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

Identifying the research question

To the best of our knowledge, no reviews of long-term adverse effects of antipsychotics in older adults with intellectual disabilities have been carried out. Therefore, this scoping review was carried out to answer the following question: what are the adverse effects of long-term exposure to antipsychotics in older adults with intellectual disabilities?

Identification of relevant studies

A systematic search of the following electronic databases was conducted: PubMed, Cochrane Library, ScienceDirect, Embase and PsycINFO, to identify relevant studies which examined the adverse effects of long-term antipsychotic use in older adults with intellectual disability. A final Google Scholar search was also carried out to ensure that no relevant articles had been missed in the database searches. As outlined in the protocol for this scoping review, Open Grey was to be consulted to determine if any information could be gathered from previous clinical trials. However, this database is no longer available and hence MedNar, the AllCatsRGrey database, Google Scholar, and CADTH database were screened instead for any articles or pieces of grey literature that may be relevant.

The search strategy was formulated in consultation with an academic librarian in Trinity College Dublin, Andrew Jones, who advised on the appropriateness of Medical Subject Heading (MeSH) terms for each electronic database.

The key words ‘antipsychotic’, ‘long-term exposure’, ‘intellectual disability’, ‘older people’ and ‘adverse effects’ were searched with the Boolean operator ‘AND’. For each keyword a number of synonyms were also used with the Boolean operator ‘OR’ as described below.

The search was carried out from the 21st of February to the 15th of April 2022 and was limited to articles published in the English language. There were no limitations placed on publication date, place of issue, publisher or type of study.

The total number of results obtained from the original search of each database is given in Figure 1. After excluding duplicates, the abstracts of the articles identified were screened for relevance and for each article deemed to be eligible for inclusion, the full text was retrieved and read. The reference lists of eligible studies were screened to search for other studies which were eligible for inclusion in the scoping review (snowball approach).

Figure 1. Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) flow diagram (Page et al., 2021).

Inclusion criteria

Study population. The inclusion criteria for studies to be included in this scoping review are outlined in Table 1. For the purposes of this scoping review, ‘older adults’ were defined as those aged forty years or older in keeping with other research carried out on older adults with intellectual disability which account for reduced life expectancy in people with intellectual disabilities (Ahlström et al., 2021; Al Shuhaimi et al., 2022; Coppus, 2013; McCarron et al., 2011). Studies were included if they reported results specifically pertaining to adults aged 40 years or older even if the study population included participants under 40 years of age.

Intervention. Antipsychotics were defined as drugs that are used in the short term to alleviate severe anxiety and to calm disturbed and agitated patients, whatever the underlying psychopathology (Joint Formulary Committee, 2021). They may also be known as ‘neuroleptics’ and as ‘(major) tranquillisers’. All antipsychotic medication types were considered including typical and atypical, and all generations. ‘Long term exposure’ was defined as use of antipsychotics for at least three months as this is consistent with the definition outlined in a previous study focusing on the long-term exposure to antipsychotics in people with dementia (Van Leeuwen et al., 2018).

Context. This review included all care settings where people with intellectual disability may live, including nursing homes, at home independently, at home with family, community group homes and congregated settings.

Outcomes. This review included any adverse effects associated with long term exposure to antipsychotics in older adults with intellectual disabilities. These included reported outcomes and those which were measured in any way, for example by use of a scale or objectively measured.

Study design. All types of study and design of study were included.

Selecting studies and charting the data

An independent review was carried out by two team members for each of the relevant studies to ensure that the study met the inclusion criteria and any discrepancies that arose were discussed until agreement was reached (PubMed: JH & CM, ScienceDirect: AB & ES, Cochrane Library: EM & JD, Embase: JT & AH, PsycINFO: JT & AH). A prior agreement was made that where disagreements could not be resolved, a further team member would be consulted. However, this was not necessary as no such disagreements arose.

Studies were excluded from the review if they did not make any relevant conclusions regarding adults aged 40 years or older, if they did not meet the inclusion criteria, if they were in a language other than English, or if no full text was available.

The process of study selection is illustrated in Figure 1.

