Anticholinergic burden in adult and elderly people with intellectual disabilities: Results from an Italian multicenter cross-sectional study

Background Adults and older people with intellectual disabilities (ID) frequently receive anti-cholinergic drugs in chronic use, but no studies in Italy to date have investigated cumulative anticholinergic exposure and factors associated with high anticholinergic burden in this frail population. Aim To probe the cumulative exposure to anticholinergics and the demographic, social and clinical factors associated with high exposure. Methods The 2012 updated version of the Anticholinergic Burden Score (ACB) was calculated for a multicentre sample of 276 adult and older people over 40 years with ID and associations with factors assessed. Results Overall, antipsychotics, antiepileptics, anxiolytics, and antidepressants were the most frequent classes contributing to the total ACB score. People living in residential care were more likely exposed to high anticholinergic burden (an ACB score of 3+): both community housing (odds ratio [OR] 4.63, 95%CI 1.08–19.95) and nursing home facility ([OR] 9.99, 95%CI 2.32–43.04). There was also a significant association between an ACB score of 3+ and reporting mental health conditions ([OR] 25.56, 95% CI 8.08–80.89) or a neurological disease ([OR] 4.14, 95%CI 1.32–12.94). Neither demographic characteristics (age and gender) nor other clinical conditions (somatic comorbidity, levels and typology of ID) were associated with higher anticholinergic load. A high burden of anticholinergic was significantly more frequent in laxative users (22.6% ACB3+ vs. 5.1% ACB 0) (p = 0.003). Conclusions Psychotropics drugs were the highest contributors to the anticholinergic burden in adult and old age ID, especially in those people living in institutional settings with mental health and/or neurological conditions. High anticholinergic load has shown to be associated with the use of laxatives.


Introduction
Many drugs used to treat multiple health conditions prevalent in the elderly general population possess intrinsic anticholinergic (AC) properties. Some AC medications achieve the intended therapeutic effect through inhibition of acetylcholine-mediated responses by competitively binding any of the five muscarinic receptors (M1-M5) within specific organ systems (Table 1). Other medicines have unintended AC effects that are not the primary therapeutic activity (Table 1) [1].
A growing body of evidence shows that exposure to long term individual drug use with AC effects or high overall AC load in neurotypical elderly (frail) people is associated with increased risk of falls, cognitive and functional impairment, hospital admission, longer length of hospital stay, institutionalization, and of all-cause dementia and mortality [2][3][4][5][6].
Higher incidence and prevalence rates of organic, neurologic and mental health comorbidity in adults and elderly people with ID compared with the general population [7][8][9], increase the risk to be exposed to polypharmacy and as a result to AC burden. Moreover, aging people with ID may be especially sensitive to neuropsychiatric, motor and cognitive AC adverse reactions because of their lifelong organic brain dysfunction associated with augmented bloodbrain barrier permeability and a putative deficit in central cholinergic transmission [10].
This may be particular true for people with Down syndrome (DS) in whom Alzheimer's Disease neuropathology is universally present from their fourth decade, driving a genetically elevated risk for Dementia in Alzheimer's Disease associated with a decrease of central acetylcholine in both concentration and function [11].
Yet, to the best of our knowledge, only the study by O'Dwyer et al. [12] investigated the association of AC exposure with demographic and clinical factors and with central (e.g., daytime dozing) and peripheral (e.g., chronic constipation, dental status) side effects in a representative cohort of 736 persons with ID (mean age of 54.1 years; range 41-90 years). More than half of the study sample (n = 522, 70.9%) received at least one AC activity medicine. Also, age over 65 years, concomitant mental health condition, daytime drowsiness and chronic constipation were significantly associated with higher AC exposure. The authors did not consider the typology of ID within the clinical factors, distinguishing DS from other types of ID ((henceforth referred to as non-DS).
In Italy, despite the increasing interest towards the adverse cognitive and functional outcomes of medications with AC activities in the general older population with or without dementia [13][14][15][16], no studies have investigated so far the prevalence and burden of AC medication and its association with demographic, social and clinical factors in adults and older people with ID. So we decided to analyze the reported medication in an Italian sample of people over 40 years with ID, using the updated 2012 Anticholinergic Cognitive Burden (ACB) Scale [17,18] developed by Boustani et al. [19]. The ACB scale includes 99 individual medicines with possible or definite AC properties assessed by a multi-disciplinary panel based on a systematic literature review and on expert opinion and it is currently the most frequently validated expert based AC scale on adverse cognitive and functional outcomes [20].
In particular, the goals of this study were: to determine each individual's cumulative exposure to AC medications using the ACB scale; to examine demographic and social characteristics, typology (DS vs. non-DS) and levels of ID, and comorbidity associated with higher AC burden exposure

