Association between antipsychotics and adverse outcomes in dementia

Prolonged use of antipsychotics continues to be a controversial subject area, especially in the older adult population due to age-related changes in pharmacokinetic and pharmacodynamics parameters. Best practice guidelines recommends that they should be used at their lowest dosage for no longer than 6–12 weeks. Here, the authors discuss the prevalence of antipsychotic use to treat the behavioural and psychological symptoms of dementia in the older adult population and the dilemma it poses.

More than 90% of people with dementia will experience at least one behavioural and psychological symptom of dementia (BPSD) such as hallucinations, delusions, agitation and aggression during the course of their condition. Health care guidelines recommend that antipsychotics should not be used beyond 6–12 weeks. However, the long–term use remains frequent in care homes and psychiatric wards.1,2

Expert consensus suggests that the use of antipsychotics can be appropriate in those with dangerous agitation or psychosis and can minimise the risk of violence and reduce patient distress. However, there is growing research that the benefits are at best small and that antipsychotics are associated with an increased risk of cardiovascular deaths, cerebrovascular events, venous thromboembolism, falls, sedation, hyperprolactinemia and sudden death in elderly people with dementia.2,3 Antipsychotics are also associated with an increased risk of metabolic side-effects such as weight gain, hyperlipidaemia and diabetes; anticholinergic effects such as confusion, and extrapyramidal side effects such as tardive dyskinesia.4,5

There has been extensive research into the use of antipsychotics in dementia, including their safety profiles, however, studies have mainly focussed on the association between antipsychotics and a few adverse outcomes such as cerebrovascular events and mortality. Research into other adverse outcomes is limited. Such studies include three literature reviews6–8, a meta-analysis9, two systematic reviews10,11. This study was undertaken to investigate the rate of use of antipsychotics in patients with dementia and the rate of any adverse outcome known to be associated with their use.

Methods

The older people’s community mental health team of the Birmingham and Solihull Mental Health Foundation Trust is divided into north, west, east and south hubs. Patients are seen in outpatient clinics, care homes and their own homes. A retrospective cohort study was conducted on 1000 patients from August 31st 2013 to August 31st 2015. The hubs cover varying socioeconomic and ethnic groups. Sample size calculation was not done. However, in order to achieve a population sample representative of the diverse population in Birmingham, 250 patients were taken from each hub.

Patients with a diagnosis of any type of dementia in accordance with ICD-10 criteria were included. Those with a premorbid or comorbid history of a non-dementing psychotic illness were excluded from the study.

Electronic notes and letters to / from GPs were examined to ascertain the frequency of antipsychotic use and adverse outcomes associated with their use.

Research ethics committee approval was not sought due to the study being undertaken on anonymised patient notes, which had already been collected as part of normal care procedure. However, approval had been given by the Trust’s Research and Development department.

Results

Characteristics of the study cohort

The cohort comprised mainly of women (59%) and patients in the 75–84 year old group (43%). The majority of patients had a diagnosis of Alzheimer’s disease. Two hundred and three (20%) received antipsychotics whereas 797 (80%) did not. One hundred and fifty (74%) were care home residents at the time of receiving antipsychotic medication. Adverse effects were seen in 51 (24%) cases (Table 1).


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Table 1. Demographic characteristics of study cohort

Clinical characteristics of patients taking antipsychotics

The majority of patients (48%) took risperidone (mean dose 0.5mg daily, mean duration 210 days). Thirty per cent took quetiapine, 7% took olanzapine, 5% took aripiprazole, 5% took amisulpride and 5% took haloperidol (Table 2). Agitation was the main indication for prescribing antipsychotics (Table 3).


Table 2. Clinical characteristics of patients taking antipsychotics


Table 3. Indications for prescribing antipsychotics

Adverse effects were seen mostly in risperidone users (55%) including muscle stiffness, falls, cogwheel rigidity, tremors, sedation and increased agitation. Confusion was seen in users of quetiapine and amisulpride (Table 4). The mean time to adverse effect varied for each antipsychotic (Table 6). There were no reports of cerebrovascular events, including strokes and transient ischemic attacks, in the patient notes.