Reporting the data

Of the selected studies, the data were extracted using a data extraction form developed for this study. This was used as a summary of the key information from the studies. The data extraction form for each study was reviewed independently by another member of the research team to ensure that the process was consistent and reliable. The data extracted from studies found on Pubmed was reviewed by JH & CM; on ScienceDirect by AB & ES; on Cochrane Library by EM & JD; on Embase by JT & AH; on PsycINFO by JT & AH.

Consultation with Stakeholders

Experts in the topic under review were contacted via email for their insights and feedback in order to gain a broader understanding of the context and limitations to this scoping review. Stakeholders from different organisations were contacted including: The Royal College of Psychiatrists of Ireland (intellectual disability subgroup); Providers in Ireland: Daughters of Charity Service; Down Syndrome Ireland; the National Intellectual Disability Memory Service, Tallaght Hospital; and The International Association for the Scientific Study of Intellectual and Developmental Disabilities (IASSIDD). A detailed letter explaining the research project and an accompanying copy of the first draft of the review was forwarded to each expert.

Description of studies

Initial database searches returned a total of 3656 records. Screening of all titles identified a total of 291 potentially relevant titles. Screening of abstracts identified a total of 82 potentially relevant studies, and screening of full text of these titles identified a total of 10 relevant references (de Kuijper et al., 2013; de Silva et al., 1992; de Winter et al., 2012a; de Winter et al., 2016; Fodstad et al., 2010; Goodbar et al., 2016; Matson et al., 2010; Orfan & Kolski, 1993; Rao et al., 1987; Youssef & Waddington, 1988). A further 3 references were identified through snowball searching (Buzan et al., 1998; de Winter et al., 2011; de Winter et al., 2012b) bringing the total number of references for inclusion to 13.

The publication dates of the included studies ranged from 1987 to 2016. The studies were carried out in four countries: five studies from the Netherlands (de Kuijper et al., 2013; de Winter et al., 2011; de Winter et al., 2012a; de Winter et al., 2012b; de Winter et al., 2016), five from the United States (Buzan et al., 1998; Fodstad et al., 2010; Goodbar et al., 2016; Matson et al., 2010; Orfan & Kolski, 1993), two from the United Kingdom (de Silva et al., 1992; Rao et al., 1987) and one from Ireland (Youssef & Waddington, 1988). Three of the studies were retrospective reviews (Buzan et al., 1998; Rao et al., 1987; Youssef & Waddington, 1988), three were observational studies (de Kuijper et al., 2013; Fodstad et al., 2010; Matson et al., 2010), three were case reports (de Silva et al., 1992; Goodbar et al., 2016; Orfan & Kolski, 1993), two were cohort studies (de Winter et al., 2012b; de Winter et al., 2016), and two were cross-sectional studies (de Winter et al., 2011; de Winter et al., 2012a). Seven studies reported extrapyramidal side-effects (Buzan et al., 1998; de Kuijper et al., 2013; Fodstad et al., 2010; Matson et al., 2010; Orfan & Kolski, 1993; Rao et al., 1987; Youssef & Waddington, 1988), five studies reported cardiovascular and metabolic effects (de Kuijper et al., 2013; de Winter et al., 2011; de Winter et al., 2012a; de Winter et al., 2012b; de Winter et al., 2016), one study reported rhinorrhea (Orfan & Kolski, 1993), one study reported hypothermia (Goodbar et al., 2016), and one study reported ischaemic colitis (de Silva et al., 1992).

Extrapyramidal symptoms

Tardive dyskinesia. An observational study of 166 people in the United States taking antipsychotics found that 42% of its participants showed symptoms of tardive dyskinesia (Fodstad et al., 2010). The study population was made up of adults aged 17 to 82 years old with a diagnosed intellectual disability and Axis I disorder who resided at one of two developmental centres in the US. The antipsychotics most commonly used in this population were olanzapine and risperidone. Participants were assessed under the CNS-Parkinsonism/Dyskinesia (CNS-PD) subscale of the Matson evaluation of drug side-effects (MEDS). Increasing age (p=0.016) and duration of antipsychotic use (p=0.038) were among the variables significantly associated with higher MEDS scores. In particular, people over 60 years old were significantly (p=0.02) more likely to experience extrapyramidal symptoms such as tardive dyskinesia. This study concluded that older age and longer duration of antipsychotic use posed a greater risk of experiencing symptoms of tardive dyskinesia. The authors hypothesised that this increased prevalence may be due to reduced metabolic activity in older patients, or possibly due to greater overall duration of antipsychotic use.