Study design
Medication data for this study was drawn from a multicenter Italian validation study of the Dementia Screening Questionnaire in Intellectual Disabilities (DSQIID) which has been described in detail elsewhere [21,22]. In summary, 15 organizations and structures each one with previous experience in DMR-I screening [23] enrolled 398 subjects with ID aged 40 years and over. Demographic, social and clinical data, including medication use and organic, neurological and psychiatric comorbidities, were drawn from the updated medical and pharmaceutical records maintained by the centres, as required by the National Task Group-Early Detection Screen for Dementia (NTG-EDSD) [24] (available at https://aadmd.org/index.php?q=ntg/ screening). Complete data on dispensed medication prescription together with complete demographic, social and clinical data was achieved in this way for 276 subjects.
Following the Italian privacy statement, each different organization collected a written consent form (informed consent was obtained from those participants who were able to consent; when obtaining such consent was not possible, family members or legal representatives provided assent to indicate the ID individual's willingness to partake in the study). All data was anonymized.
polypharmacy (the use of 5-9 drugs), no polypharmacy (taking four or less drugs, included those taking no medicines) following O'Dwyer et al.'s clustering method [30].

Statistical analyses
Descriptive statistics, percentages, and 95% confidence intervals (CI) describe the demographic, social and clinical characteristics of the study sample. Chi-square tests for independence (with effect sizes computed by means of Cramér's ϕ (c) ) were applied to the three ACB groupings (total ACB score = 0 vs. total ACB score of 1-2 vs. total ACB score of 3+) to test for a significant association between demographic, social and clinical factors. All significant variables in the latter analysis were then entered in a multivariate analysis simultaneously and covariated with demographic characteristics, polypharmacy status, level of ID and multimorbidity. This multinomial logistic regression identified factors associated with a total ACB score of 1-2 and a total ACB score of 3+, with those with no AC exposure (ACB 0) as the reference category. Results are presented as Odds Ratios with corresponding 95% CIs.

Descriptive analyses of the demographic, social and clinical factors of the study sample
Demographic characteristics and living conditions. Mean (± SD) age of participants was 54.6 (±7.5; 95% CI 53.7-55.5, range 40-80) years, with 79% aged 50 years and over. There were more males (n = 162, 58.7%) than females (n = 114, 41.3%) without reaching a level of statistical significance. More than half of this study sample (n = 159, 57.6%) lived in a residential care setting (community housing or nursing home). Those people who lived independently or with their family were combined as a single group, as the numbers in the independent setting were small (n = 6).
Typology and levels of ID. Eight-five people had DS (30.8% of the total sample). The number of the people with profound ID was small (n = 13) and therefore people with severe and profound ID were considered as a single group, representing 42% (n = 116) of the total study population. Only 44 individuals had a mild level of ID.
Health conditions superimposed on ID. Overall, more one third of the study population (38.2%, n = 107) presented with two or more concomitant chronic pathologies superimposed on ID. Lung, liver, kidney and genito-urinary chronic diseases had insufficient numbers (<5% prevalence) and were excluded from further analyses, while heart diseases, hypertension, haematological and other vascular diseases were combined as 'cardiovascular disease'. To obtain a sufficient number of cases with 'gastrointestinal disease' we combined upper and lower tract diseases. Fig 2 shows the co-pathologies in descending order of frequency. Fifty-three individuals showed cognitive decline but only five received a diagnosis of "definite dementia" (i.e., progressive cognitive decline from a previous level of performance sufficient to interfere with  [26] all of them belonging to the DS subgroup. Polypharmacy. Overall, participants reported a mean (±SD) of 1.9 (±2.6; 95% CI 1.6-2.2, range 0-13) medicines.

