Antipsychotics for people with dementia
Authors: J. O'Brien
Journal: BMJ (2008)

More than 25 million people worldwide have dementia, with a new case developing every seven seconds.1 While putative disease modifying agents are being developed, we are limited to symptomatic treatments for cognitive and non-cognitive features. Non-cognitive symptoms—referred to as behavioural and psychological symptoms of dementia—including agitation, psychosis, depression, and aggression, occur in up to half of those with dementia in the community and an even higher proportion in residential care. Antipsychotics have been widely prescribed off licence for these symptoms, and 20-50% of people with dementia in institutional care receive them.2 What is the evidence for their efficacy?

Several placebo controlled, randomised controlled trials (RCTs), especially of newer “atypical” antipsychotics like risperidone, show an improvement in agitation, aggression, and psychosis.3 But, even before current concerns over their side effects, the strength of the evidence supporting widespread prescribing in dementia was questioned. Efficacy is modest, and most studies have assessed behavioural and psychological symptoms of dementia as a general outcome rather than targeting specific symptoms.

Side effects include extrapyramidal features, sedation, metabolic disturbances, increased cognitive impairment, and severe sensitivity reactions in dementia with Lewy bodies. In 2004 it emerged that the risk of cerebrovascular events and stroke was three times higher in people treated with the atypicals olanzapine and risperidone. A subsequent meta-analysis showed increased mortality in people treated with atypical antipsychotics compared with placebo, with a number needed to harm of around 100.4

These findings combined with high prescribing rates for people with dementia led to warnings about the use of these drugs in many countries. In the United Kingdom, the Committee on Safety of Medicines went further than most to advise that “risperidone or olanzapine should not be used for the treatment of behavioural symptoms of dementia.”5 Subsequently, patients had their drugs withdrawn or were switched to typical antipsychotics, often without considering individual circumstances. This led to further guidance from professional organisations supporting the continued use of atypical antipsychotics in some circumstances.6

So where are we now? Cohort studies suggest that typical antipsychotics have a similar cerebrovascular risk to atypical antipsychotics, and possibly even higher mortality.7 8 So switching from atypical antipsychotics to typical antipsychotics is unlikely to be a sensible strategy. Questions over efficacy remain. A large pragmatic double blind placebo controlled trial, using an outcome measure of “time to treatment discontinuation,” found that the benefits of atypical antipsychotics on efficacy were largely offset by discontinuation because of side effects.9

A recent RCT showed that antipsychotics can be safely withdrawn in many people with dementia who have taken them for prolonged periods, especially if symptoms have largely resolved.10 Staff and environmental factors are important, and targeted training and support reduced the use of antipsychotics from 42% to 23% over one year.2

What are the alternatives to antipsychotics? Non-pharmacological approaches are often rightly advocated. Indeed, careful assessment for comorbid conditions and exacerbating factors—including physical illness, pain, communication difficulties, and depression—are an essential part of assessment of behavioural and psychological symptoms of dementia. For milder symptoms, watchful waiting combined with simple explanation, advice, and support may be sufficient. Increased social stimulation or personalised music may help, and aromatherapy has some evidence base.

However, all these non-pharmacological approaches are limited, not only by lack of studies but by the difficulties in undertaking truly placebo controlled trials, combined with an absence of studies in more severe behavioural disturbance.11 Cholinesterase inhibitors may be useful for symptoms such as apathy and psychosis, consistent with cholinergic deficit as a likely neurochemical cause. Initial reports that they may reduce agitation, a common and problematic symptom for which antipsychotics are often prescribed, were not confirmed by a large non-industry funded RCT, which showed no benefit of donepezil over placebo.12 Post hoc analysis of trials of memantine, an NMDA (N-methyl D-aspartate) antagonist, suggest possible benefits on agitation and aggression.13 Evidence for other drugs is limited; carbamazepine may help agitation and aggression, but no clear consensus exists on the role of antidepressants in managing behavioural and psychological symptoms of dementia.

What conclusions can we draw? Evidence based alternatives to antipsychotics are relatively few and limited to people with mild to moderate symptoms. In more severe cases no treatment or non-evidence based treatment is often not a clinical option. Antipsychotics, especially atypical ones, have the best evidence base, although their efficacy is more modest than previously supposed and their side effects more serious. Prescribing rates of up to 50% for people in residential care cannot be justified. However, given the lack of suitable alternatives, it is not reasonable to stop prescribing completely.

Current advice, such as that contained in the National Institute for Health and Clinical Excellence guidelines for dementia, is pragmatic and helpful. Management of the symptoms consists of a thorough assessment, to search for any modifiable causes. Non-pharmacological approaches should be used first, and possible alternatives—like carbamazepine for aggression, cholinesterase inhibitors for apathy and psychosis, and memantine for agitation—should be considered. Prescription of antipsychotics should be carefully targeted, time limited, and reserved for severe and distressing symptoms after careful assessment of risk and benefit. This is not easy. How, for example, can we weigh up a small but real increased risk of a stroke compared with the possible benefit of remaining in a less restricted environment (for example, at home)? These complex decisions have to involve the patient, where possible, together with the family and carers.