Another observational study in the United States assessed the prevalence of tardive dyskinesia in 264 adults with intellectual disabilities who were also taking psychotropic medications (Matson et al., 2010). The study consisted of adults with a mean age of 51.44 years old, living in one of two developmental centres in the Southeast of the United States. 45% of participants reported symptoms of tardive dyskinesia. Increasing age was significantly associated with a greater likelihood of experiencing these symptoms, with the risk increasing by 1.06 times with every year of life. While this study considered psychotropic agents in general, use of antipsychotics was noted as a particularly significant risk factor for developing symptoms of tardive dyskinesia. This study also made similar conclusions regarding this increased risk in older patients, mentioning factors such as reduced metabolism and longer duration of antipsychotic use as possible explanations.

Another observational study of 99 people with intellectual disabilities in the Netherlands (aged 15 to 66 years old; mean age = 49.8) assessed patients for side effects and possible contributory factors associated with antipsychotic use longer than one year (De Kuijper et al., 2013). Participants were living in residential facilities in the Netherlands where they received specialist support and care. 53% of participants reported at least one of three extrapyramidal symptoms (akathisia, parkinsonism and tardive dyskinesia). Higher age was significantly more associated with the presence (p=0.03) and severity (p=0.02) of dyskinesia. It was estimated that the likelihood of experiencing tardive dyskinesia increased by 5% with every year of life in this cohort. This study was, however, limited by the lack of a control group, so no causative link could be established.

One case report in the United States described a 74 year old woman with an intellectual disability continuing to experience symptoms of tardive dyskinesia, four years after discontinuing treatment with fluphenazine (Orfan & Kolski, 1993). The authors suggest that this demonstrates the potentially permanent effects antipsychotics may have on extrapyramidal neural pathways in the body.

An retrospective review from the United States identified a 63 year old man experiencing severe tardive dyskinesia while taking fluphenazine, which greatly impaired his mobility (Buzan et al., 1998). However when this patient discontinued fluphenazine and started on clozapine therapy, the symptoms of tardive dyskinesia were almost completely remitted within weeks.

Orofacial dyskinesia. A retrospective review of 42 adults with intellectual disabilities in a hospital setting in Ireland sought to determine the relationship between severity of organic brain dysfunction and development of movement disorders with long-term antipsychotics treatment (0.6–27.7 years of antipsychotic use) (Youssef & Waddington, 1988). Orofacial dyskinesia was reported in 26.2% of participants. Orofacial dyskinesias are repetitive involuntary movements of the face and mouth such as smacking of the lips and the protrusion and rolling of the tongue (Kobayashi, 1976). In older patients, orofacial dyskinesia was found to be more common in those receiving antipsychotic treatment, with prevalence increasing with age as follows: <35 years, 0%; 35–54 years, 28.0%; > 55 years, 33.3%. Increasing severity of intellectual disability was also found to be associated with increased incidence of orofacial dyskinesia. The DSM-III tool was used to assign the level of intellectual disability to participants before the study commenced. This tool is divided into four categories; mild, moderate, severe and profound. Participants with orofacial dyskinesia were characterised as having a greater degree of intellectual disability in comparison to those not showing any signs of orofacial dyskinesia. However, this study also reported orofacial dyskinesia in participants who had no history of antipsychotic use. Two participants, both with severe intellectual disability, showed symptoms of uncontrollable movements which were indistinguishable from those observed as a result of long-term antipsychotic use. Therefore, older adults with severe intellectual disability may experience orofacial dyskinesia even without antipsychotic treatment.