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Table 4
. Number of adverse effects in antipsychotic users


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Table 6
. Mean time to adverse effect in days

Antipsychotics associated with adverse effects were stopped in the majority (61%) of patients that experienced adverse events whilst taking them. The remainder continued taking the antipsychotics at a reduced dose with no further adverse effects. However, four patients underwent a switchover of antipsychotics: risperidone was changed to quetiapine in a patient experiencing falls and muscle stiffness; haloperidol was changed to risperidone in a patient experiencing falls; quetiapine was changed to risperidone, and aripiprazole in two patients experiencing falls (Table 7).


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Table 7
. Actions taken in patients experiencing adverse effects

Two patients were hospitalised for urinary tract infections while taking antipsychotics. For these patients, antipsychotics were not stopped during hospitalisation. Twenty three per cent of patients were prescribed antipsychotics to be used when needed (pro re nata), however, they were all administered at least once daily.

 

Factors affecting adverse effects in patients taking antipsychotics

The notes of patients were examined to ascertain whether the development of adverse effects could have stemmed from factors other than antipsychotics such as physical health problems or other medication.

A patient taking risperidone 1mg daily experienced agitation. Memantine had been started 14 days earlier. Risperidone was stopped 25 days after commencement following which the agitation settled. Memantine was continued with no further problems occurring.

A male patient taking olanzapine 5mg daily experienced sedation. He was also taking citalopram 20mg daily. The sedation was deemed to be secondary to the use of olanzapine due to him having taken citalopram for a year. The olanzapine was then stopped after 56 days due to the sedation not improving.

A female patient taking amisulpride 50mg daily experienced sedation. However, mirtazapine 15mg daily had been started even days earlier. Despite stopping the mirtazapine the sedation did not improve and the amisulpride was stopped 30 days after its commencement.

A male patient died while taking amisulpride 100mg daily for 42 days. Death was attributed to old age and not due to other causes; he was taking atorvastatin for hyperlipidaemia. It is uncertain whether death occurred secondary to the use of amisulpride. An autopsy had not been performed at the time.

A patient taking quetiapine 50mg daily experienced falls. Lisinopril 20mg had been started 30 days earlier. It was uncertain as to which drug was causing the falls, however, the quetiapine was changed to risperidone 0.5mg daily 50 days after its commencement with no further falls occurring. Another patient taking quetiapine 50mg daily also experienced falls. However, lorazepam 0.5mg daily had been started at the same time. Quetiapine was stopped 32 days after commencement to see whether the situation would improve. There were no further reports of falls.

Discussion

In our study the majority of patients taking antipsychotics resided in care homes (74%). Patients with BPSD (and hence the use of antipsychotics) are more likely to undergo institutionalisation.12

Point prevalence of antipsychotic prescribing

The prescribing level of antipsychotics in terms of point prevalence for this study was 20%. This was difficult to compare with previous retrospective studies with similar objectives due to patients being in a variety of settings ranging from psychiatric wards to nursing homes in our study. A retrospective study was undertaken by Szczepura et al. to determine the antipsychotic prescribing point prevalence in 616 residential homes four years after the launch of the National Dementia Strategy (NDS) in 2009.13 The point prevalence was 19% (unchanged since the launch of the NDS). English studies of antipsychotic prescribing levels in care homes are few and were undertaken in single geographical areas with smaller samples (<1000 patients), however, rates similar to that seen by Szczepura were found. A nationwide audit undertaken in 2011 in care homes and psychiatric wards showed that 16% of patients were being prescribed antipsychotics. This was lower than the 25% overall population rate estimated by the Department of Health in 2009.14

Association between antipsychotics and adverse effects

Risperidone was the most commonly prescribed antipsychotic. This may have led to the association with the majority of adverse effects seen in the study. Risperidone has the most randomised controlled trials to support its use and it is the only antipsychotic indicated for the short-term management of persisting and severe aggression in people with Alzheimer’s disease who have failed non-pharmacological trials.10,11

Falls were the commonest adverse effect seen, especially in risperidone and quetiapine users. Research indicates that, of the atypical antipsychotics, both drugs are associated with falls. Antipsychotic-related orthostatic hypotension, gait abnormalities and sedation have been linked to this problem.15,16

