden was associated with greater likelihood of reporting daytime dozing, constipation and use of multiple laxatives.

Comparison with other studies

There are no equivalent studies with other cohorts with participants with intellectual disabilities. Compared with studies that used the ACB scale with cohorts of older adults without intellectual disabilities, the degree of the anticholinergic burden found in our study was much greater and the types of anticholinergic drugs were different (online Table DS4). ^{Reference Fox, Richardson, Maidment, Savva, Matthews and Smithard20,Reference Myint, Fox, Kwok, Luben, Wareham and Khaw33,Reference Richardson, Bennett, Maidment, Fox, Smithard and Kenny34}

Factors associated with anticholinergic burden and adverse effects

Our analysis showed no association between higher scores and gender, but age over 65 years was a significant factor both for exposure to a score of 1–4 and exposure to an ACB score of five or more (Table 2). After adjusting for relevant confounders, we did not find an association between the level of intellectual disabilities and anticholinergic burden; however, it was notable that 85% of those with severe or profound intellectual disabilities were exposed to anticholinergic medications, and over one-third to an ACB score of 5+. The confidence intervals across all the categories were quite wide indicating the scale of variation remaining after adjusting for confounding factors, including polypharmacy. Other studies have only examined psychotropic polypharmacy ^{Reference Tsiouris, Kim, Brown, Pettinger and Cohen35,Reference Stolker, Heerdink, Leufkens, Clerkx and Nolen36} or polypharmacy ^{Reference Haider, Ansari, Vaughan, Matters and Emerson37} and have reported varying associations with age, gender and level of intellectual disabilities, but in contrast to the general elderly population, where women are identified as being more likely to be exposed to psychotropic polypharmacy. ^{Reference Qato, Alexander, Conti, Johnson, Schumm and Lindau38} It may be that many of the conditions that are treated with anticholinergic medicines occur earlier in the lives of people with intellectual disabilities than in those without intellectual disabilities so that the use of these medicines has become similar in men and women and is increasing to a lesser extent in these older age groups.

Almost half of those with a mental health condition and four in ten of those over 65 were exposed to an ACB of 5+. The wide confidence intervals of the association of mental health conditions may reflect variability in reporting of mental health conditions; however, 12 of the 16 highest contributors to the ACB score were drugs for mental health. We found that 35% of those with antipsychotics had concurrent exposure to N04A anticholinergics, which was higher than previously reported in a UK study (14%), ^{Reference Paton, Flynn, Shingleton-Smith, McIntyre, Bhaumik and Rasmussen39} yet Parkinson's disease was reported by only 1% in this cohort. The risks associated with using these medicines in combination in patients who are vulnerable and cognitively impaired are substantial. ^{Reference Banerjee40} Our findings revealed that over one-fifth of those reporting antipsychotic use reported chlorpromazine and 14% reported haloperidol, both agents that carry significant anticholinergic, noradrenergic and antihistamine adverse effects. ^{Reference Taylor, Paton and Kapur41} These older agents are associated with more extrapyramidal side-effects ^{Reference Taylor, Paton and Kapur41} and people with intellectual disabilities may be more susceptible to these side-effects compared with the general population. ^{Reference Bhaumik and Branford17,Reference Taylor, Paton and Kapur41} Risperidone was also the second most commonly used antipsychotic, an agent also associated with extrapyramidal side-effects. ^{Reference Taylor, Paton and Kapur41} Although our findings are limited by the fact that we did not have information in relation to side-effects of medications, it is probable that these anticholinergic agents are being to some extent used to treat, or in prophylaxis of, extrapyramidal symptoms associated with antipsychotic agents. There is recent evidence of increased incident dementia associated with higher anticholinergic burden and length of exposure in those over 65 years. ^{Reference Gray, Anderson, Dublin, Hanlon, Hubbard and Walker7}

Our univariate findings must be interpreted conservatively; while a higher anticholinergic burden was associated with a risk of daytime dozing, falls in the previous year were not significantly associated, in contrast to studies in the general older population. ^{Reference Ruxton, Woodman and Mangoni6,Reference Lu, Wen, Chen and Hsiao42} Constipation is common in older people, and increases with age. ^{Reference Gallagher and O'Mahony43} People with intellectual disabilities are at risk of constipation from several factors, ^{Reference Böhmer, Taminiau, Klinkenberg-Knol and Meuwissen44} and we found an association between increasing anticholinergic burden and constipation and laxative use, and furthermore, almost 30% of those with an ACB score of 5+ had laxative polytherapy, compared with <5% of those with no anticholinergic exposure. Multiple laxative use poses risks of electrolyte disturbance and dehydration that may exacerbate constipation. ^{Reference Gallagher and O'Mahony43} The relationship between anticholinergic medications and xerostomia and tooth loss has been previously established ^{Reference Gil-Montoya, de Mello, Barrios, Gonzalez-Moles and Bravo45} but although a higher proportion of the participants with an ACB score of 5+ were edentulous (30.6%), this was not significant.