Anticholinergic Cognitive Burden Scale and contribution of therapeutic classes to total ACB score
Ninety-eight individuals (35.5%) were taking at least one medication with AC properties with more than the half (64.7%) living in nursing home facilities. Mean (±SD) total ACB score of those in AC therapy was 2.2 (±1.2; 95% CI 1.9-2.4, range 1-6) medicines. High AC burden (total ACB score of 3+) was observed in 31 individuals (11.2% of the total sample), of whom 58.1%, again, lived in generic residential care settings.

Factors associated with high AC exposure
Chi-square test. The distribution of the three levels of AC exposure (total ACB 0, ACB 1-2, ACB3+) was significantly different among the three age groups, between people with DS and non-DS, among the three living conditions and individuals with or without polypharmacy with the latter two factors showing the highest effect sizes ( Table 2). Among the health conditions, psychiatric comorbidity demonstrated the highest effect size followed by gastro-intestinal, cardiovascular, neurological and joint diseases.
Multivariate analysis. As shown in Table 3, people living in nursing home facilities were more likely to report a total ACB score of 1-2 and total ACB score of 3+ while those living in community group houses were more likely to be exposed to higher AC load (ACB score of 3 +). Having psychiatric or neurologic comorbidity was associated with having a score of ACB 1-2, and ACB 3+. Of note, however, are the wide confidence intervals across all the significant factors indicating that the scale of variation remained after adjusting for confounding factors, including polypharmacy. By contrast, age and typology of ID (DS vs. non-DS) after adjusting for confounding factors were no longer significant with either degree of AC exposure, nor were the other clinical conditions (cardiovascular, gastro-intestinal and joint disease).

Summary of the main findings
As the first study in an Italian sample of older adults with ID, our findings reveal that over one-third (35.5%) of the people reported anticholinergic activity medicines, with 11.2% exposed to a total cumulative ACB score of 3+ (ACB score 3: n = 16; ACB score 4: n = 12, ACB score 6: n = 3). Multivariable regression analysis showed that those living in ID specific small or large generic residential settings and those with mental health and neurologic conditions were much more likely to have higher AC exposure. The confidence intervals across all the significant categories were quite wide indicating that other than the considered confounding factors may contribute to the high AC load. Psychotropics, in particular antipsychotics and antiepileptic, were the most frequent class of medicines contributing to the ACB scores. Antipsychotics accounted for over three quarters (86.2%) of the cumulative AC burden, with a higher prevalence of SGA. Higher cumulative AC burden was found in laxative users.

Comparisons with previous studies
There are no equivalent studies with other Italian cohorts with ID. There is only one study that used the ACB scale with elderly inpatients without ID [14] reporting a higher prevalence of AC exposure compared to the present study (Table 4), mainly due to a prevalent use of cardiovascular medications (see [14]   to the present study. Yet, their population-based sample was nearly three-fold larger with the majority (83.4%) living in institutional settings compared to 57.6% of the present sample. Moreover, their data was drawn from a modified ACB scale with 22 medicines not included in the 2012 updated ACB scale (e.g., Biperiden (N04AA02) with ACB score of 3; (Es-) citalopram (N06AB10; N06AB04) with ACB score 1) and with some variation in ACB scoring (e.g., Haloperidol (N05AD01) switched from an ACB 1 score to an ACB score 3 [12] see Table 3).