Parkinsonism and Akathisia. Parkinsonism and akathisia have both been reported by de Kuijper et al. as adverse effects in people with intellectual disabilities receiving long-term antipsychotic treatment (de Kuijper et al., 2013). Parkinsonism is usually considered as an umbrella term including symptoms of muscle rigidity, tremors and slow movement (National Health Service, 2019). Akathisia is defined as a feeling of motor restlessness and a need for constant movement (Tachere & Modirrousta, 2017). The study was carried out in the Netherlands across three care settings and 99 people with intellectual disabilities aged between 15–66 years took part, with 78% of participants having used antipsychotic agents for over ten years. Higher age along with male sex, use of an atypical antipsychotic and higher dose were among some of the determinants of parkinsonism and akathisia. These same factors also influenced the degree of severity of akathisia. A second study of 67 adults with intellectual disabilities conducted in the United Kingdom comments on the positive correlation of parkinsonism with tardive dyskinesia and cumulative antipsychotic medication as a significant factor in the prediction of tardive dyskinesia (Rao et al., 1987). In some cases, particularly in older adults, parkinsonism was reported to be masking tardive dyskinesia.

Cardiovascular and metabolic adverse effects

A study by de Winter et al. on the prevalence of obesity in adults aged 50 and over with intellectual disabilities (n=945) found that use of atypical antipsychotics significantly increased risk of being overweight or obese in this cohort, suggesting that atypical antipsychotics may cause weight gain in this population (de Winter et al., 2012a).

A study of physical health parameters in people with intellectual disabilities living in residential care who used antipsychotics found a correlation between older age and hypertension (defined in this study as ≥130 mmHg systolic blood pressure/≥85 mmHg diastolic blood pressure/on antihypertensive therapy) in this population; a similar correlation was observed for elevated plasma triglycerides but not for other components of metabolic syndrome including elevated fasting glucose, low high-density lipoprotein and high waist circumference (de Kuijper et al., 2013). These data suggest that older people with intellectual disabilities on long-term antipsychotic therapy may be at increased risk of cardio-metabolic adverse effects; however, this study was limited by the relatively small sample size (n=99, with only 22 people using atypical antipsychotics which have a greater association with metabolic and cardiovascular adverse effects) and lack of a control group.

In one cohort study, use of atypical antipsychotics in adults with intellectual disabilities aged 50 years old and above in a range of care settings was associated with increased risk of myocardial infarction but not stroke, heart failure or all-cause mortality (n=658) (de Winter et al., 2016). The primary outcome of this study was to study the 3-year incidence of cardiovascular morbidity in older adults with intellectual disabilities; analysis of risk factors for cardiovascular morbidity (including atypical antipsychotic use) was among the secondary outcomes. Only 46 participants used atypical antipsychotics and duration of use was not reported; furthermore, as this was a cohort study randomisation was not employed, introducing the possibility of bias.

Other studies have found no correlation between the prevalence of cardiovascular risk factors and use of atypical antipsychotics in older adults with intellectual disabilities (De Winter et al., 2012b; De Winter et al., 2011). The first study was a cross-sectional study which investigated cardiovascular risk factors including diabetes mellitus, hypertension, hypercholesterolaemia and metabolic syndrome in adults with intellectual disabilities aged ≥50 years old in a range of care settings (n=980, of whom 51 people used atypical antipsychotics with duration of use not reported). This study found no correlation between use of atypical antipsychotics and presence of any of the cardiovascular risk factors studied. The second study, also a cross-sectional study, investigated the prevalence of metabolic syndrome in adults ≥50 years old with intellectual disabilities living in a range of care settings and also found no correlation between use of atypical antipsychotics and presence of metabolic syndrome (De Winter et al., 2011); however, only 5 patients in this study used atypical antipsychotics which limits any conclusions that could be drawn.

Rhinorrhoea

A case study of a 74-year old woman with an intellectual disability described severe debilitating rhinorrhoea which presented after the discontinuation of two long term medications: benztropine mesylate, an anticholinergic, and fluphenazine, a typical antipsychotic (Orfan & Kolski, 1993). The manifestation of rhinorrhoea after drug withdrawal was attributed to the prolonged muscarinic antagonist activity which may have induced hypersensitivity of the muscarinic receptors in the nasal mucosa. This case study posed the question of whether antipsychotics could cause persistent upregulation of parasympathetic efferent activity, which leads to hypersecretion of the nasal cavity.