Impact of findings on practice

Since anticholinergic activity may affect both central and peripheral systems, several factors make managing the anticholinergic burden complex in people with intellectual disabilities. Multimorbidity combined with complex mental health conditions and epilepsy increases the number and different classes of drugs with anticholinergic activity prescribed for people with intellectual disabilities and the cumulative burden. The sensitivity of people with intellectual disabilities to the effects of these drugs may be greater, and may increase with age, but is unquantifiable because of lack of evidence. Consequently, the prevalence of anticholinergic side-effects may be greater in this population, especially as the oldest age group were exposed to the greatest burden. Patient assessment is challenging, which may lead to diagnostic over-shadowing ^{Reference Tyrer, Cooper and Hassiotis14} and initiation of inappropriate drugs. Physical problems, such as constipation, may present as challenging behaviours, ^{Reference Taylor, Paton and Kapur41} which could trigger a prescribing cascade with a significant anticholinergic burden, as the association of antipsychotic, anticholinergic and laxative use in this study suggests.

A high proportion of people with intellectual disabilities are prescribed drugs with anticholinergic effects from an early age, and are likely to be exposed for many years. ^{Reference Bhaumik and Branford17} Length of exposure may increase as life expectancy of people with intellectual disabilities grows, potentially increasing the risks of chronic use of psychotropics. ^{Reference Gøtzsche, Young and Crace46} These factors imply that the extent and burden of anticholinergic side-effects in people with intellectual disabilities are greater than in the general older population, and could have an impact on their quality of life. Therefore, assessment of this burden, particularly among the oldest and those with mental health conditions and multiple morbidities, and who receive psychotropic polypharmacy is essential.

The risks of cumulative anticholinergic burden could be reduced through regular, multidisciplinary medication review. Scales such as the ACB scale, allied to review of patient symptoms, currently remain useful aids to guide clinical decision-making. ^{Reference Gerretsen and Pollock47} Little is known about the influence of ageing on people with intellectual disabilities and their response to medicines, which reinforces the need for review and education of healthcare professionals. Integrated and coordinated care is receiving increased attention in the older population, ^{Reference Oliver48} and needs to be further developed when providing care to people with intellectual disabilities. In older people and those with cognitive impairment, anticholinergic-induced cognitive impairment is more likely to occur at therapeutic doses potentially increasing risks of medication errors ^{Reference Maidment, Haw, Stubbs, Fox, Katona and Franklin49} for people with intellectual disabilities managing their own medicines. Continuing deinstitutionalisation creates challenges for primary care professionals who may not have the necessary expertise or experience to provide care for people with intellectual disabilities, nor may they be able to meet the needs of their carers. ^{Reference McCartney50} Guidelines are needed to support professionals, people with intellectual disabilities and carers to optimise anticholinergic medicines use. However, since people with intellectual disabilities are often excluded from randomised controlled trials, ^{Reference Freedman51} additional data may also need to be generated by national audits and longitudinal studies. ^{Reference Tyrer, Cooper and Hassiotis14}

Strengths and limitations

Our study has four important strengths. First, use of a large, randomly selected population-representative sample offered sufficient power for multivariate analysis, with findings generalisable to the population with intellectual disabilities in Ireland. Second, the great majority of respondents recorded detailed medication data, including over-the-counter medicines (98%). Third, participants and/or proxy respondents underwent a detailed assessment of health characteristics, providing data on potential confounders for the regression model. The use of the Bonferroni correction addressed the problem of multiplicity. Fourth, we used the ACB scale, which has been widely used, making the assessment of anticholinergic burden robust and relevant to clinical practice. ^{Reference Campbell, Boustani, Limbil, Ott, Fox and Maidment3,Reference Fox, Richardson, Maidment, Savva, Matthews and Smithard20} We added to its content validity by reviewing other anticholinergic medicines available in Ireland with an independent expert.

There are also limitations. There was no independent confirmation of medicines or conditions, but cross-checking of medicines in the pre-interview questionnaire at the time of interview improved accuracy. Information was also not recorded about disease severity. Data on dose and frequency of medicines were not always available and adverse effects may be dose dependent, ^{Reference Gerretsen and Pollock47} however, the ACB scale does not take dose into account. Although a higher dose of an anticholinergic agent would be expected to cause more central effects, the relationship may not be linear. ^{Reference Chew, Mulsant, Pollock, Lehman, Greenspan and Mahmoud52} The ACB scale has not been validated against measures of in vitro anticholinergic activity. However, assays are difficult to interpret, not readily available in practice and due to variations in blood–brain barrier permeability may not reflect levels in the central nervous system. It is currently accepted, that allied to a careful review of the patient's symptoms and medicines, scales and lists such as the ACB scale remain the best aid to guide clinical decision-making. ^{Reference Gerretsen and Pollock47} The ACB scale does not take into account influences of patient variability in drug response associated with older age, frailty, multimorbidity, cognitive reserve and individual pharmacokinetic factors.

As an observational study, we could only describe associations between anticholinergic burden and clinical and demographic factors. In our multivariate analysis, potential bias was reduced by adjusting for known confounders; however, residual confounding may remain. Although potential adverse effects associated with anticholinergic exposure were examined at univariate level, other factors such as functional status, or baseline cognitive status that could influence the prescription of anticholinergics were not measured in this study, and this analysis was descriptive and not adjusted for confounders.

In conclusion, the use of medications with anticholinergic activity is commonplace among older adults with intellectual disabilities, with psychotropic agents accounting for much of the burden. For the first time in people with intellectual disabilities a high anticholinergic burden has been shown to be associated with daytime dozing, constipation and multiple laxative use. The possible impact that anticholinergics may have on cognitive and executive function should be evaluated and more attention should be paid to the assessment of peripheral anticholinergic effects, such as constipation. People with intellectual disabilities are among the most vulnerable members of society and regular, multidisciplinary review of medications to decrease the use of anticholinergic medicines is likely to reduce morbidity and improve quality of life in this population.