Variables independently associated with anticholinergic load
The absence of a significant association between higher ACB scores and older age in the present study is in contrast with the data found by O'Dwyer et al. [12]. However, and as outlined in a previous paper [21] we found a steadily increase in the total number of psychotropic medications with advancing age except for those aged 70 years and over (n = 9) [21], (see Fig. 6, p. 43). An increasing consumption of psychotropic drugs with age has also been reported by Sheehan et al. [31] in 32,306 people with ID (mean age of 36.3 (± 16.4) years at study entry) followed by 571 General Practitioners over a 14-year period. The reason why the likelihood to be exposed to higher AC burden after adjustment for potential confounders, did not differ between people with DS and non-DS ID is unclear. On the other hand, this finding is of concern in light of the much higher prevalence of Alzheimerlike dementia in DS compared to other non-DS ID [32] a condition that may increase considerably the pharmacodynamic sensitivity to AC medications due to a decrease in cholinergic neurons or receptors in the DS brains with neuropathological hallmarks of Alzheimer's disease [11,33].
More than three quarters (76.4%) of those with a mental health condition received at least one AC drug prescription and this condition contributed 54.8% to the total number of people with an ACB score of 3 and over ( Table 2). Living in ID-specific and generic residential care settings was significantly associated with higher AC exposure. Work conducted with neurotypical older people living in nursing homes in Italy [15] (see also Table 4), in Sweden [34] and in the United States [35] have reported similar results, considering institutionalization an important risk factor for the prescription of AC drugs. Alternatively, it could also be that people with ID who are cared for in residential settings, are living there because of their psychiatric and/or neurological comorbidities with a consequent increased prescription rate of medications with anticholinergic properties. Indeed, in our sample, nearly half of those with a mental health condition (48.5%) and/or with a neurological disease (45.6%) were residents in nursing homes and one quarter of them lived in community home groups, respectively 27.9% and 20.6% (data not shown in Results section). Another difference with the study by O'Dwyer et al. Results from an Italian multicenter cross-sectional study [12] was an extremely low frequency in the prescription of N04A anticholinergic drugs (Orphenadrine with ACB score of 3; Biperiden not included in the 2012 updated ACB scale) and a higher prescription rate of SGAs (Risperidone > Quetiapine > Olanzapine > Clozapine) compared to FGAs (Chlorpromazine > Haloperidol > Pimozide) with AC properties. The reason for the non-prescription of N04A anticholinergics is not clear since we did not have information in relation to the extra-pyramidal side-effects of antipsychotic medications. Anyhow, given the lower incidence of treatment-emergent extrapyramidal side effects for SGAs than for FGAs [36] and the predominant prescription in this population of SGAs at least with AC properties, it may well be that healthcare professionals did not retain necessary to treat or in prophylaxis extrapyramidal symptoms associated with antipsychotic agents.
The higher AC load in laxative users should be interpreted with caution because a physician's diagnosis of chronic constipation was lacking. Moreover, this finding derives from a chi-square test and constipation is not exclusively a medication-related problem in the ID population [37]. On the other hand, the finding that the use of laxatives in our sample was significantly higher in people treated with antipsychotics and antiepileptics and in (psychotropic) polypharmacy (2+ psychotropics) treatment suggests that medications with or without AC activity plays an important role in chronic constipation in older adults both with [12,30] and without ID [37,38,39].

Clinical implications of the findings
Since anticholinergic activity may affect both central and peripheral systems, several factors make managing the AC exposure and anticholinergic burden arduous and complex in aging people with ID. Somatic comorbidities [7] combined with intricate often underdiagnosed or misdiagnosed mental health conditions [40], neurologic disorders [8] and problem behaviors that challenge [9,21] increase the risk of prescription of different classes of drugs with anticholinergic activity and of a cumulative AC burden. Moreover, a high proportion of people with ID are likely to be exposed for many years to AC medications as recently shown by de Kuijper et al. [41].
There is recent evidence that medications with medium or high AC activity, according to the ACB scale, are associated with reduced brain-glucose metabolism and increased brain atrophy in the brains of cognitively normal elderly accelerate cognitive decline in those with the highest total ACB scores [42]. Therefore, and although not yet scientifically demonstrated, aging brains of people with ID should be even more vulnerable to the psychotropic toxic effects of AC medications given the presence of a lifelong organic brain dysfunction, particularly in adults with DS [43] in whom the cumulative risk for developing dementia, almost invariably of the Alzheimer's type, increases from 23.4% at 50 years of age, to 88% at age 65 [44].
Assessment of AC adverse effects of people with ID is challenging, which may lead to diagnostic overshadowing and initiation of inappropriate drugs [45] much alike to what has been reported in neurotypical people with advanced (Alzheimer) dementia [46][47][48].
Although there is a considerable ongoing research effort to develop criteria to assess medication appropriateness and optimization of anticholinergic burden drug prescription in the general elderly population in recent years [49][50][51][52], a specific tool for (older) adults with ID is not yet available. However, assessment of medication appropriateness included deprescribing of AC drugs in old age ID is beginning to attract research interest, with recent (pilot) studies considering the medication regimen as a whole [53,54].
Guidelines for the adult and old age ID population are urgently needed in Italy to support healthcare professionals, people with ID when possible and (in)formal caregivers to optimize anticholinergic medicines and psychoactive drug use. However, since older people with ID are notoriously excluded from clinical trials [55], additional data may also need to be generated by national audits and observational longitudinal studies patronized by the Italian Scientific Societies dedicated to Intellectual and Developmental Disabilities in collaboration with the parental associations.