Hypothermia

A case report from the United States published in 2016 identified a first-generation antipsychotic, thioridazine, as a possible cause of hypothermia in a 59-year-old woman with an intellectual disability (Goodbar et al., 2016). When the patient’s medical history was taken upon admission to ICU, it was found that in the 8 months since commencing thioridazine, she had been admitted to hospital on 3 previous occasions, experiencing hypothermic temperatures each time.

A Naranjo analysis was undertaken to determine if the phenothiazine antipsychotic was a causative factor in the patient’s hypothermia. Other drug factors and patient-specific factors were also considered in the analysis. A score of 3 was obtained, indicating thioridazine as a possible cause of the patient’s hypothermia. Resolution of hypothermia following tapering down of the thioridazine dose also supports thioridazine as a causative agent.

This case report suggests a possible requirement for monitoring of temperature, particularly in patients with intellectual disabilities who may have communication difficulties or are unable to exercise self-care. However, this adverse event was an isolated case, not identified in other studies reviewed.

Ischaemic colitis

A case study from the United Kingdom presented a fatal case of ischaemic colitis in a 49-year-old man with an intellectual disability and discussed the possible role of long-term antipsychotic use. The details of the fatality were investigated and the case was compared to similar literature on this subject (de Silva et al., 1992). The patient’s drug history included long-term use of chlorpromazine, pericyazine and intramuscular clopenthixol. Similar cases reviewed revealed that both short and long term use of phenothiazines can cause colonic catastrophes and hypersensitive reactions to these drugs can cause colonic distension. The case concluded that treatment with long term chlorpromazine may have induced chronic neuromuscular dysfunction of the colon leading to a severe state of faecal retention and distension. This affected mucosal capillary circulation and intramural circulation, consequently disrupting mucosal integrity and allowing the growth of bacteria. The authors posed the question of whether the patient’s intellectual disability could have precluded earlier diagnosis and surgical treatment.

Strengths and limitations

The main strength of this study is that it is the first scoping review, to our knowledge, to examine the literature available on the long-term adverse effects of antipsychotics in older people with intellectual disabilities. This review will guide further research into the long-term adverse effects of antipsychotics in older adults with intellectual disabilities through its identification of gaps in the current literature base.

This scoping review has several limitations. First, despite a comprehensive search strategy, it is possible that there are studies that would meet inclusion criteria which were not identified, for example due to not being indexed in any of the databases searched or not being in the English language. Some studies were excluded as they did not report the duration of antipsychotic use, resulting in the exclusion of further potentially relevant studies. Second, the heterogeneity of the studies included and the nature of a scoping review precluded any formal assessment of quality of the studies included, limiting the conclusions that can be drawn based on results reported from these studies. Furthermore, many of the included studies were not specifically focused on older adults with intellectual disabilities taking long-term antipsychotic medication, meaning that any conclusions drawn from these studies were based on subgroups of older adults within these studies or subgroups of patients taking antipsychotics medication long-term; these subgroups were often very small and in some instances were difficult to identify and characterise due to poor reporting quality. Finally, many studies did not define intellectual disability or give any detail on the degree of intellectual disability of the participants.

Future research

This scoping review did not identify any randomised controlled trials (RCTs) designed to study the adverse effects of long-term use of antipsychotics in older adults with intellectual disabilities. Further research into this area would be of interest given the high rates of antipsychotic use in this population. Such research could help to inform prescribing and deprescribing in this cohort as possible adverse effects of long-term antipsychotic use may be more clearly defined which would help to support informed decision-making. Consultation with a representative of Down Syndrome Ireland highlighted the need for research specifically focused on the adverse effects of long-term use of antipsychotics in older adults with Down syndrome. Interest was also expressed in data exploring over-prescribing in this cohort. A representative from the IASSIDD recommended, based on the findings of this scoping review, that further studies should be conducted comparing the adverse effects of long-term use of antipsychotics in older adults with intellectual disabilities with the adverse effects of long-term use of antipsychotics in older adults without intellectual disabilities.