Sedation was the second commonest adverse effect seen, mainly in users of risperidone, quetiapine, aripiprazole and olanzapine. Previous studies indicate that individuals taking these antipsychotics are at higher risk of somnolence compared with those taking placebo.11 Extrapyramidal side-effects (muscle stiffness, tremors and cogwheel rigidity) were mainly seen in risperidone users. Research indicates that risperidone is associated with the highest risk whereas quetiapine is associated with the lowest risk.17

Agitation is often difficult to differentiate from akathisia and is commonly seen in risperidone users. Confusion (an anticholinergic effect) was seen in users of amisulpride and quetiapine. Atypical antipsychotics tend to vary in their ability to produce anticholinergic effects.15

Association between antipsychotic dose and adverse effects

The relationship between antipsychotic doses and adverse effects was also difficult to compare with previous studies due to a varying adverse outcome profiles, equivalent doses of chlorpromazine being used and a focus on adverse outcomes, including mortality, cardiovascular events and cerebrovascular events. However, research suggests that the risk of mortality is associated with longer use and higher doses.18 Despite our study indicating that adverse effects occurred when individuals took risperidone at a mean dose of 0.5mg daily (Table 5), other studies suggest that adverse outcomes are more likely to occur at 2mg dosing rather than 1mg dosing.11 Studies suggest using doses of 5–10mg/day for aripiprazole (which occurred at a mean dose of 5mg/day in our study) to avoid side-effects.19 Doses of 5–15mg/day of olanzapine and up to 100mg/day of quetiapine have been tolerated by patients in other studies without being associated with side–effects.20,21


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Table 5
. Mean dose of antipsychotic at which adverse effect occurred (mg/day)

Limitations of the study

Emerging research indicates that antipsychotic use in individuals with dementia results in a greater number of adverse effects when compared with placebo-treated individuals, including the risk of cardiovascular events, cerebrovascular events and death.22,23 However, only one patient died during our study period and no cases of cardiovascular or cerebrovascular events were found. Although, in contrast to previous retrospective studies, our study period was shorter. More adverse outcomes could have been detected with a longer study duration and if inpatient wards (where antipsychotics are more likely to be prescribed and at higher doses) had been included.

Causes of side-effects other than antipsychotics were not always documented such as whether agitation could have been related to pain. Some adverse outcomes such as transient ischemic attacks could have been missed by doctors during patient follow-up due to their short duration.

Forty three per cent of our sample received cognitive enhancers, 11% received antidepressants and 11% received benzodiazepines (Table 1). These patients did not take antipsychotics at the same time. The use of other psychotropic medications may have prevented the need for antipsychotics due to their modest effects on BPSD. Although observational studies are less effective in demonstrating direct causative effects from antipsychotics on patent mortality and morbidity than randomised controlled trials, available evidence to date warns against widespread inappropriate use.10,24

Benefits and harms of antipsychotics in dementia: a debatable issue

Many studies show that antipsychotics increase morbidity and mortality in dementia. However, a longitudinal study undertaken by Lopez et al. in 2013 found that neuropsychiatric symptoms, including psychosis and agitation, rather than antipsychotics, were associated with increased mortality. The use of antipsychotics continues to be controversial and subject to scrutiny and international policy oversight. Best practice guidelines recommend that antipsychotics must be used with caution at the lowest effective dosage; the potential consequences of adverse effects are greater in older people due to age-related changes in pharmacokinetic and pharmacodynamics parameters. There is no better evidence-supported therapy that poses a dilemma in the treatment of BPSD. The evidence for non-pharmacological interventions is increasing and needs further evaluation.19,25

Dr Bangash and Dr Stubbs are Registrars in Old Age Psychiatry; Dr Khan is a Consultant Old Age Psychiatrist; Dr Samnani, Dr Aziz and Dr Mitra are Psychiatry Senior House Officers, all at Birmingham & Solihull Mental Health NHS Foundation Trust (BSMHFT), Ashcroft Unit, Birmingham.

Declaration of interests

No conflicts of interest were declared.

References

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Association between antipsychotics and adverse outcomes in dementia

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