Strengths and limitations
Our study has several strengths. First, the 15 structures and organizations, managed by different stakeholders, parental associations, public health services, cooperatives or local institutions can be considered representative of the Italian scenario offering services to more than 3,000 adults and elderly with ID both in small rural areas and in medium and large urban areas, distributed over most of the national territory ( [22] see Fig. 1, p. 4). Second, besides the demographic and clinical variables such as the level of ID, organic and psychiatric and neurological comorbidities, we also considered the typology of ID (DS vs. non-DS) and the presence vs. absence of cognitive decline compared to a previous level of functioning. Third, although there is no standardized tool for measuring AC burden [20], we used the ACB Scale which is the most frequently validated expert based AC scale on adverse outcomes applied to both retrospective, cross-sectional, and longitudinal cohorts with neurotypical elderly in different care and clinical settings ( [20], see Table 3 pp. [11][12]. On the other hand, some limitations must be pointed out. First, data was drawn from the NTG-EDSD data collection modules filled in by healthcare professionals who consulted the updated medical and pharmaceutical records of each individual with ID. Since independent confirmation or cross-checking of the collected data were not feasible, we cannot exclude omissions or errors in reporting the information pre-arranged by NTG-EDSD. Second, information was also not recorded about severity of the reported somatic, neurologic and psychiatric diseases. Third, daily dose of drugs, length of intake of medicines, adherence to treatment and central or peripheral anticholinergic adverse effects (except for the use of N04A anticholinergics and of laxatives, see above) were not available. As regarding the dose of AC medications, it should be stressed that the ACB scale does not take dose into consideration. The present study is observational and only aimed at exploring associations between AC load and demographic, living condition and clinical factors. In our multivariate analysis, we attempted to reduce potential biases by adjusting for known confounders, although residual confounding may remain such caregiver-related factors which has been recently shown to greatly influence the long term prescription of medications with potential AC activity, in particular antipsychotic agents [41].

Conclusions
For the first time, anticholinergic exposure and cumulative burden has been investigated in an Italian sample of older adults with ID. We believe that the results of this study may well apply to other service providers for adult and elderly people with ID in Italy and beyond with regard to the prevalence of psychoactive drugs use accounting for much of the anticholinergic burden, especially in those people with comorbid psychiatric and/or neurologic comorbidities living in ID-specific or generic residential care settings. High anticholinergic burden has shown to be associated more frequent with laxative use suggestive of chronic constipation. People with DS are as likely to be exposed to anticholinergic burden medicines as those with non-DS ID, although they manifest more frequently dementia in Alzheimer's disease. The negative outcomes of central anticholinergics on cognitive, functional performance and behavior in older adults with ID should be investigated more seriously in the future and more research attention should be paid to the assessment of multiple peripheral anticholinergic side often wrongly attributed to aging process itself [33]. In the meanwhile, a good clinical practice aimed to minimize anticholinergic load (or reach a tailored anticholinergic prescription including over-the-counter medications) need to be encouraged in aging people with ID who should be considered amongst the most vulnerable members of society.